Circulating complexes between tumour necrosis factor-alpha and etanercept predict long-term efficacy of etanercept in juvenile idiopathic arthritis.

PubMed

Kahn, Robin; Berthold, Elisabet; Gullstrand, Birgitta; Schmidt, Tobias; Kahn, Fredrik; Geborek, Pierre; Saxne, Tore; Bengtsson, Anders A; Månsson, Bengt

2016-04-01

The relationship between tumour necrosis factor-alpha (TNF-α) and drug survival had not been studied in juvenile idiopathic arthritis (JIA), and there were no laboratory tests to predict the long-term efficacy of biological drugs for JIA. We studied whether serum levels of TNF-α, free or bound to etanercept, could predict long-term efficacy of etanercept in children with JIA. We included 41 biologic-naïve patients with JIA who started treatment with etanercept at Skåne University Hospital between 1999 and 2010. Serum taken at the start of treatment and at the six-week follow-up were analysed for TNF-α and the long-term efficacy of etanercept was assessed using the drug survival time. Levels of TNF-α increased significantly at the six-week follow-up, and this was almost exclusively comprised of TNF-α in complex with etanercept. The increase in TNF-α showed a dose-dependent correlation to long-term drug survival (p < 0.01). Increasing levels of circulating TNF-α at treatment initiation predicted long-term efficacy of etanercept in children with JIA, which may have been due to different pathophysiological mechanisms of inflammation. Our result may provide a helpful clinical tool, as high levels of circulating TNF-α/etanercept complexes could be used as a marker for the long-term efficacy of etanercept. ©2015 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.

Etanercept (Enbrel) and Pregnancy

MedlinePlus

... treated with etanercept. Rheumatologists responding to a study survey reported no increase in birth defects or miscarriage in 417 women exposed to etanercept or another TNF inhibitor during pregnancy. About one third of these women continued to ...

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region.

PubMed

Machado, Daniel A; Guzman, Renato; Xavier, Ricardo M; Simon, Jesus A; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354.

Systematic review, network meta-analysis and economic evaluation of biological therapy for the management of active psoriatic arthritis.

PubMed

Cawson, Matthew Richard; Mitchell, Stephen Andrew; Knight, Chris; Wildey, Henry; Spurden, Dean; Bird, Alex; Orme, Michelle Elaine

2014-01-20

An updated economic evaluation was conducted to compare the cost-effectiveness of the four tumour necrosis factor (TNF)-α inhibitors adalimumab, etanercept, golimumab and infliximab in active, progressive psoriatic arthritis (PsA) where response to standard treatment has been inadequate. A systematic review was conducted to identify relevant, recently published studies and the new trial data were synthesised, via a Bayesian network meta-analysis (NMA), to estimate the relative efficacy of the TNF-α inhibitors in terms of Psoriatic Arthritis Response Criteria (PsARC) response, Health Assessment Questionnaire (HAQ) scores and Psoriasis Area and Severity Index (PASI). A previously developed economic model was updated with the new meta-analysis results and current cost data. The model was adapted to delineate patients by PASI 50%, 75% and 90% response rates to differentiate between psoriasis outcomes. All four licensed TNF-α inhibitors were significantly more effective than placebo in achieving PsARC response in patients with active PsA. Adalimumab, etanercept and infliximab were significantly more effective than placebo in improving HAQ scores in patients who had achieved a PsARC response and in improving HAQ scores in PsARC non-responders. In an analysis using 1,000 model simulations, on average etanercept was the most cost-effective treatment and, at the National Institute for Health and Care Excellence willingness-to-pay threshold of between £20,000 to £30,000, etanercept is the preferred option. The economic analysis agrees with the conclusions from the previous models, in that biologics are shown to be cost-effective for treating patients with active PsA compared with the conventional management strategy. In particular, etanercept is cost-effective compared with the other biologic treatments.

Factors associated with improvement in disease activity following initiation of etanercept in children and young people with Juvenile Idiopathic Arthritis: results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study

PubMed Central

Kearsley-Fleet, Lianne; Davies, Rebecca; Lunt, Mark; Southwood, Taunton R.

2016-01-01

Objectives. The objectives of this study were to investigate change in disease activity, and explore factors associated with response, in children with JIA over the initial year of etanercept treatment. Methods. This analysis included children with JIA starting etanercept in the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study. Response was assessed using change in juvenile arthritis disease activity score-71 (JADAS-71), an excellent response (ACR Pedi 90), and achieving minimal disease activity (MDA) at 1 year. Change in JADAS-71 was evaluated over time. Multivariable backward stepwise logistic regression was performed to identify factors associated with ACR Pedi 90 and MDA. Results. A total of 496 children were included. Over the first year, 17 stopped due to inefficacy, 9 due to adverse events and 7 for other reasons. One child stopped for remission. At 1 year, 74, 69 and 38% reached ACR Pedi 30, 50 and 90, respectively, and 48% had achieved MDA. Independent predictors of achieving ACR Pedi 90 at 1 year included shorter disease duration [odds ratio (OR) 0.91; 95% CI: 0.85, 0.97)], no concurrent oral corticosteroid use (OR 0.48; 95% CI: 0.29, 0.80) and history of uveitis (OR 2.26; 95% CI: 1.08, 4.71). Independent predictors of achieving MDA at 1 year included younger patients (OR 0.60; 95% CI: 0.38, 0.95), and disease not treated with concurrent oral corticosteroids (OR 0.57; 95% CI: 0.35, 0.93). Conclusion. Among this real-world cohort of children with severe JIA, a significant proportion of children achieved an excellent ACR Pedi response and MDA within 1 year of starting etanercept, although few clinical factors could predict this outcome. PMID:26721878

Evaluation of the structural, physicochemical, and biological characteristics of SB4, a biosimilar of etanercept

PubMed Central

Cho, Ick Hyun; Lee, Nayoung; Song, Dami; Jung, Seong Young; Bou-Assaf, George; Sosic, Zoran; Zhang, Wei; Lyubarskaya, Yelena

2016-01-01

ABSTRACT A biosimilar is a biological medicinal product that is comparable to a reference medicinal product in terms of quality, safety, and efficacy. SB4 was developed as a biosimilar to Enbrel® (etanercept) and was approved as Benepali®, the first biosimilar of etanercept licensed in the European Union (EU). The quality assessment of SB4 was performed in accordance with the ICH comparability guideline and the biosimilar guidelines of the European Medicines Agency and Food and Drug Administration. Extensive structural, physicochemical, and biological testing was performed with state-of-the-art technologies during a side-by-side comparison of the products. Similarity of critical quality attributes (CQAs) was evaluated on the basis of tolerance intervals established from quality data obtained from more than 60 lots of EU-sourced and US-sourced etanercept. Additional quality assessment was focused on a detailed investigation of immunogenicity-related quality attributes, including hydrophobic variants, high-molecular-weight (HMW) species, N-glycolylneuraminic acid (NGNA), and α-1,3-galactose. This comprehensive characterization study demonstrated that SB4 is highly similar to the reference product, Enbrel®, in structural, physicochemical, and biological quality attributes. In addition, the levels of potential immunogenicity-related quality attributes of SB4 such as hydrophobic variants, HMW aggregates, and α-1,3-galactose were less than those of the reference product. PMID:27246928

Two-Year Safety and Efficacy Experience in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treated with Etanercept and Conventional Disease-Modifying Anti-rheumatic Drugs in the Latin American Region

PubMed Central

Machado, Daniel A.; Guzman, Renato; Xavier, Ricardo M.; Simon, Jesus A.; Mele, Linda; Shen, Qi; Pedersen, Ronald; Kotak, Sameer; Vlahos, Bonnie

2016-01-01

Background: Although long-term data are available from biologic studies in North American/European populations with rheumatoid arthritis (RA), long-term findings in Latin American RA populations are limited. Objective: To examine long-term safety/efficacy of etanercept, methotrexate, and/or other disease-modifying anti-rheumatic drugs (DMARDs) in Latin American patients with moderate-to-severe active RA. Methods: In the first phase of this open-label study, patients were randomized to etanercept 50 mg weekly plus methotrexate or conventional DMARD (hydroxychloroquine or sulfasalazine) plus methotrexate for 24 weeks. At the start of the second phase (week 24), investigators selected a treatment regimen that included any combination/dosage of etanercept, methotrexate, hydroxychloroquine, or sulfasalazine based on previous treatment response, preference, and local product labeling, and was continued for the 104-week extension. Results: In the extension, in the group previously randomized to etanercept-plus-methotrexate therapy, etanercept was continued in 259/260 patients; methotrexate continued in 260/260; and hydroxychloroquine and sulfasalazine added in 8/260 and 3/260, respectively. In the group previously randomized to conventional DMARD-plus-methotrexate therapy, conventional DMARD was discontinued in 86/126 and etanercept added in 105/126. Among etanercept-exposed patients (total exposure, 798.1 patient-year [PY]), rates of adverse events, serious adverse events, and serious infections per PY were 1.7, 0.07, and 0.02 events per PY. In both groups, after treatment modification was permitted, clinical response rates and improvements in clinical/patient-reported outcomes from baseline were sustained to week 128. Conclusion: After investigators were permitted to modify treatment, etanercept was part of the treatment regimen in 95% of patients. Continuation or addition of etanercept in the 2-year extension resulted in a consistently good risk:benefit profile. Trial Registration: Open-Label Study Comparing Etanercept to Conventional Disease Modifying Antirheumatic Drug (DMARD) Therapy; ClinicalTrials.gov, number NCT00848354; https://clinicaltrials.gov/ct2/show/NCT00848354 PMID:27006728

Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis.

PubMed

Dougados, Maxime; Maksymowych, Walter P; Landewé, Robert B M; Moltó, Anna; Claudepierre, Pascal; de Hooge, Manouk; Lambert, Robert G; Bonin, Randi; Bukowski, Jack F; Jones, Heather E; Logeart, Isabelle; Pedersen, Ron; Szumski, Annette; Vlahos, Bonnie; van der Heijde, Désirée

2018-02-01

To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: -0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was -0.22 (95% CI -0.38 to -0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: -1.9% versus 1.6% (adjusted difference for etanercept minus control: -4.7%,95% CI -9.9 to 0.5, p=0.07) for change in mNY criteria; -1.9% versus 7.8% (adjusted difference: -18.2%,95% CI -30.9 to -5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and -0.6% versus 6.7% (adjusted difference: -16.4%,95% CI -27.9 to -5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. NCT01258738, NCT01648907; Post-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis

PubMed Central

Dougados, Maxime; Maksymowych, Walter P; Landewé, Robert B M; Moltó, Anna; Claudepierre, Pascal; de Hooge, Manouk; Lambert, Robert G; Bonin, Randi; Bukowski, Jack F; Jones, Heather E; Logeart, Isabelle; Pedersen, Ron; Szumski, Annette; Vlahos, Bonnie

2018-01-01

Objective To compare 2 years of radiographic sacroiliac joint (SIJ) changes in patients with recent onset axial spondyloarthritis (axSpA) receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). Methods Endpoints were changes at week 104 per the modified New York (mNY) grading system in total SIJ score (primary endpoint) and net percentage of patients with progression defined three ways. Treatment effect was analysed with and without adjustment for baseline covariates. Results At 104 weeks, total SIJ score improved in the etanercept group (n=154, adjusted least-squares mean change: –0.14) and worsened in the control group (n=182, change: 0.08). The adjusted difference between groups (etanercept minus control) was –0.22 (95% CI –0.38 to –0.06), p=0.008. The net percentage of patients with progression was significantly lower in the etanercept versus the control group for two of three binary endpoints: –1.9% versus 1.6% (adjusted difference for etanercept minus control: –4.7%,95% CI –9.9 to 0.5, p=0.07) for change in mNY criteria; –1.9% versus 7.8% (adjusted difference: –18.2%,95% CI –30.9 to –5.6, p=0.005) for change ≥1 grade in ≥1 SIJ; and –0.6% versus 6.7% (adjusted difference: –16.4%,95% CI –27.9 to –5.0, p=0.005) for change ≥1 grade in ≥1 SIJ, with shift from 0 to 1 or 1 to 0 considered no change. Conclusion Despite the slow radiographic SIJ progression rate over 2 years in axSpA, this study suggests a lower rate of progression in the SIJ with etanercept than without anti-tumour necrosis factor therapy. Trial registration numbers NCT01258738, NCT01648907; Post-results. PMID:28970213

Use of etanercept in a patient with rheumatoid arthritis on hemodialysis.

PubMed

Sugioka, Yuko; Inui, Kentaro; Koike, Tatsuya

2008-01-01

Disease-modifying anti-rheumatic drugs (DMARDs) are typically used for the therapy of rheumatoid arthritis (RA), but most have some nephrotoxicity. In several clinical studies, etanercept had fewer adverse effects on renal function than other DMARDs. We report the case of a 64-year-old woman with RA and renal insufficiency on hemodialysis treated using etanercept therapy. This case suggests that etanercept therapy might be effective in the short term for such patients.

Combined Treatment with Interlukin-1 and Tumor Necrosis Factor-Alpha Antagonists Improve Type 2 Diabetes in Rats.

PubMed

DiK, Burak; Bahcivan, Emre; Eser Faki, Hatice; Uney, Kamil

2018-03-20

In the present study, combined treatment with etanercept and anakinra were tested in the streptozotocin-induced diabetic rats. Forty male Wistar albino rats were divided into 5 groups; healthy control (HC), diabetic control (DC), diabetic+anakinra (DAT), diabetic+etanercept (DET), and diabetic+etanercept+anakinra (DEAT). HC and DC groups received subcutaneous (sc.) injection with a saline solution, while DAT and DET groups received anakinra (10 mg/kg/day, sc.) or etanercept (10 mg/kg, twice a week, sc.), and DEAT rats received both anakinra and etanercept treatments for 21 days after diabetes has developed. Anakinra and etanercept treatments significantly increased insulin and homeostatic model assessment-β cell function levels and decreased glucose levels compared to the DC group as single (DAT and DET) and combined treatments (DEAT). The thiobarbituric acid reactive substances level was significantly decreased in DAT group. The combine use of etanercept and anakinra can improve insulin and blood glucose in type 2 diabetic rats. The combined treatment of anakinra and etanercept together was more effective than single treatment and might have a potential new treatment strategy and to reduce the mortality and morbidity resulting from diabetes.

Long-term safety and efficacy of etanercept in the treatment of ankylosing spondylitis

PubMed Central

Senabre-Gallego, José Miguel; Santos-Ramírez, Carlos; Santos-Soler, Gregorio; Salas-Heredia, Esteban; Sánchez-Barrioluengo, Mabel; Barber, Xavier; Rosas, José

2013-01-01

To date, anti-tumor necrosis factor alfa (anti-TNF-α) therapy is the only alternative to nonsteroidal anti-inflammatory drugs for the treatment of ankylosing spondylitis. Etanercept is a soluble TNF receptor, with a mode of action and pharmacokinetics different to those of antibodies and distinctive efficacy and safety. Etanercept has demonstrated efficacy in the treatment of ankylosing spondylitis, with or without radiographic sacroiliitis, and other manifestations of the disease, including peripheral arthritis, enthesitis, and psoriasis. Etanercept is not efficacious in inflammatory bowel disease, and its efficacy in the treatment of uveitis appears to be lower than that of other anti-TNF drugs. Studies of etanercept confirmed regression of bone edema on magnetic resonance imaging of the spine and sacroiliac joint, but failed to reduce radiographic progression, as do the other anti-TNF drugs. It seems that a proportion of patients remain in disease remission when the etanercept dose is reduced or administration intervals are extended. Etanercept is generally well tolerated with an acceptable safety profile in the treatment of ankylosing spondylitis. The most common adverse effect of etanercept treatment is injection site reactions, which are generally self-limiting. Reactivation of tuberculosis, reactivation of hepatitis B virus infection, congestive heart failure, demyelinating neurologic disorders, hematologic disorders like aplastic anemia and pancytopenia, vasculitis, immunogenicity, and exacerbation or induction of psoriasis are class effects of all the anti-TNF drugs, and have been seen in patients with ankylosing spondylitis. However, etanercept is less likely to induce reactivation of tuberculosis than the other anti-TNF drugs and it has been suggested that etanercept might be less immunogenic, especially in ankylosing spondylitis. Acute uveitis, Crohn’s disease, and sarcoidosis are other adverse events that have been rarely associated with etanercept therapy in patients with ankylosing spondylitis. PMID:24101863

Clinical and economic impact of etanercept in real-life: a prospective, non-interventional study of etanercept in the treatment of patients with moderate to severe plaque psoriasis in private dermatologist settings (ESTHER).

PubMed

Larsen, Christian Grønhøj; Andersen, Peter Hundevadt; Lorentzen, Henrik; Zachariae, Claus; Huldt-Nystrøm, Theis; Dotterud, Lars Kåre; Lindkvist, Rose-Marie; Qvitzau, Susanne

2013-01-01

Real-life data on the therapeutic effectiveness and costs of etanercept are scarce. To assess the clinical and economic impact of etanercept in patients with psoriasis in Denmark and Norway. This prospective, non-interventional study in a private dermatologist care setting in Denmark and Norway included patients ≥18 years with moderate to severe plaque psoriasis, selected for treatment with etanercept. Assessments during 1 year from etanercept initiation included Dermatology Life Quality Index (DLQI), Self-Administered Psoriasis Area and Severity Index (SAPASI) and adverse events. Direct and indirect costs were calculated. 163 subjects were enrolled. Baseline mean SAPASI was 19.1 . Proportion of patients with ≥50% decrease in SAPASI from baseline was 85% and 81% at weeks 24 and 52. DLQI decreased significantly from 11.4 (7.0) to 3.2 (4.3) and 3.7 (4.6) at weeks 24 and 52. Total annual costs increased from 78,000 to 286,000 DKK (p<0.0001), mainly due to the cost of etanercept. Outpatient-care costs and loss-of-productivity costs decreased from 9,500 to 5,000 (p = 0.0002), and from 33,000 to 18,000 DKK (p = 0.0105), respectively. The decrease in costs was more pronounced in patients who also had psoriatic arthritis. Cost increase was greatest during the first 6 months. Etanercept treatment was associated with decreased psoriasis severity and improved quality of life. Cost increase was driven by medication, while costs of outpatient care and loss-of-productivity decreased. Maintained improved quality of life was accompanied by decreasing cost during the second 6 month period of etanercept treatment. There were no new safety signals reported.

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

PubMed Central

Viswanathan, Preeti; Kapoor, Sorabh; Kumaran, Vinay; Joseph, Brigid; Gupta, Sanjeev

2014-01-01

Engraftment of transplanted cells is critical for liver-directed cell therapy but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells. To define whether TNF-α served roles in cell-transplantation-induced hepatic inflammation, we used TNF-α antagonist, etanercept, for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas etanercept prior to cell transplantation essentially normalized these responses. Moreover, ETN downregulated cell transplantation-induced intrahepatic release of secretory cytokines, such as high mobility group box 1. These effects of etanercept decreased cell transplantation-induced activation of neutrophils but not of Kupffer cells. Transplanted cell engraftment improved by several-fold in etanercept-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with etanercept before multiple cell transplantation sessions. Transplanted cell numbers did not change over time indicating absence of cell proliferation after etanercept alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after etanercept pretreatment significantly accelerated liver repopulation compared with control rats. We concluded that TNF-α played a major role in orchestrating cell transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. As TNF-α antagonism by etanercept decreased transplanted cell clearance, improved cell engraftment and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy. PMID:24844924

Development of a sensitive enzyme-linked immunosorbent assay for the measurement of biologically active etanercept in patients with ankylosing spondylitis.

PubMed

Wang, Lei; Wang, Xiaoxia; Li, Ying; Cheng, Zeneng

2016-01-01

Etanercept is the first tumor necrosis factor inhibitor to be approved for rheumatic disease treatment. Its in vivo concentration is usually detected with commercial enzyme-linked immunosorbent assay (ELISA) kits; specifically, previous researchers have mostly used double-antibody sandwich ELISA technology. Double-antibody sandwich ELISA is employed to detect the total etanercept rather than biologically active etanercept, which is more relevant in terms of therapeutic drug monitoring. In this work, a sensitive ELISA that employed its antigen TNF-α to capture biologically active etanercept for concentration detection was established and validated for etanercept pharmacokinetic (PK) study in patients with ankylosing spondylitis (AS). The proposed assay was demonstrated to be precise and accurate over the linear range of 12.5-400pg/mL. The intra- and inter-assay relative standard deviation ranged from 3.9 to 12.2% and 6.2 to 11.1%, respectively, and recovery varied between 90.1 and 99.7%, confirming the assay's reliability. The effectiveness and accuracy of the assay was also validated according to quality samples containing etanercept with different TNF-α concentrations, and with plasma samples from patients with AS. To complete the study, both the proposed assay and double-antibody sandwich ELISA were applied to the PK study of etanercept in patients and compared. The multiple-dose results of both analytical methods were consistent, while the drug exposure of the first dose as-detected by the proposed assay was lower than that detected by double-antibody sandwich ELISA. In conclusion, the proposed ELISA was shown to provide more accurate concentration data for therapeutic drug monitoring in comparison to commercial ELISA kits. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy and safety of etanercept in patients from Latin America, Central Europe and Asia with early non-radiographic axial spondyloarthritis.

PubMed

Wei, James Cheng-Chung; Tsai, Wen-Chan; Citera, Gustavo; Kotak, Sameer; Llamado, Lyndon

2016-11-11

To evaluate etanercept in patients from Latin America, Central/Eastern Europe, and Asia with non-radiographic axial spondyloarthritis (nr-axSpA). A subset analysis was performed on nr-axSpA patients from Argentina, Colombia, the Czech Republic, Hungary, Russia and Taiwan who were enrolled in EMBARK (NCT01258738). Patients received either etanercept 50 mg or placebo once weekly. The primary endpoint was proportion of patients achieving 40% improvement from baseline based on Assessment of SpondyloArthritis International Society (ASAS) criteria. Secondary endpoints included other efficacy assessments, health-related quality of life (HRQoL) and safety. Of the 117 patients in this subset, 59 were treated with etanercept and 58 received placebo. At week 12, numerically greater improvements from baseline were observed for all efficacy endpoints in etanercept-treated patients compared with those receiving placebo. Statistically significant differences between the two treatment groups were observed for proportion of patients achieving ASAS40 (P = 0.0413, at week 8), ASAS5/6 (P = 0.0126), Ankylosing Spondylitis Disease Activity Score - C-reactive protein (CRP) inactive disease (P = 0.0093), Spondyloarthritis Research Consortium of Canada magnetic resonance imaging of sacroiliac joint scores (P = 0.0014), high-sensitivity CRP (P=0.032), and erythrocyte sedimentation rate (P = 0.0082). Statistically significant improvements in the etanercept-treated group compared with placebo group were observed for nocturnal back pain (P = 0.040), total back pain (P = 0.025), physician global assessment of disease (P = 0.023), and Work Productivity and Activity Impairment Questionnaire percent impairment while working (P = 0.047). Adverse events were similar between the two treatment groups. In this subset of patients with nr-axSpA from Latin America, Central/Eastern Europe, and Asia, treatment with etanercept, compared with placebo, resulted in improved disease symptoms and patient HRQoL. Etanercept was well tolerated. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration.

PubMed

Brown, S Lori; Greene, Mark H; Gershon, Sharon K; Edwards, Evelyne T; Braun, M Miles

2002-12-01

Etanercept and infliximab are tumor necrosis factor (TNF) antagonists that have been recently approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents. Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed. We identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of anti-TNF treatment, in the absence of specific cytotoxic therapy directed toward the lymphoma. Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti-TNF drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association.

Secukinumab in plaque psoriasis--results of two phase 3 trials.

PubMed

Langley, Richard G; Elewski, Boni E; Lebwohl, Mark; Reich, Kristian; Griffiths, Christopher E M; Papp, Kim; Puig, Lluís; Nakagawa, Hidemi; Spelman, Lynda; Sigurgeirsson, Bárður; Rivas, Enrique; Tsai, Tsen-Fang; Wasel, Norman; Tyring, Stephen; Salko, Thomas; Hampele, Isabelle; Notter, Marianne; Karpov, Alexander; Helou, Silvia; Papavassilis, Charis

2014-07-24

Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

Application of a TNF-alpha-inhibitor into the scala tympany after cochlear electrode insertion trauma in guinea pigs: preliminary audiologic results.

PubMed

Ihler, Friedrich; Pelz, Sabrina; Coors, Melanie; Matthias, Christoph; Canis, Martin

2014-11-01

Cochlear implantation trauma causes both macroscopic and inflammatory trauma. The aim of the present study was to evaluate the effectiveness of the TNF-alpha inhibitor etanercept applied after cochlear implantation trauma on the preservation of acoustic hearing. Guinea pigs were randomly assigned to three groups receiving cochlear implantation trauma by cochleostomy. In one group, the site was sealed by bone cement with no further treatment. A second group was additionally implanted with an osmotic minipump delivering artificial perilymph into the scala tympani for seven days. In the third group, etanercept 1 mg/ml was added to artificial perilymph. Hearing was assessed by auditory brainstem responses at 2, 4, 6, and 8 kHz prior to and after surgery and on days 3, 5, 7, 14, 28. Fifteen healthy guinea pigs. The trauma led to threshold shifts from 50.3 dB ± 16.3 dB to 68.0 dB ± 19.3 dB. Hearing thresholds were significantly lower in etanercept-treated animals compared to controls on day 28 at 8 kHz and from day 3 onwards at 4 and 2 kHz (p < 0.01; two-way RM ANOVA / Bonferroni t-test). The application of etanercept led to preservation of acoustic hearing after cochlear implantation trauma.

Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.

PubMed

Griffiths, Christopher E M; Reich, Kristian; Lebwohl, Mark; van de Kerkhof, Peter; Paul, Carle; Menter, Alan; Cameron, Gregory S; Erickson, Janelle; Zhang, Lu; Secrest, Roberta J; Ball, Susan; Braun, Daniel K; Osuntokun, Olawale O; Heffernan, Michael P; Nickoloff, Brian J; Papp, Kim

2015-08-08

Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Eli Lilly and Co. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cost per treated patient for etanercept, adalimumab, and infliximab across adult indications: a claims analysis.

PubMed

Bonafede, Machaon M K; Gandra, Shravanthi R; Watson, Crystal; Princic, Nicole; Fox, Kathleen M

2012-03-01

This paper aims to estimate the annual cost of etanercept, adalimumab, and infliximab per treated patient across adult indications using US-managed care drug use data. Adult patients who used etanercept, adalimumab, or infliximab were identified in the Thomson Reuters MarketScan® Commercial Claims and Encounters Database (Thomson Reuters Healthcare, Ann Arbor, MI, USA) between January 1, 2005 and June 30, 2009. The index event was the first use of etanercept, adalimumab, or infliximab preceded by a diagnosis for rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis. Patients were defined as either newly initiating or continuing tumor necrosis factor (TNF) blocker treatment based on their use during the 6 months before the index event. Annual cost per treated patient was the sum of the etanercept, adalimumab, and infliximab medication and administration costs during the 12 months following the index claim. Annual costs were calculated across all patients as well as within each indication group and patient type (new initiator or continuing). In total, 21,652 patients met the study criteria (etanercept n = 12,065; adalimumab n = 5,685; infliximab n = 3,902); 43% of patients were new initiators. Patient characteristics were similar across treatment groups in terms of age (mean = 49, SD = 10) and gender (66% female). Across indications, the mean annual TNF-blocker cost per treated patient was $15,345 for etanercept, $18,046 for adalimumab, and $24,018 for infliximab. In new initiators, the TNF-blocker cost per treated patient across indications was $14,543 for etanercept, $16,978 for adalimumab, and $21,086 for infliximab; among patients continuing therapy, annual costs were $15,836 for etanercept, $19,457 for adalimumab, and $25,748 for infliximab. Patients on etanercept had the lowest TNF-blocker cost per treated patient for adult indications when applying actual drug use from a US-managed care population. TNF-blocker costs per treated patient on adalimumab and infliximab were approximately 18% and 57% higher than etanercept, respectively, using real-world drug use data.

Impact of 24 months of anti-TNF therapy versus methotrexate on body weight in patients with rheumatoid arthritis: a prospective observational study.

PubMed

Sfriso, Paolo; Caso, Francesco; Filardo, Giuseppe Sebastiano; Botsios, Costantino; Costa, Luisa; Scarpa, Raffaele; Todesco, Silvano; Spinella, Paolo; Oliviero, Francesca; Punzi, Leonardo

2016-06-01

To evaluate the impact of anti-TNF-α therapy on the body weight of rheumatoid arthritis (RA) patients following 24 months of treatment. Data were collected on all RA patients included in the Veneto Region's Registry of Biological Therapy from January 2007 to July 2012. Inclusion criteria were: start of monotherapy with adalimumab, etanercept, or methotrexate, no previous use of biologic therapy, and at least 24 months of treatment. At baseline, 12, and 24 months, each patient completed a questionnaire about physical activity, smoking, alcohol, and food habits. One hundred and thirty-one RA patients in monotherapy with etanercept (n = 47), adalimumab (n = 44), and methotrexate (n = 40) were enrolled for this study. After 24 months of therapy, there was an increase of weight only in patients treated with anti-TNF-α. Patients on etanercept and adalimumab therapy showed a risk to gain weight six times greater compared to those on methotrexate therapy. The results of present study show that the use of anti-TNF-α in RA patients can be associated to a significant increase of body weight. This increase is not shown in patients under treatment with methotrexate. A more careful evaluation of weight changes needs to be considered in RA patients under anti-TNF-α treatment.

Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis.

PubMed

Nakamura, T; Higashi, S; Tomoda, K; Tsukano, M; Baba, S

2007-01-01

The efficacy of biological therapies in rheumatoid arthritis (RA) is well known, but their hypothetical benefit in amyloid A (AA) amyloidosis secondary to RA still remains to be considered. We evaluated the efficacy and safety of etanercept in serum amyloid A (SAA) 1.3 allele Japanese patients with AA amyloidosis secondary to RA. Seven RA patients with histologically confirmed AA amyloidosis and renal involvement who were treated with etanercept were enrolled. They all had the SAA1.3 allele, which has been shown to be a risk factor not only for the association of AA amyloidosis but also for a poor prognosis in Japanese RA patients. Efficacy was assessed as a sustained decrease in RA inflammation and an amelioration of renal function. RA inflammation and AA amyloidosis were improved and stabilized after 43.4 +/- 16.5 weeks. At week 20 the number of tender (p = 0.017) and swollen (p = 0.017) joints, and levels of serum C-reactive protein (p = 0.018) and albumin (p = 0.045) had improved. The values for SAA, serum creatinine, calculated creatinine clearance, and proteinuria also ameliorated. No severe adverse events were observed. One patient eventually had to go on hemodialysis but her tolerance of etanercept remained stable. Etanercept can be used safely and effectively in AA amyloidosis secondary to RA with renal involvement, and is of clinical benefit in the short-term, even in patients on hemodialysis. It appears that SAA1.3 allele may be used as a clinical parameter for the introduction of etanercept in Japanese RA with AA amyloidosis.

Longitudinal analysis of the use of etanercept versus infliximab determined from medical chart audit.

PubMed

Abarca, Jacob; Malone, Daniel C; Armstrong, Edward P; Grizzle, Amy J; Cohen, Marc D

2004-01-01

To describe the dosing of etanercept and infliximab for the treatment of rheumatoid arthritis (RA). Adult patients with a diagnosis of RA who were treated with either etanercept or infliximab between 1999 and 2002 were selected from 16 rheumatology practices in the western and southeastern United States. Patients with a terminal illness or those receiving a tumor necrosis factor (TNF)-alpha inhibitor for an indication other than RA were excluded. Data were collected through a review of the patient medical records. Data collected on each patient included demographics, concurrent disease-modifying antirheumatic drug therapy, TNF-alpha inhibitor dose, frequency, duration of TNF-alpha inhibitor therapy, and discontinuation of TNF-alpha inhibitor therapy. A total of 244 patients were included in the evaluation (etanercept only [n=128; 52%], infliximab only [n=89; 36%], both [n=27; 11%]). The mean age of these patients was 55.1+/-13.3 years, 54.9+/-13.5 years, and 52.8+/-14.0 years, respectively; the mean duration of RA was 13.3 +/- 8.8 years, 13.4+/-8.0 years, and 14.0 +/- 9.9 years, respectively. Female patients constituted 70% of the sample. Health maintenance organization insurance was the most common form of medical insurance (45.8%), followed by Medicare (22.3%). The mean duration of follow-up for etanercept and infliximab treatment was 29.3+/-14.1 months and 14.8+/-6.9 months, respectively. Among patients who were still receiving therapy at the time of review, the mean initial and last etanercept doses were 25.0 mg versus 25.8 mg (P=0.16); the mean initial and last infliximab doses were 3.38 mg/kg versus 4.51 mg/kg (P<0.001). The dosing of etanercept and infliximab therapy was consistent with the approved labeling of both medications.

Formation of protein sub-visible particles during vacuum degassing of etanercept solutions.

PubMed

Wang, Haibin; Zheng, Hong-Jian; Wang, Zhao; Bai, Hua; Carpenter, John F; Chen, Shuqing; Fang, Wei-Jie

2014-05-01

The main purpose of this manuscript is to describe a phenomenon in which vacuum degassing a reconstituted freeze-dried fusion protein etanercept formulation caused a significant amount of protein sub-visible particles (SbVP). Physical stability of etanercept was monitored by micro-flow imaging (MFI), dynamic light scattering (DLS), size-exclusion high pressure liquid chromatography (SE-HPLC) and far- and near-ultraviolet circular dichroism (far- and near-UV CD). One potential explanation of this phenomenon is that bubble collapses when the vacuum is applied, leads to substantial heat formation, and ultimately free radical formation. Subsequently, the effect of a free-radical scavenger (ascorbic acid, AA) on SbVP formation was also evaluated. Degassing of etanercept solution by applying vacuum caused substantial increase of SbVP, as detected by MFI and DLS. However, traditional techniques such as SE-HPLC could not detect any change. The addition of free-radical scavenger had minimal effect on SbVP formation, therefore the formation of free radicals was probably not the main cause for this effect. Copyright © 2014 Elsevier B.V. All rights reserved.

Treatment of rheumatoid arthritis with biologic DMARDS (Rituximab and Etanercept).

PubMed

Gashi, Afrim A; Rexhepi, Sylejman; Berisha, Idriz; Kryeziu, Avni; Ismaili, Jehona; Krasniqi, Gezim

2014-01-01

To determine efficacy and safety of treatment with Rituximab and Etanercept plus Methotrexate in patients with active Rheumatoid Arthritis (RA), who had an inadequate response to nonbiologic DMARDS therapies and to explore the pharmacogenetics and pharmacodynamics of Rituximab and Etanercept in our populations. Study was done at Rheumatology Clinic of University Clinical Centre in Prishtina during 2009-2011 years. We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the study of long-term efficacy of Rituximab and Etanercept. Patients with active Rheumatoid Arthritis and an inadequate response to 1 or more non biologic DMARDS were randomized to receive intravenous Rituximab (1 course consisting of 2 infusions of 1.000 mg each -one group, and Etanercept 25 mg twice weekly -second group, but both groups with background MTX. The primary efficacy end point was a response on the ACR 20%, improvement criteria at 24 weeks, Secondary end points were responses on the ACR 50 and ACR 70, improvement criteria, the DAS 28, and EULAR response criteria at 24 weeks. During our investigations we treated 20 patients, 15 females and 5 males, in the treated group with RTX and 13 patients 8 females and 5 males in the treated group with ETN. Patients of group 1 and group 2 were of ages 37-69 years old and 19-69 years old (average 47-44) Most of the patients belong in 2nd and 3rd functional stage according to Steinbrocker. All ACR response parameters were significantly improved in RTX treated patients who also had clinically meaningful improvement in fatigue, disability and quality of life. Patients showed a trend less progression in radiographic end points. Most adverse events occurred with the first RTX infusion and were mild to moderate severity. At 24 weeks, a single course of RTX and ETN provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more nonbiologic DMARDS.

Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33.

PubMed

Kageyama, Yasunori; Torikai, Eiji; Tsujimura, Kunio; Kobayashi, Masato

2012-02-01

To investigate the role of interleukin (IL)-33 in rheumatoid arthritis (RA) patients, we measured the serum levels of IL-33 in RA patients before and after the administration of etanercept. Twenty-four patients with RA were treated with etanercept. Clinical and laboratory examinations, including serum levels of C-reactive protein (CRP) and hemoglobin (Hb); white blood cell (WBC) and red blood cell (RBC) counts; and the Disease Activity Score of 28 joints including CRP (DAS28-CRP), were performed at the baseline and at 3 and 6 months after the initial treatment with etanercept. The mean serum IL-33 levels had decreased significantly at 3 and 6 months after the initial treatment with etanercept. Serum IL-33 levels showed a significant correlation with the number of tender joints, CRP, DAS28-CRP, and the WBC count, and an inverse correlation with the RBC count and Hb level. These findings indicated that the decrease of serum IL-33 levels was a novel function of etanercept, shown for the first time in this study. Measurement of serum levels of IL-33 may become a useful control marker for RA treatment.

The effect of the use of a TNF-alpha inhibitor in hypothermic machine perfusion on kidney function after transplantation.

PubMed

Diuwe, Piotr; Domagala, Piotr; Durlik, Magdalena; Trzebicki, Janusz; Chmura, Andrzej; Kwiatkowski, Artur

2017-08-01

One of the most important problems in transplantation medicine is the ischemia/reperfusion injury of the organs to be transplanted. The aim of the present study was to assess the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitor etanercept on the machine perfusion hypothermia of renal allograft kidney function and organ perfusion. No statistically significant differences were found in the impact of the applied intervention on kidney machine perfusion during which the average flow and vascular resistance were evaluated. There were no statistically significant differences in the occurrence of delayed graft function (DGF). Fewer events in patients who received a kidney from the etanercept treated Group A compared to the patients who received a kidney from the control Group B were observed when comparing the functional DGF and occurrence of acute rejection episodes, however, there was no statistically significant difference. In summary, no effect of treatment with etanercept an inhibitor of TNF-alpha in a hypothermic machine perfusion on renal allograft renal survival and its perfusion were detected in this study. However, treatment of the isolated organ may be important for the future of transplantation medicine. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate.

PubMed

Foster, C Stephen; Tufail, Fehma; Waheed, Nadia Khalida; Chu, David; Miserocchi, Elisabetta; Baltatzis, Stefanos; Vredeveld, Cindy M

2003-04-01

To evaluate the efficacy of etanercept vs placebo in preventing relapses of uveitis in patients taking methotrexate with control of uveitis and whose methotrexate dosage was being tapered. Patients with chronic or recurrent noninfectious uveitis with inflammation controlled by low-dose methotrexate were randomized to either the drug or placebo group in a double-masked manner, given a methotrexate taper schedule, and followed for 24 weeks. The main outcome measures were control of inflammation, visual acuity, and adverse reactions. Data were analyzed both as an attempt-to-treat analysis and an analysis only of those patients who completed the study. A total of 20 patients were randomized to the drug and placebo groups. Relapse of uveitis occurred in 3 of 10 patients in the treatment group and 5 of 10 patients in the control group. Two patients in the treatment group withdrew prematurely from the study due to adverse effects. There was no significant difference between the treatment and placebo groups with regard to the rate of relapse and the final visual acuity. No patient suffered from any irreversible, long-term morbidity or mortality. Etanercept has no significant efficacy over placebo in preventing relapses of uveitis in patients being tapered from methotrexate.

Etanercept in methotrexate-resistant JIA-related uveitis.

PubMed

Saeed, Muhammad Usman; Raza, Syed Hamid; Goyal, Sudeshna; Cleary, Gavin; Newman, William David; Chandna, Arvind

2014-01-01

We report our results with systemic Etanercept in patients with juvenile idiopathic arthritis in a joint ophthalmology-rheumatology clinic at a tertiary hospital. Patients with JIA on Etanercept were identified from a dedicated uveitis database. A retrospective review of electronic and paper-based patient records was performed. Nine patients with JIA and current or previous treatment with Etanercept were identified, including six females and three males. Five patients with previous or current uveitis were noted. A further four were under observation for uveitis and required Etanercept for their joint disease. All nine patients had previously been taking Methotrexate, which had a suboptimal response in controlling arthritis or uveitis. Six out of nine patients did not show any uveitis activity at their last follow-up. Eyes of three patients still show signs of active inflammation in the anterior chamber (two on Etanercept and one off Etanercept). Severely impaired visual acuity (PL) was recorded in both eyes of one patient with long-standing persistent uveitis. Moderate visual loss in one eye of one patient was seen. The remaining seven patients did not show any significant loss of vision. Intraocular inflammation was not induced in any patient started on Etanercept. Etanercept may be useful in controlling JIA-related uveitis or arthritis in a pediatric patient when Methotrexate has had a suboptimal response in controlling the inflammatory activity.

Efficiency of adalimumab, etanercept and infliximab in rheumatoid arthritis patients: dosing patterns and effectiveness in daily clinical practice.

PubMed

Ramírez-Herráiz, Esther; Escudero-Vilaplana, Vicente; Alañón-Plaza, Estefanía; Trovato-López, Nicolás; Herranz-Alonso, Ana; Morell-Baladrón, Alberto; Sanjurjo-Sáez, María

2013-01-01

This retrospective, multicentre, observational study aimed to assess the mean annual doses and associated costs of three anti-tumour necrosis factor agents in daily clinical practice in rheumatoid arthritis patients, correlating these costs with disease activity. Adult rheumatoid arthritis patients were treated and followed at the Rheumatology departments of two Spanish hospitals for at least 6 months, with adalimumab, etanercept or infliximab over a 4-year period. ANOVA and multivariate statistical analyses of dosing patterns, disease activity and annualised costs were carried out. A total of 198 patients, comprising 215 cases, met the inclusion criteria (73 on adalimumab, 81 etanercept and 61 infliximab). Compared to recommended doses, mean doses of adalimumab and etanercept decreased by 7% and 19%, respectively, while the mean dose of infliximab increased by 36%. There were no statistical differences between treatments in terms of clinical effectiveness. The hazard of dose escalation was significantly higher for either adalimumab (4.4-fold) or infliximab (11.8-fold) compared to etanercept (p<0.05). Clinical control was achieved and maintained in more than half of the patients treated with reduced doses of etanercept. Associated mean patient-year costs were significantly higher in adalimumab patients (€11.962.58) (etanercept €9.594.73; infliximab €10.094.53; [p<0.05]). In rheumatoid arthritis patients, it is possible to reduce doses and associated costs of biological therapies while controlling disease activity. Mean doses used in our clinical practice were significantly lower with etanercept than with the anti-TNF monoclonal antibodies, adalimumab and infliximab. Dose differences impact directly on associated patient-year costs, and thus on treatment efficiency.

Use of etanercept in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients.

PubMed

Ting, Patricia T; Koo, John Y

2006-06-01

Etanercept (Enbrel, Amgen, Thousand Oaks, CA), a soluble p75 tumor necrosis factor receptor:FC (TNFR:FC) fusion protein for plasma cytokines, specifically tumor necrosis factor-alpha (TNF-alpha), is used in the treatment of immune-mediated rheumatic diseases. To our knowledge, the use of etanercept in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) is relatively uncommon. The main purpose of this short review is to examine the safety of etanercept in patients with HIV/AIDS. A Medline search was conducted using the keywords etanercept and HIV and/or AIDS for any published articles between 1966 to the present (September 2004). A case report, one case series, and one clinical trial pertained to the use of etanercept in HIV patients. No reports were found on the use of etanercept in AIDS. In addition, two case reports were found documenting the use of infliximab in HIV patients. Preliminary reports indicate that the administration of etanercept does not appear to increase the morbidity or mortality rates in HIV. The inhibition of TNF-alpha may actually improve the symptoms of HIV/AIDS-associated aphthous ulcers, cachexia, dementia, fatigue, and fever, as well as help manage concomitant rheumatic diseases and psoriasis. The use of etanercept shows promise for applications in disease management in patients with HIV/AIDS. Continued research efforts are necessary to establish the long-term safety and efficacy of etanercept and other biologic agents in this patient population.

Satisfaction with Subcutaneous Golimumab and its Auto-Injector among Rheumatoid Arthritis Patients with Inadequate Response to Adalimumab or Etanercept.

PubMed

Dehoratius, Raphael J; Brent, Lawrence H; Curtis, Jeffrey R; Ellis, Lorie A; Tang, Kezhen L

2018-06-01

Patient perceptions of treatment success, including satisfaction/preference, may complement clinical efficacy assessments. Our objective was to evaluate satisfaction with subcutaneous golimumab and its auto-injector in patients with rheumatoid arthritis (RA) and an inadequate adalimumab/etanercept response. In the multicenter, assessor-blinded GO-SAVE study, 433 patients with active RA (28-joint Disease Activity Score incorporating erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.6 and six or more swollen and six or more tender joints) despite methotrexate and past adalimumab/etanercept treatment received open-label subcutaneous golimumab 50 mg every 4 weeks (q4w) through week 12. Week 16 responders (DAS28-ESR improvement from baseline > 1.2 and score ≤ 3.2) continued therapy through week 52; nonresponders were randomized (1:2) to double-blind subcutaneous golimumab 50 mg q4w or intravenous golimumab 2 mg/kg [weeks 16, 20, every 8 weeks (q8w)]. Patients rated satisfaction with their injection experience on a 5-point scale (1 = very dissatisfied; 5 = very satisfied) at screening, week 8 (all enrolled patients), and week 44 (for patients continuing open-label subcutaneous golimumab 50 mg q4w). Discomfort, pain, stinging, burning, and redness related to injection were assessed (none, mild, moderate, severe). Similar proportions of patients (N = 433) had most recently received adalimumab (50.3%) or etanercept (49.7%) prior to golimumab. Overall satisfaction (somewhat/very) with the golimumab injection experience was reported by 84.4% of patients at week 8 versus 63.4% of patients who were satisfied with prior adalimumab/etanercept. Patients receiving open-label subcutaneous golimumab through week 44 (N = 75) reported much less discomfort (60.9%), redness (60.9%), pain (59.4%), stinging (67.2%), and burning (65.6%) with the golimumab injection than with their previous tumor necrosis factor antagonist medication injection. Most patients with RA receiving golimumab following adalimumab/etanercept inadequate response were satisfied with their overall golimumab experience, including its auto-injector versus their previous injection device. CLINICAL TRIALS.GOV: NCT01004432; EudraCT 2009-010582-23.

Which one is more effective for the treatment of rat sepsis model: thalidomide or etanercept?

PubMed

Ilhan, N; Susam, S; Gul, H F; Bardas, R; Ilhan, N

2017-01-01

We aimed to investigate the protective effect of selected treatment agents on liver injury in lipopolysaccharide (LPS)-induced rat sepsis model. The sepsis includes complex inflammatory responses between a microbial pathogen and the host immune system, and leads to organ failure and also death. This study was performed with 29 male Wistar Albino rats. Rats were divided randomly into five groups: Sham group, LPS-treated sepsis group, LPS+thalidomide treated group, LPS+etanercept treated group and LPS+thalidomide+etanercept treated group, respectively. Liver tissue tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) levels were determined by enzyme-linked immuno-sorbent assay (ELISA) method. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was performed using western blot analysis. The levels of tissue TNF-α, IL-1β and IL-6 were found statistically significantly higher in sepsis group than in the sham group. TNF-α levels were found statistically significantly decreased in LPS+etanercept and LPS+thalidomide+etanercept treated groups when compared with LPS group (p < 0.05). For IL-1β and IL-6 levels a statistically significant decline was observed in the LPS+thalidomide and LPS+etanercept treated groups compared to the LPS group (p < 0.05). Expression of NF-κB protein in liver tissue was significantly elevated in the LPS group compared to sham group (p < 0.001). In treatment groups, a marked decrease was observed in NF-κB protein expression. The results of this investigation suggested that etanercept and thalidomide administration may have a beneficial effect on LPS-induced sepsis. So, the present study may have significant clinical relevance, but clinical trials are needed to confirm these results (Tab. 1, Fig. 1, Ref. 36).

Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study

PubMed Central

van Bezooijen, Ji Sun; Balak, Deepak M.W.; van Doorn, Martijn B.A.; Looman, Caspar W.N.; Schreurs, Marco W.J.; Koch, Birgit C.P.; van Gelder, Teun; Prens, Errol P.

2016-01-01

Background Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. Objective To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. Methods Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. Results In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. Conclusion Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability. PMID:27576483

Baseline factors that influence ASAS 20 response in patients with ankylosing spondylitis treated with etanercept.

PubMed

Davis, John C; Van der Heijde, Désirée M F M; Dougados, Maxime; Braun, Jurgen; Cush, John J; Clegg, Daniel O; Inman, Robert D; de Vries, Todd; Tsuji, Wayne H

2005-09-01

To examine the baseline demographic and disease characteristics that might influence improvement as measured by the Assessment in Ankylosing Spondylitis Response Criteria (ASAS 20) in patients with ankylosing spondylitis (AS). A multicenter Phase 3 study was performed to compare the safety and efficacy of 24 weeks of etanercept 25 mg subcutaneous injection twice weekly (n = 138) and placebo (n = 139) in patients with AS. The ASAS 20 was measured at multiple time points. Using a significance level of 0.05, a repeated measures logistic regression model was used to determine which baseline factors influenced response in the etanercept-treated patients during the 24-week double blind portion of the trial. The following baseline factors were used in the model: demographic and disease severity variables, concomitant medications, extra-articular manifestations, and HLA-B27 status. The predictive capability of the model was then tested on the patients receiving placebo after they had received open-label etanercept treatment. Baseline factors that were significant predictors of an ASAS 20 response in etanercept-treated patients were C-reactive protein (CRP), back pain score, and Bath Ankylosing Spondylitis Functional Index (BASFI) score. Although clinical response to etanercept was seen at all levels of baseline disease activity, responses were consistently more likely with higher CRP levels or back pain scores and less likely with increased BASFI scores at baseline. Higher CRP values and back pain scores and lower BASFI scores at baseline were significant predictors of a higher ASAS 20 response in patients with AS receiving etanercept but predictive value was of insufficient magnitude to determine treatment in individual patients.

Etanercept and adalimumab treatment patterns in psoriatic arthritis patients enrolled in a commercial health plan.

PubMed

Chastek, Benjamin; Fox, Kathleen M; Watson, Crystal; Gandra, Shravanthi R

2012-08-01

Treatment patterns, including persistence, gaps in therapy, switching, and discontinuation, were examined in patients with psoriatic arthritis (PsA) who received the tumor necrosis factor (TNF)-blockers etanercept or adalimumab. This retrospective study utilized administrative claims data from a United States commercial health plan. Adults (age 18-64 years) with PsA who started therapy with etanercept or adalimumab as index therapy between January 1, 2006 and December 31, 2008 were included in the analysis. Patients were continuously enrolled in the health plan for at least 6 months before and at least 12 months after the start of index therapy. Initial TNF-blocker dose and rates of therapy persistence (continuous use of index medication without a gap of at least 60 days), therapy gaps, and discontinuation (gap in therapy of at least 60 days) were estimated. Those who discontinued were further classified as: (1) discontinued all biologic therapy, (2) restarted index medication, (3) switched to another biologic therapy, or (4) other. A total of 346 patients with PsA (202 etanercept, 144 adalimumab) were eligible. Most (90.6% etanercept; 88.9% adalimumab) started index therapy at the labeled dose. Persistence with index therapy for 12 months was observed in 50% of patients on etanercept and 45% of patients on adalimumab (P = 0.37). Patients on etanercept had a longer duration of persistence (434 vs. 353 days; P = 0.02), more pauses of at least 7 days (4.7 vs. 3.5; P = 0.004), and a longer mean pause length (48.6 vs. 29.3 days; P = 0.01) than patients on adalimumab. Of patients who discontinued (24.8% etanercept; 35.1% adalimumab), 46.4% and 41.5% restarted etanercept and adalimumab, respectively; 24.8% and 35.1% discontinued all TNF-blockers; 20.0% and 19.2% switched to another biologic; and 8.8% and 4.3% had other therapy changes. Approximately half of PsA patients were persistent on their index TNF-blocker for 12 months. Pauses in therapy and therapy discontinuation were common, but more than 40% of patients restarted their index TNF-blocker after discontinuation.

Influence of etanercept on leptin and ghrelin secretion in children with juvenile idiopathic arthritis.

PubMed

Maciejewska-Paszek, Izabela; Grochowska-Niedworok, Elżbieta; Siwiec, Andrzej; Gruenpeter, Anna; Dul, Lechosław; Irzyniec, Tomasz

2017-04-01

Objective To assess possible changes in leptin and ghrelin secretion due to etanercept in juvenile idiopathic arthritis (JIA). Methods 50 patients with JIA and 16 age-matched controls were enrolled into this prospective, cross-sectional study. Serum leptin, total and acyl ghrelin were measured in addition to white blood cell (WBC) and lymphocyte counts. Results 25 patients received etanercept and 25 conventional therapies (including methotrexate) for JIA. There was no difference between treatment and control groups in leptin or ghrelin levels and no evidence of a relationship between leptin and ghrelin in patients with JIA. In all children with JIA there was a correlation between leptin and body mass index (BMI). However, compared with children in the conventional treatment group, children in the etanercept group showed a positive correlation between total ghrelin and BMI and those with a low BMI showed a negative correlation between acyl ghrelin and BMI. Conclusion No differences in leptin and ghrelin concentrations were found when patients with JIA and controls were compared or when patients who received etanercept were compared with those who received conventional treatment for JIA.

Influence of etanercept on leptin and ghrelin secretion in children with juvenile idiopathic arthritis

PubMed Central

Maciejewska-Paszek, Izabela; Grochowska-Niedworok, Elżbieta; Siwiec, Andrzej; Gruenpeter, Anna; Dul, Lechosław

2017-01-01

Objective To assess possible changes in leptin and ghrelin secretion due to etanercept in juvenile idiopathic arthritis (JIA). Methods 50 patients with JIA and 16 age-matched controls were enrolled into this prospective, cross-sectional study. Serum leptin, total and acyl ghrelin were measured in addition to white blood cell (WBC) and lymphocyte counts. Results 25 patients received etanercept and 25 conventional therapies (including methotrexate) for JIA. There was no difference between treatment and control groups in leptin or ghrelin levels and no evidence of a relationship between leptin and ghrelin in patients with JIA. In all children with JIA there was a correlation between leptin and body mass index (BMI). However, compared with children in the conventional treatment group, children in the etanercept group showed a positive correlation between total ghrelin and BMI and those with a low BMI showed a negative correlation between acyl ghrelin and BMI. Conclusion No differences in leptin and ghrelin concentrations were found when patients with JIA and controls were compared or when patients who received etanercept were compared with those who received conventional treatment for JIA. PMID:28415953

Pediatric Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Halted by Etanercept.

PubMed

Gavigan, Geneviève M; Kanigsberg, Nordau D; Ramien, Michele L

2018-02-01

We report a case of an 11-year-old female with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) overlap, most likely triggered by sulfamethoxazole-trimethoprim, who was treated with the combination of methylprednisolone, cyclosporine, and etanercept. Her condition stabilized and her skin involvement did not progress after the addition of etanercept. To our knowledge, this is the first report of etanercept for pediatric SJS/TEN.

Real-life 10-year retention rate of first-line anti-TNF drugs for inflammatory arthritides in adult- and juvenile-onset populations: similarities and differences.

PubMed

Favalli, Ennio Giulio; Pontikaki, Irene; Becciolini, Andrea; Biggioggero, Martina; Ughi, Nicola; Romano, Micol; Crotti, Chiara; Gattinara, Maurizio; Gerloni, Valeria; Marchesoni, Antonio; Meroni, Pier Luigi

2017-08-01

The aim of this study is to retrospectively analyze 10-year drug survival of first-line TNF inhibitor (TNFi) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) patients, comparing withdrawal rates and discontinuation pattern between adult- and juvenile-onset populations. RA, AS, PsA, and JIA patients treated with infliximab, etanercept, or adalimumab as first TNFi between 1999 and 2015 were extracted from a local registry. Drug survival up to 10-year follow-up was evaluated by the Kaplan-Meier method and compared according to age (adult vs juvenile onset), TNFi agent, and discontinuation reason by a stratified log-rank test. Three hundred sixty JIA (205 etanercept, 66 adalimumab, and 89 infliximab) and 951 (607 RA, 188 AS, and 156 PsA) adult patients (464 infliximab, 262 adalimumab, and 225 etanercept) were included. After exclusion of systemic-onset JIA (18.5%), overall 10-year retention rate was 31.8%, with no difference between adult- and juvenile-onset patients (32.1 and 30.2%, respectively; HR 0.938 [95% CI 0.782-1.125]). Etanercept showed the highest drug survival in adult-onset population (p < 0.0001 vs both monoclonal antibodies) and infliximab the lowest in juvenile-onset population (p = 0.005 vs adalimumab and p < 0.0001 vs etanercept). Inefficacy was the most frequent reason for TNFi withdrawal in adult population (29.75%) with a significantly higher risk of discontinuation than in juvenile-onset subgroup (HR 1.390 [95% CI 1.060-1.824]). Serious infections and malignancies caused TNFi withdrawal only in adult whereas gastrointestinal, neuropsychiatric, and ocular complications quite only in juvenile patients. Despite a similar 10-year drug survival, adult- and juvenile-onset subpopulations showed a significantly different pattern of TNFi reasons for discontinuation.

Two-year survival rates of anti-TNF-α therapy in psoriatic arthritis (PsA) patients with either polyarticular or oligoarticular PsA.

PubMed

Iannone, F; Lopriore, S; Bucci, R; Scioscia, C; Anelli, M G; Notarnicola, A; Lapadula, G

2015-05-01

To evaluate the 2-year drug survival rates of the tumour necrosis factor (TNF)-α blockers adalimumab, etanercept, and infliximab in psoriatic arthritis (PsA) patients with either oligoarticular (oligo-PsA) or polyarticular PsA (poly-PsA). We studied a prospective cohort of 328 PsA patients with peripheral arthritis (213 with poly-PsA and 115 with oligo-PsA), beginning their first ever anti-TNF-α treatment with adalimumab, etanercept, or infliximab. The aim of the study was to evaluate the drug survival rates and possible baseline predictors at 2 years. After 24 months, persistence in therapy with the first anti-TNF-α blocker was not statistically different in the oligo-PsA (70.4%) and poly-PsA (65.7%) subsets. Predictors of drug discontinuation were female sex [hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.00-2.68, p = 0.04] and starting the therapy in years 2003-8 (HR 0.51, 95% CI 0.33-0.80, p = 0.003). In poly-PsA, the persistence of etanercept (68.3%) was significantly higher than that of adalimumab (51.9%, p = 0.01), whereas in oligo-PsA no significant difference was detected. In poly-PsA, the period 2003-8 was a negative predictor (HR 0.36, 95% CI 0.21-0.62, p = 0.0001) whereas in oligo-PsA female gender was a positive predictor of drug discontinuation (HR 2.08, 95% CI 1.02-4.24, p = 0.04). With regard to clinical outcomes, the best responses in terms of European League Against Rheumatism (EULAR) 'good' response or Disease Activity Score (DAS28) remission, crude or adjusted according to the LUND Efficacy indeX (LUNDEX), were seen in patients on etanercept or infliximab. Our study provides some evidence that anti-TNF-α drugs may perform differently in PsA, and that the analysis of clinical disease subsets may improve our knowledge and promote better management of PsA.

Treatment of Rheumatoid Arthritis with Biologic DMARDS (Rituximab and Etanercept)

PubMed Central

Gashi, Afrim A.; Rexhepi, Sylejman; Berisha, Idriz; Kryeziu, Avni; Ismaili, Jehona; Krasniqi, Gezim

2014-01-01

ABSTRACT Goal: To determine efficacy and safety of treatment with Rituximab and Etanercept plus Methotrexate in patients with active Rheumatoid Arthritis (RA), who had an inadequate response to nonbiologic DMARDS therapies and to explore the pharmacogenetics and pharmacodynamics of Rituximab and Etanercept in our populations. Study was done at Rheumatology Clinic of University Clinical Centre in Prishtina during 2009-2011 years. Methods: We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the study of long term efficacy of Rituximab and Etanercept. Patients with active Rheumatoid Arthritis and an inadequate response to 1 or more non biologic DMARDS were randomized to receive intravenous Rituximab (1 course consisting of 2 infusions of 1.000 mg each –one group, and Etanercept 25 mg twice weekly –second group, but both groups with background MTX. The primary efficacy end point was a response on the ACR 20%, improvement criteria at 24 weeks, Secondary end points were responses on the ACR 50 and ACR 70, improvement criteria, the DAS 28, and EULAR response criteria at 24 weeks. Results: During our investigations we treated 20 patients, 15 females and 5 males, in the treated group with RTX and 13 patients 8 females and 5 males in the treated group with ETN. Patients of group 1 and group 2 were of ages 37-69 years old and 19-69 years old (average 47-44) Most of the patients belong in 2nd and 3 rd functional stage according to Steinbrocker. All ACR response parameters were significantly improved in RTX treated patients who also had clinically meaningful improvement in fatigue, disability and quality of life. Patients showed a trend less progression in radiographic end points. Most adverse events occurred with the first RTX infusion and were mild to moderate severity. Conclusion: At 24 weeks, a single course of RTX and ETN provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more nonbiologic DMARDS. PMID:24783914

Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe, Latin America, and Asia.

PubMed

Damjanov, Nemanja; Shehhi, Waleed Al; Huang, Feng; Kotak, Sameer; Burgos-Vargas, Ruben; Shirazy, Khalid; Bananis, Eustratios; Szumski, Annette; Llamado, Lyndon J Q; Mahgoub, Ehab

2016-05-01

Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran-Mantel-Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America.

Blueberry Improves the Therapeutic Effect of Etanercept on Patients with Juvenile Idiopathic Arthritis: Phase III Study.

PubMed

Zhong, Yingjie; Wang, Ye; Guo, Jun; Chu, Haifeng; Gao, Yong; Pang, Limin

2015-11-01

Juvenile idiopathic arthritis (JIA) is the most common arthritis in the adolescents under the age of 16. Etanercept, an inhibitor of tumor necrosis factor, is often used to treat JIA despite its significant side effects. Homeopathic remedies, such as blueberries, have anti-inflammatory properties with fewer unwanted effects and should be considered as a primary treatment. We aimed to explore the efficacy and safety of combination therapy of blueberry and etanercept for JIA. Two hundred and one JIA patients were selected, and randomly and evenly assigned to three groups: ETA (50 mg of etanercept twice weekly), ETABJ (matched etanercept and 50 ml blueberry juice daily) and ETAPJ (matched etanercept and placebo juice). The severity of JIA was measured using American College of Rheumatology scales (ACR) 20, 50 and 70. The levels of pro-inflammatory cytokines, interleukin-1 (IL1) alpha and IL1 beta, and interleukin-1 receptor antagonist (IL1RA) were measured by qRT-PCR and ELISA. After a 6-month follow-up, the ACR20, ACR50 and ACR70 in an ETABJ group were higher than those in other two groups (P < 0.05), suggesting clinically meaningful improvement in JIA. Meanwhile, the symptoms and side effects were reduced significantly or absent in an ETABJ group, including mental diseases, retrobulbar optic neuritis, gaining weight, infection, cutaneous vasculitis, diarrhea, uveitis and pancytopenia. Blueberries reduced the levels of IL1 alpha and beta, and increased the level of IL1RA. Thus, a combination therapy of blueberry and etanercept can reduce the severity of JIA and should be developed as a new method for JIA therapy.

Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept.

PubMed

Peper, Shana M; Lew, Robert; Mikuls, Ted; Brophy, Mary; Rybin, Denis; Wu, Hongseng; O'Dell, James

2017-10-01

Although it is common for rheumatologists to initiate biologic agents after failure of methotrexate monotherapy in rheumatoid arthritis (RA), ample data support the initial use of combinations of conventional therapies in this clinical scenario. Our study explores the durability of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) versus methotrexate-etanercept in RA. RA patients with suboptimal response to methotrexate (n = 353) were randomized to either triple therapy or methotrexate-etanercept therapy in a 48-week, double-blinded, noninferiority trial. Patients without clinical improvement at 24 weeks were switched to the alternative treatment. Of the total, 289 participated in followup. We report treatment durability, Disease Activity Score in 28 joints (DAS28), and other measures during an open-label extension for an additional period up to 72 weeks. Mean ± SD duration of open-label followup was 11 ± 6 months. The likelihood of continuing conventional therapy at 1 year was 78% for triple therapy versus 63% for methotrexate-etanercept, with most treatment changes occurring at the start of followup. More patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept (P = 0.005). DAS28 scores and other disease activity measures were not different for the 2 treatments and were stable during followup. In RA patients with suboptimal methotrexate response randomized to receive triple therapy or methotrexate-etanercept, the former was found to be significantly more durable. Given cost differences and similar outcomes, the variable durability demonstrated provides additional evidence supporting conventional combinations over biologic agent combinations as the first choice after methotrexate inadequate response. © 2017, American College of Rheumatology.

Cost-efficacy of biologic therapies for psoriatic arthritis from the perspective of the Taiwanese healthcare system.

PubMed

Yang, Tsong-Shing; Chi, Ching-Chi; Wang, Shu-Hui; Lin, Jing-Chi; Lin, Ko-Ming

2016-10-01

Biologic therapies are more effective but more costly than conventional therapies in treating psoriatic arthritis. To evaluate the cost-efficacy of etanercept, adalimumab and golimumab therapies in treating active psoriatic arthritis in a Taiwanese setting. We conducted a meta-analysis of randomized placebo-controlled trials to calculate the incremental efficacy of etanercept, adalimumab and golimumab, respectively, in achieving Psoriatic Arthritis Response Criteria (PsARC) and a 20% improvement in the American College of Rheumatology score (ACR20). The base, best, and worst case incremental cost-effectiveness ratios (ICERs) for one subject to achieve PsARC and ACR20 were calculated. The annual ICER per PsARC responder were US$27 047 (best scenario US$16 619; worst scenario US$31 350), US$39 339 (best scenario US$31 846; worst scenario US$53 501) and US$27 085 (best scenario US$22 716; worst scenario US$33 534) for etanercept, adalimumab and golimumab, respectively. The annual ICER per ACR20 responder were US$27 588 (best scenario US$20 900; worst scenario US$41 800), US$39 339 (best scenario US$25 236; worst scenario US$83 595) and US$33 534 (best scenario US$27 616; worst scenario US$44 013) for etanercept, adalimumab and golimumab, respectively. In a Taiwanese setting, etanercept had the lowest annual costs per PsARC and ACR20 responder, while adalimumab had the highest annual costs per PsARC and ACR responder. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Cochlear Pericytes Are Capable of Reversibly Decreasing Capillary Diameter In Vivo After Tumor Necrosis Factor Exposure.

PubMed

Bertlich, Mattis; Ihler, Friedrich; Weiss, Bernhard G; Freytag, Saskia; Strupp, Michael; Canis, Martin

2017-12-01

The aim of this work was to evaluate the effect of tumor necrosis factor (TNF) and its neutralization with etanercept on the capability of cochlear pericytes to alter capillary diameter in the stria vascularis. Twelve Dunkin-Hartley guinea pigs were randomly assigned to one of three groups. Each group was treated either with placebo and then placebo, TNF and then placebo, or TNF and then etanercept. Cochlear pericytes were visualized using diaminofluorescein-2-diacetate and intravasal blood flow by fluorescein-dextrane. Vessel diameter at sites of pericyte somas and downstream controls were quantified by specialized software. Values were obtained before treatment, after first treatment with tumor necrosis factor or placebo and after second treatment with etanercept or placebo. Overall, 199 pericytes in 12 animals were visualized. After initial treatment with TNF, a significant decrease in vessel diameter at sites of pericyte somas (3.6 ±4.3%, n = 141) compared with placebo and downstream controls was observed. After initial treatment with TNF, the application of etanercept caused a significant increase (3.3 ±5.5%, n = 59) in vessel diameter at the sites of pericyte somata compared with placebo and downstream controls. We have been able to show that cochlear pericytes are capable of reducing capillary diameter after exposition to TNF. Moreover, the reduction in capillary diameter observed after the application of TNF is revertible after neutralization of tumor necrosis factor by the application of etanercept. It seems that contraction of cochlear pericytes contributes to the regulation of cochlear blood flow.

Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab.

PubMed

Luong, B T; Chong, B S; Lowder, D M

2000-06-01

To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. All controlled and uncontrolled trials were reviewed. Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

Uveitis Events During Adalimumab, Etanercept, and Methotrexate Therapy in Juvenile Idiopathic Arthritis: Data From the Biologics in Pediatric Rheumatology Registry.

PubMed

Foeldvari, Ivan; Becker, Ingrid; Horneff, Gerd

2015-11-01

Uveitis is a major extraarticular quality of life-restricting manifestation of juvenile idiopathic arthritis (JIA). The aim of the study is to describe the occurrence of uveitis in JIA patients receiving tumor necrosis factor inhibitors or methotrexate (MTX). Patients' characteristics, treatment, and the reported first occurrence of uveitis as an adverse event were searched in the Biologics in Pediatric Rheumatology Registry. The rates per exposed patients, exposure time, and time until event were calculated. Uveitis was reported as an adverse event in 75 of 3,467 patients; 51 of 2,844 patients were receiving MTX, 37 of 1,700 patients were receiving etanercept, and 13 of 364 patients were receiving adalimumab. Patients with uveitis were younger (mean ± SD age 4.6 ± 4.2 versus 7.4 ± 4.5 years; P < 0.0001), more likely to be antinuclear antibody positive (69% versus 43%; odds ratio [OR] 2.7, P < 0.0001), and had extended oligoarticular JIA (OR 2.2, P = 0.0005). Patients with a uveitis diagnosis before starting treatment more often had a uveitis event (n = 28, 8.4%; OR 8.5, P < 0.0001), and more often received adalimumab (OR 2.15 [95% confidence interval 1.58-2.94], P < 0.0001). In 16 patients, a new uveitis event occurred: 11 while taking MTX (3.2 per 1,000 patient-years), 2 while taking etanercept monotherapy (1.9 per 1,000 patient-years), and 3 while taking etanercept and MTX combination (0.9 per 1,000 patient-years). A new uveitis event occurred early in the disease course after a median disease duration of 1.5 years (interquartile range [IQR] 1.3-3.8) while taking etanercept and 1.8 years (IQR 1.8-2.1) for the MTX cohort. A recurrent uveitis event was reported after a disease duration of 7.6 years (IQR 4.3-10.0) in the etanercept cohort and 4.8 years (IQR 1.0-5.8) in the MTX cohort. Univariate analysis showed that MTX, but not etanercept or adalimumab, led to a lower rate of uveitis. Patients with a history of uveitis had higher risks for uveitis events while taking both etanercept and adalimumab. Methotrexate turned out to be protective. Few patients developed a first uveitis event while taking etanercept, while the rate is comparable to that with MTX. Uveitis may not be attributed to be an adverse drug reaction to etanercept. © 2015, American College of Rheumatology.

Stevens-Johnson syndrome in a patient with rheumatoid arthritis during long-term etanercept therapy.

PubMed

Owczarczyk-Saczonek, Agnieszka; Zdanowska, Natalia; Znajewska-Pander, Aleksandra; Placek, Waldemar

2016-03-31

Etanercept and other anti-TNF-alpha agents have been indicated as a therapeutic option in severe drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Etanercept has been shown to quickly reduce the detachment of the epidermis and shorten healing time. Cases of etanercept-induced severe adverse drug reactions were also described. A 27-year-old woman with a 4-year history of etanercept and sulfasalazine treatment for rheumatoid arthritis was admitted with Stevens-Johnson syndrome. The patient received one dose of an OTC drug containing acetaminophen, phenylephrine and pheniramine two days prior to developing fist mucocutaneous symptoms. The most probable causative agent was paracetamol. Throughout the successful routine therapy of Stevens-Johnson syndrome etanercept therapy was continued. Sulfosalazin administration was stopped and administered again after recovery with no recurrence of the skin and mucosal symptoms. This case indicates that there is no justification for discontinuation of long-term anti-TNF-alpha treatment in patients who develop Stevens- Johnson syndrome / toxic epidermal necrolysis.

Maintenance of remission with combination etanercept-DMARD therapy versus DMARDs alone in active rheumatoid arthritis: results of an international treat-to-target study conducted in regions with limited biologic access.

PubMed

Pavelka, Karel; Akkoç, Nurullah; Al-Maini, Mustafa; Zerbini, Cristiano A F; Karateev, Dmitry E; Nasonov, Evgeny L; Rahman, Mahboob U; Pedersen, Ronald; Dinh, Andrew; Shen, Qi; Vasilescu, Radu; Kotak, Sameer; Mahgoub, Ehab; Vlahos, Bonnie

2017-09-01

In this transglobal, randomized, double-blind, placebo-controlled, treat-to-target study, the maintenance of efficacy was compared between biologic-and biologic-free-disease-modifying antirheumatic drug (DMARD) combination regimens after low disease activity (LDA) was achieved with biologic DMARD induction therapy. Patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy received open-label etanercept 50 mg subcutaneously once weekly plus methotrexate with or without other conventional synthetic (cs) DMARDs for 24 weeks. Patients achieving LDA [disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) <3.2] at week 24 were randomized to receive etanercept-methotrexate combination therapy or placebo-methotrexate combination therapy, with or without other csDMARDs, for 28 weeks. In the open-label period, 72% of patients achieved DAS28-ESR LDA at week 24. Patients enrolled in the double-blind period had long-standing rheumatoid arthritis and high disease activity at baseline (mean duration, 8.1 years; DAS28-ESR, 6.4). In the etanercept and placebo combination groups, 44% versus 17% achieved DAS28-ESR LDA and 34 versus 13% achieved DAS28-ESR remission at week 52 (p < 0.001). Adverse events were reported in 37 and 43%, serious adverse events in 0 and 4%, and serious infections in 0 and 2% in these groups, respectively, in the double-blind period. After induction of response with etanercept combination therapy following a treat-to-target approach in patients with long-standing rheumatoid arthritis and high disease activity at baseline, the etanercept combination regimen was significantly more effective in maintaining LDA and remission than a biologic-free regimen. ClinicalTrials.gov identifier. NCT01578850.

Infection risk in patients with rheumatoid arthritis treated with etanercept or adalimumab.

PubMed

Chiang, Yi-Chun; Kuo, Li-Na; Yen, Yu-Hsuan; Tang, Chao-Hsiun; Chen, Hsiang-Yin

2014-10-01

To compare the risk of infection for rheumatoid arthritis (RA) patients who took etanercept or adalimumab medication in a nationwide population. RA patients who took etanercept or adalimumab were identified in the Taiwan's National Health Insurance Research Database. The composite outcome of serious infections, including hospitalization for infection, reception of an antimicrobial injection, and tuberculosis were followed for 365 days. A Kaplan-Meier survival curve with a log-rank test and Cox proportional hazards regression were used to compare risks of infection between the two cohorts of tumor necrosis factor (TNF)-α antagonists users. Hazard ratios (HRs) were obtained and adjusted with propensity scores and clinical factors. Sensitivity analyses and subgroup analyses were also performed. In total, 1660 incident etanercept users and 484 incident adalimumab users were eligible for the analysis. The unadjusted HR for infection of the etanercept users was significantly higher than that of the adalimumab users (HR: 1.93; 95% confidence interval (CI): 1.09-3.42; p=0.024). The HRs were 2.04 (95% CI: 1.14-3.65; p=0.016) and 2.02 (95% CI: 1.13-3.61; p=0.018) after adjusting for propensity scores and for propensity scores in addition to clinical factors, respectively. The subgroup analyses revealed that HRs for composite infection was significantly higher in patient subgroups of older age, female, as well as patients who did not have DM, COPD, and hospitalization history at the baseline. In this head-to-head cohort study involving a nationwide population of patients with RA, etanercept users demonstrated a higher risk of infection than adalimumab users. Results of this study suggest the possible existence of an intra-class difference in infection risk among TNF-α antagonists. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Serious neutropenia following etanercept administration in a 62 years female patient of rheumatoid arthritis.

PubMed

Datta, K; Ghosh, R K; Ghosh, S M

2010-10-01

Tumor necrosis factor (TNF) plays an important role in the inflammatory process of RA and the resulting joint pathology. Etanercept is a member of anti TNF family which is indicated in patients with moderate to severe active rheumatoid arthritis either alone or in combination with MTX. Very few cases of neutropenia with etanercept treatment have been reported worldwide so far. The mechanism of etanercept induced neutropenia is not yet established. We report a case of 62 year female patient, developing etanercept induced neutropenia after 1 month of starting treatment. The absolute neutrophil count (ANC) came down to 150/microl on the 6th day of diagnosis. Bone marrow examination revealed a maturation arrest of granulocytic cells. Other marrow components were normal. Causality assessment of adverse drug reactions was done as per Naranjo's Algorithm. It was a probable ADR. We propose the possible mechanism of neutropenia is bone marrow toxicity. This is contrary to a previous case report which suggested peripheral consumption of neutrophil as a cause of neutropenia. Recently, there are some reports of leukemia and other hematological malignancies associated with the use of etanercept and in those conditions neutropenia could be the first manifestation. Neither product label of the drug nor US FDA warns for periodic blood investigation during etanercept therapy. There is a definite need for total and differential count estimation at the beginning and regular interval during etanercept treatment to rule out possibilities of neutropenia.

Etanercept prevents decrease of cochlear blood flow dose-dependently caused by tumor necrosis factor alpha.

PubMed

Ihler, Friedrich; Sharaf, Kariem; Bertlich, Mattis; Strieth, Sebastian; Reichel, Christoph A; Berghaus, Alexander; Canis, Martin

2013-07-01

Tumor necrosis factor alpha (TNF-alpha) is a mediator of inflammation and microcirculation in the cochlea. This study aimed to quantify the effect of a local increase of TNF-alpha and study the effect of its interaction with etanercept on cochlear microcirculation. Cochlear lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. First, 24 animals were randomly distributed into 4 groups of 6 each. Exposed vessels were superfused repeatedly either with 1 of 3 different concentrations of TNF-alpha (5.0, 0.5, and 0.05 ng/mL) or with placebo (0.9% saline solution). Second, 12 animals were randomly distributed into 2 groups of 6 each. Vessels were pretreated with etanercept (1.0 microg/ mL) or placebo (0.9% saline solution), and then treated by repeated superfusion with TNF-alpha (5.0 ng/mL). TNF-alpha was shown to be effective in decreasing cochlear blood flow at a dose of 5.0 ng/mL (p < 0.01, analysis of variance on ranks). Lower concentrations or placebo treatment did not lead to significant changes. After pretreatment with etanercept, TNF-alpha at a dose of 5.0 ng/mL no longer led to a change in cochlear blood flow. The decreasing effect that TNF-alpha has on cochlear blood flow is dose-dependent. Etanercept abrogates this effect.

[Preference for etanercept pen versus syringe in patients with chronic arthritis. Nurse education workshop].

PubMed

Garcia-Diaz, Silvia; Girabent-Farrés, Montserrat; Roig-Vilaseca, Daniel; Reina, Delia; Cerdà, Dacia; González, Marina; Torrente-Segarra, Vicenç; Fíguls, Ramon; Corominas, Hèctor

2013-01-01

The aims of this study are to evaluate the level of fear of post-injection pain prior to the administration, the difficulty in handling the device, and the level of satisfaction of patients using a pre-filled syringe versus an etanercept pen, as well as to evaluate the usefulness of the training given by nursing staff prior to starting with the pen, and the preferences of patients after using both devices. A prospective study was designed to follow-up a cohort of patients during a 6 months period. The data was collected using questionnaires and analyzed with SPSS 18.00. Rank and McNemar tests were performed. Statistical significance was pre-set at an α level of 0.05. A total of 29 patients were included, of whom 69% female, and with a mean age 52.5±10.9 years. Of these, 48% had rheumatoid arthritis, 28% psoriatic arthritis, 21% ankylosing spondylitis, and 3% undifferentiated spondyloarthropathy. There were no statistically significant differences either with the fear or pain or handling of the device between the syringe and the pen (P=.469; P=.812; P=.169 respectively). At 6 months, 59% of patients referred to being satisfied or very satisfied with the pen. Almost all (93%) found useful or very useful the training given by nursing staff prior to using the pen, and 55% preferred the pen over the pre-filled syringe. The etanercept pen is another subcutaneous device option for patients with chronic arthritis. According to the present study, nursing educational workshops before starting this therapy are recommended. Copyright © 2012 Elsevier España, S.L. All rights reserved.

The safety of etanercept for the treatment of plaque psoriasis

PubMed Central

Papp, Kim A

2007-01-01

Effective treatment with etanercept results from a congregation of immunological signaling and modulating roles played by tumor necrosis factor-alpha (TNF-alpha), a pervasive member of the TNF super-family of cytokines participating in numerous immunologic and metabolic functions. Macrophages, lymphocytes and other cells produce TNF as part of the deregulated immune response resulting in psoriasis or other chronic inflammatory disorders. Tumor necrosis factor is also produced by macrophages and lymphocytes responding to foreign antigens as a primary response to potential infection. Interference with cytokine signaling by etanercept yields therapeutic response. At the same time, interference with cytokine signaling by etanercept exposes patients to potential adverse events. While the efficacy of etanercept for the treatment of psoriasis is evident, the risks of treatment continue to be defined. Of the potential serious adverse events, response to infection is the best characterized in terms of physiology, incidence, and management. Rare but serious events: activation of latent tuberculosis, multiple sclerosis, lymphoma, and others, have been observed but have questionable or yet to be defined association with therapeutic uses of etanercept. The safe use of etanercept for the treatment of psoriasis requires an appreciation of potential adverse events as well as screening and monitoring strategies designed to manage patient risk PMID:18360633

Annual acquisition and administration cost of biologic response modifiers per patient with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis.

PubMed

Bonafede, Machaon; Joseph, George J; Princic, Nicole; Harrison, David J

2013-09-01

To estimate annual biologic response modifier (BRM) cost per treated patient with rheumatoid arthritis, psoriasis, psoriatic arthritis, and/or ankylosing spondylitis receiving etanercept, abatacept, adalimumab, certolizumab, golimumab, infliximab, rituximab, or ustekinumab. This was a cohort study of 69,349 commercially insured individuals in a nationwide claims database with one of these conditions that had a claim for one of these BRMs between January 2008 and December 2010 (the index BRM/index date). Cost per treated patient was calculated as the total BRM acquisition and administration cost to the payer in the first year after the index date (including costs of other BRMs after switching) divided by the number of patients who received the index BRM. Etanercept was selected as the reference for comparisons. Etanercept was the most commonly used index BRM (n = 32,298; 47%), followed by adalimumab (n = 20,582; 30%), infliximab (n = 11,157; 16%), abatacept (n = 2633; 4%), rituximab (n = 1359; 2%), golimumab (n = 687; <1%), ustekinumab (n = 388; <1%), and certolizumab (n = 245; <1%). Using etanercept as the reference, the cost per treated patient in the first year across all four conditions was 102% for adalimumab and 108% for infliximab. Newer BRMs had costs relative to etanercept that were 90% to 102% for rheumatoid arthritis, 132% for psoriasis, 100% for psoriatic arthritis, and 94% for ankylosing spondylitis. Potential study limitations were the lack of clinical information (e.g., disease severity, treatment outcomes) or indirect costs, the inability to compare costs of newer BRMs across all four conditions, and much smaller sample sizes for newer BRMs. Of the BRMs that are approved for indications within all four conditions studied, etanercept had the lowest cost per treated patient when assessed across all four conditions.

Anti-TNFα agents and methotrexate in spondyloarthritis related uveitis in a Chinese population.

PubMed

Lian, Fan; Zhou, Jun; Wei, Cui; Wang, Yu; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

2015-11-01

This study seeks to evaluate the clinical characteristics of spondyloarthritis (SpA)-related uveitis in a cohort from South China and to assess the efficacy and safety of therapies based on TNF blockers. SpA patients with uveitis admitted to a south China hospital were enrolled. Demographic information, clinical characteristics, laboratory findings, intraocular inflammation, visual acuity, macular thickness, and treatments were documented. Of the 1,036 SpA patients reviewed, 182 had uveitis. Ankylosing spondylitis (AS) was the most common subtype. Unilateral uveitis was found in 51 cases (51/182, 28.0%), and unilateral alternating uveitis was found in 75 cases (75/182, 41.2%). Half of the cases were recurrent uveitis (52.2%), and acute onset was common (76.4%). The most serious complication was vision loss (0.5%). No significant difference in disease activity was found between the SpA patients with or without uveitis. Predominant improvements were found in cases treated with all three anti-TNFs (infliximab, adalimumab, and etanercept) and anti-TNFs plus methotrexate (MTX). Monotherapy of methotrexate was not adequate for inducing remission. Monotherapy of etanercept was not as effective as adalimumab and infliximab, mainly in the prevention of recurrence. No significant difference in effectiveness was found among the three anti-TNFs if MTX was added. Etanercept plus MTX were well tolerated. Infliximab and adalimumab were associated with more tuberculosis and/or hepatitis flares. Uveitis is common in SpA patients. Severe complications may develop in prolonged and intractable cases. Treatments based on anti-TNFs had good clinical response, and better safety documentation were observed in etanercept plus MTX compared to the other two anti-TNF monoclonal antibodies plus MTX.

TNF-α inhibition using etanercept prevents noise-induced hearing loss by improvement of cochlear blood flow in vivo.

PubMed

Arpornchayanon, Warangkana; Canis, Martin; Ihler, Friedrich; Settevendemie, Claudia; Strieth, Sebastian

2013-08-01

Exposure to loud noise can impair cochlear microcirculation and cause noise-induced hearing loss (NIHL). TNF-α signaling has been shown to be activated in NIHL and to control spiral modiolar artery vasoconstriction that regulates cochlear microcirculation. It was the aim of this experimental study to analyse the effects of the TNF-α inhibitor etanercept on cochlear microcirculation and hearing threshold shift in NIHL in vivo. After assessment of normacusis using ABR, loud noise (106 dB SPL, 30 minutes) was applied on both ears in guinea pigs. Etanercept was administered systemically after loud noise exposure while control animals received a saline solution. In vivo fluorescence microscopy of strial capillaries was performed after surgical exposure of the cochlea for microcirculatory analysis. ABR measurements were derived from the contralateral ear. Guinea pigs (n = 6, per group). Compared to controls, cochlear blood flow in strial capillary segments was significantly increased in etanercept-treated animals. Additionally, hearing threshold was preserved in animals receiving the TNF-α inhibitor in contrast to a significant threshold raising in controls. TNF-α inhibition using etanercept improves cochlear microcirculation and protects hearing levels after loud noise exposure and appears as a promising treatment strategy for human NIHL.

Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital.

PubMed

Wick, M C; Ernestam, S; Lindblad, S; Bratt, J; Klareskog, L; van Vollenhoven, R F

2005-01-01

To determine whether the tumour necrosis factor-alpha (TNF-alpha) antagonist adalimumab (Humira) can be efficacious after secondary loss of efficacy (i.e. loss of clinical response in patients who had initially demonstrated clinical response) to infliximab (Remicade) or etanercept (Enbrel). We studied 36 patients from the Stockholm TNF-alpha follow-up registry (STURE) who received adalimumab after secondary loss of efficacy to infliximab (group A, n = 27) or etanercept (group B, n = 9), and 26 patients who were started on adalimumab as the first TNF-alpha antagonist (group C). In group A, the baseline disease activity score 28 (DAS28) at infliximab institution was 5.5+/-0.2. During infliximab treatment, the mean best DAS28 was 3.7+/-0.2 (p<0.001), but increased to 5.2+/-0.3 when infliximab was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.5+/-0.3 (p<0.003), and then to 4.2+/-0.2 at 6 months (p<0.001). In group B, the baseline DAS28 at etanercept institution was 6.6+/-0.5. During etanercept treatment, the mean best DAS28 was 4.6+/-0.5 (p<0.01), but increased to 5.7+/-0.4 by the time etanercept was stopped. After 3 months on adalimumab, the mean DAS28 decreased to 4.8+/-0.3 (p<0.005), and to 4.1+/-0.2 at 6 months (p<0.001). In group C, the mean baseline DAS28 was 5.6+/-0.3. After 6 months of adalimumab therapy, the DAS28 decreased to 3.5+/-0.4 (p<0.001). ACR20 responses with adalimumab in groups A, B, and C were similar (70-78%). For patients with secondary loss of efficacy from infliximab or etanercept, switching to adalimumab can restore a good clinical response.

Impact of etanercept on work and activity impairment in employed moderate to severe rheumatoid arthritis patients in the United States.

PubMed

Hone, Devon; Cheng, Annie; Watson, Crystal; Huang, Baisong; Bitman, Bojena; Huang, Xing-Yue; Gandra, Shravanthi R

2013-10-01

To quantify the impact of etanercept on work and activity impairment in employed US patients with moderate to severe rheumatoid arthritis (RA). This prospective, observational, longitudinal study recruited RA patients initiating etanercept (50 mg/week) between January 2009 and March 2010. The Work Productivity and Activity Impairment Questionnaire (WPAI) and domestic productivity questionnaire were administered by telephone interviews at baseline and at 1, 2, 3, and 6 months after etanercept initiation. The human capital approach was used to estimate the costs of work impairment. Changes in WPAI measures were analyzed using Wilcoxon's signed rank test. RA patients (n = 204) initiating etanercept were a mean ± SD age of 46.6 ± 10.9 years and 72% were women. After 6 months, 153 patients continued treatment (continuers) and showed significant decreases in overall work impairment (41.9% at baseline versus 25.2% at 6 months; P < 0.0001), absenteeism (8.4% versus 2.3%; P = 0.0001), presenteeism (38.9% versus 24.3%; P < 0.0001), and activity impairment (55.7% versus 30.9%; P < 0.0001) and a 76.4% reduction in work hours lost weekly due to RA (3.2 versus 0.8; P = 0.0001). The projected 12-month gain in work productivity for continuers was 284.5 hours per patient, equating to $3,233-22,533 depending on annual income level, which partially or completely offset the annual cost of etanercept ($20,190). Domestic productivity improved from 41.5% at baseline to 69.6% at 6 months (P < 0.0001). In US employed moderate to severe RA patients, etanercept led to significant reductions in overall work and activity impairment; the value of increased work productivity partially or completely offset the cost of treatment. Copyright © 2013 by the American College of Rheumatology.

Cost-Effectiveness Analysis of Ixekizumab vs Etanercept and Their Manufacturer-Recommended Dosing Regimens in Moderate to Severe Plaque Psoriasis.

PubMed

Udkoff, Jeremy; Eichenfield, Lawrence F

2017-10-01

Biologic therapies have revolutionized the treatment of psoriasis; however, their use is limited by costs. Ixekizumab was more effective than etanercept in the UNCOVER trials, and the Food and Drug Administration (FDA) approved ixekizumab for treating psoriasis. Evaluating the cost-effectiveness of these therapies is crucial for medical decision making and our objective was to determine the cost-effectiveness of various ixekizumab dosing frequencies compared with etanercept. We utilized published data from the UNCOVER comparative efficacy trials, including transitional probabilities and treatment response rates, to create a Markov model simulating the clinical course and cost-effectiveness of three treatment algorithms for patients with moderate to severe plaque psoriasis over 60-weeks: (1) ixekizumab every 2 weeks for 12 weeks then every 4 weeks, (2) ixekizumab every 4 weeks throughout the treatment period, (3) biweekly etanercept for 12 weeks then once weekly. We utilized a standard willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) and Medicaid drug acquisition costs for our calculations. Ixekizumab every 4 weeks was $28,681 (USD) less expensive than biweekly etanercept, and $21,375 less expensive, and 0.006 QALY less effective, than ixekizumab every 2 weeks-- a savings of $28.7 and $21.4 million, respectively, per 1,000 patients. A 95.6% cost reduction to $197.83 per dose is required for ixekizumab every 2 weeks to be more cost-effective than every 4 weeks. Biweekly etanercept requires a 29.5% cost reduction ($743.82 per dose) to be competitive with ixekizumab every 4 weeks. This cost-effectiveness model utilizes strong input data but is a limited approximation of real-life scenarios. Treatment with ixekizumab every 2 weeks is unlikely to be cost-effective compared with ixekizumab every 4 weeks at current U.S. market prices. Yet, the U.S. FDA approval and manufacturer's recommendation are for ixekizumab every 2 weeks. Accordingly, we suggested selecting biologic therapies using cost-effectiveness analyses.

J Drugs Dermatol. 2017;16(10):964-970.

Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence.

PubMed

Strohal, Robert; Chimenti, Sergio; Vena, Gino Antonio; Girolomoni, Giampiero

2013-06-01

The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long-term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs.

Educational session as a tool to increase patient satisfaction of switching etanercept from the prefilled syringe to the autoinjection pen.

PubMed

Borrás-Blasco, Joaquín; Gracia-Pérez, Antonio; Casterá, M Dolores-Elvira; Rosique-Robles, J Dolores; Abad, Javier

2013-08-01

To assess patients' acceptability of switching etanercept from the prefilled syringe to the autoinjection pen in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis patients. A two-phase cross-sectional study was designed. First phase: consisted of a 2 h information/education session to present the pen and learning its use. At the end of the session, patients completed a self-administered questionnaire regarding the meeting usefulness. Second phase: eight single-use prefilled Enbrel® Pen Myclic were provided. The number of patients included were 104 (rheumatoid arthritis 58, psoriatic arthritis 31, ankylosing spondylitis 15). Attendees showed a high satisfaction degree with the meeting. A high percentage of patients (74.4 - 95.1%) rated the items of the questionnaire as 'very much'. Patients reported > 95% adherence to etanercept autoinjection pen. The percentage of patients self-administering etanercept increased from 66 to 94% and the percentage of those attending primary care for injection decreased from 23 to 2%. It produced important cost savings, in our study represents > 22.000 euros/year. Pain at the injection site was significantly reduced with the use of autoinjection pen. Ninty seven (93%) patients considered that the use of the autoinjection pen was easier than the syringe and 94.2% chose the pen as their preferred delivery system. The autoinjection pen is an advantageous delivery option for etanercept. This study provides further evidence to support that the education strategy is a valid method for switching anti-TNF-α drugs from syringe to pen in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Etanercept (Enbrel®) alternative storage at ambient temperature.

PubMed

Shannon, Edel; Daffy, Joanne; Jones, Heather; Paulson, Andrea; Vicik, Steven M

2017-01-01

Biologic disease-modifying antirheumatic drugs, including tumor necrosis factor inhibitors such as etanercept (Enbrel ® ), have improved outcomes for patients with rheumatic and other inflammatory diseases, with sustained remission being the optimal goal for patients with rheumatoid arthritis. Flexible and convenient treatment options, compatible with modern lifestyle, are important in helping patients maintain treatment and manage their disease. Etanercept drug product (DP) is available in lyophilized powder (Lyo) for solution injection, prefilled syringe, and prefilled pen presentations and is typically stored under refrigerated conditions. We aimed to generate a comprehensive analytical data package from stability testing of key quality attributes, consistent with regulatory requirements, to determine whether the product profile of etanercept is maintained at ambient temperature. Test methods assessing key attributes of purity, quality, potency, and safety were performed over time, following storage of etanercept DP presentations under a range of conditions. Results and statistical analysis from stability testing (based on size exclusion high-performance liquid chromatography, hydrophobic interaction chromatography, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis Coomassie) across all etanercept presentations (10 and 25 mg/vial Lyo DP; 25 and 50 mg prefilled syringe DP; 50 mg prefilled pen DP) showed key stability-indicating parameters were within acceptable limits through the alternative storage condition of 25°C±2°C for 1 month. Stability testing performed in line with regulatory requirements supports a single period of storage for etanercept DP at an alternative storage condition of 25°C±2°C for up to 1 month within the approved expiry of the product. This alternative storage condition represents further innovation in the etanercept product lifecycle, providing greater flexibility and enhanced overall convenience for patients.

A retrospective study to investigate racial and ethnic variations in the treatment of psoriasis with etanercept.

PubMed

Shah, Sejal K; Arthur, Angele; Yang, Yu-Ching; Stevens, Seth; Alexis, Andrew F

2011-08-01

Psoriasis is a chronic inflammatory condition that occurs worldwide; however, few studies have examined this condition in non-Caucasian populations. The purpose of this study was to investigate racial/ethnic differences in demographics, psoriasis severity, efficacy, safety, and health-related quality of life in patients treated with etanercept using data from the Etanercept Assessment of Safety and Effectiveness (EASE) in Psoriasis trial. This is an investigator-initiated evaluation of data from the EASE study. The study included 2511 patients (Caucasian n=2164; Hispanic/Latino n=173; African American n=98; Asian n=76). Although baseline Physicians' Global Assessment (PGA) scores were similar, we found significant baseline differences in patient characteristics, prior therapy, percentage of body surface area (%BSA) affected and Dermatology Life Quality Index (DLQI) scores between the groups. At baseline, the Caucasian group had the longest disease duration (19 years), but the lowest percentage of BSA involvement (28%). The Asian group had the highest percentage of BSA involvement (41%). Baseline DLQI score was lowest for Caucasians (12.0) and highest for Hispanic/Latinos (14.6). At week 12, response to therapy was similar in all ethnic/racial groups. The BSA involvement was reduced by more than 50 percent for all groups, but remained significantly higher for the Asian group (17%) than for the Caucasian (13%; P=0.0105) and African American groups (13%; P=0.0461). At week 12, the mean Asian DLQI score of 5.2 was significantly higher (worse) than scores for the Caucasian (3.5; P=0.0001) and Hispanic/Latino groups (3.8; P=0.028). For both percentage of BSA and DLQI, differences among racial/ethnic groups in the percentage improvement from baseline were not statistically significant. Adverse event rates were similar for the groups. Patient characteristics at enrollment differed among ethnic groups, but no significant racial/ethnic differences were found in safety or efficacy of etanercept. However, racial/ethnic differences in the impact of psoriasis on quality of life were observed.

Differences in annual medication costs and rates of dosage increase between tumor necrosis factor-antagonist therapies for rheumatoid arthritis in a managed care population.

PubMed

Ollendorf, Daniel A; Klingman, David; Hazard, Elisabeth; Ray, Saurabh

2009-04-01

Tumor necrosis factor (TNF) antagonists are commonly used to treat rheumatoid arthritis (RA). Differences in the dosage and mode of administration of these agents may result in differential rates of dosage adjustment and costs of care. This study compared dosing patterns and annual costs associated with the use of the subcutaneous TNF antagonists adalimumab and etanercept, and the intravenous TNF antagonist infliximab. A large managed care database (PharMetrics) was used to identify patients with RA who newly initiated TNF-antagonist therapy with adalimumab, etanercept, or infliximab on or after January 1, 2003, and had at least 6 months of continuous health plan enrollment before initiation of therapy and 12 months of continuous enrollment after initiation. The patients were followed over 12 months of enrollment. Annual pharmacy, inpatient, and outpatient costs were estimated based on plan reimbursements and were compared between cohorts. The average daily dosage (ADD) between prescription refills was used to compare the percentages of patients with greater-than-expected dosing (GTED), defined as 2 consecutive increases in ADD relative to the patient's established maintenance dosage. A total of 2382 patients (568 adalimumab, 1181 etanercept, 633 infliximab) were included in the analysis. Significantly more patients had GTED with infliximab compared with adalimumab and etanercept (32.1%, 8.5%, and 4.7%, respectively; both comparisons, P < 0.05). For patients with a dosage increase, the mean time to the first GTED was significantly shorter for infliximab compared with adalimu-mab and etanercept (154.5, 173.3, and 167.9 days; both, P < 0.05). The mean annual costs of anti-TNF therapy, adjusted for baseline differences, were significantly greater for infliximab compared with adalimumab and etanercept ($15,617, $12,200, and $12,146; both, P < 0.05). There were also significant differences between infliximab relative to adalimumab and etanercept in total RA-related medication costs ($16,280, $12,989, and $12,794; P < 0.05) and total pharmacy costs ($17,854, $14,805, and $14,398; P < 0.05). Patients initiating TNF-antagonist treatment for RA with infliximab incurred annual medication costs that were nearly 30% greater than costs in those initiating therapy with adalimumab or etanercept, in part because of the significantly greater rate of GTED in infliximab recipients.

Successful treatment of pemphigus vulgaris with etanercept in four patients.

PubMed

Shetty, Anjali; Marcum, Catherine B; Glass, L Frank; Carter, John D

2009-10-01

Pemphigus vulgaris is an autoimmune disease characterized by intraepidermal blister formation. The treatment of pemphigus vulgaris is generally regarded as difficult. Corticosteroids, the drug class of first choice, often must be combined with steroid-sparing agents to prevent hazardous, long-term side effects. The authors describe four patients with severe pemphigus vulgaris who were treated with the tumor necrosis factor (TNF)-alpha antagonist, etanercept, twice weekly. In all four cases, the addition of etanercept produced dramatic clinical improvement and facilitated the reduction of corticosteroids necessary to maintain symptom control. Thus, etanercept may be an effective therapeutic agent for pemphigus vulgaris and should be considered as an alternative treatment option for patients presenting with recalcitrant disease.

[Cost-effectiveness analysis of etanercept compared with other biologic therapies in the treatment of rheumatoid arthritis].

PubMed

Salinas-Escudero, Guillermo; Vargas-Valencia, Juan; García-García, Erika Gabriela; Munciño-Ortega, Emilio; Galindo-Suárez, Rosa María

2013-01-01

to conduct cost-effectiveness analysis of etanercept compared with other biologic therapies in the treatment of moderate or severe rheumatoid arthritis in patients with previous unresponse to immune selective anti-inflammatory derivatives failure. a pharmacoeconomic model based on decision analysis to assess the clinical outcome after giving etanercept, infliximab, adalimumab or tocilizumab to treat moderate or severe rheumatoid arthritis was employed. Effectiveness of medications was assessed with improvement rates of 20 % or 70 % of the parameters established by the American College of Rheumatology (ACR 20 and ACR 70). the model showed that etanercept had the most effective therapeutic response rate: 79.7 % for ACR 20 and 31.4 % for ACR 70, compared with the response to other treatments. Also, etanercept had the lowest cost ($149,629.10 per patient) and had the most cost-effective average ($187,740.40 for clinical success for ACR 20 and $476,525.80 for clinical success for ACR 70) than the other biologic therapies. we demonstrated that treatment with etanercept is more effective and less expensive compared to the other drugs, thus making it more efficient therapeutic option both in terms of means and incremental cost-effectiveness ratios for the treatment of rheumatoid arthritis.

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports.

PubMed

Hooper, Michele; Wenkert, Deborah; Bitman, Bojena; Dias, Virgil C; Bartley, Yessenia

2013-10-02

Malignancy risk may be increased in chronic inflammatory conditions that are mediated by tumor necrosis factor (TNF), such as juvenile idiopathic arthritis (JIA), but the role of TNF in human cancer biology is unclear. In response to a 2011 United States Food & Drug Administration requirement of TNF blocker manufacturers, we evaluated reporting rates of all malignancies in patients =30 years old who received the TNF blocker etanercept. All malignancies in etanercept-exposed patients aged =30 years from the Amgen clinical trial database (CTD) and postmarketing global safety database (PMD) were reviewed. PMD reporting rates were generated using exposure information based on commercial sources. Age-specific incidence rates of malignancy for the general US population were generated from the Surveillance Epidemiology and End Results (SEER) database v7.0.9. There were 2 malignancies in the CTD: 1 each in etanercept and placebo/comparator arms (both in patients 18-30 years old). Postmarketing etanercept exposure was 231,404 patient-years (62,379 patient-years in patients 0-17 years; 168,485 patient-years in patients 18-30 years). Reporting rates of malignancy per 100,000 patient-years in the PMD and incidence rates in SEER were 32.0 and 15.9, respectively, for patients 0-17 years and 46.9 and 42.1 for patients 18-30 years old. Reporting rates were higher than SEER incidence rates for Hodgkin lymphoma in the 0-17 years age group. PMD reporting rates per 100,000 patient-years and SEER incidence rates per 100,000 person-years for Hodgkin lymphoma were 9.54 and 0.9, respectively, for patients 0-17 years and 1.8 and 4.2 for patients 18-30 years old. There were =5 cases of leukemia, lymphoma, melanoma, thyroid, and cervical cancers. Leukemia, non-Hodgkin lymphoma, melanoma, thyroid cancer, and cervical cancer rates were similar in the PMD and SEER. Overall PMD malignancy reporting rates in etanercept-treated patients 0-17 years appeared higher than incidence rates in SEER, attributable to rates of Hodgkin lymphoma. Comparison to patients with similar burden of disease cannot be made; JIA, particularly very active disease, may be a risk factor for lymphoma. No increased malignancy reporting rate in the PMD relative to SEER was observed in the young-adult age group.

Etanercept Exacerbates Inflammation and Pathology in a Rabbit Model of Active Pulmonary Tuberculosis

PubMed Central

Tsenova, Liana; O'Brien, Paul; Holloway, Jennifer; Peixoto, Blas; Soteropoulos, Patricia; Fallows, Dorothy; Subbian, Selvakumar

2014-01-01

Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB. PMID:24831609

Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.

PubMed

van Herwaarden, Noortje; van der Maas, Aatke; Minten, Michiel J M; van den Hoogen, Frank H J; Kievit, Wietske; van Vollenhoven, Ronald F; Bijlsma, Johannes W J; van den Bemt, Bart J F; den Broeder, Alfons A

2015-04-09

To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. Randomised controlled, open label, non-inferiority strategy trial. Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval -12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216. © van Herwaarden et al 2015.

Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues.

PubMed

Zhao, Yu-Ying; Yang, Rui; Xiao, Mo; Guan, Min-Jie; Zhao, Ning; Zeng, Tao

2017-09-01

Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl 3 ) and TNF-α antagonist (etanercept) on binge drinking-induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl 3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl 3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl 3 nor etanercept could affect binge drinking-induced decrease of PPAR-α, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl 3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-α could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-α antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking-induced fatty liver by TNF-α mediated activation of lipolysis in white adipose tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of tumour necrosis factor-α receptor 1 genetic deletion on carrageenan-induced acute inflammation: a comparison with etanercept

PubMed Central

Mazzon, E; Esposito, E; Di Paola, R; Muià, C; Crisafulli, C; Genovese, T; Caminiti, R; Meli, R; Bramanti, P; Cuzzocrea, S

2008-01-01

In the present study, we used tumour necrosis factor-α receptor 1 knock-out mice (TNF-αR1KO) to evaluate an in vivo role of TNF-αR1 on the pathogenesis of inflammatory diseases. We used a murine model of carrageenan-induced acute inflammation (pleurisy), a preclinical model of airway inflammation. The data proved that TNF-αR1KO were resistant to carrageenan-induced acute inflammation compared with TNF-α wild-type mice. TNF-αR1KO showed a significant reduction in accumulation of pleural exudate and in the number of inflammatory cells, in lung infiltration of polymorphonuclear leucocytes and lipid peroxidation and showed a decreased production of nitrite/nitrate in pleural exudates. Furthermore, the intensity and degree of the adhesion molecule intercellular adhesion molecule-1 and P-selectin, Fas ligand (FasL), inducible nitric oxide sythase and nitrotyrosine determined by immunohistochemical analysis were reduced markedly in lung tissues from TNF-αR1KO at 4 h and 24 h after carrageenan injection. Moreover, TNF-α and interleukin-1β concentrations were reduced in inflamed areas and in pleural exudates from TNF-αR1KO. To support the results generated using pleural inflammation, carrageenan-induced paw oedema models were also performed. In order to elucidate whether the observed anti-inflammatory effects were related to the inhibition of TNF-α, we also investigated the effect of etanercept, a TNF-α soluble receptor construct, on carrageenan-induced pleurisy. The treatment with etanercept (5 mg/kg subcutaneously 2 h before the carrageenan injection) reduces markedly both laboratory and histological signs of carrageenan-induced pleurisy. Our results showed that administration of etanercept resulted in the same outcome as that of deletion of the TNF-αR1 receptor, adding a new insight to TNF-α as an excellent target by therapeutic applications. PMID:18505433

Economic Impact of Above-Label Dosing with Etanercept, Adalimumab, or Ustekinumab in Patients with Psoriasis.

PubMed

Feldman, Steven R; Zhao, Yang; Zhou, Huanxue; Herrera, Vivian; Tian, Haijun; Li, Yunfeng

2017-05-01

Patients with moderate-to-severe psoriasis may be treated with above-label doses of biologics in an attempt to optimize outcomes. Dose escalation will have an effect on the cost of treatment. To examine costs related to above-label use of etanercept, adalimumab, and ustekinumab among patients with moderate-to-severe psoriasis. A retrospective study was performed using a large U.S. claims database. Patients were included in the study if they were aged ≥ 18 years with a diagnosis of psoriasis (excluding psoriatic arthritis) and had at least 1 medication fill for etanercept, adalimumab, or ustekinumab between January 1, 2011, and June 30, 2012. In addition, patients were required to have continuous enrollment for 12 months before, and 18 months after, the first biologic use (index biologic) during the maintenance period (defined as the period following the induction period in which each agent was titrated to its recommended maintenance dose per label) and at least 1 prescription filled for the index biologic during the 18 months after the maintenance period. Extensive above-label use was defined as taking an above-label dose (at least 10% higher than indicated in the label) for ≥ 180 days over a 12-month period following the maintenance period. Percentages of patients with extensive above-label use, mean number of days of above-label use, and additional costs associated with extensive above-label use (abovelabel cost minus on-label cost) were examined. The study included 3,310 patients who started treatment with etanercept (n = 1,443), adalimumab (n = 1,447), or ustekinumab (n = 420). Extensive above-label use occurred in 20.0% of etanercept patients, 2.6% of adalimumab patients, and 14.8% of ustekinumab patients. The mean duration of extensive above-label use was roughly similar for the 3 biologics (mean days [±SD]: 282 [±55] for etanercept, 279 [±57] for adalimumab, and 305 [±43] for ustekinumab). Additional annual costs per patient because of extensive above-label use were $19,458 for etanercept, $18,972 for adalimumab, and $21,045 for ustekinumab. Total additional annual costs were $5,623,362 for etanercept, $701,964 for adalimumab, and $1,304,790 for ustekinumab. Psoriasis patients treated with etanercept, adalimumab, or ustekinumab had extensive above-label use over the 12-month follow-up period, which subsequently led to higher costs. Novartis Pharmaceuticals Corporation sponsored this study and the resultant publication. BioScience Communications provided medical writing and editorial support, which was also funded by Novartis Pharmaceuticals Corporation. Feldman was engaged by Novartis Pharmaceuticals as a paid clinical expert and scientific advisor for this study. He has received research support and speaking and/or consulting fees from AbbVie, Advance Medical, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Caremark, Celgene, Eli Lilly, Galderma, GSK/Stiefel, Informa, Janssen, LEO Pharma, Merck, Merz, Mylan, National Biological, National Psoriasis Foundation, Pfizer, Qurient, Suncare Research, UpToDate, and Valeant; is the founder and majority owner of www.DrScore.com ; and is founder and part owner of Causa Research. Zhao, Herrera, Tian, and Li are employees of Novartis Pharmaceuticals. Zhou is a paid consultant for Novartis Pharmaceuticals and is an employee of KMK Consulting. Study concept and design were contributed by Feldman, Zhao, Herrera, and Li. Zhou and Li were responsible for data collection. Data were interpreted by Feldman and Zhao, with assistance from Zhou, Herrera, Tian, and Li. The manuscript was written primarily by Feldman and Zhao, with assistance from Zhou and Li. The manuscript was revised by Feldman and Zhao, assisted by Zhou, Herrera, Tian, and Li. Portions of this work were presented at the 34th Anniversary Fall Clinical Dermatology Conference in Las Vegas, Nevada, October 1-4, 2015.

Secukinumab Significantly Reduces Psoriasis-Related Work Impairment and Indirect Costs Compared With Ustekinumab and Etanercept in the United Kingdom.

PubMed

Warren, R B; Halliday, A; Graham, C N; Gilloteau, I; Miles, L; McBride, D

2018-05-30

Psoriasis causes work productivity impairment that increases with disease severity. Whether differential treatment efficacy translates into differential indirect cost savings is unknown. To assess work hours lost and indirect costs associated with secukinumab versus ustekinumab and etanercept in the United Kingdom (UK). This was a post hoc analysis of work impairment data collected in the CLEAR study (secukinumab vs. ustekinumab) and applied to the FIXTURE study (secukinumab vs. etanercept). Weighted weekly and annual average indirect costs per patient per treatment were calculated from (1) overall work impairment derived from Work Productivity and Activity Impairment data collected in CLEAR at 16 and 52 weeks by Psoriasis Area and Severity Index (PASI) response level; (2) weekly/annual work productivity loss by PASI response level; (3) weekly and annual indirect costs by PASI response level, based on hours of work productivity loss; and (4) weighted average indirect costs for each treatment. In the primary analysis, work impairment data for employed patients in CLEAR at Week 16 were used to compare secukinumab and ustekinumab. Secondary analyses were conducted at different timepoints and with patient cohorts, including FIXTURE. In CLEAR, 452 patients (67%) were employed at baseline. At Week 16, percentages of weekly work impairment/mean hours lost decreased with higher PASI: PASI <50: 22.8%/7.60 hours; PASI 50-74: 13.3%/4.45 hours; PASI 75-89: 6.4%/2.14 hours; PASI ≥90: 4.9%/1.65 hours. Weighted mean weekly/annual work hours lost were significantly lower for secukinumab than ustekinumab (1.96/102.51 vs. 2.40/125.12; P=0.0006). Results were consistent for secukinumab versus etanercept (2.29/119.67 vs. 3.59/187.17; Ρ<0.0001). Average annual indirect cost savings with secukinumab were £355 versus ustekinumab and £1,061 versus etanercept. Results at 52 weeks were similar. Secukinumab significantly reduced work impairment and associated indirect costs of psoriasis compared with ustekinumab and etanercept at Week 16 through 52 in the UK. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Cost-Effectiveness of Triple Therapy Versus Etanercept Plus Methotrexate in Early Aggressive Rheumatoid Arthritis.

PubMed

Jalal, Hawre; O'Dell, James R; Bridges, S Louis; Cofield, Stacey; Curtis, Jeffrey R; Mikuls, Ted R; Moreland, Larry W; Michaud, Kaleb

2016-12-01

To evaluate the cost-effectiveness of all 4 interventions in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) clinical trial: immediate triple (IT), immediate etanercept (IE), step-up triple (ST), and step-up etanercept (SE). Step-up interventions started with methotrexate and added either etanercept or sulfasalazine plus hydroxychloroquine to patients with persistent disease activity. We built a Markov cohort model that uses individual-level data from the TEAR trial, published literature, and supplemental clinical data. Costs were in US dollars, benefits in quality-adjusted life years (QALYs), perspective was societal, and the time horizon was 5 years. The immediate strategies were more efficacious than step-up strategies. SE and IE were more costly than ST and IT, primarily due to treatment cost differences. In addition, IT was the least expensive and most effective strategy when the time horizon was 1 and 2 years. When the time horizon was 5 years, IE was marginally more effective than IT (3.483 versus 3.476 QALYs), but IE was substantially more expensive than IT ($148,800 versus $52,600), producing an incremental cost-effectiveness ratio of $12.5 million per QALY. These results were robust to both one-way deterministic and joint probabilistic sensitivity analyses. IT was highly cost-effective in the majority of scenarios. Although IE was more effective in 5 years, a substantial reduction in the cost of biologic agents was required in order for IE to become cost-effective in early aggressive RA under willingness-to-pay thresholds that most health care settings may find acceptable. © 2016, American College of Rheumatology.

Open-label study of etanercept treatment in patients with moderate-to-severe plaque psoriasis who lost a satisfactory response to adalimumab.

PubMed

Bagel, J; Tyring, S; Rice, K C; Collier, D H; Kricorian, G; Chung, J; Iles, J; Stolshek, B S; Kaliyaperumal, A; Papp, K A

2017-08-01

Some patients with plaque psoriasis experience secondary failure of tumour necrosis factor inhibitor therapy. To evaluate efficacy, safety and patient-reported outcomes (PROs) with etanercept in patients with secondary adalimumab failure. This phase IV open-label single-arm estimation study (NCT01543204) enrolled patients on adalimumab who had achieved static Physician's Global Assessment (sPGA) score 0/1 (clear/almost clear). Patients subsequently lost response, defined as sPGA ≥ 3 or loss of 50% improvement in Psoriasis Area and Severity Index (PASI 50). At baseline, patients had involved body surface area ≥ 10%, sPGA ≥ 3 and PASI ≥ 10. Antiadalimumab antibodies (ADAs) were measured at screening. Patients received etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly. The primary end point was sPGA 0/1 at week 12 (intention-to-treat analysis; no hypothesis tested). Additional outcomes included rates of sPGA 0/1, PASI responses, safety, PROs of itch, pain and flaking, Dermatology Life Quality Index, treatment satisfaction and Work Productivity and Activity Impairment questionnaire. Sixty-four patients enrolled; 67% had ADAs. sPGA 0/1 rates at week 12 were 39·7% [95% confidence interval (CI) 27·6-52·8; primary end point] and 45% (95% CI 29·3-61·5) for patients positive for ADAs and 35% (95% CI 15·4-59·2) for patients negative for ADAs. PASI 75 response rates at week 12 were 47·5% (95% CI 31·5-63·9) for patients who were positive for ADAs and 50% (95% CI 27·2-72·8) for patients negative for ADAs. No new safety signals were observed. PROs of itch, pain and flaking consistently improved at week 12 and were maintained through week 24. Patients with psoriasis who experienced secondary failure of adalimumab achieved satisfactory response to etanercept regardless of ADA status. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Cost Per Additional Responder Associated With Ixekizumab and Etanercept in the Treatment of Moderate-to-Severe Psoriasis.

PubMed

Feldman, Steven R; Foster, Shonda A; Zhu, Baojin; Burge, Russel; Al Sawah, Sarah; Goldblum, Orin M

2017-12-01

BACKGROUND: Newer psoriasis treatments can achieve greater levels of efficacy than older systemic therapies; however, current psoriasis costs are substantial. We sought to estimate costs per additional responder associated with ixekizumab and etanercept, versus placebo, using efficacy data from phase 3 clinical trials (UNCOVER-2 and UNCOVER-3). METHODS: In UNCOVER-2/UNCOVER-3, patients received subcutaneous placebo, etanercept 50 mg twice weekly (BIW), or ixekizumab one 80 mg injection every 2 weeks (Q2W) after a 160-mg starting dose. Twelve-week induction-phase Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 response rates for ixekizumab, etanercept, and placebo were obtained from pooled data from the overall and United States (US) subgroup intention-to-treat (ITT) populations, and used to calculate numbers needed to treat (NNTs) to achieve one additional PASI 75, PASI 90, or PASI 100 response for ixekizumab Q2W and etanercept BIW versus placebo. Twelve-week drug costs per patient were calculated based on the UNCOVER-2/UNCOVER-3 dosing schedule and wholesale acquisition costs. Mean costs per additional responder for PASI 75, PASI 90, and PASI 100 for each treatment versus placebo were calculated for pooled UN-COVER-2/UNCOVER-3 overall and US subgroup ITT populations. RESULTS: Pooled overall ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $37,540, US $46,299, or US $80,710 for ixekizumab Q2W and US $57,533, US $120,720, or US $404,695 for etanercept BIW, respectively. US subgroup ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $38,165, US $49,740, or US $93,536 for ixekizumab Q2W and US $69,580, US $140,881, or US $631,875 for etanercept BIW, respectively. CONCLUSIONS: Twelve-week costs per additional responder were lower for ixekizumab Q2W than for etanercept BIW across all levels of clearance (PASI 75, PASI 90, and PASI 100) in the pooled UNCOVER-2/UNCOVER-3 overall and US subgroup ITT populations.

The antifibrogenic effect of etanercept on development of liver cirrhosis induced by thioacetamide in rats.

PubMed

Abdul-Hamid, Manal; Ahmed, Rasha R; Moustafa, Nadia; Nady, Rehab

2017-01-01

Liver cirrhosis is an elevating cause of morbidity and mortality worldwide. TNF-α/TNF-R1 signal is implicated in progression of many liver diseases. This study provides histological and ultrastructural view that clarifies the effect of etanercept, a TNF-α inhibitor, on development of thioacetamide (TAA)-induced liver cirrhosis and the accompanied hemosiderosis in rats, highlighting the implication and distribution pattern of hepatic TNF-R1. Sixty male albino rats (Rattus norvegicus) were equally randomized into three groups. Group I served as the control. Liver cirrhosis was triggered in the other two groups by intraperitoneal injection of TAA twice a week for five months. Group II received TAA only, while group III subcutaneously injected with etanercept one hour before TAA, along five months. At the end of the experiment, blood was collected for biochemical analysis and livers were excised for histological, immunohistochemical, and electron microscopical preparations. Rats treated with TAA only developed hepatic cirrhosis accompanied by massive deposition of hemosiderin; strong and widespread expression of hepatic TNF-R1 in sinusoidal endothelial cells (SECs), Kupffer cells (KCs), and many hepatocytes; and frequent appearance of fibrogenic, plasma, and mast cells, at the ultrastructural level. By contrast, administration of etanercept diminished the expression of TNF-R1, attenuated the accumulation of collagen and hemosiderin, and preserved the hepatic histoarchitecture. In conclusion, TNF-α signal via TNF-R1 may be implicated in the mechanism of fibrogenesis and the associated hemosiderosis. Etanercept may provide a promising therapeutic approach not only for attenuating the progression of fibrogenesis, but also for hepatic iron overload-associated disorders.

52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis

PubMed Central

Emery, Paul; Vencovský, Jiří; Sylwestrzak, Anna; Leszczyński, Piotr; Porawska, Wieslawa; Baranauskaite, Asta; Tseluyko, Vira; Zhdan, Vyacheslav M.; Stasiuk, Barbara; Milasiene, Roma; Barrera Rodriguez, Aaron Alejandro; Cheong, Soo Yeon; Ghil, Jeehoon

2017-01-01

Abstract Objective To compare the 52-week efficacy and safety of SB4 [an etanercept biosimilar] with reference etanercept (ETN) in patients with active RA. Methods In a phase 3, randomized, double-blind, multicentre study, patients with moderate to severe RA despite MTX treatment were randomized to receive 50 mg/week of s.c. SB4 or ETN up to week 52. Efficacy assessments included ACR response rates, 28-joint DAS, Simplified and Clinical Disease Activity Indices and changes in the modified total Sharp score (mTSS). Safety and immunogenicity were also evaluated. Results A total of 596 patients were randomized to receive either SB4 (n = 299) or ETN (n = 297) and 505 (84.7%) patients completed 52 weeks of the study. At week 52, the ACR20 response rates in the per-protocol set were comparable between SB4 (80.8%) and ETN (81.5%). All efficacy results were comparable between the two groups and they were maintained up to week 52. Radiographic progression was also comparable and the change from baseline in the mTSS was 0.45 for SB4 and 0.74 for ETN. The safety profile of SB4 was similar to that of ETN and the incidence of anti-drug antibody development up to week 52 was 1.0 and 13.2% in the SB4 and ETN groups, respectively. Conclusion Efficacy including radiographic progression was comparable between SB4 and ETN up to week 52. SB4 was well tolerated and had a similar safety profile to that of ETN. Trial registration number ClinicalTrials.gov NCT01895309, EudraCT 2012-005026-30 PMID:28968793

Secukinumab sustains early patient-reported outcome benefits through 1 year: Results from 2 phase III randomized placebo-controlled clinical trials comparing secukinumab with etanercept.

PubMed

Strober, Bruce; Gottlieb, Alice B; Sherif, Bintu; Mollon, Patrick; Gilloteau, Isabelle; McLeod, Lori; Fox, Todd; Mordin, Margaret; Gnanasakthy, Ari; Papavassilis, Charis; Lebwohl, Mark G

2017-04-01

Psoriasis is a chronic condition with negative impact on patients' quality of life that most often requires lifelong effective and safe treatment. This analysis focused on the effect of secukinumab treatment on patient-reported health-related quality of life as assessed by the Dermatology Life Quality Index (DLQI) in patients with moderate to severe psoriasis. The proportion of subjects achieving DLQI score 0/1 response at week 24, time to DLQI score 0/1 response, and sustained DLQI score 0/1 response up to week 52 were compared between secukinumab and etanercept. Of 1470 subjects, 1144 received secukinumab and 326 received etanercept. DLQI score 0/1 response rates were significantly higher for secukinumab than for etanercept at week 24. The median time to DLQI score 0/1 response was significantly shorter for secukinumab versus etanercept (12 vs 24 weeks; P < .01). The majority of secukinumab-treated subjects achieved DLQI score 0/1 response at week 24 and sustained it through week 52 along with a 90% to 100% reduction in the Psoriasis Area and Severity Index total score response. Placebo comparisons are limited during the maintenance period because of rerandomization at week 12. Secukinumab treatment provided faster and greater sustained improvements in quality of life than etanercept over 52 weeks, consistent with greater clinical response. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Malignancies in children and young adults on etanercept: summary of cases from clinical trials and post marketing reports

PubMed Central

2013-01-01

Background Malignancy risk may be increased in chronic inflammatory conditions that are mediated by tumor necrosis factor (TNF), such as juvenile idiopathic arthritis (JIA), but the role of TNF in human cancer biology is unclear. In response to a 2011 United States Food & Drug Administration requirement of TNF blocker manufacturers, we evaluated reporting rates of all malignancies in patients ≤30 years old who received the TNF blocker etanercept. Methods All malignancies in etanercept-exposed patients aged ≤30 years from the Amgen clinical trial database (CTD) and postmarketing global safety database (PMD) were reviewed. PMD reporting rates were generated using exposure information based on commercial sources. Age-specific incidence rates of malignancy for the general US population were generated from the Surveillance Epidemiology and End Results (SEER) database v7.0.9. Results There were 2 malignancies in the CTD: 1 each in etanercept and placebo/comparator arms (both in patients 18–30 years old). Postmarketing etanercept exposure was 231,404 patient-years (62,379 patient-years in patients 0–17 years; 168,485 patient-years in patients 18–30 years). Reporting rates of malignancy per 100,000 patient-years in the PMD and incidence rates in SEER were 32.0 and 15.9, respectively, for patients 0–17 years and 46.9 and 42.1 for patients 18–30 years old. Reporting rates were higher than SEER incidence rates for Hodgkin lymphoma in the 0-17 years age group. PMD reporting rates per 100,000 patient-years and SEER incidence rates per 100,000 person-years for Hodgkin lymphoma were 9.54 and 0.9, respectively, for patients 0–17 years and 1.8 and 4.2 for patients 18–30 years old. There were ≥5 cases of leukemia, lymphoma, melanoma, thyroid, and cervical cancers. Leukemia, non-Hodgkin lymphoma, melanoma, thyroid cancer, and cervical cancer rates were similar in the PMD and SEER. Conclusions Overall PMD malignancy reporting rates in etanercept-treated patients 0–17 years appeared higher than incidence rates in SEER, attributable to rates of Hodgkin lymphoma. Comparison to patients with similar burden of disease cannot be made; JIA, particularly very active disease, may be a risk factor for lymphoma. No increased malignancy reporting rate in the PMD relative to SEER was observed in the young-adult age group. PMID:24225257

Metastatic bone lesion due to methotrexate and etanercept 24 years after breast cancer treatment

PubMed Central

Yano, Shuichi

2014-01-01

A 72-year-old woman with rheumatoid arthritis presented with lumbar vertebral bone metastasis 24 years after mammectomy and radiotherapy for breast cancer. She was treated with prednisolone and methotrexate (MTX) for 11 months to which 10 mg of etanercept twice a week was added for a further 8 months. On the basis of this result, the possibility of a metastatic bone lesion appearing many years after cancer treatment should be considered when planning MTX and etanercept therapy. PMID:24729113

Uptake of rheumatology biosimilars in the absence of forced switching.

PubMed

Di Giuseppe, Daniela; Frisell, Thomas; Ernestam, Sofia; Forsblad-D'Elia, Helena; Lindqvist, Elisabet; Lindström, Ulf; Sjöwall, Christopher; Askling, Johan

2018-05-01

To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching. We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima® and Inflectra®) and etanercept (Benepali®) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naïve patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type. From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9 months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s). Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke.

PubMed

Wu, Ming-Hsiu; Huang, Chao-Ching; Chio, Chung-Ching; Tsai, Kuen-Jer; Chang, Ching-Ping; Lin, Nan-Kai; Lin, Mao-Tsun

2016-09-01

Ischemic stroke, caused by obstruction of blood flow to the brain, would initiate microglia activation which contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation could be a therapeutic strategy for ischemic stroke. This study was aimed to elucidate the anti-inflammatory effects of alpha-lipoic acid and etanercept given either singly or in combination in rats subjected to middle cerebral artery occlusion. Both α-lipoic acid and etanercept markedly reduced cerebral infarct, blood-brain barrier disruption, and neurological motor deficits with the former drug being more effective with the dosage used. Furthermore, when used in combination, the reduction was more substantial. Remarkably, a greater diminution in the serum levels of tumor necrosis factor-alpha as well as the brain levels of microglial activation (e.g., microgliosis, amoeboid microglia, and microglial overexpression of tumor necrosis factor-α) was observed with the combined drug treatment as compared to the drugs given separately. We conclude that inhibition of peripheral tumor necrosis factor-alpha as well as downregulation of brain microglial activation by alpha-lipoic acid or etanercept protect rat brain against ischemic stroke. Moreover, when both drugs were used in combination, the stroke recovery was promoted more extensively.

Involvement of peripheral and spinal tumor necrosis factor α in spinal cord hyperexcitability during knee joint inflammation in rats.

PubMed

König, Christian; Zharsky, Maxim; Möller, Christian; Schaible, Hans-Georg; Ebersberger, Andrea

2014-03-01

Tumor necrosis factor α (TNFα) is produced not only in peripheral tissues, but also in the spinal cord. The purpose of this study was to address the potential of peripheral and spinal TNFα to induce and maintain spinal hyperexcitability, which is a hallmark of pain states in the joints during rheumatoid arthritis and osteoarthritis. In vivo recordings of the responses of spinal cord neurons to nociceptive knee input under normal conditions and in the presence of experimental knee joint inflammation were obtained in anesthetized rats. TNFα, etanercept, or antibodies to TNF receptors were applied to either the knee joint or the spinal cord surface. Injection of TNFα into the knee joint cavity increased the responses of spinal cord neurons to mechanical joint stimulation, and injection of etanercept into the knee joint reduced the inflammation-evoked spinal activity. These spinal effects closely mirrored the induction and reduction of peripheral sensitization. Responses to joint stimulation were also enhanced by spinal application of TNFα, and spinal application of either etanercept or anti-TNF receptor type I significantly attenuated the generation of inflammation-evoked spinal hyperexcitability, which is characterized by widespread pain sensitization beyond the inflamed joint. Spinally applied etanercept did not reduce established hyperexcitability in the acute kaolin/carrageenan model. In antigen-induced arthritis, etanercept decreased spinal responses on day 1, but not on day 3. While peripheral TNFα increases spinal responses to joint stimulation, spinal TNFα supports the generation of the full pattern of spinal hyperexcitability. However, established spinal hyperexcitability may be maintained by downstream mechanisms that are independent of spinal TNFα. Copyright © 2014 by the American College of Rheumatology.

CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents.

PubMed

Zhang, Feng; Shu, Jin-Ling; Li, Ying; Wu, Yu-Jing; Zhang, Xian-Zheng; Han, Le; Tang, Xiao-Yu; Wang, Chen; Wang, Qing-Tong; Chen, Jing-Yu; Chang, Yan; Wu, Hua-Xun; Zhang, Ling-Ling; Wei, Wei

2017-01-01

Paeoniflorin-6'- O -benzene sulfonate (code: CP-25) was the chemistry structural modifications of Paeoniflorin (Pae). CP-25 inhibited B cells proliferation stimulated by B cell activating factor belonging to the TNF family (BAFF) or Tumor necrosis factor alpha (TNF-alpha). CP-25, Rituximab and Etanercept reduced the percentage and numbers of CD19 + B cells, CD19 + CD20 + B cells, CD19 + CD27 + B cells and CD19 + CD20 + CD27 + B cells induced by BAFF or TNF-alpha. There was significant difference between CP-25 and Rituximab or CP-25 and Etanercept. CP-25 down-regulated the high expression of BAFFR, BCMA, and TACI stimulated by BAFF or TNF-alpha. The effects of Rituximab and Etanercept on BAFFR or BCMA were stronger than that of CP-25. CP-25, Rituximab and Etanercept down-regulated significantly the expression of TNFR1 and TNFR2 on B cell stimulated by BAFF or TNF-alpha. CP-25, Rituximab and Etanercept down-regulated the expression of MKK3, P-p38, P-p65, TRAF2, and p52 in B cells stimulated by BAFF and the expression of TRAF2 and P-p65 in B cells stimulated by TNF-alpha. These results suggest that CP-25 regulated moderately activated B cells function by regulating the classical and alternative NF-κB signaling pathway mediated by BAFF and TNF-alpha-TRAF2-NF-κB signaling pathway. This study suggests that CP-25 may be a promising anti-inflammatory immune and soft regulation drug.

Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis.

PubMed

Aldrich, Melissa B; Velasquez, Fred C; Kwon, Sunkuk; Azhdarinia, Ali; Pinkston, Kenneth; Harvey, Barrett R; Chan, Wenyaw; Rasmussen, John C; Ross, Russell F; Fife, Caroline E; Sevick-Muraca, E M

2017-05-31

Evidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy. We first characterized nanotopography (SOFUSA™) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSA™) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity. Even though all three modes of administration delivered an equal amount of etanercept, SOFUSA™ delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs. Locoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares.

Effects of annealing on the physical properties of therapeutic proteins during freeze drying process.

PubMed

Lim, Jun Yeul; Lim, Dae Gon; Kim, Ki Hyun; Park, Sang-Koo; Jeong, Seong Hoon

2018-02-01

Effects of annealing steps during the freeze drying process on etanercept, model protein, were evaluated using various analytical methods. The annealing was introduced in three different ways depending on time and temperature. Residual water contents of dried cakes varied from 2.91% to 6.39% and decreased when the annealing step was adopted, suggesting that they are directly affected by the freeze drying methods Moreover, the samples were more homogenous when annealing was adopted. Transition temperatures of the excipients (sucrose, mannitol, and glycine) were dependent on the freeze drying steps. Size exclusion chromatography showed that monomer contents were high when annealing was adopted and also they decreased less after thermal storage at 60°C. Dynamic light scattering results exhibited that annealing can be helpful in inhibiting aggregation and that thermal storage of freeze-dried samples preferably induced fragmentation over aggregation. Shift of circular dichroism spectrum and of the contents of etanercept secondary structure was observed with different freeze drying steps and thermal storage conditions. All analytical results suggest that the physicochemical properties of etanercept formulation can differ in response to different freeze drying steps and that annealing is beneficial for maintaining stability of protein and reducing the time of freeze drying process. Copyright © 2017 Elsevier B.V. All rights reserved.

Toxic epidermal necrolysis successfully treated with etanercept.

PubMed

Gubinelli, Emanuela; Canzona, Flora; Tonanzi, Tiziano; Raskovic, Desanka; Didona, Biagio

2009-03-01

Toxic epidermal necrolysis (TEN) is a rare and acute severe adverse reaction to drugs, characterised by massive apoptosis and widespread epidermal and mucosal detachment. Although no gold standard therapy exists, human i.v. immunoglobulins have recently been described as an effective treatment for this disease. We report a case of phenobarbital-induced TEN in a 59-year-old white woman where the epidermal detachment stopped 48 h after beginning the etanercept treatment with complete healing after 20 days. To the best of our knowledge, this is only the second reported case of TEN successfully treated with etanercept.

Cost-utility of COBRA-light versus COBRA therapy in patients with early rheumatoid arthritis: the COBRA-light trial.

PubMed

Ter Wee, Marieke M; Coupé, Veerle Mh; den Uyl, Debby; Blomjous, Birgit S; Kooijmans, Esmee; Kerstens, Pit Jsm; Nurmohamed, Mike T; van Schaardenburg, Dirkjan; Voskuyl, Alexandre E; Boers, Maarten; Lems, Willem F

2017-01-01

To evaluate if COmbinatie therapie Bij Reumatoïde Artritis (COBRA)-light therapy is cost-effective in treating patients with early rheumatoid arthritis (RA) compared with COBRA therapy. This economic evaluation was performed next to the open-label, randomised non-inferiority COBRA-light trial in 164 patients with early RA. Non-responders to COBRA or COBRA-light received etanercept (50 mg/week) for 3-6 months. The societal perspective analysis took medical direct, non-medical direct and indirect costs into account. Costs were measured with patient cost diaries for the follow-up period of 52 weeks. Bootstrapping techniques estimated uncertainty around the cost-effectiveness ratios, presented in cost-effectiveness planes. 164 patients were randomised to either COBRA or COBRA-light strategy. At week 52, COBRA-light proved to be non-inferior to COBRA therapy on all clinical outcome measures. The results of the base-case cost-utility analysis (intention-to-treat analyses) revealed that COBRA-light strategy is more expensive (k€9.3 (SD 0.9) compared with COBRA (k€7.2 (SD 0.8)), but the difference in costs were not significant (k€2.0; 95% CI -0.3 to 4.4). Also, both strategies produced similar quality-adjusted life-years (QALYs). The sensitivity analyses showed robustness of these results. In a per-protocol sensitivity analysis, in which costs of etanercept were assumed to be provided as prescribed according to protocol, both arms had much higher costs: COBRA-light: k€11.5 (8.3) compared with k€8.5 (6.8) for COBRA, and the difference in costs was significant (k€2.9; 0.6 to 5.3). In the base-case cost-utility analysis, the two strategies produced similar QALYs for similar costs. But it is anticipated that if protocol had been followed correctly, the COBRA-light strategy would have been more costly due to additional etanercept costs, for a limited health gain. Given the limited added benefit and high costs of starting etanercept in the presence of low disease activity in our trial, such a strategy needs better justification than is available now. 55552928, Results.

[Economic impact of etanercept and adalimumab biosimilars on hospitals scale covered by PharmAlp'Ain, a hospitals grouping of orders for health products].

PubMed

Berreur, B; Guerin, F; Christophe, B; Limido, G; Paubel, P

2018-01-01

To evaluate the economic impact of future prescriptions of etanercept and adalimumab biosimilars at the territorial scale covered by PharmAlp'Ain, a hospitals grouping of orders for health products. Determination of the number and status of patients (naive or in continuation of treatment) from the National Database "Datamart de Consommation Inter-Régimes" of health insurance, concerned by a dispensation in a pharmacy of etanercept or adalimumab in 2015. Calculation of potential savings in case of biosimilar requirements according to 3 hypotheses: 63% (rate observed in a previous study) of initiations are treated with biosimiliaries and the others by princeps (H 1 ); all initiations under biosimilars and continuation therapy with the princeps (H 2 ) or all patients are treated with biosimilars (H 3 ). The annual savings are estimated at 237,000 € with the H 1 hypothesis. In the case of H 2 , the expected savings would be 376,200 € per year. In the case of H 3 , savings for the community could reach almost 1,282,800 € per year. The arrival of biosimilars allows significant savings for medicines market. According to the French recommendations in 2016, the expected savings are between the H 1 and H 2 hypothesis. The rate of penetration of biosimilars depends on many factors such as the involvement of health professionals, patient adherence, or health authority recommendations. Copyright © 2017 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

[Etanercept].

PubMed

Sparsa, A

2005-11-01

Etanercept (Enbrel, Wyeth Pharmaceuticals) is a fusion protein composed of a soluble TNF alpha receptor issued from bio-technology. It is a member of TNF alpha's family with two others marked infliximab (Remicade, Scheringh Plough Laboratory), chimeric monoclonal antibody (25 p. 100 mouse) and adalimumab (Humira, Abbott France Laboratory), humanized monoclonal antibody (100 p. 100 human). In United States, etanercept is approved by Food and Drug Administration, since 1998, to treat rheumatoid arthritis showing an inadequate response to prior therapy with other disease-modifying antirheumatic drugs (DMARDS). In France, the MA (Marketing Authorization) is more recent, in 2000, etanercept to treat active rheumatoid arthritis who showed an inadequate response to others DMARDS (like methotrexate for example), with opportunity, in 2002, to administer etanercept in active, severe RA, in first line treatment without previous use of methotrexate. Others MA have been obtained in ankylosing spondylitis (2004) polyarticular-course juvenile rheumatoid arthritis (2000), and in the treatment of psoriasic arthritis (2002). Request of MA have been realised to treat cutaneous mild to severe psoriasis in adult, which failed to respond, contradication or no tolerance with systemic treatment as methotrexate, cyclosporine or phototherapy. Among the others anti-TNF therapy, only infliximab can be prescribed, in dermatology, to treat psoriatic arthritis in France. Encouraging good results were the subject of cases report, but lacking clinical trial, predicting probably administration of etanercept in others indications in future. TNF alpha is a proinflammatory cytokine and plays an important role in the physiopathology of large inflammatory diseases. Logically, in future, we should increased prescription of biotherapy, particularly anti-TNF alpha. We have to mind short or mild-term adverse events, widely described in the literature, but long-term side effects remained unknown. Moreover, these biotherapic agents have a high cost and should be estimate.

[Pharmaceutical care of patients with rheumatoid and psoriatic arthritis receiving etanercept].

PubMed

Romero Crespo, I; Antón Torres, R; Borrás Blasco, J; Navarro Ruiz, A

2005-01-01

To evaluate a pharmaceutical care protocol for patients with rheumatoid arthritis (RA) or psoriatic arthritis who begin treatment with etanercept with the objective of identifying potential medication-related problems and implementing therapeutic measures to improve the way this drug is used. An observational, prospective, 3-month study of patients with RA receiving etanercept therapy from March to December 2003 was conducted and a pharmaceutical care protocol was set up. During the first visit, a pharmacotherapeutic record was initiated for each patient, including socio-demographic data, personal history, diagnosis, DMARDs (disease-modifying anti-rheumatic drugs) previously received, and concomitant therapies for other underlying conditions. Patients were briefed on dosage, administration route, and potential adverse events both orally and in writing. Correct drug administration and preservation were verified during the second visit, where potential adverse effects were identified, treatment adherence was confirmed, and, if needed, potential drug interactions with other ongoing medications were disclosed. During the third visit, adherence was assessed, adverse events were recorded, and patients evaluated their response to treatment. Fifty patients were included, 40 with a diagnosis of rheumatoid arthritis (80%) and 10 diagnosed with psoriatic arthritis (20%). In all, 72% had received previous treatment with methotrexate (MTX), 40% with leflunomide, 20% with infliximab, 56% with corticoids, 2% with analgesics, 56% with NSAIDs, and 30% with other DMARDs. No significant drug interactions were found. Regarding adherence to treatment, 7.7% of patients skipped one or more doses, with travelling being the most common reason. Adverse events reported included: injection site reaction (27%), headache (7.7%) and nausea (7.7%). At 3 months after treatment onset, a reduction of MTX doses was seen in 18% of patients, of leflunomide dosage in 8%, of corticoids in 18%, of analgesic usage in 6%, and of NSAIDs in 8% of patients. In agreement with these results, 92% of patients reported having experienced improvment.

Osteoarticular Expression of Musashi-1 in an Experimental Model of Arthritis

PubMed Central

O'Valle, Francisco; Peregrina, Magdalena; Crespo-Lora, Vicente; Galindo-Moreno, Pablo; Roman, Maria; Aneiros-Fernandez, Jose; Aguilar, David; Gonzalez-Rey, Elena; Delgado, Mario; Hernandez-Cortes, Pedro

2015-01-01

Background. Collagen-induced arthritis (CIA), a murine experimental disease model induced by immunization with type II collagen (CII), is used to evaluate novel therapeutic strategies for rheumatoid arthritis. Adult stem cell marker Musashi-1 (Msi1) plays an important role in regulating the maintenance and differentiation of stem/precursor cells. The objectives of this investigation were to perform a morphological study of the experimental CIA model, evaluate the effect of TNFα-blocker (etanercept) treatment, and determine the immunohistochemical expression of Msi1 protein. Methods. CIA was induced in 50 male DBA1/J mice for analyses of tissue and serum cytokine; clinical and morphological lesions in limbs; and immunohistochemical expression of Msi1. Results. Clinically, TNFα-blocker treatment attenuated CIA on day 32 after immunization (P < 0.001). Msi1 protein expression was significantly higher in joints damaged by CIA than in those with no lesions (P < 0.0001) and was related to the severity of the lesions (Spearman's rho = 0.775, P = 0.0001). Conclusions. Treatment with etanercept attenuates osteoarticular lesions in the murine CIA model. Osteoarticular expression of Msi1 protein is increased in joints with CIA-induced lesion and absent in nonlesioned joints, suggesting that this protein is expressed when the lesion is produced in order to favor tissue repair. PMID:26064941

Comparing Biologic Cost Per Treated Patient Across Indications Among Adult US Managed Care Patients: A Retrospective Cohort Study.

PubMed

Gu, Tao; Shah, Neel; Deshpande, Gaurav; Tang, Derek H; Eisenberg, Debra F

2016-12-01

The relative cost of biologics in the treatment of autoimmune disorders, including rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis, is a key consideration for managed care payers. Our objective was to estimate biologic costs and treatment patterns in US managed care patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis. This retrospective study used administrative claims data from the HealthCore Integrated Research Database (HIRD SM ) for adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, and/or ankylosing spondylitis who received abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab between 1 July 2009 and 31 January 2013. Biologic costs (based on drug utilization) and treatment patterns (discontinued, restarted after a >45-day gap, switched to another biologic, or persisted without switching or stopping) were analyzed for the first year post-index. Most of the 24,460 patients received etanercept (48 %), adalimumab (29 %), or infliximab (12 %) as the index biologic. On the index date, 44 % were new to biologic therapy and 56 % were continuing biologic therapy. Biologic cost per treated patient for 1 year was as follows: etanercept $US24,859, adalimumab $US26,537, and infliximab $US26,468. Treatment patterns across indications for etanercept, adalimumab, and infliximab were as follows: persistent (52, 49, 67 %), restarted (23, 21, 12 %), switched (12, 13, 11 %), and discontinued (14, 18, 10 %). These findings from a large health benefits organization in the USA are similar to those of several previous cost analyses assessing different populations, which demonstrates the external validity of the results from the previous studies, both over time and across large populations.

The impact of disease activity and tumour necrosis factor-α inhibitor therapy on cytokine levels in juvenile idiopathic arthritis.

PubMed

Walters, H M; Pan, N; Lehman, T J A; Adams, A; Kalliolias, G D; Zhu, Y S; Santiago, F; Nguyen, J; Sitaras, L; Cunningham-Rundles, S; Walsh, T J; Toussi, S S

2016-06-01

The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)-α inhibitors. TNF-α inhibitor-naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time-points after initiation of TNF-α inhibition for anti-TNF-α-treated (anti-TNF) JIA subjects, and at two subsequent time-points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti-TNF, 31 non-TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti-TNFs) had higher baseline TNF-α, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (P < 0·05). TNF-α and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-α inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab-treated subjects showed that TNF-α and IL-17 increased significantly in etanercept but not adalimumab-treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF-α inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF-treated subjects, but was also associated with elevated TNF-α and IL-17 in etanercept-treated subjects. © 2016 British Society for Immunology.

Identification of 7 Proteins in Sera of RA Patients with Potential to Predict ETA/MTX Treatment Response

PubMed Central

Obry, Antoine; Hardouin, Julie; Lequerré, Thierry; Jarnier, Frédérique; Boyer, Olivier; Fardellone, Patrice; Philippe, Peggy; Marcelli, Christian; Loët, Xavier Le; Vittecoq, Olivier; Cosette, Pascal

2015-01-01

Objective: The recent growth of innovating biologics has opened fascinating avenues for the management of patients. In rheumatoid arthritis, many biologics are currently available, the choice of which being mostly determined empirically. Importantly, a given biologic may not be active in a fraction of patients and may even provoke side effects. Here, we conducted a comparative proteomics study in attempt to identify a predictive theranostic signature of non-response in patients with rheumatoid arthritis treated by etanercept/methotrexate combination. Methods: A serum sample was collected prior to treatment exposure from a cohort of 22 patients with active RA. A proteomic “label free” approach was then designed to quantitate protein biomarkers using mass spectrometry. To verify these results, a relative quantification followed by an absolute quantification of interesting protein candidates were performed on a second cohort. The criterion of judgment was the response to etanercept/methotrexate combination according to the EULAR criteria assessed at 6 months of treatment. Results: These investigations led to the identification of a set of 12 biomarkers with capacity to predict treatment response. A targeted quantitative analysis allowed to confirm the potential of 7 proteins from the latter combination on a new cohort of 16 patients. Two highly discriminating proteins, PROS and CO7, were further evaluated by ELISA on this second cohort. By combining the concentration threshold of each protein associated to a right classification (responders vs non-responders), the sensitivity and specificity reached 88.9 % and 100 %, respectively. Conclusion: Prior to methotrexate/etanercept treatment, abundance of several sera proteins, notably PROS and CO7, were associated to response status of RA patients 6 month after treatment initiation. PMID:26379787

Efficacy, safety and cost per responder of biologics in the treatment of non-radiographic axial spondyloarthritis.

PubMed

Olivieri, Ignazio; Fanizza, Caterina; Gilio, Michele; Ravasio, Roberto

2016-01-01

Anti-tumour necrosis factor (TNF) agents are recommended as second-line therapy for patients with axial spondyloarthropathies. This analysis reviewed data on studies investigating the efficacy and tolerability of anti-TNF agents in patients with non-radiographic axial spondyloarthritis (nr-axSpA) who had failed first-line non-steroidal anti-inflammatory (NSAID) treatment. Efficacy data from RCTs were used to calculate the number needed to treat (NNT) for individual anti-TNFs and then the cost per responder was determined to provide an indication of the value of each therapy. A systematic literature review and analysis of search results over the period January 2008 to September 2014 identified four randomised placebo-controlled trials that were included in the analysis. Adalimumab, etanercept and certolizumab pegol were all effective and well tolerated in patients with nr-axSpA. A patient was more likely to reach ASAS20 or ASAS40 when treated with etanercept or adalimumab, the NNT was lowest for adalimumab, and the risk of adverse events was higher with certolizumab pegol 200 mg every 2 weeks. The cost per responder (NNT) was lowest for adalimumab, followed closely by certolizumab 400 mg every 4 weeks, intermediate for certolizumab 200 mg every 2 weeks and highest for etanercept. Although all anti-TNF agents were associated with clinical improvement in patients with nr-axSpA, adalimumab presented a better cost per responder than etanercept and certolizumab pegol.

Evaluation of whether extremely high enthesitis or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores suggest fibromyalgia and confound the anti-TNF response in early non-radiographic axial spondyloarthritis.

PubMed

Dougados, Maxime; Logeart, Isabelle; Szumski, Annette; Coindreau, Javier; Jones, Heather

2017-01-01

Differentiating between pain from spondyloarthritis (SpA) and pain from fibromyalgia is challenging. We evaluated patients with non-radiographic axial SpA (nr-axSpA) to determine the percentage of patients with extremely high enthesitis and/or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, the relationship between extreme scores and depression, and the effect of extreme scores on treatment outcomes with etanercept. Patients with nr-axSpA received double-blind etanercept 50 mg or placebo weekly and were divided into those who did vs did not have extreme scores at baseline. Extreme scores were defined as the highest quintile for enthesitis score (≥6), and/or scores ≥8 on three of five BASDAI items (excluding morning stiffness duration). Depression was assessed with the Hospital Anxiety and Depression Scale, depression subscale (HADS-D) and medication use. Week 12 outcomes included Assessment of SpondyloArthritis (ASAS) 40 and ASAS partial remission. At baseline, 35/213 (16.4%) patients met extreme enthesitis criteria, 31 (14.6%) met extreme BASDAI criteria, 12 (5.6%) met both, and 135 (63.4%) met neither. More patients with extreme scores than without met the HADS-D definition of depression: 35/68 (51.5%) vs. 27/118 (22.9%), p<0.0001. For patients with vs. without extreme scores who received etanercept, no significant difference existed in week 12 ASAS 40: 13/41 (31.7%) vs. 21/60 (35.0%), respectively, or ASAS partial remission: 8/41 (19.5%) vs. 19/60 (31.7%). Extreme enthesitis and/or BASDAI scores were associated with measurements of depression, but did not affect week 12 ASAS 40 or ASAS partial remission.

In etanercept-treated psoriatic arthritis patients clinical improvement correlated with an increase of serum cortisol relative to other adrenal hormones.

PubMed

Atzeni, F; Sarzi-Puttini, P; DePortu, S; Cutolo, M; Carrabba, M; Straub, R H

2008-01-01

In patients with rheumatoid arthritis (RA), long-term therapy with anti-tumor necrosis factor (TNF) antibodies sensitizes the pituitary gland and improves adrenal androgen secretion in prednisolone-naïve patients. However, whether this is similar in psoriatic arthritis (PsA) is not known. The aim of this study was to assess the effect of 12 weeks of etanercept treatment upon the function of the HPA axis in patients with PsA. Eleven prednisolone-naïve patients (mean age 47.3+/-8.9 years) with PsA were included. We measured serum levels of adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17OHP), cortisol, and androstenedione (ASD), at baseline and at 4 and 12 weeks after initiation of anti-TNF therapy (etanercept, 50 mg every week as a single dose by sc. injection). Clinical improvement was assessed using the Disease Activity Score-28 (DAS-28). Mean levels of serum ACTH, serum cortisol, serum 17OHP and serum ASD did not markedly change during 12 weeks of etanercept treatment. Similarly, the ratio of serum cortisol divided by serum ACTH did not change during 12 weeks of anti-TNF treatment. However, an increase of serum cortisol relative to serum 17OHP or ASD was related to clinical improvement. This indicates that improvement was linked to higher serum cortisol levels relative to others adrenal hormones. This is the first study to demonstrate baseline serum levels and the course of HPA axis-related hormones in patients with PsA. An increase of serum cortisol relative to others adrenocortical hormones (i.e., androstenedione and ACTH) was accompanied by clinical improvement.

Cost-utility of COBRA-light versus COBRA therapy in patients with early rheumatoid arthritis: the COBRA-light trial

PubMed Central

ter Wee, Marieke M; Coupé, Veerle MH; den Uyl, Debby; Blomjous, Birgit S; Kooijmans, Esmee; Kerstens, Pit JSM; Nurmohamed, Mike T; van Schaardenburg, Dirkjan; Voskuyl, Alexandre E; Boers, Maarten; Lems, Willem F

2017-01-01

Objective To evaluate if COmbinatie therapie Bij Reumatoïde Artritis (COBRA)-light therapy is cost-effective in treating patients with early rheumatoid arthritis (RA) compared with COBRA therapy. Methods This economic evaluation was performed next to the open-label, randomised non-inferiority COBRA-light trial in 164 patients with early RA. Non-responders to COBRA or COBRA-light received etanercept (50 mg/week) for 3–6 months. The societal perspective analysis took medical direct, non-medical direct and indirect costs into account. Costs were measured with patient cost diaries for the follow-up period of 52 weeks. Bootstrapping techniques estimated uncertainty around the cost-effectiveness ratios, presented in cost-effectiveness planes. Results 164 patients were randomised to either COBRA or COBRA-light strategy. At week 52, COBRA-light proved to be non-inferior to COBRA therapy on all clinical outcome measures. The results of the base-case cost-utility analysis (intention-to-treat analyses) revealed that COBRA-light strategy is more expensive (k€9.3 (SD 0.9) compared with COBRA (k€7.2 (SD 0.8)), but the difference in costs were not significant (k€2.0; 95% CI –0.3 to 4.4). Also, both strategies produced similar quality-adjusted life-years (QALYs). The sensitivity analyses showed robustness of these results. In a per-protocol sensitivity analysis, in which costs of etanercept were assumed to be provided as prescribed according to protocol, both arms had much higher costs: COBRA-light: k€11.5 (8.3) compared with k€8.5 (6.8) for COBRA, and the difference in costs was significant (k€2.9; 0.6 to 5.3). Conclusions In the base-case cost-utility analysis, the two strategies produced similar QALYs for similar costs. But it is anticipated that if protocol had been followed correctly, the COBRA-light strategy would have been more costly due to additional etanercept costs, for a limited health gain. Given the limited added benefit and high costs of starting etanercept in the presence of low disease activity in our trial, such a strategy needs better justification than is available now. Trial registration number 55552928, Results. PMID:29119006

Case reports of etanercept in inflammatory dermatoses.

PubMed

Norman, Robert; Greenberg, Robert G; Jackson, J Mark

2006-03-01

Skin disfigurations and pruritus can pose severe threats to quality of life, and treatment options for patients with recalcitrant diseases are limited. Tumor necrosis factor alpha, a proinflammatory cytokine, appears to play a central role in mediating the symptoms of many skin disorders. We report cases in which etanercept (Enbrel; Immunex Corp, Thousand Oaks, Calif), a tumor necrosis factor alpha antagonist that is approved for the treatment of moderate to severe psoriasis, was administered to ameliorate the symptoms of acute and chronic dermatologic conditions, including Hailey-Hailey disease, severe psoriasis, dermatomyositis, and subacute cutaneous lupus erythematosus. Treatment with etanercept substantially improved the clinical symptoms and quality of life in these patients, and may offer a therapeutic option for some patients with severe skin disorders.

A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel®) in healthy subjects

PubMed Central

Shin, Donghoon; Kim, Youngdoe; Kang, Jungwon; Gauliard, Anke; Fuhr, Rainard

2016-01-01

Aims SB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union ‐sourced etanercept (EU‐ETN), SB4 and United States‐sourced etanercept (US‐ETN), and EU‐ETN and US‐ETN. The safety and immunogenicity were also compared between the treatments. Methods This was a single‐blind, three‐part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU‐ETN; part B: SB4 or US‐ETN; and part C: EU‐ETN or US‐ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80–125%. Results The geometric least squares means ratios of AUCinf, AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU‐ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US‐ETN); and 100.51%, 101.27% and 103.29% (part C: EU‐ETN vs. US‐ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80–125 %. The incidence of treatment‐emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products. Conclusions The present study demonstrated PK equivalence between SB4 and EU‐ETN, SB4 and US‐ETN, and EU‐ETN and US‐ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products. PMID:26972584

Risk of Serious Infection in Juvenile Idiopathic Arthritis Patients Associated With Tumor Necrosis Factor Inhibitors and Disease Activity in the German Biologics in Pediatric Rheumatology Registry.

PubMed

Becker, Ingrid; Horneff, Gerd

2017-04-01

To examine the effects of tumor necrosis factor inhibitors on the risk for serious infections and other influencing factors in a registry. Patients exposed for the first time to etanercept, adalimumab, or methotrexate and serious infections were identified in the German Biologic Registry for Pediatric Rheumatology (BIKER) registry. Serious infection rates per 1,000 observation-years and relative risks were calculated. Cox regression identified risk factors and provided hazard ratios (HRs) for occurrence of infections. A total of 3,350 patients with 5,919 observation-years fulfilled the inclusion criteria for the study. The first biologic agents were etanercept (1,720 cases) and adalimumab (177 cases). A total of 1,453 patients were treated with methotrexate and no biologic agent. In total, 28 serious infections were reported in 26 patients (4.7 per 1,000 patient-years), 5 with methotrexate (1.6 per 1,000 patient-years), 21 with etanercept (8.1 per 1,000 patient-years), and 2 with adalimumab (9.7 per 1,000 patient-years). Significant univariate risk factors for infection were therapy with biologic agents, disease duration before therapy start, corticosteroid medication, nonbiologic premedications, higher clinical Juvenile Arthritis Disease Activity Score including maximal 10 joints (cJADAS10) at therapy start, and higher mean cJADAS10 during therapy. In multivariate Cox regression, only biologic therapy and cJADAS10 at therapy start remained significant. Risk for infection was increased by etanercept (univariate HR 6.0 [95% confidence interval (95% CI) 2.0-17.5]) or adalimumab (HR 7.3 [95% CI 1.3-40.0]) compared to methotrexate as well as by an elevated cJADAS10 at therapy start (HR 1.1 [95% CI 1.0-1.2] per unit increase). The total rate of serious infections reported in the BIKER registry seems low. Treatment with etanercept or adalimumab increases the risk for serious infection slightly, compared to methotrexate. Disease activity expressed by cJADAS10 appears to be an independent risk factor. © 2016, American College of Rheumatology.

Tumor Necrosis Factor-induced Decrease of Cochlear Blood Flow Can Be Reversed by Etanercept or JTE-013.

PubMed

Sharaf, Kariem; Ihler, Friedrich; Bertlich, Mattis; Reichel, Christoph A; Berghaus, Alexander; Canis, Martin

2016-08-01

This study aimed to quantify the effects of tumor necrosis factor (TNF) inhibitor Etanercept and sphingosine-1-phosphate receptor 2 antagonist JTE-013 on cochlear blood flow in guinea pigs after TNF-induced decrease. Sudden sensorineural hearing loss is a common cause for disability and reduced quality of life. Good understanding of the pathophysiology and strong evidence-based therapy concepts are still missing. In various inner ear disorders, inflammation and impairment of cochlear blood flow (CBF) have been considered factors in the pathophysiology. A central mediator of inflammation and microcirculation in the cochlea is TNF. S1P acts downstream in one TNF pathway. Cochlea lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. Twenty-eight animals were randomly distributed into four groups of seven each. Exposed vessels were superfused by TNF (5.0 ng/ml) and afterward repeatedly either by Etanercept (1.0 μg/ml), JTE-013 (10 μmol/L), or vehicle (0.9 % NaCl solution or ethanol: phosphate-buffered saline buffer, respectively). After decreasing CBF with TNF (p <0.001, two-way RM ANOVA), both treatments reversed CBF, compared with vehicle (p <0.001, two-way RM ANOVA). The comparison of the vehicle groups showed no difference (p = 0.969, two-way RM ANOVA), while there was also no difference between the treatment groups (p = 0.850, two-way RM ANOVA). Both Etanercept and JTE-013 reverse the decreasing effect of TNF on cochlear blood flow and, therefore, TNF and the S1P-signalling pathway might be targets for treatment of microcirculation-related hearing loss.

Long-term etanercept therapy favors weight gain and ameliorates cachexia in rheumatoid arthritis patients: roles of gut hormones and leptin.

PubMed

Chen, Chih-Yen; Tsai, Chang-Youh; Lee, Pui-Ching; Lee, Shou-Dong

2013-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease that damages the synovial joints, and patients with it are often anorexic and cachectic with high morbidity and mortality. Biological therapy with anti-tumor necrosis factor (TNF)-α has been proven effective as a treatment for RA. However, the long-term effects of anti-TNF-α therapy on body weight, appetite, plasma gut hormones and leptin have not been investigated. Twenty RA patients received subcutaneous injections of etanercept, a chimeric protein of human IgG1 Fc and TNF receptor p75, twice weekly for 12 consecutive months. Sequential changes in body weight, body fat, appetite rating, lipid profiles, gut hormones and leptin were measured at baseline and at 3 and 12 months after treatment. Ten RA patients who received non-biological disease modifying anti-rheumatic drugs were enrolled as the controls and were appraised at baseline and at 12 months after treatment (a nonrandomized study). Significant weight gain, hyperuricemia, decreased fasting plasma glucose-dependent insulinotropic polypeptide (GIP) levels, and loss of post-oral glucose suppression of plasma leptin concentration were found in the patients after the 12-month course of etanercept therapy, but not in the controls. A transient decrease in fasting plasma acyl ghrelin occurred at 3 months during etanercept treatment. Appetite score and serum lipid profiles did not change in either group. Long-term therapy with anti-TNF-α is promising in ameliorating body mass decrease in patients with active RA. Plasma levels of ghrelin, GIP and leptin may play significant roles in maintaining energy homeostasis in the anti-inflammatory responses during RA remission.

Etanercept overcomes P-glycoprotein-induced drug resistance in lymphocytes of patients with intractable rheumatoid arthritis.

PubMed

Tsujimura, Shizuyo; Saito, Kazuyoshi; Nakayamada, Shingo; Tanaka, Yoshiya

2010-04-01

P-glycoprotein (P-gp) on activated lymphocytes is an adenosine triphosphate (ATP)-binding cassette transporter that causes drug resistance by exclusion of intracellular drugs in patients with active rheumatoid arthritis (RA). However, infliximab with methotrexate (MTX) can overcome P-gp-mediated drug resistance. We encounter patients who cannot continue infliximab or MTX. Here we tested how etanercept affected P-gp-mediated drug resistance in such intractable RA patients. Peripheral lymphocytes of 11 RA patients (3 switched from infliximab and 8 who could not be treated with MTX) were analyzed for P-gp expression by flow cytometry and for drug exclusion using radioisotope-labeled dexamethasone. Activated lymphocytes of RA patients overexpressed P-gp and coexpressed CD69. Incubation of these lymphocytes with dexamethasone in vitro reduced intracellular dexamethasone levels. Two-week etanercept therapy significantly reduced P-gp expression and eliminated such P-gp- and CD69-high-expressing subgroup. The reduction in P-gp resulted in recovery of intracellular dexamethasone levels in lymphocytes and improvement of disease activity, thus allowing tapering of corticosteroids. None of the patients experienced any severe adverse effects. Etanercept is useful for overcoming P-gp-mediated treatment resistance in intractable RA patients who have to discontinue infliximab or are intolerant to MTX.

Successful ovulation induction, conception, and normal delivery after chronic therapy with etanercept: a recombinant fusion anti-cytokine treatment for rheumatoid arthritis.

PubMed

Sills, E S; Perloe, M; Tucker, M J; Kaplan, C R; Palermo, G D

2001-11-01

Etanercept (Enbrel; Wyeth-Ayerst/Immunex Inc, Seattle, WA, USA) is a subcutaneously administered novel fusion protein consisting of the extracellular ligand-binding domain of the 75 kD receptor for tumor necrosis factor-alpha (anti-TNFalpha) and the Fc portion of human IgG1. The agent is synthesized by plasmid transfection of a Chinese hamster ovary cell line, utilizing recombinant DNA technology. Etanercept was approved by the US FDA for treatment of multi-drug resistant rheumatoid arthritis in 1998, but no human data exist regarding the impact of anti-TNFalpha therapy on human reproductive function or its use before ovulation induction. As TNFalpha potentiates collagenolysis via matrix metalloproteinase gene expression (thereby facilitating ovulation), there exists a theoretical risk that TNFalpha-inhibition could exert an undesirable effect on ovulation and pregnancy. In this report, we describe the first case of ovulation induction, intrauterine insemination, normal pregnancy and singleton delivery of a healthy infant following chronic ( > 1 year) pre-ovulatory TNFalpha-inhibitor therapy for rheumatoid arthritis. Reproductive endocrinologists and obstetrician-gynecologists should be familiar with etanercept therapy in the context of severe rheumatic disease, and offer appropriate reassurance regarding its safe use for infertility patients planning ovulation induction.

Effective treatment of etanercept and phototherapy-resistant psoriasis using the excimer laser.

PubMed

Park, Kelly K; Swan, James; Koo, John

2012-03-15

Treatment of moderate-to-severe plaque psoriasis often requires the use of phototherapy or systemic therapy, which includes immunosuppressants, retinoids, and biologic agents. Although biologic use is becoming increasingly popular, it is not uncommon for patients to experience treatment failure. We describe a patient who had a suboptimal response to etanercept monotherapy after twelve weeks of induction dosing (50 mg twice weekly), as well as to a combination of etanercept (50 mg once weekly-maintenance dosing) and narrowband ultraviolet B (NB-UVB) phototherapy three times weekly for an additional twelve weeks. Noticeable improvement was noted after the addition of NB-UVB and the patient's promising response to phototherapy influenced further management. Etanercept and NB-UVB were discontinued and the patient was initiated on excimer laser treatments twice weekly. After 4 weeks, the patient had a 75 percent reduction in Psoriasis Area Severity Index (PASI) score and after 7 weeks had over 95 percent clearance of psoriasis. The unique properties of the excimer laser may account for its clinical efficacy in our patient as well as in other cases of recalcitrant psoriasis. We propose that the excimer laser be considered in cases of biologic or conventional phototherapy failure in addition to being a standard treatment option or adjunct for the treatment of psoriasis.

Age-related trends in injection site reaction incidence induced by the tumor necrosis factor-α (TNF-α) inhibitors etanercept and adalimumab: the Food and Drug Administration adverse event reporting system, 2004-2015

PubMed Central

Matsui, Toshinobu; Umetsu, Ryogo; Kato, Yamato; Hane, Yuuki; Sasaoka, Sayaka; Motooka, Yumi; Hatahira, Haruna; Abe, Junko; Fukuda, Akiho; Naganuma, Misa; Kinosada, Yasutomi; Nakamura, Mitsuhiro

2017-01-01

Tumor necrosis factor-α (TNF-α) inhibitors are increasingly being used as treatment for rheumatoid arthritis (RA). However, the administration of these drugs carries the risk of inducing injection site reaction (ISR). ISR gives rise to patient stress, nervousness, and a decrease in quality of life (QoL). In order to alleviate pain and other symptoms, early countermeasures must be taken against this adverse event. In order to improve understanding of the risk factors contributing to the induction of ISR, we evaluated the association between TNF-α inhibitors and ISR by applying a logistic regression model to age-stratified data obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The FAERS database contains 7,561,254 reports from January 2004 to December 2015. Adjusted reporting odds ratios (RORs) (95% Confidence Intervals) were obtained for interaction terms for age-stratified groups treated with etanercept (ETN) and adalimumab (ADA). The adjusted RORs for ETN* ≥ 70 and ADA* ≥ 70 groups were the lowest among the age-stratified groups undergoing the respective monotherapies. Furthermore, we found that crude RORs for ETN + methotrexate (MTX) combination therapy and ADA + MTX combination therapy were lower than those for the respective monotherapies. This study was the first to evaluate the relationship between aging and ISR using the FAERS database. PMID:28260984

Monoclonal Antibody and Fusion Protein Biosimilars Across Therapeutic Areas: A Systematic Review of Published Evidence.

PubMed

Jacobs, Ira; Petersel, Danielle; Shane, Lesley G; Ng, Chee-Keng; Kirchhoff, Carol; Finch, Gregory; Lula, Sadiq

2016-12-01

Despite regulatory efforts to formalize guidance policies on biosimilars, there remains a need to educate healthcare stakeholders on the acknowledged definition of biosimilarity and the data that underpin it. The objectives of the study were to systematically collate published data for monoclonal antibodies and fusion protein biosimilars indicated for cancer, chronic inflammatory diseases, and other indications, and to explore differences in the type and weight (quantity and quality) of available evidence. MEDLINE, Embase, and ISI Web of Science were searched to September 2015. Conference proceedings (n = 17) were searched 2012 to July 2015. Included studies were categorized by originator, study type, and indication. To assess data strength and validity, risk of bias assessments were undertaken. Across therapeutic areas, 43 named (marketed or proposed) biosimilars were identified for adalimumab, abciximab, bevacizumab, etanercept, infliximab, omalizumab, ranibizumab, rituximab, and trastuzumab originators. Infliximab CT-P13, SB2, and etanercept SB4 biosimilars have the greatest amount of published evidence of similarity with their originators, based on results of clinical studies involving larger numbers of patients or healthy subjects (N = 1405, 743, and 734, respectively). Published data were also retrieved for marketed intended copies of etanercept and rituximab. This unbiased synthesis of the literature exposed significant differences in the extent of published evidence between molecules at preclinical, clinical, and post-marketing stages of development, providing clinicians and payers with a consolidated view of the available data and remaining gaps.

Sarcoidosis during etanercept treatment for rheumatoid arthritis in women with a history of bilateral oophorectomy.

PubMed

Sawahata, Michiru; Sigiyama, Yukihiko; Yamasawa, Hideaki; Miki, Atsushi; Yamamoto, Hisashi; Muto, Shigeaki; Yamamoto, Hironori; Bando, Masashi

2016-08-01

nd in immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Paradoxically, this treatment induces sarcoidosis in a small population of RA patients as a class effect. A safer anti-TNF therapeutic strategy requires understanding of the risk factors for sarcoidosis. In Japan, TNF inhibitor was introduced in 2003. We reviewed 226 consecutive patients (65 men and 161 women) who were newly diagnosed with sarcoidosis between 2003 and 2012 at Jichi Medical University Hospital, Japan. We detected 3 cases in which sarcoidosis developed during etanercept treatment for RA. All 3 cases were women who had undergone bilateral oophorectomy more than 20 years earlier. Taken together with our previous epidemiologic findings of a consistently maintained second peak after menopause in the age-specific distribution of sarcoidosis in women over four decades, long-term insidious ovarian dysfunction was a possible risk factor for sarcoidosis under certain conditions, especially during etanercept treatment.

Generalised pustular psoriasis induced by cyclosporin a withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept.

PubMed

Kamarashev, J; Lor, P; Forster, A; Heinzerling, L; Burg, G; Nestle, F O

2002-01-01

We report a 50-year-old male patient with a 15-year history of psoriasis including mutilating psoriatic arthritis, in whom the withdrawal of cyclosporin A induced a generalised pustular exacerbation and a aggravation of the joint condition. Two weekly injections of 25 mg of the tumour necrosis factor alpha inhibitor etanercept led to a rapid improvement of his psoriatic arthritis, as well as regression of the pustular eruption, while residual erythema was still present. The clinical response was reflected by an increase in circulating interleukin (IL) 10 and a decrease in IL-6 and IL-8 serum levels during treatment. We conclude that etanercept may be a safe and effective therapy not only in severe psoriatic arthritis, but also in cases of pustular rebound after withdrawal of immunosuppressive agents. Copyright 2002 S. Karger AG, Basel

Persistence with biologic therapies in the Medicare coverage gap.

PubMed

Tamariz, Leonardo; Uribe, Claudia L; Luo, Jiacong; Hanna, John W; Ball, Daniel E; Krohn, Kelly; Meadows, Eric S

2011-11-01

To describe persistence with teriparatide and other biologic therapies in Medicare Part D plans with and without a coverage gap. Retrospective (2006) cohort study of Medicare Part D prescription drug plan beneficiaries from a large benefits company. Two plans with a coverage gap (defined as "basic") were combined and compared with a single plan with coverage for generic and branded medications (defined as "complete"). Patients taking alendronate (nonbiologic comparator), teriparatide, etanercept, adalimumab, interferon β-1a, or glatiramer acetate were selected for the study. For patients with complete coverage, equivalent financial thresholds were used to define the "gap."The definition of discontinuation was failure to fill the index prescription after reaching the gap. For alendronate, 27% of 133,260 patients had enrolled in the complete plan. Patients taking biologic therapies had more commonly enrolled in complete plans: teriparatide (66% of 6221), etanercept (58% of 1469), adalimumab (52% of 824), interferon β-1a (60% of 438), and glatiramer acetate (53% of 393). For patients taking either alendronate or teriparatide, discontinuation rates were higher in the basic, versus complete, plan (adjusted odds ratios, 2.02 and 3.56, respectively). Discontinuation did not significantly vary by plan type for etanercept, adalimumab, interferon β-1a, or glatiramer acetate. For patients who reached the coverage gap, discontinuation was more likely for patients taking osteoporosis (OP) medication. Not having a coverage gap was associated with improved persistence with OP treatment.

Photoacoustic tomography of joints aided by an Etanercept-conjugated gold nanoparticle contrast agent—an ex vivo preliminary rat study

NASA Astrophysics Data System (ADS)

Chamberland, David L.; Agarwal, Ashish; Kotov, Nicholas; Fowlkes, J. Brian; Carson, Paul L.; Wang, Xueding

2008-03-01

Monitoring of anti-rheumatic drug delivery in experimental models and in human diseases would undoubtedly be very helpful for both basic research and clinical management of inflammatory diseases. In this study, we have investigated the potential of an emerging hybrid imaging technology—photoacoustic tomography—in noninvasive monitoring of anti-TNF drug delivery. After the contrast agent composed of gold nanorods conjugated with Etanercept molecules was produced, ELISA experiments were performed to prove the conjugation and to show that the conjugated anti-TNF-α drug was biologically active. PAT of ex vivo rat tail joints with the joint connective tissue enhanced by intra-articularly injected contrast agent was conducted to examine the performance of PAT in visualizing the distribution of the gold-nanorod-conjugated drug in articular tissues. By using the described system, gold nanorods with a concentration down to 1 pM in phantoms or 10 pM in biological tissues can be imaged with good signal-to-noise ratio and high spatial resolution. This study demonstrates the feasibility of conjugating TNF antagonist pharmaceutical preparations with gold nanorods, preservation of the mechanism of action of TNF antagonist along with preliminary evaluation of novel PAT technology in imaging optical contrast agents conjugated with anti-rheumatic drugs. Further in vivo studies on animals are warranted to test the specific binding between such conjugates and targeted antigen in joint tissues affected by inflammation.

Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis

PubMed Central

Hueber, Wolfgang; Tomooka, Beren H; Batliwalla, Franak; Li, Wentian; Monach, Paul A; Tibshirani, Robert J; Van Vollenhoven, Ronald F; Lampa, Jon; Saito, Kazuyoshi; Tanaka, Yoshiya; Genovese, Mark C; Klareskog, Lars; Gregersen, Peter K; Robinson, William H

2009-01-01

Introduction Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers. Methods Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept. Results We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%). Conclusions We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients. PMID:19460157

Persistence, switch rates, drug consumption and costs of biological treatment of rheumatoid arthritis: an observational study in Italy.

PubMed

Degli Esposti, Luca; Favalli, Ennio Giulio; Sangiorgi, Diego; Di Turi, Roberta; Farina, Giuseppina; Gambera, Marco; Ravasio, Roberto

2017-01-01

The aim of this analysis was to provide an estimate of drug utilization indicators (persistence, switch rate and drug consumption) on biologics and the corresponding costs (drugs, admissions and specialist care) incurred by the Italian National Health Service in the management of adult patients with rheumatoid arthritis (RA). We conducted an observational retrospective cohort analysis using the administrative databases of three local health units. We considered all patients aged ≥18 years with a diagnosis of RA and at least one biologic drug prescription between January 2010 and December 2012 (recruitment period). Persistence was defined as maintenance over the last 3 months of the follow-up period of the same biological therapy administered at the index date. A switch was defined as the presence of a biological therapy other than that administered at the index date during the last 3 months of the follow-up period. Hospital admissions (with a diagnosis of RA or other RA-related diagnoses), specialist outpatient services, instrumental diagnostics and pharmaceutical consumption were assessed. The drug utilization analysis took into account only biologics with at least 90 patients on treatment at baseline (adalimumab n=144, etanercept n=236 and infliximab n=94). In each year, etanercept showed better persistence with initial treatment than adalimumab or infliximab. Etanercept was characterized by the lowest number of patients increasing the initial drug consumption (2.6%) and by the highest number of patients reducing the initial drug consumption (10.5%). The mean cost of treatment for a patient persisting with the initial treatment was €12,388 (€14,182 for adalimumab, €12,103 for etanercept and €11,002 for infliximab). The treatment costs for patients switching from initial treatment during the first year of follow-up were higher than for patients who did not switch (€12,710 vs. €11,332). Persistence, switch rate and drug consumption seem to directly influence treatment costs. In subjects not persisting with initial treatment, other health care costs were approximately three times higher than for persistent patients. This difference could suggest a positive effect on the quality of life for persistent patients. Etanercept showed the highest persistence with treatment.

Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

PubMed Central

Irwin, Michael R.; Olmstead, Richard; Valladares, Edwin M.; Breen, Elizabeth Crabb; Ehlers, Cindy L.

2009-01-01

Background In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-α (TNF-α) normalizes REM sleep in alcohol-dependent adults. Methods In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Results Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Conclusions Pharmacologic neutralization of TNF-α activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-α may have a physiologic role in the regulation of REM sleep in humans. PMID:19185287

The role of concomitant methotrexate dosage and maintenance over time in the therapy of rheumatoid arthritis patients treated with adalimumab or etanercept: retrospective analysis of a local registry.

PubMed

Favalli, Ennio Giulio; Becciolini, Andrea; Biggioggero, Martina; Bertoldi, Ilaria; Crotti, Chiara; Raimondo, Maria Gabriella; Marchesoni, Antonio

2018-01-01

To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan-Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p =0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p =0.031). In a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.

Rheumatoid and psoriatic knee synovitis: clinical, grey scale, and power Doppler ultrasound assessment of the response to etanercept

PubMed Central

Fiocco, U; Ferro, F; Vezzu, M; Cozzi, L; Checchetto, C; Sfriso, P; Botsios, C; Ciprian, L; Armellin, G; Nardacchione, R; Piccoli, A; Todesco, S; Rubaltelli, L

2005-01-01

Objective: To determine the effect of tumour necrosis factor α (TNFα) blockade with etanercept in refractory knee joint synovitis (KJS) in rheumatoid and psoriatic arthritis, by local and systemic disease activity assessment and combined grey scale and power Doppler ultrasonographic monitoring. Methods: 27 knees affected by rheumatoid KJS (n = 12) and psoriatic KJS (n = 8) were assessed before receiving treatment and at 3 and 12 months' follow up. Time dependent clinical changes in disease activity were monitored by C reactive protein, erythrocyte sedimentation rate (ESR), global health status (GHS), and Ritchie (RAI) and knee joint articular (KJAI) indices; synovial changes were monitored by ultrasonographic and power Doppler indices for grey scale synovial thickening and for distinct intrasynovial vessel power Doppler flow configurations (fluid/synovium interface (F/SI-PD) and pannus/cartilage interface (P/CI-PD)). Interobserver and intraobserver variability of grey scale and power Doppler ultrasonographic was evaluated. Response to treatment was assessed by analysis of variance for repeated measures on clinical and ultrasonographic variables. Results: Rapid (3 months) reduction in F/SI-PD flow (p<0.001), parallel to reductions of C reactive protein (p<0.05), ESR (p<0.001), KJAI (p<0.002), RAI, and GHS (p<0.001), was sustained at 12 months when it was accompanied by reduction in both synovial thickening and P/CI-PD flow (p<0.001). No differences (ANOVA) were noted at baseline or at 12 months in clinical and ultrasonographic variables between either the rheumatoid or the psoriatic KJS groups. Conclusion: Grey scale and power Doppler ultrasonography are reliable measures of long term change in rheumatoid and psoriatic KJS disease activity in response to anti-TNFα treatment with etanercept. PMID:15567814

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas.

PubMed

Ordonez, Alvaro A; Pokkali, Supriya; Kim, Sunhwa; Carr, Brian; Klunk, Mariah H; Tong, Leah; Saini, Vikram; Chang, Yong S; McKevitt, Matthew; Smith, Victoria; Gossage, David L; Jain, Sanjay K

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas

PubMed Central

Kim, Sunhwa; Carr, Brian; Klunk, Mariah H.; Tong, Leah; Saini, Vikram; Chang, Yong S.; McKevitt, Matthew; Smith, Victoria; Gossage, David L.; Jain, Sanjay K.

2018-01-01

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments. PMID:29758082

Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long‐Term Treatment Response in Rheumatoid Arthritis

PubMed Central

Jani, Meghna; Chinoy, Hector; Warren, Richard B.; Griffiths, Christopher E. M.; Plant, Darren; Fu, Bo; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, KimmeL.; Prouse, P. J.; Moitra, R. K.; Shawe, D. J.; Nisar, M.; Fairburn, K.; Nixon, J.; Barnes, T.; Hui, M.; Coady, D.; Wright, D.; Morley, C.; Raftery, G.; Bracewell, C.; Bridges, M.; Armstrong, D.; Chuck, A. J.; Hailwood, S.; Kumar, N.; Ashok, D.; Reece, R.; O'Reilly, S. C.; Ding, T.; Badcock, L. J.; Deighton, C. M.; Raj, N.; Regan, M. R.; Summers, G. D.; Williams, R. A.; Lambert, J. R.; Stevens, R.; Wilkinson, C.; Kelly, C. A.; Hamilton, J.; Heycock, C. R.; Saravanan, V.; Cope, A.; Garrood, T.; Ng, N.; Kirkham, B.; Green, M.; Gough, A.; Lawson, C.; Das, D.; Borbas, E.; Wazir, T.; Emery, P.; Bingham, S.; Bird, H. A.; Conaghan, P.G.; Pease, C. T.; Wakefield, R. J.; Buch, M.; Bruce, I.; Gorodkin, R.; Ho, P.; Parker, B.; Smith, W.; Jenkins, E.; Mukhtyar, C.; Gaffney, K.; Macgregor, A. J.; Marshall, T.; Merry, P.; DeSilva, C.; Birrell, F. N.; Crook, P. R.; Szebenyi, B.; Bates, D.; James, D.; Gillott, T.; Alvi, A.; Grey, C.; Browning, J.; McHale, J. F.; Gaywood, I.C.; Jones, A. C.; Lanyon, P.; Pande, I.; Doherty, M.; Gupta, A.; Courtney, P. A.; Srikanth, A.; Abhishek, A.; Das, L.; Pattrick, M.; Snowden, H. N.; Bowden, A. P.; Smith, E. E.; Klimiuk, P.; Speden, D. J.; Naz, S.; Ledingham, J. M.; Hull, R. G.; McCrae, F.; Cooper, A.; Young‐Min, S. A.; Wong, E.; Shaban, R.; Woolf, A. D.; Davis, M.; Hutchinson, D.; Endean, A.; Mewar, D.; Tunn, E. J.; Nelson, K.; Kennedy, T. D.; Dubois, C.; Pauling, J.; Korendowych, E.; Jenkinson, T.; Sengupta, R.; Bhalla, A.; McHugh, N.; O'Neil, T.; Herrick, A. L.; Jones, A. K.; Cooper, R. G.; Dixon, W. G.; Harrison, B.; Buckley, C. D.; Carruthers, D. C.; Elamanchi, R.; Gordon, P. C.; Grindulis, K. A.; Khattak, F.; Raza, K.; Situnayake, K.; Akil, M.; Till, S.; Dunkley, L.; Tattersall, R.; Kilding, R.; Tait, T.; Maxwell, J.; Till, S.; Kuet, K.-P.; Plant, M. J.; Clarke, F.; Fordham, J. N.; Tuck, S.; Pathare, S. K.; Paul, A.; Marguerie, C. P.; Rigby, S. P.; Dunn, N.; Abbas, I.; Filer, C.; Abernethy, V. E.; Clewes, A. R.; Dawson, J. K.; Kitas, G.; Erb, N.; Klocke, R.; Whallett, A. J.; Douglas, K.; Pace, A.; Sandhu, R.; John, H.; Shand, L.; Lane, S.; Foster, H.; Griffiths, B.; Griffiths, I.; Kay, L.; Ng, W.-F.; Platt, P. N.; Walker, D. J.; Peterson, P.; Lorenzi, A.; Friswell, M.; Thompson, B.; Lee, M.; Pratt, A.; Hopkinson, N. D.; Dunne, C. A.; Quilty, B.; Marks, J.; Mukherjee, S.; Mulherin, D.; Chalam, S. V.; Price, T.; Sheeran, T.; Venkatachalam, S.; Baskar, S.; Al- Allaf, W.; McKenna, F.; Shah, P.; Filer, A.; Bowman, S. J.; Jobanputra, P.; Rankin, E. C.; Allen, M.; Chaudhuri, K.; Dubey, S.; Price‐Forbes, A.; Ravindran, J.; Samanta, A.; Sheldon, P.; Hassan, W.; Francis, J.; Kinder, A.; Neame, R.; Moorthy, A.; Bukhari, M.; Ottewell, L.; Palkonyai, E.; Hider, S.; Hassell, A.; Menon, A.; Dowson, C.; Kamath, S.; Packham, J.; Dutta, S.; Price, S.; Roddy, E.; Paskins, Z.; O'Reilly, D. T.; Rajagopal, V.; Bhagat, S.; Chattopadhyay, C. B.; Green, M.; Quinn, D.; Isdale, A.; Brown, A.; Saleem, B.; Foo, B.; Al Saffar, Z.; Koduri, G.

2015-01-01

Objective To investigate whether antidrug antibodies and/or drug non‐trough levels predict the long‐term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions. Methods A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme‐linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non‐trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated. Results Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels. Conclusion Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months. PMID:26109489

Assessing the overall benefit of a medication: cumulative benefit of secukinumab over time in patients with moderate-to-severe plaque psoriasis.

PubMed

Armstrong, April W; Feldman, Steven R; Korman, Neil J; Meng, Xiangyi; Guana, Adriana; Nyirady, Judit; Herrera, Vivian; Zhao, Yang

2017-05-01

Conventional measurements for assessing psoriasis treatment effects capture improvements at fixed, pre-specified timepoints, failing to account for cumulative clinical benefit over time. Explore the innovative concept of "cumulative clinical benefit" by examining the effect of secukinumab over 52 weeks in moderate-to-severe psoriasis patients. Cumulative clinical benefit was determined as the area-under-the-curve of the percentage of responders over 52 weeks (AUC 0-52 wks ), using pooled data from two phase III trials for patients receiving secukinumab (300 or 150 mg) or etanercept. Normalized cumulative benefit with secukinumab 300 mg, secukinumab 150 mg, and etanercept was 74.2%, 63.2%, and 50.5%, respectively, for PASI 75; 58.0%, 42.5%, and 29.5%, respectively, for PASI 90; 32.3%, 18.8%, and 8.7%, respectively, for PASI 100; and 58.3%, 47.9%, and 38.3%, respectively, for DLQI 0/1. 52-week PASI 75 clinical benefit ratios for secukinumab 300 and 150 mg versus etanercept were 1.47 and 1.25, respectively; the ratio of the two secukinumab doses was 1.17, favoring 300 mg. Post hoc analysis. Cumulative clinical benefit estimated by AUC 0-52 wks is a novel measure for comparing psoriasis treatments. Secukinumab 300 mg provides greater cumulative clinical benefit than secukinumab 150 mg; both provide greater cumulative benefit than etanercept.

Biological agents for controlling excessive scarring.

PubMed

Berman, Brian

2010-01-01

The potential of various biological agents to reduce or prevent excessive scar formation has now been evaluated in numerous in-vitro studies, experimental animal models and preliminary clinical trials, in some cases with particularly promising results. Perhaps prominent among this group of biological agents, and, to some degree, possibly representing marketed compounds already being used 'off label' to manage excessive scarring, are the tumor necrosis factor alpha antagonist etanercept, and immune-response modifiers such as IFNalpha2b and imiquimod. Additional assessment of these novel agents is now justified with a view to reducing or preventing hypertrophic scars, keloid scars and the recurrence of post-excision keloid lesions.

Treatment of recalcitrant cicatricial pemphigoid with the tumor necrosis factor alpha antagonist etanercept.

PubMed

Sacher, Christopher; Rubbert, Andrea; König, Cathrin; Scharffetter-Kochanek, Karin; Krieg, Thomas; Hunzelmann, Nicolas

2002-01-01

The treatment of cicatricial pemphigoid is generally regarded as difficult and usually relies on individual clinical experience. Corticosteroids, as drugs of first choice, often have to be combined with steroid-sparing agents to prevent hazardous, long-term side effects. We describe a 72-year-old woman with long-standing cicatricial pemphigoid recalcitrant to established treatment regimens who responded rapidly and lastingly to therapy with the tumor necrosis factor alpha antagonist etanercept. To our knowledge, this is the first report of its use in the treatment of a bullous autoimmune disease.

[Biological agents].

PubMed

Amano, Koichi

2009-03-01

There are two types of biological agents for the treatment of rheumatoid arthritis (RA); monoclonal antibodies and recombinant proteins. Among the latter, etanercept, a recombinant fusion protein of soluble TNF receptor and IgG was approved in 2005 in Japan. The post-marketing surveillance of 13,894 RA patients revealed the efficacy and safety profiles of etanercept in the Japanese population, as well as overseas studies. Abatacept, a recombinant fusion protein of CTLA4 and IgG, is another biological agent for RA. Two clinical trials disclosed the efficacy of abatacept for difficult-to-treat patients: the AIM for MTX-resistant cases and the ATTAIN for patients who are resistant to anti-TNF. The ATTEST trial suggested abatacept might have more acceptable safety profile than infliximab. These biologics are also promising for the treatment of RA for not only relieving clinical symptoms and signs but retarding structural damage.

Effect of illicit direct to consumer advertising on use of etanercept, mometasone, and tegaserod in Canada: controlled longitudinal study.

PubMed

Law, Michael R; Majumdar, Sumit R; Soumerai, Stephen B

2008-09-02

To assess the impact of direct to consumer advertising of prescription drugs in the United States on Canadian prescribing rates for three heavily marketed drugs-etanercept, mometasone, and tegaserod. Controlled quasi-experimental study using interrupted time series analysis. Representative sample of 2700 Canadian pharmacies and prescription data from 50 US Medicaid programmes. Differences in number of filled prescriptions per 10,000 population per month between English speaking and French speaking (control) Canadian provinces before and after the start of direct to consumer advertising in the United States. Spending on direct to consumer advertising for study drugs ranged from $194m to $314m ( pound104m- pound169m; euro131m-euro212m) over the study period. Prescription rates for etanercept and mometasone did not increase in English speaking provinces relative to French speaking controls after the start of direct to consumer advertising. In contrast, tegaserod prescriptions increased 42% (0.56 prescriptions/10,000 residents, 95% confidence interval 0.37 to 0.76) in English speaking provinces immediately after the start of US direct to consumer advertising. Uncontrolled analysis of US Medicaid data showed a larger 56% increase in tegaserod prescriptions. However, this increase did not persist over time in either country, despite continued advertising. Exposure to US direct to consumer advertising transiently influenced both Canadian and US prescribing rates for tegaserod, a drug later withdrawn owing to safety concerns. The impact of direct to consumer advertising on drug use seems to be highly variable and probably depends on the characteristics of the advertised drug, the level of exposure to direct to consumer advertising, and the cultural context.

Effect of illicit direct to consumer advertising on use of etanercept, mometasone, and tegaserod in Canada: controlled longitudinal study

PubMed Central

Majumdar, Sumit R; Soumerai, Stephen B

2008-01-01

Objective To assess the impact of direct to consumer advertising of prescription drugs in the United States on Canadian prescribing rates for three heavily marketed drugs—etanercept, mometasone, and tegaserod. Design Controlled quasi-experimental study using interrupted time series analysis. Population Representative sample of 2700 Canadian pharmacies and prescription data from 50 US Medicaid programmes. Main outcome measures Differences in number of filled prescriptions per 10 000 population per month between English speaking and French speaking (control) Canadian provinces before and after the start of direct to consumer advertising in the United States. Results Spending on direct to consumer advertising for study drugs ranged from $194m to $314m (£104m-£169m; €131m-€212m) over the study period. Prescription rates for etanercept and mometasone did not increase in English speaking provinces relative to French speaking controls after the start of direct to consumer advertising. In contrast, tegaserod prescriptions increased 42% (0.56 prescriptions/10 000 residents, 95% confidence interval 0.37 to 0.76) in English speaking provinces immediately after the start of US direct to consumer advertising. Uncontrolled analysis of US Medicaid data showed a larger 56% increase in tegaserod prescriptions. However, this increase did not persist over time in either country, despite continued advertising. Conclusions Exposure to US direct to consumer advertising transiently influenced both Canadian and US prescribing rates for tegaserod, a drug later withdrawn owing to safety concerns. The impact of direct to consumer advertising on drug use seems to be highly variable and probably depends on the characteristics of the advertised drug, the level of exposure to direct to consumer advertising, and the cultural context. PMID:18765444

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

PubMed

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

PubMed Central

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs. PMID:26356639

New side effect of TNF-alpha inhibitors: morphea.

PubMed

Stewart, Faith A; Gavino, Alde Carlo P; Elewski, Boni E

2013-01-01

An otherwise healthy 45-year-old man with a 3-year history of poorly controlled psoriasis (no arthritis) was treated with etanercept 50-mg subcutaneous injections twice weekly for 3 months and then once weekly. Alternative treatment options were either unavailable (long commute for phototherapy) or contraindicated (history of alcohol abuse). The patient initially tolerated etanercept well with significant clinical improvement and had an uneventful course; however, approximately 18 months after initiating therapy, he abruptly developed dusky, indurated, and tender plaques on his abdomen and thighs at the sites of etanercept injections (Figure 1). There was also diffuse woody induration involving his flanks and back where injections had not been performed. His only recent prior exposure to an injectable medication was rabies vaccination in his arm 1 year earlier. The patient denied any systemic symptoms. Upon noting these findings, etanercept was immediately discontinued. Biopsy of an indurated plaque on his right lower abdomen revealed a superficial and deep perivascular lymphoplasmacytic inflammatory infiltrate in a background of thickened and hyalinized collagen fibers with notable loss of perieccrine fat (Figure 2). These features were most consistent with the inflammatory stage of morphea. Further work-up revealed a negative antinuclear antibody, anti-double-stranded DNA, anti-Scl-70, and anti-centromere. Borrelia titers were not obtained. The differential diagnosis included scleredema and scleromyxedema; serum and urine protein electrophoresis were within normal limits. The sites were treated with intralesional corticosteroids. During the next 3 months, there was minimal progression of disease although the plaques of morphea had not yet resolved.

Determining the Value of Two Biologic Drugs for Chronic Inflammatory Skin Diseases: Results of a Multi-Criteria Decision Analysis.

PubMed

Zozaya, Néboa; Martínez-Galdeano, Lucía; Alcalá, Bleric; Armario-Hita, Jose Carlos; Carmona, Concepción; Carrascosa, Jose Manuel; Herranz, Pedro; Lamas, María Jesús; Trapero-Bertran, Marta; Hidalgo-Vega, Álvaro

2018-06-01

Multi-criteria decision analysis (MCDA) is a tool that systematically considers multiple factors relevant to health decision-making. The aim of this study was to use an MCDA to assess the value of dupilumab for severe atopic dermatitis compared with secukinumab for moderate to severe plaque psoriasis in Spain. Following the EVIDEM (Evidence and Value: Impact on DEcision Making) methodology, the estimated value of both interventions was obtained by means of an additive linear model that combined the individual weighting (between 1 and 5) of each criterion with the individual scoring of each intervention in each criterion. Dupilumab was evaluated against placebo, while secukinumab was evaluated against placebo, etanercept and ustekinumab. A retest was performed to assess the reproducibility of weights, scores and value estimates. The overall MCDA value estimate for dupilumab versus placebo was 0.51 ± 0.14. This value was higher than those obtained for secukinumab: 0.48 ± 0.15 versus placebo, 0.45 ± 0.15 versus etanercept and 0.39 ± 0.18 versus ustekinumab. The highest-value contribution was reported by the patients' group, followed by the clinical professionals and the decision makers. A fundamental element that explained the difference in the scoring between pathologies was the availability of therapeutic alternatives. The retest confirmed the consistency and replicability of the analysis. Under this methodology, and assuming similar economic costs per patient for both treatments, the results indicated that the overall value estimated of dupilumab for severe atopic dermatitis was similar to, or slightly higher than, that of secukinumab for moderate to severe plaque psoriasis.

Central Diabetes Insipidus in Refractory Antineutrophil Cytoplasmic Antibody-associated Vasculitis

PubMed Central

Ohashi, Keiji; Morishita, Michiko; Watanabe, Haruki; Sada, Ken-Ei; Katsuyama, Takayuki; Miyawaki, Yoshia; Katsuyama, Eri; Narazaki, Mariko; Tatebe, Noriko; Watanabe, Katsue; Kawabata, Tomoko; Wada, Jun

2017-01-01

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case. PMID:28943556

Central Diabetes Insipidus in Refractory Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

PubMed

Ohashi, Keiji; Morishita, Michiko; Watanabe, Haruki; Sada, Ken-Ei; Katsuyama, Takayuki; Miyawaki, Yoshia; Katsuyama, Eri; Narazaki, Mariko; Tatebe, Noriko; Watanabe, Katsue; Kawabata, Tomoko; Wada, Jun

2017-11-01

We herein describe two cases of refractory antineutrophil cytoplasmic antibody-associated vasculitis (AAV) complicated with diabetes insipidus (DI) possibly related to hypertrophic pachymeningitis (HP). One patient had microscopic polyangiitis and HP, which were refractory to cyclophosphamide, azathioprine, rituximab, mycophenolate mofetil (MMF), and mizoribine. Remission was finally achieved with the use of etanercept, but DI occurred 5 years later. The other patient had granulomatosis with polyangiitis, which that was refractory to cyclophosphamide, methotrexate, MMF, and rituximab. DI subsequently developed, but was successfully treated with etanercept. Dura mater hypertrophy was macroscopically observed in the latter case.

Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis.

PubMed

Jani, Meghna; Chinoy, Hector; Warren, Richard B; Griffiths, Christopher E M; Plant, Darren; Fu, Bo; Morgan, Ann W; Wilson, Anthony G; Isaacs, John D; Hyrich, KimmeL; Barton, Anne

2015-05-01

To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions. A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated. Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody-positive patients received lower median dosages of methotrexate compared with antidrug antibody-negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m(2) and poor adherence were associated with lower drug levels. Pharmacologic testing in anti-tumor necrosis factor-treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months. © 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade

PubMed Central

2011-01-01

Introduction Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA. Methods Arthritic mice were treated with RB200 alone or in combination with the TNF receptor fusion protein etanercept. We performed immunohistochemistry to assess CD31 and in vivo fluorescent imaging using anti-E-selectin antibody labelled with fluorescent dye to elucidate the effect of RB200 on the vasculature in CIA. Results RB200 significantly abrogated CIA by reducing paw swelling and clinical scores. Importantly, low-dose RB200 combined with a suboptimal dose of etanercept led to complete abrogation of arthritis. Moreover, the combination of RB200 with etanercept abrogated the intensity of the E-selectin-targeted signal to the level seen in control animals not immunised to CIA. Conclusions The human pan-EGF receptor bispecific ligand trap RB200, when combined with low-dose etanercept, abrogates CIA, suggesting that inhibition of events downstream of EGF receptor activation, in combination with TNFα inhibitors, may hold promise as a future therapy for patients with RA. PMID:21982514

Cost effectiveness of etanercept (Enbrel) in combination with methotrexate in the treatment of active rheumatoid arthritis based on the TEMPO trial.

PubMed

Kobelt, G; Lindgren, P; Singh, A; Klareskog, L

2005-08-01

To estimate the cost effectiveness of combination treatment with etanercept plus methotrexate in comparison with monotherapies in patients with active rheumatoid arthritis (RA) using a new model that incorporates both functional status and disease activity. Effectiveness data were based on a 2 year trial in 682 patients with active RA (TEMPO). Data on resource consumption and utility related to function and disease activity were obtained from a survey of 616 patients in Sweden. A Markov model was constructed with five states according to functional status (Health Assessment Questionnaire (HAQ)) subdivided into high and low disease activity. The cost for each quality adjusted life year (QALY) gained was estimated by Monte Carlo simulation. Disease activity had a highly significant effect on utilities, independently of HAQ. For resource consumption, only HAQ was a significant predictor, with the exception of sick leave. Compared with methotrexate alone, etanercept plus methotrexate over 2 years increased total costs by 14,221 euros and led to a QALY gain of 0.38. When treatment was continued for 10 years, incremental costs were 42,148 euros for a QALY gain of 0.91. The cost per QALY gained was 37,331 euros and 46,494 euros, respectively. The probability that the cost effectiveness ratio is below a threshold of 50,000 euros/QALY is 88%. Incorporating the influence of disease activity into this new model allows better assessment of the effects of anti-tumour necrosis factor treatment on patients' general wellbeing. In this analysis, the cost per QALY gained with combination treatment with etanercept plus methotrexate compared with methotrexate alone falls within the acceptable range.

Anti-TNF-α Drugs Differently Affect the TNFα-sTNFR System and Monocyte Subsets in Patients with Psoriasis

PubMed Central

Bianchini, Elena; Bartolomeo, Regina; Fabiano, Antonella; Manfredini, Marco; Ferrari, Federica; Albertini, Giuseppe; Trenti, Tommaso; Nasi, Milena; Pinti, Marcello; Iannone, Anna; Salvarani, Carlo; Pellacani, Giovanni

2016-01-01

TNF-α has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-α drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-α drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFα-TNFα receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-α therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-α, TNF-α soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-α and TNF-α soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-α levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-α and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-α and sTNFRII than patients responding to infliximab; vi) anti- TNF-α drugs significantly altered monocyte subsets. A complex remodelling of the TNFα-TNFα receptor system thus takes place in patients treated with anti-TNF-α drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity. PMID:27936119

Cost-effectiveness Analysis of Treatment Sequence Initiating With Etanercept Compared With Leflunomide in Rheumatoid Arthritis: Impact of Reduced Etanercept Cost With Patent Expiration in South Korea.

PubMed

Park, Sun-Kyeong; Park, Seung-Hoo; Lee, Min-Young; Park, Ji-Hyun; Jeong, Jae-Hong; Lee, Eui-Kyung

2016-11-01

In south Korea, the price of biologics has been decreasing owing to patent expiration and the availability of biosimilars. This study evaluated the cost-effectiveness of a treatment strategy initiated with etanercept (ETN) compared with leflunomide (LFN) after a 30% reduction in the medication cost of ETN in patients with active rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR). A cohort-based Markov model was designed to evaluate the lifetime cost-effectiveness of treatment sequence initiated with ETN (A) compared with 2 sequences initiated with LFN: LFN-ETN sequence (B) and LFN sequence (C). Patients transited through the treatment sequences, which consisted of sequential biologics and palliative therapy, based on American College of Rheumatology (ACR) responses and the probability of discontinuation. A systematic literature review and a network meta-analysis were conducted to estimate ACR responses to ETN and LFN. Utility was estimated by mapping an equation for converting the Health Assessment Questionnaire-Disability Index score to utility weight. The costs comprised medications, outpatient visits, administration, dispensing, monitoring, palliative therapy, and treatment for adverse events. A subanalysis was conducted to identify the influence of the ETN price reduction compared with the unreduced price, and sensitivity analyses explored the uncertainty of model parameters and assumptions. The ETN sequence (A) was associated with higher costs and a gain in quality-adjusted life years (QALYs) compared with both sequences initiated with LFN (B, C) throughout the lifetime of patients with RA and MTX-IR. The incremental cost-effectiveness ratio (ICER) for strategy A versus B was ₩13,965,825 (US$1726) per QALY and that for strategy A versus C was ₩9,587,983 (US$8050) per QALY. The results indicated that strategy A was cost-effective based on the commonly cited ICER threshold of ₩20,000,000 (US$16,793) per QALY in South Korea. The robustness of the base-case analysis was confirmed using sensitivity analyses. When the unreduced medication cost of ETN was applied in a subanalysis, the ICER for strategy A versus B was ₩20,909,572 (US$17,556) per QALY and that for strategy A versus C was ₩22,334,713 (US$18,753) per QALY. This study indicated that a treatment strategy initiated with ETN was more cost-effective in patients with active RA and MTX-IR than 2 sequences initiated with LFN. The results also indicate that the reduced price of ETN affected the cost-effectiveness associated with its earlier use. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Impact of Biologics With and Without Concomitant MTX and at Reduced Doses in Older Rheumatoid Arthritis Patients

PubMed Central

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2014-01-01

Background This study examines whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-TNF therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. Methods We conducted a retrospective cohort study among RA patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologics using Cox proportional hazard regression adjusting for demographics and baseline co-morbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Results Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients initiated biologic monotherapy were 1.4 (95% CI, 1.3–1.5) times more likely to discontinue at 1-year and 1.8 (95% CI, 1.7–2.0) times more likely if starting infliximab monotherapy. Approximately 10–20% of patients who initiated and adhered to etanercept and adalimumab for ≥ 12 months subsequently used reduced-dose therapy for an 12 additional months and beyond. Conclusion In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. PMID:25370912

Secukinumab long-term safety experience: A pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis.

PubMed

van de Kerkhof, Peter C M; Griffiths, Christopher E M; Reich, Kristian; Leonardi, Craig L; Blauvelt, Andrew; Tsai, Tsen-Fang; Gong, Yankun; Huang, Jiaqing; Papavassilis, Charis; Fox, Todd

2016-07-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated efficacy and safety in patients with moderate to severe plaque psoriasis. We reviewed safety data from the secukinumab psoriasis phase II/III program. Data were pooled from 10 phase II/III secukinumab psoriasis studies. Analysis included 3993 subjects; 3430 received secukinumab, representing 2725 subject-years (SYs) of exposure. Over 52 weeks, for secukinumab 300 mg, 150 mg, and etanercept, respectively, exposure-adjusted incidence rates (IRs) per 100 SYs were comparable across treatments for total adverse events (AEs; 236.1, 239.9, and 243.4, respectively); infections (91.1, 85.3, and 93.7, respectively); serious AEs (7.4, 6.8, and 7.0, respectively); serious infections (1.4, 1.1, and 1.4, respectively); malignant or unspecified tumors (0.77, 0.97, and 0.68, respectively); and adjudicated major adverse cardiovascular events (0.42, 0.35, and 0.34, respectively). AEs were not dose-related except for nonserious, mild/moderate, skin/mucosal candidiasis (IRs 3.55, 1.85, and 1.37 for secukinumab 300 mg, 150 mg, and etanercept, respectively). There was a limited number of patients in comparator groups and the exposure to placebo was short. Secukinumab had a favorable safety profile, had no meaningful difference between the 300- and 150-mg doses and, in terms of safety, was comparable to etanercept over 52 weeks in patients with moderate to severe plaque psoriasis. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept.

PubMed

Berookhim, Boback; Fischer, Harry D; Weinberg, Jeffrey M

2004-10-01

The treatment of pemphigus vulgaris (PV) is generally regarded as challenging. Patients with the disease require long-term systemic therapy, creating concern for the toxicities of these treatments. Corticosteroids, as drugs of first choice, often must be combined with steroid-sparing agents to prevent hazardous long-term side effects. We describe a 62-year-old woman with long-standing PV whose cutaneous disease responded to therapy with the tumor necrosis factor alpha (TNF-alpha) antagonist etanercept, which was started for treatment of her inflammatory seronegative arthritis. To our knowledge, this is the first report of its efficacy in the treatment of PV.

Linear immunoglobulin A dermatosis mimicking toxic epidermal necrolysis: a case report of etanercept treatment.

PubMed

Prieto-Barrios, M; Velasco-Tamariz, V; Tous-Romero, F; Burillo-Martinez, S; Zarco-Olivo, C; Rodriguez-Peralto, J L; Ortiz-Romero, P L

2018-03-01

A 65-year-old pluripathological woman attended our hospital with a cutaneous eruption of sudden appearance after vancomycin treatment. She presented targetoid lesions affecting approximately 25-30% of her body surface, large erosions with mucosal lesions and positive Nikolsky sign. Under the initial clinical suspicion of toxic epidermal necrolysis (TEN), and considering the recent literature of successful use of etanercept in these cases, she was treated with a single dose of this antitumour necrosis factor (anti-TNF) agent. Subsequently, the exanthema progression stopped and resolution of the lesions happened in a few days. Later on, histopathology revealed a subepidermal blister with dense neutrophilic infiltrate and linear deposits of immunoglobulin A (IgA) on the dermoepidermal junction, allowing us to establish the diagnosis of drug-induced linear IgA dermatosis mimicking TEN. Linear IgA dermatosis can have severe clinical manifestations, even mimicking TEN, and can have high mortality, especially in drug-induced cases. We have not found any other report of linear IgA dermatosis treated with etanercept in the English literature. Anti-TNF medications could represent useful therapeutic alternatives in this dermatosis. © 2017 British Association of Dermatologists.

Intensive combination treatment regimens, including prednisolone, are effective in treating patients with early rheumatoid arthritis regardless of additional etanercept: 1-year results of the COBRA-light open-label, randomised, non-inferiority trial.

PubMed

ter Wee, Marieke M; den Uyl, Debby; Boers, Maarten; Kerstens, Pit; Nurmohamed, Mike; van Schaardenburg, Dirkjan; Voskuyl, Alexandre E; Lems, Willem F

2015-06-01

Recently, we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy (methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day) compared with the original COBRA therapy (methotrexate 7.5 mg/week, sulfasalazine 2 g/day, with initial prednisolone 60 mg/day) after 26 weeks in patients with early active rheumatoid arthritis (RA). To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity (DAS44), functional outcome (Health Assessment Questionnaire (HAQ)) and radiographic progression (Sharp/van der Heijde score (SHS)), and to assess the effect of adding etanercept. An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA, following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39. Both groups showed major improvements in DAS44 after 52 weeks: mean (SD) -2.41 (1.2) in the COBRA and -2.02 (1.0) in the COBRA-light group (p=ns). In both groups, functional ability improved and radiological progression of joints was minimal. At least one adverse event was reported in 96% of the patients in both groups. In total, 25 serious adverse events occurred: 9 vs 16 in COBRA and COBRA-light, respectively. Treatment actually instituted was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 67 of these (62%) actually received it. Intensive COBRA or COBRA-light therapy has major, comparably favourable effects on disease activity, functional ability and radiological outcome after 1 year in patients with early RA. Protocolised addition of etanercept was often not implemented by treating rheumatologists, and patients receiving it appeared to have limited added benefit, probably because of low disease activity levels at its initiation. ISRCTN55552928. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Profile of users of anticytokines offered by the health care system in the state of Paraná for the treatment of rheumatoid arthritis.

PubMed

Wiens, Astrid; Grochocki, Mônica Cavichiolo; Pontarolli, Deise Regina Sprada; Venson, Rafael; Correr, Cassyano Januário; Pontarolo, Roberto

2012-01-01

The Brazilian Unified Health Care System (SUS) offers treatment for patients with RA through federal funding (Ministry of Health) and state co-financing. The Clinical Protocol and Therapeutic Guidelines for the treatment of rheumatoid arthritis describe the therapeutic regimen for the disease, including the anticytokines adalimumab, etanercept or infliximab. The aim of this study was to evaluate the profile of registered users of those anticytokines, biologics registered in the Information System of the Pharmaceutical Assistance Specialized Division, managed by the Paraná State Drug Center. A cross-sectional study regarding data from March 2010 was conducted. Based on dispensation data, information regarding the following variables were collected: age; gender; regional health care centers; International Classification of Diseases (ICD); and drug dispensed. In addition, the monthly cost with anticytokines for the SUS was calculated. In the state of Paraná, 923 patients on anticytokines were identified, 40%, 44% and 16% of whom receiving adalimumab, etanercept and infliximab, respectively. This generated a monthly cost of R$3,403,195.59. Regarding the ICD, the distribution of patients was as follows: 55% had ICD M05.8; 27%, ICD M06.0; 9%, ICD M6.8; 8%, ICD M5.0; and 1% had other ICDs related to the disease. The regional health care centers of the state of Paraná with the largest number of patients on anticytokines were in the following municipalities: Ponta Grossa; Cornélio Procópio; Londrina; Cianorte; Maringá; Irati; and Campo Mourão. This study assessed the distribution and profile of users of anticytokines for the rheumatoid arthritis treatment covered by the SUS in the state of Paraná, in March 2010.

Correlation of serum MMP3 and other biomarkers with clinical outcomes in patients with ankylosing spondylitis: A pilot study

USDA-ARS?s Scientific Manuscript database

The studies aimed to assess a set of biomarkers for their correlations with disease activity/severity of patients with ankylosing spondylitis (AS). A total of 24 AS patients were treated with etanercept and prospectively followed for 12 weeks. Serum levels of TNF-alpha, IFN-gamma, TGF-beta, IL6, IL1...

Hearing status in patients with rheumatoid arthritis.

PubMed

Ahmadzadeh, A; Daraei, M; Jalessi, M; Peyvandi, A A; Amini, E; Ranjbar, L A; Daneshi, A

2017-10-01

Rheumatoid arthritis is thought to induce conductive hearing loss and/or sensorineural hearing loss. This study evaluated the function of the middle ear and cochlea, and the related factors. Pure tone audiometry, speech reception thresholds, speech discrimination scores, tympanometry, acoustic reflexes, and distortion product otoacoustic emissions were assessed in rheumatoid arthritis patients and healthy volunteers. Pure tone audiometry results revealed a higher bone conduction threshold in the rheumatoid arthritis group, but there was no significant difference when evaluated according to the sensorineural hearing loss definition. Distortion product otoacoustic emissions related prevalence of conductive or mixed hearing loss, tympanometry values, acoustic reflexes, and speech discrimination scores were not significantly different between the two groups. Sensorineural hearing loss was significantly more prevalent in patients who used azathioprine, cyclosporine and etanercept. Higher bone conduction thresholds in some frequencies were detected in rheumatoid arthritis patients that were not clinically significant. Sensorineural hearing loss is significantly more prevalent in refractory rheumatoid arthritis patients.

Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials.

PubMed

Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Kawai, Shinichi; Sugiyama, Naonobu; Yuasa, Hirotoshi; Yamashita, Noriaki; Sugiyama, Noriko; Wagerle, Lorin Craig; Vlahos, Bonnie; Wajdula, Joseph

2015-03-01

Abstract Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

Protective Role of Eosinophils and TNFa after Ozone Inhalation.

PubMed

Fryer, Allison D; Jacoby, David B; Wicher, Sarah A

2017-03-01

Exposure to ozone induces deleterious responses in the airways that include shortness of breath, inflammation, and bronchoconstriction. People with asthma have increased airway sensitivity to ozone and other irritants. Dr. Allison Fryer and colleagues addressed how exposure to ozone affects the immune and physiological responses in guinea pigs. Guinea pigs are considered a useful animal model for studies of respiratory and physiological responses in humans; their response to airborne allergens is similar to that in humans and shares some features of allergic asthma. Fryer and colleagues had previously observed that within 24 hours of exposure, ozone not only induced bronchoconstriction but also stimulated the production of new cells in the bone marrow, where all white blood cells develop. As a result of ozone exposure, increased numbers of newly synthesized white blood cells, particularly eosinophils, moved into the blood and lungs. The central hypothesis of the current study was that newly synthesized eosinophils recruited to the lungs 3 days after ozone exposure were beneficial to the animals because they reduced ozoneinduced bronchoconstriction. The investigators also hypothesized that the beneficial effect seen in normal (nonsensitized) animals was lost in animals that had been injected with an allergen, ovalbumin (sensitized). They also planned to explore the effects of inhibitors of certain cytokines (cellsignaling molecules). Immune responses in sensitized animals are dominated by a Th2 pattern, which is characterized by the synthesis of cytokines (interleukin [IL]-4, IL-5, and IL-13) and the Th2 subset of CD4+ T lymphocytes and the cells they activate (predominantly eosinophils, and B lymphocytes that switch to making immunoglobulin E [IgE]). Thus, sensitized animals were used as a model of allergic humans, whose immune responses tend to be dominated by IgE. Fryer and colleagues exposed normal and sensitized (allergic) guinea pigs to 2 ppm ozone or filtered air for 4 hours and measured changes in cell numbers and airway responses 1 or 3 days later. They counted the numbers of eosinophils and other white blood cells (macrophages, neutrophils, and lymphocytes) in bone marrow, blood, and bronchoalveolar lung lavage fluid. The investigators also measured important physiological responses, including bronchoconstriction. Some animals were pretreated with etanercept and monoclonal anti-IL-5, which block tumor necrosis factor-a (TNFa) and IL-5, respectively. TNFa and IL-5 blockers have been used to treat patients with asthma. A key feature of the study was a technique to distinguish which white blood cells were synthesized after exposure from those that already existed, by injecting animals with bromodeoxyuridine (BrdU). BrdU is a thymidine analogue that is incorporated into the DNA of dividing cells, serving as a marker of newly produced cells. Therefore, a snapshot can be obtained of the proportion of newly synthesized (BrdU-positive) versus pre-existing (BrdU-negative) cell types. 1. Allergic and normal animals differed in the time course of bronchoconstriction and changes in cell types after ozone exposure. In normal animals, bronchoconstriction increased substantially at day 1 but decreased by day 3 after ozone exposure. In contrast, in allergic animals bronchoconstriction remained high at day 3. Ozone also increased the percentage of newly formed, BrdU2 positive eosinophils in the bone marrow and lungs of normal but not allergic animals. 2. Pretreatment with the TNFa blocker etanercept had complex effects, which differed between normal and allergic animals. In normal animals, etanercept decreased ozone-induced new synthesis of eosinophils in the bone marrow and blocked eosinophil migration to the lung; it also increased bronchoconstriction at day 3 (relative to day 1 without etanercept). In allergic animals, etanercept had no effect on any cell type in the bone marrow or lung after exposure to ozone and did not change bronchoconstriction compared with allergic animals not treated with etanercept. Etanercept tended to increase the numbers of blood monocytes and lymphocytes in air- and ozone-exposed normal and allergic animals at day 3, but had no effect on eosinophils in blood at this time point. This was one of the few statistically significant findings in the blood of exposed animals in the study. 3. Anti-IL-5 reduced bronchoconstriction at day 3 after exposure of allergic animals to ozone. In contrast, bronchoconstriction was greatly increased in normal animals treated with anti-IL-5. Fryer and colleagues explored the airway and cellular responses in guinea pigs exposed to ozone. The HEI Review Committee, which conducted an independent review of the study, agreed that the findings supported the authors’ hypothesis (1) that exposure to ozone stimulates production of eosinophils in bone marrow, (2) that these newly formed eosinophils migrate to the lungs, and (3) that those eosinophils play a delayed but potentially beneficial role in reducing ozone-induced inflammation in the airways of healthy normal animals, but not in allergen-sensitized animals. The Committee also agreed that guinea pigs were a good model for studying responses to an allergen, because a major subtype of asthma (the high Th2 or allergic type) is associated with high levels of eosinophils in the blood. A novel finding was that the TNFa blocker etanercept decreased ozone-induced formation of eosinophils in the bone marrow and blocked eosinophil migration to the lung in normal animals. However, because injecting etanercept had little effect on eosinophils and did not decrease bronchoconstriction in allergic guinea pigs, the potential for treating patients with allergic asthma with TNFa blockers is uncertain. This is consistent with the poor performance of TNFa blockers in clinical studies of asthma treatment. Blocking the cytokine IL-5 with an anti-IL-5 antibody substantially decreased bronchoconstriction in sensitized animals. This suggests that therapies targeting IL-5 and eosinophils would be promising in at least some types of asthma. The Committee expressed caution toward experiments with cytokine blockers, both in animal models and humans, because such blockers are often not specific to a particular cell type and may differ at different sites in the body. Without further detailed confirmation of the effects of the blockers, interpreting these experiments can be challenging. The Committee concluded that the study by Fryer and colleagues raises several intriguing directions for future research, including exploring ways in which newly formed eosinophils differ from pre-existing ones, and how such findings apply to humans with allergy or asthma.

Etanercept therapy for toxic epidermal necrolysis.

PubMed

Paradisi, Andrea; Abeni, Damiano; Bergamo, Fabio; Ricci, Francesco; Didona, Dario; Didona, Biagio

2014-08-01

Toxic epidermal necrolysis (TEN) is a severe and potentially lethal drug reaction for which no standard treatment is available. To describe a case series of patients with TEN treated with a single dose of etanercept. We observed 10 consecutive patients with TEN. For each patient, we recorded the presence of comorbidities and all the drugs recently started (ie, in the last month). In all cases, 50 mg of etanercept was administered in a single subcutaneous injection. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Using the probabilities of death linked to each level of SCORTEN score, we calculated the expected probability of death in our patients. Healing was defined as complete reepithelialization, and a time to healing curve was then obtained using the Kaplan-Meier method. All patients promptly responded to treatment, reaching complete reepithelialization without complications or side effects. The median time to healing was 8.5 days. This is a small, uncontrolled case series. These preliminary results suggest the possibility that tumor necrosis factor-alfa may be an effective target for control of TEN, a dangerous skin condition for which no effective cure has yet been found. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Manufacturing history of etanercept (Enbrel®): Consistency of product quality through major process revisions.

PubMed

Hassett, Brian; Singh, Ena; Mahgoub, Ehab; O'Brien, Julie; Vicik, Steven M; Fitzpatrick, Brian

2018-01-01

Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production. Multiple orthogonal biochemical analyses, which included evaluation of attributes indicative of product purity, potency, and quality, were assessed on >2,000 batches of ETN from three sites of DS manufacture, during the period 1998-2015. Based on the key quality attributes of product purity (assessed by hydrophobic interaction chromatography HPLC), binding activity (to TNF by ELISA), potency (inhibition of TNF-induced apoptosis by cell-based bioassay) and quality (N-linked oligosaccharide map), we show that the integrity of ETN DS has remained consistent over time. This consistency was maintained through three major enhancements to the initial process of manufacturing that were supported by detailed comparability assessments, and approved by the European Medicines Agency. Examination of results for all major quality attributes for ETN DS indicates a highly consistent process for over 18 years and throughout changes to the manufacturing process, without affecting safety and efficacy, as demonstrated across a wide range of clinical trials of ETN in multiple inflammatory diseases.

Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients.

PubMed

Zhang, Jie; Xie, Fenglong; Delzell, Elizabeth; Yun, Huifeng; Lewis, James D; Haynes, Kevin; Chen, Lang; Beukelman, Timothy; Saag, Kenneth G; Curtis, Jeffrey R

2015-05-01

To examine whether concomitant methotrexate (MTX) use is associated with better biologic persistence and whether self-administered anti-tumor necrosis factor (anti-TNF) therapies are used at reduced doses in real-world clinical care settings, not just clinical trials. We conducted a retrospective cohort study among rheumatoid arthritis (RA) patients using Medicare claims data from 2006 to 2012. Subjects were new initiators of etanercept, infliximab, adalimumab, abatacept, and tocilizumab with at least 12 months of continuous medical and pharmacy coverage after treatment initiation. We examined the association between concomitant MTX use and persistence on biologic agents using Cox proportional hazards regression, adjusting for demographics and baseline comorbidities. We further identified a subgroup of patients who initiated and were adherent on etanercept or adalimumab for at least 12 months and examined the proportion of patients who subsequently used these therapies at reduced doses continuously for an additional 12, 18, and 24 months. Of 26,510 eligible RA patients, 10,511 initiated biologic monotherapy. Overall, patients who initiated biologic monotherapy were 1.4 (95% confidence interval [95% CI] 1.3-1.5) times more likely to discontinue at 1 year compared to those who initiated combination therapy, and 1.8 (95% CI 1.7-2.0) times more likely if starting infliximab monotherapy. Approximately 10-20% of patients who initiated and adhered to etanercept and adalimumab for ≥12 months subsequently received reduced-dose therapy for an 12 additional months and beyond. In real-world practice, concomitant MTX was associated with improved persistence on biologic therapy, especially for infliximab users; reduced-dose injectable anti-TNF therapy was used by a substantial proportion of RA patients. © 2015, American College of Rheumatology.

Treatment patterns among patients with rheumatic disease (rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and undifferentiated arthritis (UnA)) treated with subcutaneous TNF inhibitors.

PubMed

Tymms, Kathleen; Littlejohn, Geoff; Griffiths, Hedley; de Jager, Julien; Bird, Paul; Joshua, Fred; Nash, Peter; Handel, Malcolm; McManus, Hamish; Butcher, Belinda E; Youssef, Peter

2018-06-01

The aim was to describe the real-world treatment persistence of subcutaneous TNF inhibitors (TNFi) for patients with inflammatory rheumatic disease newly initiating treatment with biologic disease-modifying antirheumatic drugs (bDMARD). This was a retrospective cohort study that extracted data for new users of TNFi between 1 August 2010 and 31 August 2016 from the Australian Optimising Patient outcome in Australian RheumatoLogy (OPAL) registry. Patients were 1:1 propensity-score matched with golimumab based on their age, sex, year of index, C-reactive protein level, baseline treatment combination and disease. Treatment persistence was calculated. Data from 3749 patients were extracted (adalimumab n = 1518; certolizumab n = 298; etanercept n = 1068; golimumab n = 865). The mean (SD) ages of patients were 51.7 (14.2) years for adalimumab, 53.7 (14.0) years for certolizumab, 52.8 (14.3) years for etanercept and 52.3 (14.6) years for golimumab, with disease durations 7.7 (10.5), 8.8 (9.2), 8.1 (10.4) and 7.3 (9.7) years, respectively. Two thirds of the patients were women. There was no significant difference in treatment persistence by treatment in the overall population (adalimumab 33.6 [95% CI 28.6-40.7], certolizumab 24.8 [95% CI 21.3-42.1], etanercept 27.6 [95% CI 23.4-36.5], golimumab 30.3 [95% CI 23.26-36.5]; months, p = 0.545), or in the propensity score-matched population. No safety signals were detected. In this real-world biologic-naïve Australian inflammatory rheumatic disease cohort treated with subcutaneous TNF inhibitors during the period 2010-2016, there was no difference in treatment persistence between agents.

The effect of new biosimilars in rheumatology and gastroenterology specialities on UK healthcare budgets: Results of a budget impact analysis.

PubMed

Aladul, Mohammed I; Fitzpatrick, Raymond W; Chapman, Stephen R

2018-05-15

The approval of new biosimilars of infliximab, etanercept and adalimumab by the European Medicines Agency is expected to produce further cost savings to the healthcare system budget. This study aimed to estimate the budget impact of the introduction of new biosimilars Flixabi ® , Erelzi ® , Solymbic ® , Amgevita ® and Imraldi ® in rheumatology and gastroenterology specialities in the UK. A published budget impact model was adapted to estimate the expected cost savings following the entry of new biosimilars Flixabi ® , Erelzi ® , Solymbic ® , Amgevita ® and Imraldi ® in the UK over three-year time horizon. This model was based on retrospective market shares of biologics used in rheumatology and gastroenterology which were derived from DEFINE Software and healthcare professional perspectives. The model predicted that infliximab and etanercept biosimilars would replace their corresponding reference agents by 2020. Adalimumab biosimilars were predicted to achieve 19% of the rheumatology and gastroenterology market by 2020. Without the introduction of further biosimilars, the model predicted a reduction in expenditure of £44 million on biologics over the next three years. With the entry of Flixabi ® , Erelzi ® , Solymbic ® , Amgevita ® and Imraldi ® the model estimates cumulative savings of £285 million by 2020. The introduction of new infliximab, etanercept and adalimumab biosimilars will be associated with considerable cost savings and have a substantial favourable impact on the UK NHS budget. The number of biosimilars and time of entry of is critical to create competition which will result in maximum cost savings. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmaceutical Approval Update.

PubMed

Kaufman, Michele B

2016-12-01

Lisinopril oral solution (Qbrelis) for the treatment of hypertension, heart failure, and acute myocardial infarction; etanercept-szzs (Erelzi) for multiple autoimmune disorders; and lumacaftor/ivacaftor (Orkambi) for cystic fibrosis.

How Long Does the Benefit of Biologics Last? An Update on Time To Relapse and Potential for Rebound of Biologic Agents for Psoriasis.

PubMed

Kamaria, Monique; Liao, Wilson; Koo, J Y

2010-01-01

The biologic agents vary considerably in terms of their long-term duration of effect. Using the definitions provided by the National Psoriasis Foundation Medical Board, the objective of this review was to compare all biologic agents with respect to time to relapse and potential for rebound. Overall, alefacept had the longest off-treatment benefit (29.9 weeks in Psoriasis Area and Severity Index [PASI] 75 responders), followed by ustekinumab (22 weeks), infliximab (19.5 weeks), adalimumab (18 weeks), etanercept (12.1 weeks in PASI 50 responders), and, lastly, efalizumab (9.6 weeks). Rebound was reported commonly for efalizumab (14%) and, extremely rarely, for etanercept (0.002%).

Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter.

PubMed

Shinohara, Mayuka; Sumino, Yasuhiro; Sato, Fuminori; Kiyono, Tohru; Hashimoto, Naohiro; Mimata, Hiromitsu

2017-06-01

To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence. © 2017 The Japanese Urological Association.

Etanercept Injection

MedlinePlus

... own joints, causing pain, swelling, and loss of function) in adults, psoriatic arthritis (condition that causes joint ... its own joints, causing pain, swelling, loss of function, and delays in growth and development) in children ...

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study

PubMed Central

Maksymowych, Walter P; Dougados, Maxime; Sieper, Joachim; Braun, Jürgen; Citera, Gustavo; Van den Bosch, Filip; Logeart, Isabelle; Wajdula, Joseph; Jones, Heather; Marshall, Lisa; Bonin, Randi; Pedersen, Ron; Vlahos, Bonnie; Kotak, Sameer; Bukowski, Jack F

2016-01-01

Objective To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Methods Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. Results 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by −1.1 for ETN/ETN and by −3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Conclusions Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. Trial registration number NCT01258738. PMID:26269397

Zymographic analysis using gelatin-coated film of the effect of etanercept on the extracellular matrix-degrading activity in synovial fluids of rheumatoid arthritis patients.

PubMed

Kamataki, Akihisa; Ishida, Mutsuko; Komagamine, Masataka; Yoshida, Masaaki; Ando, Takanobu; Sawai, Takashi

2016-04-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Most RA patients develop cartilage and bone destruction, and various proteinases are involved in the destruction of extracellular matrix of cartilage and bone. The aim of this study is to evaluate the utility of our newly developed method to measure total gelatinolytic activity. We adopted this method for measurement in synovial fluid from RA patients treated by the anti-rheumatic drug etanercept (ETN), a recombinant human soluble tumor necrosis factor receptor fusion protein, and compared the findings with clinical and laboratory data. Enzymatic activity of synovial fluid was analyzed by zymography using gelatin-coated film, and compared with the index of Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP), CRP and matrix metalloproteinase (MMP)-3 level before and after ETN therapy. Synovial fluids of 19 patients were collected before and after administration of ETN therapy. In nine of 19 patients, who showed a decrease in gelatin-degrading activity in synovial fluid, the index of DAS28-CRP (4.85-2.85, ΔDAS = -2.00) and CRP (3.30-0.94 mg/dL, ΔCRP = -2.36) was alleviated after ETN therapy, while cases with no change or an increase in gelatin-degrading activity showed a modest improvement in clinical data: DAS28-CRP (4.23-3.38, ΔDAS = -0.85) and CRP (1.70-0.74 mg/dL, ΔCRP = -0.96). Our newly developed method for measurement of gelatin-degrading activity in synovial fluid from RA patients is highly practicable and useful for predicting the effect of ETN therapy. © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy.

PubMed

Yun, Huifeng; Xie, Fenglong; Delzell, Elizabeth; Chen, Lang; Levitan, Emily B; Lewis, James D; Saag, Kenneth G; Beukelman, Timothy; Winthrop, Kevin; Baddley, John W; Curtis, Jeffrey R

2015-05-01

To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs. © 2015, American College of Rheumatology.

Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis.

PubMed

Chou, Richard C; Kane, Michael; Ghimire, Sanjay; Gautam, Shiva; Gui, Jiang

2016-11-01

It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.

Recent progress in ankylosing spondylitis treatment.

PubMed

Toussirot, Eric; Wendling, Daniel

2003-01-01

Ankylosing spondylitis (AS) is a systemic inflammatory rheumatic disease responsible for back pain, stiffness and loss of functional capacity. The therapeutic management of AS includes regular physical exercise together with the use of NSAIDs. Second-line treatments, such as sulfasalazine, are required in cases of NSAID-refractory AS. Some patients have severe and inadequately controlled disease, explaining the need for the development of new treatments. This therapeutic development in AS involves the assessment of new NSAIDs, namely COX2 selective agents and new second-line treatments, such as methotrexate (MTX), pamidronate and anti-TNFalpha agents. Controlled studies are lacking for MTX. Pamidronate showed to be effective in NSAID refractory AS patients in open and controlled trials. Anti-TNFalpha agents (infliximab and etanercept) gave promising results with dramatic improvement of AS symptoms in open and preliminary controlled trials, but further studies are required to evaluate the real long-term effects and tolerability of these drugs.

Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis

PubMed Central

Tanida, Atsushi; Kishimoto, Yuji; Okano, Toru; Hagino, Hiroshi

2013-01-01

Background Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA). Methods Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration. Results TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration. Conclusion Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis. PMID:24031147

Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors.

PubMed

Cathcart, Shelley; Sami, Naveed; Elewski, Boni

2012-05-01

Tumor necrosis factor inhibitors are valuable tools for dermatologists. As their use increases, rare adverse events are more likely to be encountered. We describe one patient who developed sarcoidosis while being treated for psoriasis with etanercept. We sought to review to previously reported cases and further characterize the nature of this reaction. A literature search was performed with the key words "sarcoidosis, sarcoid, etanercept, infliximab, adalimumab, granulomatous, and drug reaction." All relevant cases in the English language were included and evaluated for demographic data, duration of therapy prior to developing sarcoid, duration of sarcoid signs/symptoms, treatments used and time to resolution after discontinuation of the drug. Including the present case, there are 34 cases of sarcoidosis developing during anti-tumor necrosis factor therapy. All previously reported cases were patients with a primarily rheumatologic diagnosis. In all but one case, discontinuation of the drug resulted in complete resolution of symptoms. The lung and surrounding lymph nodes were the areas most commonly affected. The average amount of time between initiation of therapy and onset of symptoms was 22 months. The average time to resolution of symptoms after discontinuation of the drug was 5.2 months. This is a retrospective case review. These data indicated that sarcoid is a possible adverse effect of tumor necrosis factor inhibitor therapy that should be noted by dermatologists using these drugs. While it has been reported in the rheumatology literature, it may be under-recognized by dermatologists.

Number needed to treat and costs per responder among biologic treatments for moderate-to-severe psoriasis: a network meta-analysis.

PubMed

Armstrong, April W; Betts, Keith A; Signorovitch, James E; Sundaram, Murali; Li, Junlong; Ganguli, Arijit X; Wu, Eric Q

2018-04-23

The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response. To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA-approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder. The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs, were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually. Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300 mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150 mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300 mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150 mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90. The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments.

Efficacy and cost-efficacy of biologic therapies for moderate to severe psoriasis: a meta-analysis and cost-efficacy analysis using the intention-to-treat principle.

PubMed

Chi, Ching-Chi; Wang, Shu-Hui

2014-01-01

Compared to conventional therapies, biologics are more effective but expensive in treating psoriasis. To evaluate the efficacy and cost-efficacy of biologic therapies for psoriasis. We conducted a meta-analysis to calculate the efficacy of etanercept, adalimumab, infliximab, and ustekinumab for at least 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) and Physician's Global Assessment clear/minimal (PGA 0/1). The cost-efficacy was assessed by calculating the incremental cost-effectiveness ratio (ICER) per subject achieving PASI 75 and PGA 0/1. The incremental efficacy regarding PASI 75 was 55% (95% confidence interval (95% CI) 38%-72%), 63% (95% CI 59%-67%), 71% (95% CI 67%-76%), 67% (95% CI 62%-73%), and 72% (95% CI 68%-75%) for etanercept, adalimumab, infliximab, and ustekinumab 45 mg and 90 mg, respectively. The corresponding 6-month ICER regarding PASI 75 was $32,643 (best case $24,936; worst case $47,246), $21,315 (best case $20,043; worst case $22,760), $27,782 (best case $25,954; worst case $29,440), $25,055 (best case $22,996; worst case $27,075), and $46,630 (best case $44,765; worst case $49,373), respectively. The results regarding PGA 0/1 were similar. Infliximab and ustekinumab 90 mg had the highest efficacy. Meanwhile, adalimumab had the best cost-efficacy, followed by ustekinumab 45 mg and infliximab.

Brief Report: Utilization of the First Biosimilar Infliximab Since Its Approval in South Korea.

PubMed

Kim, Seoyoung C; Choi, Nam-Kyong; Lee, Joongyub; Kwon, Kyoung-Eun; Eddings, Wesley; Sung, Yoon-Kyoung; Ji Song, Hong; Kesselheim, Aaron S; Solomon, Daniel H

2016-05-01

The US Food and Drug Administration is considering an application for a biosimilar version of infliximab, which has been available in South Korea since November 2012. The aim of the present study was to examine the utilization patterns of both branded and biosimilar infliximab and other tumor necrosis factor (TNF) inhibitors in South Korea before and after the introduction of this biosimilar infliximab. Using claims data from April 2009 to March 2014 from the Korean Health Insurance Review and Assessment Service database, which includes the entire South Korean population, the number of claims for biosimilar infliximab was assessed. A segmented linear regression model was used to examine the utilization patterns of infliximab (the branded and biosimilar versions) and other TNF inhibitors (adalimumab and etanercept) before and after the introduction of the biosimilar infliximab. In total, 20,976 TNF inhibitor users were identified from the South Korean claims database, including 983 with a prescription claim for biosimilar infliximab. Among all of the claims for any version of infliximab, the proportion of biosimilar infliximab claims increased to 19% through March 2014. Before November 2012, each month there were 33 (95% confidence interval [95% CI] 32, 35) more infliximab claims, 44 (95% CI 40, 48) more etanercept claims, and 50 (95% CI 47, 53) more adalimumab claims. After November 2012, there were significant changes in the slopes for trend in usage, with additional increases in the use of branded and biosimilar infliximab (9 more claims per month, 95% CI 2, 17) and decreases in the use of etanercept (-52 claims per month, 95% CI -66, -38) and adalimumab (-21 claims per month, 95% CI -35, -6). During the first 15 months since its introduction in South Korea, one-fifth of all infliximab claims were for the biosimilar version. Introduction of biosimilar infliximab may affect the use of other TNF inhibitors, and the magnitude of change in usage will likely differ in other countries. © 2016, American College of Rheumatology.

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report.

PubMed

Gómez-Reino, Juan J; Carmona, Loreto; Valverde, Vicente Rodríguez; Mola, Emilio Martín; Montero, Maria Dolores

2003-08-01

The long-term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long-term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active-surveillance system following the commercialization of the drugs. We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti-TNF treatment. Seventy-one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January). Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.

Contextual factors influence work outcomes in employed patients with ankylosing spondylitis starting etanercept: 2-year results from AS@Work.

PubMed

Boonen, Annelies; Boone, Caroline; Albert, Adelin; Mielants, Herman

2018-05-01

The aim was to determine changes over time in work outcomes and investigate the predictive value of baseline personal and work-related factors on the evolution of work outcomes among employed patients with AS initiating etanercept. Employment status, absenteeism and presenteeism were assessed using the Work Productivity and Activity Impairment for AS questionnaire in a 24-month open-label, observational study (NCT01421303). The potential effect of baseline factors on work outcomes was analysed using predictive modelling (Cox regression and linear mixed models). After 24 months, 11/75 (14.7%) patients had permanently withdrawn from employment (seven because of AS). Absenteeism and presenteeism decreased significantly within 6 months of etanercept treatment and remained stable thereafter. Predictive modelling indicated that male sex (hazard ratio = 0.18; 95% CI: 0.04, 0.85), (log) number of working hours per week (hazard ratio = 0.13; 95% CI: 0.03, 0.51) and the possibility of developing skills (hazard ratio = 0.42; 95% CI: 0.19, 0.91) positively influenced time in employment. Over time, lower absenteeism was significantly associated with the quality of contact with colleagues [coefficient (s.e.): -0.35 (0.10)] and importance of the job for quality of life [-0.49 (0.17)], and higher absenteeism with current smoking [1.66 (0.44)] and change in job because of illness [1.51 (0.66)]. Over time, lower presenteeism was associated with male sex [-14.5 (2.64)], the possibility of postponing work [-6.60 (2.73)], quality of contact with colleagues [-2.04 (0.96)] and >50 workers in the company [-7.65 (2.76)], and higher presenteeism with manual profession [8.41 (2.72)]. Contextual factors influence work outcomes over time and should not be ignored when aiming to improve work outcomes in patients with AS. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01421303.

Discordance between patient and physician assessments of global disease activity in rheumatoid arthritis and association with work productivity.

PubMed

Smolen, Josef S; Strand, Vibeke; Koenig, Andrew S; Szumski, Annette; Kotak, Sameer; Jones, Thomas V

2016-05-21

Discordance between patient and physician ratings of rheumatoid arthritis (RA) severity occurs in clinical practice and correlates with pain scores and measurements of joint disease. However, information is lacking on whether discordance impacts patients' ability to work. We evaluated the discordance between patient and physician ratings of RA disease activity before and after treatment with etanercept and investigated the associations between discordance, clinical outcomes, and work productivity. In the PRESERVE clinical trial, patients with moderate RA received open-label etanercept 50 mg once weekly plus methotrexate for 36 weeks. Baseline and week-36 disease characteristics and clinical and work productivity outcomes were categorized according to week-36 concordance category, defined as positive discordance (patient global assessment - physician global assessment ≥2), negative discordance (patient global assessment - physician global assessment ≤ -2), and concordance (absolute difference between the two disease activity assessments = 0 or 1). Correlations between discordance, clinical outcomes, and predictors of discordance were determined. At baseline, 520/762 (68.2 %) patient and physician global assessment scores were concordant, 194 (25.5 %) were positively discordant, and 48 (6.3 %) were negatively discordant. After 36 weeks of therapy, 556/763 (72.9 %) scores were concordant, 189 (24.8 %) were positively discordant, and 18 (2.4 %) were negatively discordant. Patients with week-36 concordance had the best 36-week clinical and patient-reported outcomes, and overall, the greatest improvement between baseline and week 36. Baseline pain, swollen joint count, duration of morning stiffness, fatigue, and patient general health significantly correlated with week-36 discordance, p < 0.0001 to p < 0.05. Additionally, baseline pain, patient general health, and C-reactive protein were predictors of week-36 discordance (odds ratios 1.22, 1.02, and 0.98, respectively). For the employed patients, percent impairment while working and percent overall work impairment were highest (greatest impairment) at baseline and 36 weeks in the group with positive discordance. The percentage of patients with concordance increased after 36 weeks of treatment with etanercept, with concordant patients demonstrating the greatest improvement in clinical and patient-reported outcomes. Discordance correlated with several measures of disease activity and was associated with decreased work productivity. ClinicalTrials.gov identifier: NCT00565409 . Registered 28/11/2007.

Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy

PubMed Central

Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

2018-01-01

AIM: This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). METHODS: In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen’s method. RESULTS: Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no evidence of radiographic progression comparing to the group of patients with monotherapy. CONCLUSIONS: Based on our results achieved during 2 years we can conclude that ETN in combination with MTX reduced disease activity, slowed radiographic progression and improved clinical manifestations more effectively than MTX alone. No serious adverse events were noticed in the group with combination treatment. PMID:29875847

Evaluation of the Efficacy of Combined Therapy of Methotrexate and Etanercept versus Methotrexate as a Mono-Therapy.

PubMed

Rexhepi, Sylejman; Rexhepi, Mjellma; Rexhepi, Blerta; Sahatçiu-Meka, Vjollca; Mahmutaj, Vigan

2018-05-20

This study aims to evaluate the efficacy of Methotrexate (MTX) alone and combined therapy with Etanercept (ETN) and Methotrexate in patients with active rheumatoid arthritis (RA). In the randomised control study, conducted in the period from March 2014 until March 2016, we evaluated the efficacy of the treatment of patients with RA with MTX as monotherapy and combination treatment with MTX and ETN. In the Clinic of Rheumatology in Prishtina, 90 adult patients with RA were treated in combination with ETN (doses of 50 mg subcutaneously/weekly), with oral MTX (doses up to 20 mg weekly), and MTX alone (doses up to 20 mg weekly) during this period of two years. Clinical response was assessed using European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) Criteria and the Disease Activity Score (DAS28). Radiographic changes were measured in the beginning and at the end of the study using Larsen's method. Of the cohort groups of 90 patients, mean age of 55.63, 15 patients, (16.6 %) were treated with combined therapy (ETN plus MTX) and 75 patients (83.3%) with monotherapy (MTX). After two years of treatment the group with combined therapy resulted with improvement of acute phase reactants as erythrocyte sedimentation rate (ESR) for the first hour (41.1 vs. 10.3 mm/hour) and C - reactive protein (CRP) (40.8 vs. 6 mg/liter), and compared to the group treated with monotherapy, there were no significant changes (ESR: 45.7 vs 34.3 mm/hour; CRP: 48 vs 24 mg/liter). Before the treatment, the severity of the disease was high, wherein the group with combined therapy DAS28 was 5.32, compared to the monotherapy group whom DAS28 was 5.90. After 2 years of treatment, we had significant changes in the results of DAS28, wherein the group treated with ETN plus MTX DAS28 was 2.12 ± 0.15, while in the group of patients treated with MTX DAS28 were 3.75 ± 0.39 (t = 13.03; df = 58; p < 0.0001). The group with combined therapy showed no evidence of radiographic progression comparing to the group of patients with monotherapy. Based on our results achieved during 2 years we can conclude that ETN in combination with MTX reduced disease activity, slowed radiographic progression and improved clinical manifestations more effectively than MTX alone. No serious adverse events were noticed in the group with combination treatment.

New antirheumatic drugs: any real added value? A critical overview of regulatory criteria for their marketing approval.

PubMed

Bertele', Vittorio; Assisi, Alessandro; Di Muzio, Valeria; Renzo, Danila; Garattini, Silvio

2007-09-01

Rheumatoid arthritis (RA) is a systemic autoimmune disorder causing chronic polyarticular synovial inflammation and progressive joint damage. New anti-rheumatic drugs, such as leflunomide, infliximab, etanercept, adalimumab and anakinra, have recently become available. The aim of this paper is to summarize and critically evaluate the type of studies and clinical endpoints accepted by the European Medicines Agency (EMEA) to approve these new drugs. Information regarding the approval of antirheumatic drugs was obtained from European Public Assessment Reports (EPARs) and published pivotal studies. Leflunomide is the only non-biological disease-modifying anti-rheumatic drug (DMARD) to receive recent approval for RA treatment, but strong evidence of its superiority over conventional therapies is lacking. Anakinra in combination with methotrexate received approval as a DMARD for RA on the basis of two pivotal trials in which American College of Rheumatology response criteria (ACR 20 response) were used as the sole primary endpoint. For easier demonstration of efficacy, studies leading to first approval of etanercept, infliximab and adalimumab were carried out on non-responders to DMARDs. Once on the market, these drugs gained an extension of the indication to methotrexate-naïve patients. Studies that provided the basis for approval were not adequately designed, given the lack of an active control and the choice of ACR response as the only clinical endpoint. Consequently, only a weak proof of efficacy emerged for the treatment of signs and symptoms of RA, and these drugs failed to show real benefit in slowing radiographic progression. Serious infections, changes in blood cell counts, severe skin and hepatic infections were the main adverse events that emerged from the clinical studies. Therefore, the unconvincing benefit of the new antirheumatic drugs can scarcely outweigh the risk associated with their use. Moreover, the monthly costs in Italy of the new biological preparations are several fold higher than those of the reference drugs. Recently approved anti-RA products should be a therapeutic option only for patients refractory to conventional drugs.

76 FR 80332 - Foreign-Trade Zone 7-Mayaguez, PR, Expansion of Manufacturing Authority; Amgen Manufacturing...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-23

... approved by the Board in 2008 for the manufacture of epogen[reg] (epoetin alfa), neupogen[reg] (filgrastim), aransep[reg] (darbepoetin alfa), enbrel[reg] (etanercept), kineret[reg] (anakinra), and neulasta[reg...

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

PubMed Central

Benucci, M; Saviola, G; Baiardi, P; Manfredi, M; Sarzi Puttini, P; Atzeni, Fabiola

2012-01-01

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence. PMID:22655000

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study.

PubMed

Maksymowych, Walter P; Dougados, Maxime; van der Heijde, Désirée; Sieper, Joachim; Braun, Jürgen; Citera, Gustavo; Van den Bosch, Filip; Logeart, Isabelle; Wajdula, Joseph; Jones, Heather; Marshall, Lisa; Bonin, Randi; Pedersen, Ron; Vlahos, Bonnie; Kotak, Sameer; Bukowski, Jack F

2016-07-01

To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks. NCT01258738. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

[Cost-minimization analysis of subcutaneous abatacept in the treatment of rheumatoid arthritis in Spain].

PubMed

Ariza, R; Van Walsem, A; Canal, C; Roldán, C; Betegón, L; Oyagüez, I; Janssen, K

2014-07-01

To compare the cost of treating rheumatoid arthritis patients that have failed an initial treatment with methotrexate, with subcutaneous abatacept versus other first-line biologic disease-modifying antirheumatic drugs. Subcutaneous abatacept was considered comparable to intravenous abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab and tocilizumab, based on indirect comparison using mixed treatment analysis. A cost-minimization analysis was therefore considered appropriate. The Spanish Health System perspective and a 3 year time horizon were selected. Pharmaceutical and administration costs (Euros 2013) of all available first-line biological disease-modifying antirheumatic drugs were considered. Administration costs were obtained from a local costs database. Patients were considered to have a weight of 70 kg. A 3% annual discount rate was applied. Deterministic and probabilistic sensitivity analyses were performed. Subcutaneous abatacept proved in the base case to be less costly than all other biologic antirrheumatic drugs (ranging from Euros -831.42 to Euros -9,741.69 versus infliximab and tocilizumab, respectively). Subcutaneous abatacept was associated with a cost of Euros 10,760.41 per patient during the first year of treatment and Euros 10,261.29 in subsequent years. The total 3-year cost of subcutaneous abatacept was Euros 29,953.89 per patient. Sensitivity analyses proved the model to be robust. Subcutaneous abatacept remained cost-saving in 100% of probabilistic sensitivity analysis simulations versus adalimumab, certolizumab, etanercept and golimumab, in more than 99.6% versus intravenous abatacept and tocilizumab and in 62.3% versus infliximab. Treatment with subcutaneous abatacept is cost-saving versus intravenous abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab and tocilizumab in the management of rheumatoid arthritis patients initiating treatment with biological antirheumatic drugs. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor.

PubMed

Zhou, Qing-Hui; Sumbria, Rachita; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang; Boado, Ruben J; Pardridge, William M

2011-11-01

Biologic tumor necrosis factor (TNF)-α inhibitors do not cross the blood-brain barrier (BBB). A BBB-penetrating TNF-α inhibitor was engineered by fusion of the extracellular domain of the type II human TNF receptor (TNFR) to the carboxyl terminus of the heavy chain of a mouse/rat chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb-TNFR fusion protein and etanercept bound human TNF-α with high affinity and K(D) values of 374 ± 77 and 280 ± 80 pM, respectively. Neuroprotection in brain in vivo after intravenous administration of the fusion protein was examined in a mouse model of Parkinson's disease. Mice were also treated with saline or a non-BBB-penetrating TNF decoy receptor, etanercept. After intracerebral injection of the nigral-striatal toxin, 6-hydroxydopamine, mice were treated every other day for 3 weeks. Treatment with the cTfRMAb-TNFR fusion protein caused an 83% decrease in apomorphine-induced rotation, a 67% decrease in amphetamine-induced rotation, a 82% increase in vibrissae-elicited forelimb placing, and a 130% increase in striatal tyrosine hydroxylase (TH) enzyme activity. In contrast, chronic treatment with etanercept, which does not cross the BBB, had no effect on neurobehavior or striatal TH enzyme activity. A bridging enzyme-linked immunosorbent assay specific for the cTfRMAb-TNFR fusion protein showed that the immune response generated in the mice was low titer. In conclusion, a biologic TNF inhibitor is neuroprotective after intravenous administration in a mouse model of neurodegeneration, providing that the TNF decoy receptor is reengineered to cross the BBB.

The Canadian Methotrexate and Etanercept Outcome Study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis

PubMed Central

Pope, Janet E; Haraoui, Boulos; Thorne, J Carter; Vieira, Andrew; Poulin-Costello, Melanie; Keystone, Edward C

2014-01-01

Objective To determine if withdrawing methotrexate (MTX) after 6 months of combination etanercept (ETN)+MTX, in MTX-inadequate responders with active rheumatoid arthritis (RA), is non-inferior to continuing ETN+MTX. Methods Tumour necrosis factor-inhibitor naïve RA patients with disease activity score 28 (DAS28)≥3.2, swollen joint count≥3, despite stable MTX, were treated with ETN+MTX for 6 months, followed by randomisation to either continue ETN+MTX or switch to ETN monotherapy for an additional 18 months. The primary endpoint was change in DAS28 from 6-month randomisation to 12 months. The non-inferiority margin of change in DAS28 was 0.6, with prespecified analyses (DAS28<3.2 vs DAS28≥3.2). Results 205 patients were randomised. DAS28 was stable in patients on ETN+MTX and increased slightly in patients on ETN monotherapy from 6 to 12 months. Non-inferiority was not achieved, with an adjusted difference of 0.4 (0.1 to 0.7) between the ETN and the ETN+MTX groups, for the month 6–12 change in DAS28. However, patients who achieved low disease activity (LDA; DAS28<3.2) at 6 months had a similar disease activity at 12 months, whether on monotherapy or combination therapy (DAS28 change 0.7 ETN vs 0.57 ETN+MTX, p=0.8148). Conversely, for patients who did not reach LDA at 6 months, those on ETN monotherapy had increased disease activity at 12 months, while disease activity continued to decrease for patients on combination therapy, at 12 months (DAS28 change 0.4 ETN vs −0.4 ETN+MTX, p=0.0023). Conclusions Non-inferiority was not achieved. Withdrawing MTX after 6 months of continuation ETN+MTX in MTX inadequate responders did not yield the same degree of improvement between 6 and 12 months compared with continuing ETN+MTX. Trial Registration ClinicalTrials.gov−NCT00654368. PMID:23979914

Tumor necrosis factor-α enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling.

PubMed

Scherer, Elias Q; Yang, Jingli; Canis, Martin; Reimann, Katrin; Ivanov, Karolina; Diehl, Christian D; Backx, Peter H; Wier, W Gil; Strieth, Sebastian; Wangemann, Philine; Voigtlaender-Bolz, Julia; Lidington, Darcy; Bolz, Steffen-Sebastian

2010-11-01

We sought to demonstrate that tumor necrosis factor (TNF)-α, via sphingosine-1-phosphate signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. We performed intravital fluorescence microscopy to measure blood flow and capillary diameter in anesthetized guinea pigs. To measure capillary diameter ex vivo, capillary beds from the gerbil spiral ligament were isolated from the cochlear lateral wall and maintained in an organ bath. Isolated gerbil spiral modiolar arteries, maintained and transfected in organ culture, were used to measure calcium sensitivity (calcium-tone relationship). In a clinical study, a total of 12 adult patients presenting with typical symptoms of sudden hearing loss who were not responsive or only partially responsive to prednisolone treatment were identified and selected for etanercept treatment. Etanercept (25 mg s.c.) was self-administered twice a week for 12 weeks. TNF-α induced a proconstrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing sphingosine-1-phosphate receptor 2 subtype signaling (by 1 μmol/L JTE013) attenuated the effects of TNF-α in all models. TNF-α activated sphingosine kinase 1 (Sk1) and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1(G82D)) eliminated both baseline spiral modiolar artery calcium sensitivity and TNF-α effects, whereas a nonphosphorylatable Sk1 mutant (Sk1(S225A)) blocked the effects of TNF-α only. A small group of etanercept-treated, hearing loss patients recovered according to a 1-phase exponential decay (half-life=1.56 ± 0.20 weeks), which matched the kinetics predicted for a vascular origin. TNF-α indeed reduces cochlear blood flow via activation of vascular sphingosine-1-phosphate signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis, and treatment.

Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70

PubMed Central

Orme, Michelle E; MacGilchrist, Katherine S; Mitchell, Stephen; Spurden, Dean; Bird, Alex

2012-01-01

Background Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate. Methods Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks’ follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data. Results The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-α inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results. Conclusion Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-α inhibitor combination therapies are not equally effective. PMID:23269860

Evaluation of Health Outcomes with Etanercept Treatment in Patients with Early Nonradiographic Axial Spondyloarthritis.

PubMed

Dougados, Maxime; Tsai, Wen-Chan; Saaibi, Diego L; Bonin, Randi; Bukowski, Jack; Pedersen, Ron; Vlahos, Bonnie; Kotak, Sameer

2015-10-01

Analyses were conducted to examine the baseline burden of illness and compare the effect of etanercept (ETN) versus placebo (PBO) on quality of life (QOL) in patients with nonradiographic axial spondyloarthritis (nr-axSpA) who failed nonsteroidal antiinflammatory drugs (NSAID). Patients fulfilling the Assessment of Spondyloarthritis International Society axSpA criteria, not meeting the modified New York criteria for ankylosing spondylitis (AS), who were symptomatic 3 months to 5 years, with a Bath AS Disease Activity Index score ≥ 4, and failed ≥ 2 NSAID were randomized to ETN 50 mg weekly or PBO (double-blind) for 12 weeks, followed by open-label ETN 50 mg for 92 weeks. Stable NSAID were allowed throughout our study. QOL outcomes over 24 weeks were analyzed using ANCOVA models. At baseline, Multidimensional Fatigue Inventory (MFI; ETN mean 14.7, PBO mean 15.0), EQ-5D utility (0.52, 0.57), EQ-5D visual analog scale (56.5, 56.4), and Medical Outcomes Study (MOS) Sleep Index II (45.5, 48.1) were worse than population norms (6.6-8.0, 0.86, 82.5, and 25.8, respectively). At Week 12, Bath AS Patient Global Score, nocturnal and average back pain, MOS Short Form-36 (SF-36) physical component, and Work Productivity and Activity Index (WPAI) presenteeism and activity impairment favored ETN (p < 0.05). Nonsignificant improvements for ETN were seen in other WPAI domains, MFI, MOS-Sleep Index I and II, Hospital Anxiety and Depression Scale, EQ-5D utility score, and SF-36 mental component (p > 0.05). At Week 24, patients in the PBO group who had switched to ETN at Week 12 showed improvement in most QOL assessments, similar to that seen in patients receiving ETN for 24 weeks. Improvements favored ETN in QOL and productivity measures, with limited improvement on general QOL measures. Short disease duration, a short PBO-controlled period, and a wide range of QOL scores at baseline may have influenced improvements.

Efficacy and Safety Outcomes for Originator TNF Inhibitors and Biosimilars in Rheumatoid Arthritis and Psoriasis Trials: A Systematic Literature Review.

PubMed

Moots, Robert J; Curiale, Cinzia; Petersel, Danielle; Rolland, Catherine; Jones, Heather; Mysler, Eduardo

2018-05-22

Regulatory approval of biosimilar versions of originator biotherapeutics requires that new biological products be highly similar to originator products, with no clinically meaningful differences in safety, purity, and potency. In some trials of biosimilars of tumor necrosis factor inhibitors for the treatment of rheumatoid arthritis (RA) and plaque psoriasis (PsO), pre-specified margins for efficacy and safety have been met, but differences in treatment responses between pivotal originator trials and biosimilar trials have been noted. The objective of this systematic review was to examine these differences. Searches were conducted to identify comparative randomized clinical trials of approved or proposed biosimilars of adalimumab, etanercept, and infliximab. Of 83 publications identified, 16 publications were included for analysis (RA: originators, n = 5; biosimilars, n = 6; PsO: originators, n = 2; biosimilars, n = 3). American College of Rheumatology 20% response rates were higher among patients with RA receiving originator biologics and biosimilars in biosimilar trials than among patients receiving the originator biologics in pivotal trials. In etanercept studies in PsO, a difference was observed in Psoriasis Area and Severity Index 75% response rates between biosimilar and pivotal trials. Insufficient efficacy data were available from adalimumab and infliximab biosimilar studies in PsO to determine any differences in treatment responses between pivotal and biosimilar studies. Observed differences in treatment response rates between pivotal originator trials and trials of originator biologics and their respective biosimilars may be attributable to fundamental differences in study design and/or baseline patient characteristics, which require further analysis.

Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor-negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication.

PubMed

Aquilani, Angela; Pires Marafon, Denise; Marasco, Emiliano; Nicolai, Rebecca; Messia, Virginia; Perfetti, Francesca; Magni-Manzoni, Silvia; De Benedetti, Fabrizio

2018-05-01

To evaluate the rate of flare after etanercept (ETN) withdrawal in patients with juvenile idiopathic arthritis (JIA) who attained clinical remission while taking medication, and to identify predictors of flare. Patients were included with oligo- (oJIA) and rheumatoid factor-negative polyarticular JIA (pJIA) who received a first course of ETN for at least 18 months, maintained clinically inactive disease (CID) for at least 6 months during treatment, and were followed for 12 months after ETN withdrawal. Demographic and clinical features were collected at onset, at baseline (initiation of ETN), and at time of disease flare. After ETN withdrawal, 66 of the 110 patients enrolled (60%) flared with arthritis (of whom 7 flared with concurrent anterior uveitis; none with uveitis alone). The median time to flare was 4.3 months (interquartile range 2.5-6.4) with no evident differences between oJIA and pJIA. The number and type of joints involved at baseline and characteristics of ETN treatment/discontinuation were not associated with flare. Patients who flared were more frequently males (p = 0.034), positive for antinuclear antibody (ANA; p = 0.047), and had higher values of C-reactive protein (CRP; p = 0.012) at baseline. These variables remained significantly associated with flare in a multivariate logistic analysis, a model accounting for only 14% of the variability of the occurrence of the flare. Our results show that a significant proportion of patients with JIA who maintain CID for at least 6 months experience a relapse after ETN withdrawal. Male sex, presence of ANA, and elevated CRP at baseline were associated with higher risk of flare.

Pharmacology of biosimilar candidate drugs in rheumatology: a literature review.

PubMed

Araújo, F; Cordeiro, I; Teixeira, F; Gonçalves, J; Fonseca, J E

2014-01-01

To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis.

Cost per responder of TNF-α therapies in Germany.

PubMed

Gissel, Christian; Repp, Holger

2013-12-01

Tumor necrosis factor α (TNF-α) inhibitors ranked highest in German pharmaceutical expenditure in 2011. Their most important application is the treatment of rheumatoid arthritis (RA). Our objective is to analyze cost per responder of TNF-α inhibitors for RA from the German Statutory Health Insurance funds' perspective. We aim to conduct the analysis based on randomized comparative effectiveness studies of the relevant treatments for the German setting. For inclusion of effectiveness studies, we require results in terms of response rates as defined by European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) criteria. We identify conventional triple therapy as the relevant comparator. We calculate cost per responder based on German direct medical costs. Direct clinical comparisons could be identified for both etanercept and infliximab compared to triple therapy. For infliximab, cost per responder was 216,392 euros for ACR50 and 432,784 euros for ACR70 responses. For etanercept, cost per ACR70 responder was 321,527 euros. Cost was lower for response defined by EULAR criteria, but data was only available for infliximab. Cost per responder is overestimated by 40% due to inclusion of taxes and mandatory rebates in German drugs' list prices. Our analysis shows specific requirements for cost-effectiveness analysis in Germany. Cost per responder for TNF-α treatment in the German setting is more than double the cost estimated in a similar analysis for the USA, which measured against placebo. The difference in results shows the critical role of the correct comparator for a specific setting.

Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

PubMed Central

2011-01-01

Introduction The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice. Methods The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents. Results A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001). Conclusions The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection. PMID:21745378

Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report.

PubMed

Shakiba, Khashayar; Falcone, Tommaso

2006-09-01

Several studies have shown that tumour necrosis factor (TNF)-alpha levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF-alpha concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids' TNF-alpha levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF-alpha receptor immunoglobulin fusion protein which inhibits TNF-alpha activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF-alpha blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF-alpha-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF-alpha showed no effect on infertility. However, use of TNF-alpha-blockers before IVF might increase the success rate in advanced endometriosis.

[Importance of the new biologicals and cytokine antagonists in the treatment of juvenile idiopathic arthritis (JIA)].

PubMed

Horneff, G

2005-06-01

Juvenile idiopathic arthritis is group of diseases of unknown aetiology characterised by the occurrence of chronic arthritis during childhood. Compared to adult onset rheumatoid arthritis, its course is more variable. Increasing knowledge of the inflammatory process as well as in molecular genetics and biotechnology has enable the production of new drugs, the biologicals. These are able to specifically block mechanisms of immune activation and thereby interfere with the inflammatory process. An increasing number of biologicals have been tried in clinical studies in adults suffering from rheumatoid arthritis, psoriasis or psoriasis arthritis and a couple of them were already licensed for treatment. Treatment of juvenile idiopathic arthritis by blockade of tumournecrosis-factor (TNF) using the soluble receptor Etanercept or the monoclonal antibodies Infliximab and Adalimumab showed comparable clinical efficacy. Blockade of TNF therefore already reached a certain place in the therapeutic algorythm for treatment of juvenile idiopathic arthritis. Currently, only Etanercept is licensed for treatment of active juvenile polyarthritis refractory to methotrexate. Studies using Infliximab and Adalimumab will be completed in the near future. However, antibodies blocking TNF may already be used in patients suffering from active uncontrolled chronic uveitis in whom visual impairment is threatening. TNF blockers may also be indicated in juvenile ankylosing spondylitis. The use of further biologicals, the interleukin-1 receptor antagonist Anakinra, Atlizumab (MRA) blocking the receptor for interleukin-6 or Abatacept, an inhibitory ligand of the co-stimulatory T cell membrane molecule CD28, remain experimental and should be preserved for clinical studies.

Long-term survival of subcutaneous anti-tumor necrosis factor biological drugs administered between 2008 and 2012 in a cohort of rheumatoid arthritis patients.

PubMed

Alvarez Rivas, Noelia; Vazquez Rodriguez, Tomas R; Miranda Filloy, Jose A; Garcia-Porrua, Carlos; Sanchez-Andrade Fernández, Amalia

2017-05-25

To compare the survival of subcutaneous anti-tumor necrosis factor (TNF) drugs used between 2008 and 2012 prescribed in accordance with clinical practice. Retrospective, observational study of the patients in our center diagnosed with rheumatoid arthritis (RA). We included patients who had received a subcutaneous anti-TNF agent for at least 6 months. The data were analyzed using the SPSS V17.0 statistical package. Forty-nine RA patients started subcutaneous biological treatment with an anti-TNF agent (32 with etanercept and 17 with adalimumab). The mean age was 45.94 years (75.5% female). The mean disease duration prior to starting anti-TNF administration was 2.67 years. The mean age at the start of treatment was 51.84 years, and the average Disease Activity Score 28 was 4.93. The median survival of the anti-TNF treatment was 8.40 years; the survival of etanercept was the longer of the two. The main reason for discontinuation was secondary failure (90.9%). In routine clinical practice, the survival of subcutaneous anti-TNF treatment was extensive and was independent of whether or not the patients received concomitant immunosuppressive therapy. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Changing patterns of tumor necrosis factor inhibitor use in 9074 patients with rheumatoid arthritis.

PubMed

Yazici, Yusuf; Krasnokutsky, Svetlana; Barnes, Jaime P; Hines, Patricia L; Wang, Jason; Rosenblatt, Lisa

2009-05-01

Patients with rheumatoid arthritis (RA) commonly switch between tumor necrosis factor (TNF) inhibitors after failing to control disease activity. Much of the clinical data that support switching to a second TNF agent when one agent fails to work has come from small, short-term studies. We utilized a US insurance claims database to determine patterns of use such as dose escalation, time to discontinuation, and switching between TNF inhibitors in patients with RA. A retrospective analysis was performed using an insurance claims database in the US from 2000 to 2005. TNF inhibitor use, time to switch, dose escalation, and continuation times were analyzed in patients with RA. Nine thousand seventy-four patients with RA started TNF inhibitors during the period 2000 to 2005. Etanercept was the most commonly used TNF inhibitor; infliximab had the highest duration of continuation, about 50% at 2 years. In addition, infliximab showed higher rates of dose escalation compared to etanercept and adalimumab. For all TNF inhibitors, time to switching decreased from 2000 to 2005. TNF inhibitor use patterns changed from 2000 to 2005, with more frequent changes among the different TNF inhibitors and a shorter duration of treatment before the change. Only about 50% of TNF inhibitors are still continued at 2 years, reflecting the difference between randomized clinical trials and real-world experience.

TNF-α gene polymorphisms: association with disease susceptibility and response to anti-TNF-α treatment in psoriatic arthritis.

PubMed

Murdaca, Giuseppe; Gulli, Rossella; Spanò, Francesca; Lantieri, Francesca; Burlando, Martina; Parodi, Aurora; Mandich, Paola; Puppo, Francesco

2014-10-01

The tumor necrosis factor-α (TNF-α) gene has been proposed as a major candidate gene in psoriatic arthritis (PsA). TNF-α is a therapeutic target for patients responding poorly to conventional treatments. We investigated the role of single-nucleotide polymorphisms (SNPs) at positions -238, -308, and +489 of the TNF-α gene in the genetic susceptibility to PsA, in the severity of the disease, and, finally, in the response to TNF-α inhibitors (adalimumab, etanercept, or infliximab). Fifty-seven Caucasian PsA patients and 155 healthy matched controls were studied. The SNP +489 variant allele A was significantly associated with PsA susceptibility (P=0.0136) and severity of clinical (Psoriasis Area and Severity Index score, American College of Rheumatology criteria, Disease Activity Score 28, and Disability Index Health Assessment Questionnaire) and laboratory (C-reactive protein and erythrocyte sedimentation rate) parameters (P-values ranging from 0.016 to 2.908 × 10(-12)). The difference in severity was accounted for by the differences between the AA and GA genotypes with respect to the GG genotype. The SNP +489A allele shows a trend of association with the response to PsA treatment with etanercept. These findings suggest a role of the SNP +489A allele in the susceptibility and severity of PsA.

Selective TNF-α inhibitor-induced injection site reactions.

PubMed

Murdaca, Giuseppe; Spanò, Francesca; Puppo, Francesco

2013-03-01

During the last decade, many new biological immune modulators entered the market as new therapeutic principles. TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases. TNF-α blockers have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs. Although generally well tolerated and safe, potential adverse events may be associated with TNF-α inhibitor treatment. The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions (ISRs) in patients treated with etanercept and adalimumab. Patients treated with TNF-α inhibitors can develop ISR around the sites of injections. 'Type IV delayed type reaction' or 'recall ISRs'. Eosinophilic cellulitis or 'Wells syndrome', 'type III' and 'type I' reactions are reported. Long-term studies are necessary to determine the durability of response and the real risk of ISRs with golimumab and certolizumab pegol. Further studies are also necessary to evaluate the immunogenicity of these drugs.

Optic neuritis occurring with anti‐tumour necrosis factor α therapy

PubMed Central

Simsek, Ismail; Erdem, Hakan; Pay, Salih; Sobaci, Gungor; Dinc, Ayhan

2007-01-01

Objective Various demyelinating disorders have been reported in association with anti‐tumour necrosis factor α (TNFα) agents. The objective of this study was to review the occurrence, clinical features and outcome of optic neuritis (ON) during treatment with anti‐TNFα agents. Methods A PubMed search was conducted to identify literature addressing the potential association between anti‐TNFα agents and ON, following our experience with a patient having rheumatoid arthritis in whom ON developed while being treated with infliximab. Results 15 patients including the case presented here with ON in whom the symptoms developed following TNFα antagonist therapy were evaluated. Eight of these patients had received infliximab, five had received etanercept and two patients had received adalimumab. Among them, nine patients experienced complete resolution, and two patients had partial resolution, while four patients continued to have symptoms. Discussion Patients being treated with a TNFα antagonist should be closely monitored for the development of ophthalmological or neurological signs and symptoms. Furthermore, consideration should be given to avoiding such therapies in patients with a history of demyelinating disease. If clinical evaluation leads to the diagnosis of ON, discontinuation of the medication and institution of steroid treatment should be a priority. PMID:17456525

A case of neurosarcoidosis secondary to treatment of etanercept and review of the literature.

PubMed

Berrios, Idanis; Jun-O'Connell, Adalia; Ghiran, Sorina; Ionete, Carolina

2015-07-06

There are only three cases in the literature that describe development of neurosarcoidosis in a patient who is on tumour necrosis factor α inhibitors. We describe a case of a 33-year-old woman with a history of juvenile rheumatoid arthritis and refractory uveitis (with previous treatment trials of adalimumab, infliximab, mycophenolate, methotrexate) who had been stable for 2 years on etanercept. She was diagnosed with biopsy-proven systemic sarcoidosis with meningeal and parenchymal neurosarcoidosis. She was switched to infliximab and methotrexate, with clinical and imaging improvements. This is a case that demonstrates the difficulty of choosing tumour necrosis factor α (TNF-α) inhibitors when treating patients with multiple clinical autoimmune entities. It is also a case where a change in the mechanism of TNF-α inhibition pathway can still be used to treat refractory sarcoidoisis and rheumatoid arthritis. It is still unclear what the exact difference between the TNF-α blockers and their neurological complications is, and who the patients at risk of developing neurological complications are. 2015 BMJ Publishing Group Ltd.

[Immunogenicity of biosimilars].

PubMed

van Aerts, L A G J M; Franken, A A M; Leufkens, H G M

2016-01-01

Biosimilars of more complex recombinant protein drugs, such as monoclonal antibodies and fusion proteins, are entering the market. The manufacturer should demonstrate that its product does not show any relevant differences in terms of quality characteristics, biological activity, safety and efficacy compared to the reference product, as outlined in EMA guidelines. This should be established with an extensive comparability exercise. One aspect that is subject to particular scrutiny is the immunogenicity of the biosimilar and the reference medicinal product. For three cases, one etanercept and two infliximab biosimilars, we describe how data are assessed and an opinion is reached by authorities. Not in all cases unanimity exists whether all remaining uncertainties on biosimilarity have been resolved satisfactorily before marketing authorisation. The Dutch Medicines Evaluation Board therefore emphasises that even after marketing authorisation, biosimilars and other biologicals should be properly monitored.

Use of a validated algorithm to estimate the annual cost of effective biologic treatment for rheumatoid arthritis.

PubMed

Curtis, Jeffrey R; Schabert, Vernon F; Yeaw, Jason; Korn, Jonathan R; Quach, Caroleen; Harrison, David J; Yun, Huifeng; Joseph, George J; Collier, David

2014-08-01

To estimate biologic cost per effectively treated patient with rheumatoid arthritis (RA) using a claims-based algorithm for effectiveness. Patients with RA aged 18-63 years in the IMS PharMetrics Plus database were categorized as effectively treated if they met all six criteria: (1) a medication possession ratio ≥80% (subcutaneous) or at least as many infusions as specified in US labeling (intravenous); (2) no biologic dose increase; (3) no biologic switch; (4) no new non-biologic disease-modifying anti-rheumatic drug; (5) no new or increased oral glucocorticoid; and (6) ≤1 glucocorticoid injection. Biologic cost per effectively treated patient was defined as total cost of the index biologic (drug plus intravenous administration) divided by the number of patients categorized by the algorithm as effectively treated. Similar methods were used for the index biologic in the second year and for a second biologic after a switch. Rates that the index biologic was categorized as effective in the first year were 31.0% etanercept (2243/7247), 28.6% adalimumab (1426/4991), 28.6% abatacept (332/1160), 27.2% golimumab (71/261), and 20.2% infliximab (474/2352). Mean biologic cost per effectively treated patient, per the algorithm, was $50,141 etanercept, $53,386 golimumab, $56,942 adalimumab, $73,516 abatacept, and $114,089 infliximab. Biologic cost per effectively treated patient, using this algorithm, was lower for patients who continued the index biologic in the second year and higher after switching. When a claims-based algorithm was applied to a large commercial claims database, etanercept was categorized as the most effective and had the lowest estimated 1-year biologic cost per effectively treated patient. This proxy for effectiveness from claims databases was validated against a clinical effectiveness scale, but analyses of the second year or the year after a biologic switch were not included in the validation. Costs of other medications were not included in cost calculations.

Estimating effectiveness and cost of biologics for rheumatoid arthritis: application of a validated algorithm to commercial insurance claims.

PubMed

Curtis, Jeffrey R; Schabert, Vernon F; Harrison, David J; Yeaw, Jason; Korn, Jonathan R; Quach, Caroleen; Yun, Huifeng; Joseph, George J; Collier, David H

2014-07-01

The aim of this analysis was to implement a claims-based algorithm to estimate biologic cost per effectively treated patient for biologics approved for moderate to severe rheumatoid arthritis (RA). This retrospective analysis included commercially insured adults (aged 18-63 years) with RA in a commercial database, who initiated biologic treatment with abatacept, adalimumab, etanercept, golimumab, or infliximab between 2007 and 2010. The algorithm defined effectiveness as having all of the following: high adherence, no biologic dose increase, no biologic switching, no new nonbiologic disease-modifying antirheumatic drug, no increased or new oral glucocorticoid use, and no more than 1 glucocorticoid injection. For each biologic, cost per effectively treated patient was defined as total drug and administration costs (from allowed amounts on claims), divided by the number of patients categorized as effectively treated. Of 15,351 patients, 12,018 (78.3%) were women, and the mean (SD) age was 49.7 (9.6) years. The algorithm categorized treatment as effective in the first year for 30% (1899/6374) of etanercept, 30% (1396/4661) of adalimumab, 20% (560/2765) of infliximab, 27% (361/1338) of abatacept, and 29% (62/213) of golimumab treated patients. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was nominally lower for subcutaneously injected biologics than for infused biologics. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was lowest for etanercept ($49,952), followed by golimumab ($50,189), adalimumab ($52,858), abatacept ($71,866), and infliximab ($104,333). Algorithm-defined effectiveness was similar for biologics other than infliximab. The 1-year biologic cost per effectively treated patient, as defined by the algorithm, was nominally lower for subcutaneously injected biologics than for infused biologics. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Cost and effectiveness of biologics for rheumatoid arthritis in a commercially insured population.

PubMed

Curtis, Jeffrey R; Chastek, Benjamin; Becker, Laura; Quach, Caroleen; Harrison, David J; Yun, Huifeng; Joseph, George J; Collier, David H

2015-04-01

Administrative claims contain detailed medication, diagnosis, and procedure data, but the lack of clinical outcomes for rheumatoid arthritis (RA) historically has limited their use in comparative effectiveness research. A claims-based algorithm was developed and validated to estimate effectiveness for RA from data for adherence, dosing, and treatment modifications. To implement the claims-based algorithm in a U.S. managed care database to estimate biologic cost per effectively treated patient. The cohort included patients with RA aged 18-63 years in the Optum Research Database who initiated biologic treatment between January 2007 and December 2010 and were continuously enrolled 6 months before through 12 months after the first claim for the biologic (the index date). Patients were categorized as effectively treated by the claims-based algorithm if they met all of the following 6 criteria in the 12-month post-index period: (1) a medication possession ratio ≥ 80% for subcutaneous biologics, or at least as many infusions as specified in U.S. labeling for intravenous biologics; (2) no increase in biologic dose; (3) no switch in biologics; (4) no new nonbiologic disease-modifying antirheumatic drug; (5) no new or increased oral glucocorticoid treatment; and (6) no more than 1 glucocorticoid injection. Drug costs (all biologics) and administration costs (intravenous biologics) were obtained from allowed amounts on claims. Biologic cost per effectively treated patient was defined as total 1-year biologic cost divided by the number of patients categorized by the algorithm as effectively treated with that index biologic. Sensitivity analysis was conducted to examine the total health care costs per effectively treated patient during the first year of biologic therapy. A total of 5,474 individuals were included in the analysis. The index biologic was categorized as effective by the algorithm for 28.9% of patients overall, including 30.6% for subcutaneous biologics and 22.1% for intravenous biologics. The index biologic was categorized as effective in the first year for 32.7% of etanercept (794/2,425), 32.3% of golimumab (40/124), 30.2% of abatacept (89/295), 27.7% of adalimumab (514/1,857), and 19.0% of infliximab (147/773) patients. Mean 1-year biologic cost per effectively treated patient, as defined in the algorithm, was lowest for etanercept ($43,935), followed by golimumab ($49,589), adalimumab ($52,752), abatacept ($62,300), and infliximab ($101,402). The rank order in the sensitivity analysis was the same, except for golimumab and etanercept.  Using a claims-based algorithm in a large commercial claims database, etanercept was the most effective and had the lowest biologic cost per effectively treated patient with RA.

Niclosamide as an adjuvant to etanercept in treatment patients with active rheumatoid arthritis: an 8-week randomized controlled pilot study.

PubMed

Al-Gareeb, Ali Ismail A; Gorial, Faiq Isho; Mahmood, Ahmed S

2018-06-07

This study designed to identify the therapeutic efficacy of niclosamide (NCL) in Iraqi patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA. One hundred ten patients suffering from active rheumatoid arthritis (RA) who were using etanercept (ETN) for more than 3 months and still had high or moderate active RA were allocated randomly into two equal groups: one of them treated with 1000 mg/day NCL and the other treated with 1000 mg/day lactose in capsule dosage form. The study duration was 8 weeks. Clinical efficacy of the NCL was measured depending on scoring of the 28-joint Disease Activity Score (DAS28), simple disease activity index (SDAI), clinical disease activity index (CDAI), and Health Assessment Questionnaire Disability Index (HAQ-DI) at the baseline and at the end of the 8-week treatment period. Moreover, blood sample were taken from the patients at baseline and at after 8 weeks of treatment for measurement of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin 1β (IL-1 β), interleukin-6, tumor necrosis factor (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. At the end of the clinical study, patients had good response to NCL when added to the ETN with a high significant improvement in the SJC, TJC, DAS-28, CDAI, SDAI, and HAQ-DI compared to patients who were received placebo drug. In addition to that, 33% of patients achieved an ACR 20% response (ACR20) on NCL and ETN. Of these, 4% achieved ACR50 and another 4% achieved ACR70 response. While those group treated by placebo + ETN, 5% achieved ACR20 response and no one reached to ACR50 or ACR70 response. Twenty-seven percent of RA patients who have taken the NCL achieved moderate EULAR score while only 17% from the group that taken placebo with ETN achieved moderate response. On the other hand, no significant reduction was found in CRP, ESR, TNF-α, and IL-6, while IL-1 β reduced significantly after treatment with NCL. Treatment with NCL also exerts a significant lowering in the serum level of the E-selectin, ICAM1, and VCAM1 when compared to their value in baseline level. In RA disease, the use of NCL as adjuvant with ETN has resulted in a marked reduction in clinical assessment scoring indices and significantly decreased the E-selectin, ICAM-1, and VCAM-1 with marked improvement in the quality of life of patients.

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study.

PubMed

Moots, Robert J; Xavier, Ricardo M; Mok, Chi Chiu; Rahman, Mahboob U; Tsai, Wen-Chan; Al-Maini, Mustafa H; Pavelka, Karel; Mahgoub, Ehab; Kotak, Sameer; Korth-Bradley, Joan; Pedersen, Ron; Mele, Linda; Shen, Qi; Vlahos, Bonnie

2017-01-01

To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. This study was registered on www.ClinicalTrials.gov (NCT01981473).

Analytical ultracentrifugation with fluorescence detection system reveals differences in complex formation between recombinant human TNF and different biological TNF antagonists in various environments

PubMed Central

Krayukhina, Elena; Noda, Masanori; Ishii, Kentaro; Maruno, Takahiro; Wakabayashi, Hirotsugu; Tada, Minoru; Suzuki, Takuo; Ishii-Watabe, Akiko; Kato, Masahiko; Uchiyama, Susumu

2017-01-01

ABSTRACT A number of studies have attempted to elucidate the binding mechanism between tumor necrosis factor (TNF) and clinically relevant antagonists. None of these studies, however, have been conducted as close as possible to physiologic conditions, and so the relationship between the size distribution of TNF-antagonist complexes and the antagonists' biological activity or adverse effects remains elusive. Here, we characterized the binding stoichiometry and sizes of soluble TNF-antagonist complexes for adalimumab, infliximab, and etanercept that were formed in human serum and in phosphate-buffered saline (PBS). Fluorescence-detected sedimentation velocity analytical ultracentrifugation analyses revealed that adalimumab and infliximab formed a range of complexes with TNF, with the major complexes consisting of 3 molcules of the respective antagonist and one or 2 molcules of TNF. Considerably greater amounts of high-molecular-weight complexes were detected for infliximab in human serum. The emergence of peaks with higher sedimentation coefficients than the adalimumab monomer as a function of added human serum albumin (HSA) concentration in PBS suggested weak reversible interactions between HSA and immunoglobulins. Etanerept exclusively formed 1:1 complexes with TNF in PBS, and a small amount of complexes with higher stoichiometry was detected in human serum. Consistent with these biophysical characterizations, a reporter assay showed that adalimumab and infliximab, but not etanercept, exerted FcγRIIa- and FcγRIIIa-mediated cell signaling in the presence of TNF and that infliximab exhibited higher potency than adalimumab. This study shows that assessing distribution profiles in serum will contribute to a more comprehensive understanding of the in vivo behavior of therapeutic proteins. PMID:28387583

Minimum effective dosages of anti-TNF in rheumatoid arthritis: a cross-sectional study.

PubMed

de la Torre, Inmaculada; Valor, Lara; Nieto, Juan Carlos; Montoro, María; Carreño, Luis

2014-01-01

To evaluate the modified dosages of anti-TNF in controlling disease activity in rheumatoid arthritis (RA) measured by DAS28-ESR. Cross-sectional study: RA patients treated with etanercept (ETN), adalimumab (ADA) or infliximab (IFX), at standard or modified doses. dosage, concomitant disease modifying drugs (DMARDs), DAS28-ESR. 195 RA patients included (79% women, mean age 58.1 years): ETN=81, ADA=56, IFX=58. Mean disease duration and time to first biological treatment was higher in IFX group (P=.01). Patients distribution by dosage: standard: ETN (72.8%), ADA (69.6%), IFX (27.6%); escalated: IFX (69%), ADA (5.4%), ETN (0%); reduced: ETN (27.1%), ADA (25%), IFX (3.4%). Concomitant DMARDs use was lower in ETN (58.2%) than ADA (66.07%) and IFX (79.31%). Higher proportion of responders (DAS28 ≤3.2) in ADA (65.3%) and ETN (61.7%) than IFX (48.3%). RA clinical control can be preserved with modified anti-TNF dosages. Controlled prospective studies should be performed to define when therapy can be tailored and for which patients. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients.

PubMed

D'Amico, F; Granata, M; Skarmoutsou, E; Trovato, C; Lovero, G; Gangemi, P; Longo, V; Pettinato, M; Mazzarino, M C

2018-03-31

The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis.

The cost-effectiveness of etanercept in patients with severe ankylosing spondylitis in the UK.

PubMed

Ara, R M; Reynolds, A V; Conway, P

2007-08-01

To examine the costs and benefits associated with long-term etanercept (ETN) treatment in patients with severe ankylosing spondylitis (AS) in the UK in accordance with the BSR guidelines. A mathematical model was constructed to estimate the costs and benefits associated with ETN plus non-steroidal anti-inflammatory drugs (NSAIDs) compared with NSAIDs alone. Individual patient data from Phase III RCTs was used to inform the proportion and magnitude of initial response to treatment and changes in health-related quality of life. A retrospective costing exercise on patients attending a UK secondary care rheumatology unit was used to inform disease costs. Published evidence on long-term disease progression was extrapolated over a 25-yr horizon. Uncertainty was examined using probabilistic sensitivity analyses. Over a 25-yr horizon, ETN plus NSAIDs gave 1.58 more QALYs at an additional cost of 35,978 pounds when compared with NSAID treatment alone. This equates to a central estimate of 22,700 pounds per QALY. The incremental cost per QALYs using shorter time periods were 27,600 pounds, 23,600 pounds and 22,600 pounds at 2, 5 and 15 yrs, respectively. Using a 25-yr horizon, 93% of results from the probabilistic analyses fall below a threshold of 25,000 pounds per QALY. This study demonstrates the potential cost-effectiveness of ETN plus NSAIDs compared with NSAIDs alone in patients with severe AS treated according to the BSR guidelines in the UK.

Vaccine-induced toxic epidermal necrolysis: A case and systematic review.

PubMed

Chahal, Dev; Aleshin, Maria; Turegano, Mamina; Chiu, Melvin; Worswick, Scott

2018-01-15

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are cutaneous hypersensitivityreactions that develop in response to specific triggers such as medications and certain infections. Vaccines, which undergo rigorous safety testing prior to use in humans, are a rare cause of SJS/TEN and little is known about the frequency of such events and corresponding pathogenesis. Herein, we discuss a case of suspected TEN in a 19-year-old woman who received the meningococcal B vaccine (the first report of such an association) and conduct a systematic review of the associated literature. We also discuss management of this patient with a single dose of etanercept. Relevant literature was searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. A total of 29 articles reporting EM, SJS, or TEN following vaccination were included from >5 countries. Of the 29, 22 articles reported EM, 6/29 reported SJS, and 4/29 reported TEN (3 articlesreported cases of both EM and SJS/TEN). We suggest consideration of vaccines as an etiology for cases of SJS or TEN that begin with an EM-like presentation, and provide further evidence for the use of etanercept as a viable treatment for TEN.

Recurrent abdominal pain as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in an Asian girl: a case report and review of the literature.

PubMed

Chen, Yun-Ju; Yu, Hsin-Hui; Yang, Yao-Hsu; Lau, Yu-Lung; Lee, Wen-I; Chiang, Bor-Luen

2014-12-01

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14-year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-α inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS. Copyright © 2012. Published by Elsevier B.V.

Maintenance of Remission with Etanercept-DMARD Combination Therapy Compared with DMARDs Alone in African and Middle Eastern Patients with Active Rheumatoid Arthritis.

PubMed

Bassiouni, Hassan; Spargo, Catherine Elizabeth; Vlahos, Bonnie; Jones, Heather E; Pedersen, Ron; Shirazy, Khalid

2018-06-01

To compare etanercept (ETN) and placebo (PBO) for maintaining low disease activity (LDA) achieved with ETN in patients with rheumatoid arthritis (RA) from Africa and the Middle East. In this subset analysis of the Treat-to-Target trial (ClinicalTrials.gov identifier NCT01981473), 53 adult patients with moderate-to-severe RA nonresponsive to methotrexate were treated with 50 mg ETN/week for 24 weeks (Period 1). Patients achieving LDA were randomized to continue ETN treatment or switched to PBO for an additional 28 weeks (Period 2). The proportion of patients maintaining LDA or remission in each arm at the end of Period 2 was determined. Additional efficacy and patient-reported outcomes (PROs) were also evaluated. During Period 1, 51 patients achieved LDA according to the disease activity score-28 joints-erythrocyte sedimentation rate (DAS28-ESR LDA) and 30 achieved remission. At week 52, nine of 22 and eight of 29 in the ETN and PBO groups, respectively, remained in DAS28-ESR LDA without experiencing a flare. Additionally, six of 14 and five of 16 in the ETN and PBO groups, respectively, remained in remission. Among patients experiencing a flare during Period 2, 13 of 22 and 21 of 29 received ETN or PBO, respectively. The median time to flare was 193 and 87 days in the ETN and PBO groups, respectively. At week 52, consistently more patients in the ETN group than in the PBO group achieved predetermined efficacy and PRO endpoints. These data suggest continuing ETN maintenance therapy is beneficial to patients after they have achieved their treatment target. However, this subset analysis is limited by the small patient population and must be interpreted with caution. Pfizer. ClinicalTrials.gov identifier, NCT0198147.

Anti-TNFα Treatment for HLA-B27-Positive Ankylosing Spondylitis-Related Uveitis.

PubMed

Kim, Mirinae; Won, Jae-Yon; Choi, Seung Yong; Ju, Ji Hyeon; Park, Young-Hoon

2016-10-01

To assess the long-term efficacy of the most widely used anti-tumor necrosis factor alpha (TNFα) agents for treatment of HLA-B27-positive ankylosing spondylitis (AS)-related uveitis. Retrospective cohort study. The medical records of 143 patients with HLA-B27-positive AS who visited Seoul St. Mary's Hospital and were taking an anti-TNFα agent for at least 1 year were studied. Subjects were divided into 3 groups according to anti-TNFα treatment: Group 1 (infliximab, 66), Group 2 (adalimumab, 45), and Group 3 (etanercept, 32). Mean age was 41.0 ± 13.0 years, and 97 patients (67.8%) were male. Mean follow-up period was 70.6 ± 37.9 months. In cases of active ocular inflammation at the onset of anti-TNFα treatment, patients showed improved activity of uveitis after 24.0 ± 15.0 days (Group 1), 17.9 ± 6.0 days (Group 2), and 25.9 ± 18.0 days (Group 3). After the anti-TNFα treatment, 71 of 94 patients (32 [76.2%] in Group 1, 26 [78.8%] in Group 2, and 13 [68.4%] in Group 3) remained without uveitis relapse. A reduction in the number of systemic medications was achieved in 129 patients (90.2%). Twenty-eight cases of minor side effects were observed, and 4 cases were tuberculosis leading to discontinuation of anti-TNFα treatment. Infliximab, adalimumab, and etanercept were effective for treating and reducing the number of uveitis relapses in HLA-B27-positive AS. However, the risk of serious infections was noted, so ophthalmologists should consider the possibility that prolonged use of biologic agents may result in systemic side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

An Economic Evaluation of Tofacitinib Treatment in Rheumatoid Arthritis: Modeling the Cost of Treatment Strategies in the United States.

PubMed

Claxton, Lindsay; Jenks, Michelle; Taylor, Matthew; Wallenstein, Gene; Mendelsohn, Alan M; Bourret, Jeffrey A; Singh, Amitabh; Moynagh, Dermot; Gerber, Robert A

2016-09-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib is approved in the United States for use in adults with moderately to severely active RA and an inadequate response or intolerance to methotrexate. To (a) evaluate, using an economic model, the treatment costs of an RA strategy including tofacitinib, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic RA treatment strategies, which are commonly prescribed in the United States, and (b) assess the economic impact of monotherapy and combination therapy in patients who had an inadequate response to methotrexate therapy (MTX-IR analysis) and to combination therapy in patients who had an inadequate response to a tumor necrosis factor inhibitor (TNF-IR analysis). A transparent, Excel-based economic model with a decision-tree approach was developed to evaluate costs over a 1- and 2-year time horizon. The model compared tofacitinib 5 mg twice a day (BID) either as monotherapy or in combination with MTX with similarly labeled biologic therapies. Response to treatment was modeled as American College of Rheumatology (ACR) 20/50/70 response. ACR20 represented clinical response and determined whether patients continued therapy. ACR response rates at 6-month intervals were sourced from prescribing information and safety event rates from a published meta-analysis. Following an adverse event or a lack of response to treatment, it was assumed that 75% of patients switched to the next line of treatment (first to abatacept and then to rituximab). The perspective was that of a U.S. payer. Costs were reported in 2015 U.S. dollars and included drug wholesale acquisition costs, monitoring, drug administration, and treatment for minor and serious adverse events. The patient population eligible for treatment was based on the total number of members (i.e., RA and non-RA) in a payer organization; members with RA treated with biologic therapies were estimated using epidemiological data. Sensitivity analyses were conducted to explore the impact of varying key parameters, including treatment-switching probability, product rebate, major rates of adverse drug reaction, and ACR20 rates, on the model outcomes. Tofacitinib combination therapy after MTX failure was associated with the lowest cost per member per month (PMPM) over a 2-year time frame at $5.53, compared with $6.49 for adalimumab, $6.43 for etanercept, $5.95 for certolizumab, and $5.89 for tocilizumab. Similar savings were observed when all biologics were administered as monotherapy. Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis. Tofacitinib was also among the lowest cost per ACR20 responder in each analysis. Sensitivity analyses demonstrated that tofacitinib would potentially be cost saving even in the least optimistic scenarios. This analysis suggests that tofacitinib 5 mg BID following MTX failure is a lower cost per patient treatment option when used either as monotherapy or combination therapy, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic regimens. Tofacitinib + MTX in TNF-IR patients was also predicted to be a lower-cost treatment option compared with adalimumab+MTX and was associated with the lowest cost per ACR 20/50/70 responder. This study was funded by Pfizer, which determined the research topic and paid York Health Economics Consortium to develop the analysis and conduct the research. York Health Economics Consortium has received consultancy fees from Pfizer. Gerber, Wallenstein, Mendelsohn, Bourret, Singh, and Moynagh are employees and shareholders of Pfizer. Editorial support was funded by Pfizer and was provided by Claxton, Jenks, and Taylor, who are employees of York Health Economics Consortium. Study concept and design were contributed primarily by Taylor, Jenks, Gerber, and Singh, along with the other authors. Gerber, Moynagh, and Singh collected the data, assisted by Bouret and Mendelsohn; data interpretation was performed by Claxton, Gerber, Bouret, and Mendelsohn. The manuscript was written primarily by Claxton, with assistance from the other authors, and revised by Claxton, Gerber, Bouret, and Mendelsohn, with assistance from the other authors.

Cost-effectiveness of Secukinumab as First Biologic Treatment, Compared with Other Biologics, for Moderate to Severe Psoriasis in Germany.

PubMed

Augustin, Matthias; McBride, Doreen; Gilloteau, Isabelle; O'Neill, Caitriona; Neidhardt, Katja; Graham, Christopher N

2018-05-05

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A, has demonstrated strong and sustained efficacy in adults with moderate to severe psoriasis in clinical trials. This analysis compared the cost per responder of secukinumab as first biologic treatment of moderate to severe psoriasis, with adalimumab, infliximab, etanercept, and ustekinumab in Germany. A 52-week decision-tree model was developed. Response to treatment was assessed based on the likelihood of achieving a predefined Psoriasis Area and Severity Index (PASI) response to separate the cohort into responders (PASI ≥75), partial responders (PASI 50 to 74), and non-responders (PASI <50). Responders at week 16 continued initial treatment, whereas partial responders and non-responders were switched to standard of care, which included methotrexate, cyclosporine, phototherapy, and topical corticosteroids. Sustained response was defined as 16-week response maintained at week 52. A German health care system perspective was adopted. Clinical efficacy data was obtained from a mixed-treatment comparison; 2016 resource unit costs from national sources; and adverse events and discontinuation rates from the literature. We calculated cost per PASI 90 responder over week 16 and week 52, as well as cost per sustained responder between weeks 16 and 52. Secukinumab had the lowest cost per PASI 90 responder over 16 weeks (€18,026) compared with ustekinumab (€18,080), adalimumab (€23,499), infliximab (€29,599), and etanercept (€34,037). Over 52 weeks, costs per PASI 90 responder ranged from €42,409 (secukinumab) to €70,363 (etanercept). Likewise, secukinumab had the lowest cost per sustained 52-week PASI 90 responder (€22,690) compared with other biologic treatments. Sensitivity analyses, excluding patient copayments, showed similar results. First biologic treatment with secukinumab for moderate to severe psoriasis is cost-effective, with lowest cost per responder compared with other biologic treatments in Germany. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3).

PubMed

Reich, Kristian; Leonardi, Craig; Lebwohl, Mark; Kerdel, Francisco; Okubo, Yukari; Romiti, Ricardo; Goldblum, Orin; Dennehy, Ellen B; Kerr, Lisa; Sofen, Howard

2017-06-01

Scalp is a frequently affected and difficult-to-treat area in psoriasis patients. We assessed the efficacy of ixekizumab in the treatment of patients with scalp psoriasis over 60 weeks using the Psoriasis Scalp Severity Index (PSSI). In three Phase 3, multicenter, double-blind, placebo-controlled trials, patients with moderate-to-severe psoriasis in UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224) and UNCOVER-3 (N = 1346) were randomized to subcutaneous 80 mg ixekizumab every two weeks (Q2W) or every four weeks (Q4W) after a 160 mg starting dose, or placebo through Week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg bi-weekly etanercept through Week 12. Patients entering the open-label long-term extension (LTE) (UNCOVER-3) received ixekizumab Q4W; UNCOVER-1 and UNCOVER-2 included a blinded maintenance period in which static physician global assessment (sPGA) 0/1 responders were re-randomized to placebo, ixekizumab Q4W, or 80 mg ixekizumab every 12 weeks (Q12W) through Week 60. In patients with moderate-to-severe psoriasis with baseline scalp involvement, PSSI 90 and 100 were achieved at Week 12 in higher percentages of patients treated with ixekizumab Q2W (81.7% and 74.6%) or ixekizumab Q4W (75.6% and 68.9%) compared with patients treated with placebo (7.6% and 6.7%; p < .001 each ixekizumab arm versus placebo) or etanercept (55.5% and 48.1%; p < .001 each ixekizumab arm versus etanercept). These outcomes were maintained through Week 60 of the maintenance (UNCOVER-1 and UNCOVER-2) and LTE (UNCOVER-3) period in patients who continued on ixekizumab Q4W. Ixekizumab was efficacious in treating scalp psoriasis in patients with moderate-to-severe psoriasis, with most patients achieving complete or near-complete resolution of scalp psoriasis and maintaining this response over 60 weeks.

Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review.

PubMed

Lau, Chak Sing; Gibofsky, Allan; Damjanov, Nemanja; Lula, Sadiq; Marshall, Lisa; Jones, Heather; Emery, Paul

2017-11-01

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice.

Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

PubMed Central

Wallace, Carol A.; Giannini, Edward H.; Spalding, Steven J.; Hashkes, Philip J.; O’Neil, Kathleen M.; Zeft, Andrew S.; Szer, Ilona S.; Ringold, Sarah; Brunner, Hermine I.; Schanberg, Laura E.; Sundel, Robert P.; Milojevic, Diana; Punaro, Marilynn G.; Chira, Peter; Gottlieb, Beth S.; Higgins, Gloria C.; Ilowite, Norman T.; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J.

2011-01-01

OBJECTIVES To determine if aggressive treatment initiated early in the course of rheumatoid factor positive or negative polyarticular juvenile idiopathic arthritis (poly-JIA) can induce clinical inactive disease (CID) within 6 months. METHODS Between May 2007 and October 2010 a multi-center, prospective, double blind, randomized, placebo controlled trial of two aggressive treatments was conducted in 85 children aged 2 to 16 years with polyarticular JIA of less than 12 months duration. Patients received either methotrexate 0.5 mg/kg/wk SQ (40 mg max), etanercept 0.8 mg/kg/wk (50 mg max), prednisolone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 weeks (Arm 1), or methotrexate (same dose as Arm 1), etanercept placebo, and prednisolone placebo (Arm 2). The primary outcome was CID at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous CID) at 12 months. RESULTS By 6 months, 17 of 42 (40%) of patients in Arm 1 and 10 of 43 (23%) in Arm 2 had achieved CID (X2 = 2.91; p = 0.088). After 12 months, 9 patients in Arm 1 and 3 in Arm 2 achieved clinical remission on medication (p = 0.0534). There were no significant inter-arm differences in adverse events. CONCLUSIONS Although this study did not meet its primary endpoint, early aggressive therapy in this cohort of children with recent onset polyarticular JIA resulted in substantial proportions of patients in both arms achieving CID by 6 months and clinical remission on medication within 12 months of treatment. PMID:22183975

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

PubMed Central

Urbano, Paulo César Martins; Soccol, Vanete Thomaz; Azevedo, Valderilio Feijó

2014-01-01

Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. PMID:25114503

The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study

PubMed Central

Moots, Robert J.; Xavier, Ricardo M.; Mok, Chi Chiu; Rahman, Mahboob U.; Tsai, Wen-Chan; Al-Maini, Mustafa H.; Pavelka, Karel; Mahgoub, Ehab; Kotak, Sameer; Korth-Bradley, Joan; Pedersen, Ron; Mele, Linda; Shen, Qi; Vlahos, Bonnie

2017-01-01

Objective To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. Methods This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6–24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. Results Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. Conclusion ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. Trial registration This study was registered on www.ClinicalTrials.gov (NCT01981473). PMID:28448562

Herpes zoster in psoriasis patients treated with tofacitinib.

PubMed

Winthrop, Kevin L; Lebwohl, Mark; Cohen, Arnon D; Weinberg, Jeffrey M; Tyring, Stephen K; Rottinghaus, Scott T; Gupta, Pankaj; Ito, Kaori; Tan, Huaming; Kaur, Mandeep; Egeberg, Alexander; Mallbris, Lotus; Valdez, Hernan

2017-08-01

Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. To evaluate the relationship between tofacitinib use and HZ risk. We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox-proportional hazard models. One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Epidural steroid injections: update on efficacy, safety, and newer medications for injection.

PubMed

Kozlov, N; Benzon, H T; Malik, K

2015-08-01

The best evidence for epidural injection appears to be in the setting of radicular pain with epidural steroid and non-steroid injections more efficacious than non-epidural injections. Studies showed the efficacy of non-particulate steroid to approach the efficacy of particulate steroid and very limited comparisons demonstrated no significant difference between epidural steroid and epidural non-steroid (local anesthetic) injection. Preliminary studies evaluating epidural injection of disease modifying anti-rheumatic drugs such etanercept and tocilizumab showed conflicting results and had significant limitations. Randomized studies support better efficacy of transforaminal injection due to greater incidence of ventral epidural spread of injectate when compared to interlaminar injection. Thus, the transforaminal approach is recommended when unilateral radicular pain is limited to one nerve root. However, the transforaminal approach is associated with greater incidence of central nervous system injury, including paraplegia, attributed to embolization of the particulate steroid. Recent studies showed that non-particulate steroids potentially last as long as particulate steroids. Therefore non-particulate steroid should be used in initial transforaminal epidural injection. Future studies should look into the role of adjunct diagnostic aids, including digital subtraction angiography, in detecting intravascular injection and the ideal site of needle placement, whether it is the safe triangle or the triangle of Kambin. Finally, the role of epidural disease -modifying antirheumatic drugs in the management of back pain needs to be better elucidated.

Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug.

PubMed

Caselli, Gianfranco; Bonazzi, Albino; Lanza, Marco; Ferrari, Flora; Maggioni, Daniele; Ferioli, Cristian; Giambelli, Roberto; Comi, Eleonora; Zerbi, Silvia; Perrella, Marco; Letari, Ornella; Di Luccio, Elena; Colovic, Milena; Persiani, Stefano; Zanelli, Tiziano; Mennuni, Laura; Piepoli, Tiziana; Rovati, Lucio Claudio

2018-03-01

Prostaglandin E 2 (PGE 2 ) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively. In immune cells, IL-6 and vascular endothelial growth factor (VEGF) expression were analysed by RT-PCR, and IL-23 and IL-17 release were measured by enzyme-linked immunosorbent assay (ELISA). In collagen-induced arthritis (CIA) models, rats or mice were immunised with bovine collagen type II. Drugs were administered orally (etanercept and methotrexate intraperitoneally) starting at disease onset. Arthritis progression was evaluated by oedema, clinical score and histopathology. Anti-collagen II immunoglobulin G antibodies were measured by ELISA. CR6086 showed selectivity and high affinity for the human EP4 receptor (K i = 16.6 nM) and functioned as a pure antagonist (half-maximal inhibitory concentration, 22 nM) on PGE 2 -stimulated cAMP production. In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib. In mice, CR6086 and the biologic DMARD etanercept were highly effective, whereas the non-steroidal anti-inflammatory drug naproxen was ineffective. Importantly, in a study of CR6086/methotrexate, combined treatment greatly improved the effect of a fully immunosuppressive dose of methotrexate. CR6086 is a novel, potent EP4 antagonist showing favourable immunomodulatory properties, striking DMARD effects in rodents, and anti-inflammatory activity targeted to immune-mediated inflammatory diseases and distinct from the general effects of cyclooxygenase inhibitors. These results support the clinical development of CR6086, both as a stand-alone DMARD and as a combination therapy with methotrexate. The proof-of-concept trial in patients with RA is ongoing.

Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis.

PubMed

Wallace, Carol A; Giannini, Edward H; Spalding, Steven J; Hashkes, Philip J; O'Neil, Kathleen M; Zeft, Andrew S; Szer, Ilona S; Ringold, Sarah; Brunner, Hermine I; Schanberg, Laura E; Sundel, Robert P; Milojevic, Diana; Punaro, Marilynn G; Chira, Peter; Gottlieb, Beth S; Higgins, Gloria C; Ilowite, Norman T; Kimura, Yukiko; Hamilton, Stephanie; Johnson, Anne; Huang, Bin; Lovell, Daniel J

2012-06-01

To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ(2) = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 (P = 0.053). There were no significant interarm differences in adverse events. Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms. Copyright © 2012 by the American College of Rheumatology.

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

PubMed

Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

2010-12-01

Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Evaluation of Real-World Experience with Tofacitinib Compared with Adalimumab, Etanercept, and Abatacept in RA Patients with 1 Previous Biologic DMARD: Data from a U.S. Administrative Claims Database.

PubMed

Harnett, James; Gerber, Robert; Gruben, David; Koenig, Andrew S; Chen, Connie

2016-12-01

Real-world data comparing tofacitinib with biologic disease-modifying antirheumatic drugs (bDMARDs) are limited. To compare characteristics, treatment patterns, and costs of patients with rheumatoid arthritis (RA) receiving tofacitinib versus the most common bDMARDs (adalimumab [ADA], etanercept [ETN], and abatacept [ABA]) following a single bDMARD in a U.S. administrative claims database. This study was a retrospective cohort analysis of patients aged ≥ 18 years with an RA diagnosis (ICD-9-CM codes 714.0x-714.4x; 714.81) and 1 previous bDMARD filling ≥ 1 tofacitinib or bDMARD claim in the Truven MarketScan Commercial and Medicare Supplemental claims databases (November 1, 2012-October 31, 2014). Monotherapy was defined as absence of conventional synthetic DMARDs within 90 days post-index. Persistence was evaluated using a 60-day gap. Adherence was assessed using proportion of days covered (PDC). RA-related total, pharmacy, and medical costs were evaluated in the 12-month pre- and post-index periods. Treatment patterns and costs were adjusted using linear models including a common set of clinically relevant variables of interest (e.g., previous RA treatments), which were assessed separately using t-tests and chi-squared tests. Overall, 392 patients initiated tofacitinib; 178 patients initiated ADA; 118 patients initiated ETN; and 191 patients initiated ABA. Tofacitinib patients were older versus ADA patients (P = 0.0153) and had a lower proportion of Medicare supplemental patients versus ABA patients (P = 0.0095). Twelve-month pre-index bDMARD use was greater in tofacitinib patients (77.6%) versus bDMARD cohorts (47.6%-59.6%). Tofacitinib patients had greater 12-month pre-index RA-related total costs versus bDMARD cohorts (all P < 0.0001) and greatest index use of monotherapy (P = 0.0080 vs. ABA). A similar (all P > 0.10) proportion of patients were persistent with tofacitinib (42.6%) versus ADA (37.6%), ETN (42.4%), and ABA (43.5%). Mean PDC was 0.55 for tofacitinib versus 0.57 (ADA), 0.59 (ETN), and 0.44 (ABA; P = 0.0003). Adjusted analyses generated similar findings to the unadjusted treatment patterns. Tofacitinib had lower adjusted 12-month post-index mean RA-related total costs ($23,568) versus ADA ($29,278; P < 0.0001), ETN ($26,885; P = 0.0248), and ABA ($30,477; P < 0.0001). In this study, tofacitinib was more commonly used as monotherapy and yielded at least comparable persistence and adherence with lower adjusted mean RA-related total costs versus ADA, ETN, and ABA. Further analysis is warranted given the greater 12-month pre-index bDMARD use and RA-related costs for tofacitinib versus bDMARDs. This study was sponsored by Pfizer. Harnett, Gerber, Gruben, Koenig, and Chen are employees and shareholders of Pfizer. Some data reported in this manuscript have been previously presented at the Academy of Managed Care Nexus 2015; Orlando, Florida; October 26-29, 2015, and was submitted in abstract form to the European League Against Rheumatism Congress; London, United Kingdom; June 8-11, 2016. All authors were involved in the conception and design of this study. Harnett and Gruben were involved in data collection and analysis. All authors interpreted the data, critically reviewed and revised the manuscript, and read and approved the final manuscript.

New drugs for the treatment of rheumatoid arthritis.

PubMed

Schuna, A A; Megeff, C

2000-02-01

New pharmacologic treatment options for rheumatoid arthritis (RA) are described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for RA but are limited by the risk of adverse effects, especially gastrointestinal and renal toxicity. The therapeutic effects of these agents are mediated primarily through inhibition of cyclooxygenase (COX) and prevention of subsequent formation of prostaglandins and related inflammatory mediators. Nonspecific COX inhibition appears to be responsible for much of the toxicity of NSAIDs. Agents have been developed that can selectively inhibit the COX-2 isoform, while sparing COX-1. Celecoxib and other COX-2 inhibitors appear to be no more efficacious than conventional NSAIDs, but offer superior safety. COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Unlike disease-modifying antirheumatic drugs (DMARDs), these agents do not alter underlying disease progression. Leflunomide is a newer DMARD that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as methotrexate but, unlike that drug, does not necessitate monitoring for bone marrow toxicity. Etanercept, the first biological agent with FDA-approved labeling for use in RA, has shown efficacy and minimal toxicity, except for injection-site reactions. Other biologicals that have been investigated for use in RA include infliximab and interleukin-1-receptor antagonist. COX-2 inhibitors, leflunomide, and etanercept are promising new drugs available for treating RA. Other agents are under development.

Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

PubMed

Ramaekers, Bram L T; Wolff, Robert F; Pouwels, Xavier; Oosterhoff, Marije; Van Giessen, Anoukh; Worthy, Gill; Noake, Caro; Armstrong, Nigel; Kleijnen, Jos; Joore, Manuela A

2018-02-26

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz ® ), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Patient Perceptions and Preferences of Two Etanercept Autoinjectors for Rheumatoid Arthritis: Findings from a Patient Survey in Europe.

PubMed

Thakur, Kunal; Biberger, Anna; Handrich, Alexandra; Rezk, Mourad Farouk

2016-12-01

Benepali ® was the first etanercept (Enbrel ® ) biosimilar to be approved in the European Union. Both Benepali and Enbrel are available as autoinjector devices. In a recent survey, nurses from France, Germany, Italy, Spain, and the United Kingdom (UK) reported that their patients with rheumatoid arthritis (RA) would prefer the Benepali autoinjector compared to the Enbrel MYCLIC autoinjector. To determine whether patients' perceptions were similar to those of the nurses, this survey evaluated patients' perceptions and preferences of the Benepali autoinjector versus the Enbrel MYCLIC autoinjector in the same five European countries. Patients with RA using the Enbrel MYCLIC autoinjector participated in a 25-min, face-to-face questionnaire-interview. Patients were also shown an instructional video and device-handling leaflet, received a live demonstration on the Benepali autoinjector, and had access to both Benepali and Enbrel MYCLIC training autoinjectors. Patients rated the importance of ten autoinjector attributes on a seven-point scale (1 = not important at all; 7 = extremely important) and provided their autoinjector preferences based on specific attributes. Patients also gave their opinion on which autoinjector they would prefer to use for self-injection. Overall, 220 patients participated in the survey (France, n = 30; Germany, n = 65; Italy, n = 67; Spain, n = 12; UK, n = 46). 'Easy to operate the self-injection' was ranked as the most important attribute (mean score of 6.8), followed by 'easy to grip' (6.5), and 'intuitive/self-explaining usage' (6.3). Patients preferred the Benepali autoinjector, with the attribute of 'easier to operate' being a strong differentiator compared to the Enbrel MYCLIC autoinjector. Most patients (74%) reported that they would prefer to use the Benepali autoinjector over the Enbrel MYCLIC autoinjector. 'Easy to operate the self-injection' and 'button-free autoinjector' were key drivers when selecting an autoinjector. Patients in Europe reported a preference for the Benepali autoinjector compared to the Enbrel MYCLIC autoinjector. This finding is consistent with results from a recently reported nurse survey. Biogen.

Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis.

PubMed

Constantin, Tamas; Foeldvari, Ivan; Vojinovic, Jelena; Horneff, Gerd; Burgos-Vargas, Ruben; Nikishina, Irina; Akikusa, Jonathan D; Avcin, Tadej; Chaitow, Jeffrey; Koskova, Elena; Lauwerys, Bernard R; Calvo Penades, Inmaculada; Flato, Berit; Gamir, Maria Luz; Huppertz, Hans-Iko; Jaller Raad, Juan Jose; Jarosova, Katerina; Anton, Jordi; Macku, Marie; Otero Escalante, William J; Rutkowska-Sak, Lidia; Trauzeddel, Ralf; Velez-Sanchez, Patricia J; Wouters, Carine; Wajdula, Joseph; Zang, Chuanbo; Bukowski, Jack; Woodworth, Deborah; Vlahos, Bonnie; Martini, Alberto; Ruperto, Nicolino

2016-04-01

The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [I]: anti-tumor necrosis factor-α agents).

PubMed

Baddley, J W; Cantini, F; Goletti, D; Gómez-Reino, J J; Mylonakis, E; San-Juan, R; Fernández-Ruiz, M; Torre-Cisneros, J

2018-06-01

The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. To review, from an Infectious Diseases perspective, the safety profile of agents targeting tumour necrosis factor-α (TNF-α) and to suggest preventive recommendations. Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. Preclinical and clinical evidence indicate that anti-TNF-α therapy (infliximab, adalimumab, golimumab, certolizumab pegol and etanercept) is associated with a two-to four-fold increase in the risk of active tuberculosis and other granulomatous conditions (mostly resulting from the reactivation of a latent infection). In addition, it may lead to the occurrence of other serious infections (bacterial, fungal, opportunistic and certain viral infections). These associated risks seem to be lower for etanercept than other agents. Screening for latent tuberculosis infection should be performed before starting anti-TNF-α therapy, followed by anti-tuberculosis therapy if appropriate. Screening for chronic hepatitis B virus (HBV) infection is also recommended, and antiviral prophylaxis may be warranted for hepatitis B surface antigen-positive individuals. No benefit is expected from the use of antibacterial, anti-Pneumocystis or antifungal prophylaxis. Pneumococcal and age-appropriate antiviral vaccinations (i.e. influenza) should be administered. Live-virus vaccines (i.e. varicella-zoster virus or measles-mumps-rubella) may be contraindicated in people receiving anti-TNF-α therapy, although additional data are needed before definitive recommendations can be made. Prevention measures should be implemented to reduce the risk of latent tuberculosis or HBV reactivation among individuals receiving anti-TNF-α therapy. Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Impact of etanercept tapering on work productivity in patients with early rheumatoid arthritis: results from the PRIZE study

PubMed Central

Zhang, Wei; Bansback, Nick; Sun, Huiying; Pedersen, Ronald; Kotak, Sameer; Anis, Aslam H

2016-01-01

Objective To assess changes in work productivity in patients who have achieved response using etanercept (ETN) 50 mg+methotrexate (MTX) (phase I) are randomised to ETN 25 mg+MTX versus MTX versus placebo (phase II) and then withdrawn from treatment (phase III). Methods Patients included in the analysis were in employment entering phase II of the PRIZE trial and had one or more follow-ups. Phase II was a 39-week, randomised and double-blind comparison of the 3 dose-reduction treatments. Phase III was a 26-week observational study where treatment was withdrawn. The Valuation of Lost Productivity was completed approximately every 13 weeks to estimate productivity impacts from a societal perspective. Results A total of 120 participants were included in our analyses. During phase II, ETN25+MTX or MTX improved paid work productivity by over 100 hours compared with placebo, amounting to a gain of €1752 or €1503, respectively. ETN25+MTX compared with placebo gains €1862 in total paid/unpaid productivity. At week 52, the 3-month paid work productivity loss was 21.8, 12.8 and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52, dropped at week 76 for all treatment groups and then continued rising after week 76 for the placebo group (71.9 hours at week 91) but not for the other 2 groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX). Conclusions The work productivity gain in phase I as a result of ETN50+MTX was marginally lost in the dose-reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the placebo group during phase II. Trial registration number NCT00913458; Results. PMID:27486524

Differential Drug Survival of Second-Line Biologic Therapies in Patients with Psoriasis: Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

PubMed

Iskandar, Ireny Y K; Warren, Richard B; Lunt, Mark; Mason, Kayleigh J; Evans, Ian; McElhone, Kathleen; Smith, Catherine H; Reynolds, Nick J; Ashcroft, Darren M; Griffiths, Christopher E M

2018-04-01

Little is known about the drug survival of second-line biologic therapies for psoriasis in routine clinical practice. We assessed drug survival of second-line biologic therapies and estimated the risk of recurrent discontinuation due to adverse events or ineffectiveness in patients with psoriasis who had failed a first biologic therapy and switched to a second in a large, multicenter pharmacovigilance registry (n = 1,239; adalimumab, n = 538; etanercept, n = 104; ustekinumab, n = 597). The overall drug survival rate in the first year after switching was 77% (95% confidence interval = 74-79%), falling to 58% (55-61%) in the third year. Female sex, multiple comorbidities, concomitant therapy with cyclosporine, and a high Psoriasis Area and Severity Index at switching to the second-line biologic therapy were predictors of overall discontinuation (multivariable Cox proportional hazard model). Compared to adalimumab, patients receiving etanercept were more likely to discontinue therapy (hazard ratio = 1.87, 95% confidence interval = 1.24-2.83), whereas patients receiving ustekinumab were more likely to persist (hazard ratio = 0.46; 95% confidence interval = 0.33-0.64). Discontinuation of the first biologic therapy because of adverse events was associated with an increased rate of second drug discontinuation because of adverse events (hazard ratio = 2.55; 95% confidence interval = 1.50-4.32). In conclusion, drug survival rates differed among biologic therapies and decreased over time; second-line discontinuation because of adverse events was more common among those who discontinued first-line treatment for this reason. The results of this study should support clinical decision making when choosing second-line biologic therapy for patients with psoriasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Successful leukocytapheresis therapy in a patient with rheumatoid arthritis on maintenance hemodialysis.

PubMed

Maeshima, Keisuke; Torigoe, Masataka; Iwakura, Mikako; Yamanaka, Kunitoshi; Ishii, Koji

2015-01-01

We report the case of a 44-year-old female undergoing maintenance hemodialysis in whom early-phase rheumatoid arthritis (RA) was successfully treated by leukocytapheresis (LCAP). The effects of prednisone, tacrolimus, and etanercept were limited, but LCAP was highly effective and its efficacy continued even after cessation of LCAP. Moreover, remission was maintained for 2 years after discontinuation of medication. LCAP may be an important treatment option for RA patients with end-stage renal failure who are on hemodialysis.

Improved health outcomes with etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis.

PubMed

Bae, Sang-Cheol; Gun, Suk Chyn; Mok, Chi Chiu; Khandker, Rezaul; Nab, Henk W; Koenig, Andrew S; Vlahos, Bonnie; Pedersen, Ron; Singh, Amitabh

2013-01-08

Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied. Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used. Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores. Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region. clintrials.gov # NCT00422227.

Improved health outcomes with Etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis

PubMed Central

2013-01-01

Background Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied. Methods Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used. Results Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores. Conclusion Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region. Trial registration clintrials.gov # NCT00422227 PMID:23294908

Drug immunogenicity in patients with inflammatory arthritis and secondary failure to tumour necrosis factor inhibitor therapies: the REASON study.

PubMed

Balsa, Alejandro; Sanmarti, Raimon; Rosas, José; Martin, Victor; Cabez, Ana; Gómez, Susana; Montoro, María

2018-04-01

The aims were to evaluate the prevalence of anti-drug antibodies (ADA) in patients with RA or SpA experiencing secondary failure to anti-TNF therapy and to correlate ADA presence with anti-TNF concentration and clinical response. This was a cross-sectional, observational study of patients with active RA or SpA experiencing secondary failure to etanercept (ETN), infliximab (INF) or adalimumab (ADL). Concomitant non-biologic DMARDs were permitted. Serum anti-TNF and ADA levels were measured with two-site ELISA. Among 570 evaluable patients, those with RA (n = 276) were mostly female (80 vs 39%), older (56 vs 48 years), received concomitant DMARDs (83 vs 47%) and had maintained good clinical disease control for longer (202 vs 170 weeks) compared with patients with SpA (n = 294). ADA were found in 114/570 (20.0%) patients; 51/188 (27.1%) against INF and 63/217 (29.0%) against ADL; none against ETN. Of these 114 patients, 92 (81%) had no detectable serum drug concentrations. Proportionately more patients with SpA (31.3%) had anti-INF antibodies than those with RA (21.1%; P = 0.014). A significantly lower proportion of patients receiving concomitant DMARDs (16.5%) developed ADA than those on monotherapy (26.4%; P < 0.05). In patients with RA or SpA and secondary failure, the development of ADA against ADL or INF, but not ETN, appears to be one of the main reasons for secondary treatment failure, but not the only one. Further investigations are needed to determine other causes of anti-TNF failure.

Sarcoidosis-Like Lesions: Another Paradoxical Reaction to Anti-TNF Therapy?

PubMed

Decock, Amelie; Van Assche, Gert; Vermeire, Séverine; Wuyts, Wim; Ferrante, Marc

2017-03-01

Since the introduction of anti-tumour necrosis factor [TNF] therapy in inflammatory diseases, paradoxical reactions are increasingly being reported. One of these paradoxical reactions is the development of sarcoidosis-like lesions. This presentation is paradoxical since anti-TNF therapy can also be therapeutic in refractory cases of sarcoidosis. We report two cases of sarcoidosis-like lesions under anti-TNF therapy. Both were patients with inflammatory bowel disease [IBD], treated successfully with adalimumab. Next, we reviewed the literature for similar cases. Medical subject heading terms 'adalimumab', 'infliximab', 'etanercept', 'golimumab' or 'certolizumab', and 'sarcoidosis' were used to perform key word searches of the PubMed database. We identified 90 reported cases of sarcoidosis-like lesions, which developed during anti-TNF therapy. In most cases, the anti-TNF drug involved was etanercept. The median age was 43 years and there was a predominance of female patients. The underlying disease was rheumatoid arthritis in most cases, followed by ankylosing spondylitis and psoriasiform arthritis. In six cases, the underlying disease was IBD. In 71 cases there was at least a partial resolution by discontinuation of the anti-TNF treatment, initiation of steroids or both. Re-initiation of anti-TNF therapy gave relapse in seven out of 20 cases. Sarcoidosis-like lesions are increasingly reported during anti-TNF treatment. Vigilance is appropriate when patients present with symptoms compatible with sarcoidosis. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms.

PubMed

Bruder-Nascimento, Thiago; Kennard, Simone; Antonova, Galina; Mintz, James D; Bence, Kendra K; Belin de Chantemèle, Eric J

2016-06-01

Protein tyrosine phosphatase 1b (Ptp1b) is a negative regulator of leptin and insulin-signalling pathways. Its targeted deletion in proopiomelanocortin (POMC) neurons protects mice from obesity and diabetes by increasing energy expenditure. Inflammation accompanies increased energy expenditure. Therefore, the present study aimed to determine whether POMC-Ptp1b deletion increases energy expenditure via an inflammatory process, which would impair endothelial function. We characterized the metabolic and cardiovascular phenotypes of Ptp1b+/+ and POMC-Ptp1b-/- mice. Clamp studies revealed that POMC-Ptp1b deletion reduced body fat and increased energy expenditure as evidenced by a decrease in feed efficiency and an increase in oxygen consumption and respiratory exchange ratio. POMC-Ptp1b deletion induced a 2.5-fold increase in plasma tumour necrosis factor α (TNF-α) levels and elevated body temperature. Vascular studies revealed an endothelial dysfunction in POMC-Ptp1b-/- mice. Nitric oxide synthase inhibition [N-nitro-L-arginine methyl ester (L-NAME)] reduced relaxation to a similar extent in Ptp1b+/+ and POMC-Ptp1b-/- mice. POMC-Ptp1b deletion decreased ROS-scavenging enzymes [superoxide dismutases (SODs)] whereas it increased ROS-generating enzymes [NADPH oxidases (NOXs)] and cyclooxygenase-2 (COX-1) expression, in aorta. ROS scavenging or NADPH oxidase inhibition only partially improved relaxation whereas COX-2 inhibition and thromboxane-A2 (TXA2) antagonism fully restored relaxation in POMC-Ptp1b-/- mice Chronic treatment with the soluble TNF-α receptor etanercept decreased body temperature, restored endothelial function and reestablished aortic COX-2, NOXs and SOD expression to their baseline levels in POMC-Ptp1b-/- mice. However, etanercept promoted body weight gain and decreased energy expenditure in POMC-Ptp1b-/- mice. POMC-Ptp1b deletion increases plasma TNF-α levels, which contribute to body weight regulation via increased energy expenditure and impair endothelial function via COX-2 and ROS-dependent mechanisms. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study

PubMed Central

Weber-Schoendorfer, Corinna; Oppermann, Marc; Wacker, Evelin; Bernard, Nathalie; Beghin, Delphine; Cuppers-Maarschalkerweerd, Benedikte; Richardson, Jonathan L; Rothuizen, Laura E; Pistelli, Alessandra; Malm, Heli; Eleftheriou, Georgios; Kennedy, Debra; Kadioglu Duman, Mine; Meister, Reinhard; Schaefer, Christof

2015-01-01

Aims TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. Methods Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. Results In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. Conclusions TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs. PMID:25808588

Estimating the monetary value of the annual productivity gained in patients with early rheumatoid arthritis receiving etanercept plus methotrexate: interim results from the PRIZE study

PubMed Central

Zhang, Wei; Bansback, Nick; Sun, Huiying; Pedersen, Ronald; Kotak, Sameer; Anis, Aslam H

2015-01-01

Objective To measure and value the impact of combined etanercept (ETN) and methotrexate (MTX) therapy on work productivity in patients with early rheumatoid arthritis (RA) over 52 weeks. Methods MTX- and biological-naïve patients with RA (symptom onset ≤12 months; Disease Activity Score based on a 28-joint count (DAS28) >3.2) received open-label ETN50/MTX for 52 weeks. The Valuation of Lost Productivity (VOLP) questionnaire, measuring paid and unpaid work productivity impacts, was completed approximately every 13 weeks. Bootstrapping methods were used to test changes in VOLP outcomes over time. One-year productivity impacts were compared between responders (DAS28 ≤3.2) at week 13 and non-responders using zero-inflated models for time loss and two-part models for total costs of lost productivity. Results 196 patients were employed at baseline and had ≥1 follow-up with VOLP. Compared with baseline, at week 52, patients gained 33.4 h per 3 months in paid work and 4.2 h per week in unpaid work. Total monetary productivity gains were €1322 per 3 months. Over the 1-year period, responders gained paid (231 h) and unpaid work loss (122 h) compared with non-responders, which amounted to a gain of €3670 for responders. Conclusions This is the first clinical trial to measure and value the impact of biological treatment on all the labour input components that affect overall productivity. Combination therapy with ETN50/MTX was associated with a significant productivity gain for patients with early RA who were still observed at week 52. Over the 1-year treatment period, responders at week 13 suffered significantly less productivity loss than non-responders suggesting this gain was related to treatment response. Trial registration number ClinicalTrials.gov number NCT00913458 PMID:26535135

Effects of a biologic agent in a patient with rheumatoid arthritis after treatment for methotrexate-associated B-cell lymphoma: a case report.

PubMed

Kuroda, Takeshi; Sato, Hiroe; Nakatsue, Takeshi; Wada, Yoko; Murakami, Shuichi; Nakano, Masaaki; Narita, Ichiei

2014-04-11

Several studies have suggested an increased risk of malignant tumor in patients with rheumatoid arthritis. It has been also reported that rheumatoid arthritis patients have a high incidence of lymphoma compared with the general population, and that patients receiving methotrexate, which is the anchor drug for rheumatoid arthritis treatment, can develop lymphoproliferative disease. Nevertheless, management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated. We here report a patient with rheumatoid arthritis who developed malignant lymphoma associated with methotrexate therapy. Moreover, we describe the use of a biologic agent for a rheumatoid arthritis patient after treatment for lymphoma associated with methotrexate. A 60-year-old Japanese man with a 20-year history of rheumatoid arthritis was admitted to our hospital with a left inguinal tumor. Open biopsy was performed and a biopsy specimen revealed diffuse large B-cell lymphoma. As our patient had received methotrexate for 4 years, we diagnosed the lymphoproliferative disease as being methotrexate-related. This lymphoma was not associated with Epstein- Barr virus by Epstein-Barr virus-encoded ribonucleic acid in-situ hybridization, but this patient was an Epstein-Barr virus carrier, regarding serological testing. The lymphoma went into complete remission after 6 courses of rituximab plus cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone/prednisolone therapy. Two years later, however, rheumatoid arthritis activity gradually increased and was not controlled with salazosulfapyridine. Etanercept was administered in view of its possible effect on B-cells, and this reduced the level of disease activity without recurrence of lymphoma. The management of rheumatoid arthritis after treatment for methotrexate-associated lymphoma has not been fully investigated yet. Etanercept appeared to be safe because of its B-cell effect, but further observation is necessary to make a firm conclusion. Further accumulation of cases is needed to clarify which biologics are safe and effective for treatment of methotrexate-associated B-cell lymphoma.

Is secukinumab a safe alternative treatment for ankylosing spondylitis with Guillain Barré syndrome after anti-TNF-α treatment? Case report and literature review.

PubMed

Psarelis, Savvas; Hajineocli, Andreas P D; Hadjicosta, Eleni; Elliott, Hugh St A; Johnson, Paul

2017-05-01

In this report, we aim to add to the existing body of evidence regarding a link between anti- tumor necrosis factor alpha (anti-TNF-α) treatment and demyelination leading to neurological disorders, specifically Guillain Barré syndrome (GBS), and treatment with an interleukin-17A (IL17A) antagonist as a safe alternative for ankylosing spondylitis (AS). A literature review was carried out of current research concerning anti-TNF-α and induced GBS. Only papers published in English were reviewed and only peer-reviewed journals searched. Papers published up to September 2016 were included. Animal studies were excluded. Data bases searched for publications online included: Pub Med, Google Scholar, The Cochrane Library, and Web of Science. Searched terms include "anti-TNF" and "Guillain Barré", "IL17 Ankylosing Spondylitis", "Secukinumab" and "TNF-α", "adalimumab", "infliximab", and "etanercept". All combinations and outcomes were used, and from these searches, a provisional reference list was constructed. The short-listed articles were read and their reference lists were reviewed. The electromyogram done for the patient showed demyelination, the MRI of the brain showed no pathologies, and the MRI of the spine was consistent with ankylosing spondylitis without myelopathy. The lumbar puncture results showed albuminocytological dissociation that was consistent with GBS. TNF has a proinflammatory action, and various immunoregulatory actions that, together, seem to promote the development of peripheral neuropathies syndromes in the organism. However, there is no clear mechanism of why or how anti-TNF-α treatment can induce a demyelinating event in a patient. In the case presented, it was found that the patient developed GBS due to treatment with etanercept, an anti-TNF agent. The treatment was stopped immediately. Two years later, he was switched to secukinumab and has been well controlled for the last 8 months with no neurological findings.

Tumor necrosis factor alpha inhibitors in the treatment of toxic epidermal necrolysis.

PubMed

Woolridge, Katelyn F; Boler, Patrick L; Lee, Brian D

2018-01-01

Toxic epidermal necrolysis (TEN) is a rare, life-threatening adverse drug reaction for which there is no standardized or consistently effective treatment. Due to a greater understanding of disease pathogenesis and the identification of tumor necrosis factor (TNF) α as a mediator of keratinocyte death, TNF-α antagonists have been used in the treatment of TEN. Specifically, infliximab and etanercept have been shown to be effective at halting disease progression. The objective of this study is to review published case reports and case series using anti-TNF-α medications in the treatment of TEN. Results of many of the articles reviewed support the use of TNF-α inhibitors in TEN in both adult and pediatric populations; however, the risks caused by these potent immunosuppressants must be weighed, and if administered, patients must be closely monitored for infections. Additional studies are needed to further characterize the role of TNF-α inhibition in the treatment of TEN.

Treatment of moderate rheumatoid arthritis with different strategies in a health resource-limited setting: a cost-effectiveness analysis in the era of biosimilars.

PubMed

Wu, Bin; Song, Yang; Leng, Lin; Bucala, Richard; Lu, Liang-jing

2015-01-01

This paper aims to explore the cost-effectiveness of reduced doses or discontinuation of etanercept biosimilar (Yisaipu) in patients with moderately active rheumatoid arthritis (RA). A discrete event simulation model was developed to project lifetime medical costs and quality-adjusted life-years (QALYs) in moderately active RA. Strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week, 25 mg/week or MTX maintenance were compared. Resource consumptions related to RA were estimated from the perspective of the Chinese health care system. An endpoint of the American College of Rheumatology (ACR) response was used to estimate the utility scores. Uncertainty in model parameters was analysed by sensitivity analyses. When using ACR as an endpoint for determining successful treatment, strategies starting with Yisaipu 50 mg/week for nine months following Yisaipu 50 mg/week or 25 mg/week maintenance showed the greatest number of QALYs gained (nearly 11.9 and 11.3 with or without rituximab after the failure of Yisaipu, respectively). If decision makers use a threshold of 3×the per capita GDP of China or Shanghai City in 2012, then the strategies most likely to be cost-effective are initial treatment with Yisaipu 50 mg/week for nine months following MTX maintenance and Yisaipu 25 mg/week maintenance, respectively. Results were sensitive to the cost of Yisaipu. The analysis indicates that, in China, replacing branded etanercept with Yisaipu is likely to be a cost-effective strategy in patients with moderately active RA.

Targeted, Site-specific quantitation of N- and O-glycopeptides using 18O-labeling and product ion based mass spectrometry.

PubMed

Srikanth, Jandhyam; Agalyadevi, Rathinasamy; Babu, Ponnusamy

2017-02-01

The site-specific quantitation of N- and O-glycosylation is vital to understanding the function(s) of different glycans expressed at a given site of a protein under physiological and disease conditions. Most commonly used precursor ion intensity based quantification method is less accurate and other labeled methods are expensive and require enrichment of glycopeptides. Here, we used glycopeptide product (y and Y0) ions and 18 O-labeling of C-terminal carboxyl group as a strategy to obtain quantitative information about fold-change and relative abundance of most of the glycoforms attached to the glycopeptides. As a proof of concept, the accuracy and robustness of this targeted, relative quantification LC-MS method was demonstrated using Rituximab. Furthermore, the N-glycopeptide quantification results were compared with a biosimilar of Rituximab and validated with quantitative data obtained from 2-AB-UHPLC-FL method. We further demonstrated the intensity fold-change and relative abundance of 46 unique N- and O-glycopeptides and aglycopeptides from innovator and biosimilar samples of Etanercept using both the normal-MS and product ion based quantitation. The results showed a very similar site-specific expression of N- and O-glycopeptides between the samples but with subtle differences. Interestingly, we have also been able to quantify macro-heterogeneity of all N- and O-glycopetides of Etanercept. In addition to applications in biotherapeutics, the developed method can also be used for site-specific quantitation of N- and O-glycopeptides and aglycopeptides of glycoproteins with known glycosylation pattern.

Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNF-α

PubMed Central

Warrington, Junie P.; Drummond, Heather A.; Granger, Joey P.

2015-01-01

Cerebrovascular complications and increased risk of encephalopathies are characteristic of preeclampsia and contribute to 40% of preeclampsia/eclampsia-related deaths. Circulating tumor necrosis factor-α (TNF-α) is elevated in preeclamptic women, and infusion of TNF-α into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNF-α has a mechanistic role to promote preeclampsia, the impact of TNF-α on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNF-α contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNF-α in pregnant rats (200 ng/day ip, from gestational day 14 to 19) at levels to mimic those reported in preeclamptic women. TNF-α increased mean arterial pressure (MAP, P < 0.05) and brain water content in the anterior cerebrum (P < 0.05); however, TNF-α infusion had no effect on blood-brain barrier (BBB) permeability in the anterior cerebrum or posterior cerebrum. We then assessed the role of endogenous TNF-α in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNF-α receptor (etanercept, 0.8 mg/kg sc) on gestational day 18. Etanercept reduced placental ischemia-mediated increases in MAP, anterior brain water content (P < 0.05), and BBB permeability (202 ± 44% in placental ischemic rats to 101 ± 28% of normal pregnant rats). Our results indicate that TNF-α mechanistically contributes to cerebral edema by increasing BBB permeability and is an underlying factor in the development of cerebrovascular abnormalities associated with preeclampsia complicated by placental ischemia. PMID:26400187

Disease activity-guided dose optimisation of adalimumab and etanercept is a cost-effective strategy compared with non-tapering tight control rheumatoid arthritis care: analyses of the DRESS study.

PubMed

Kievit, Wietske; van Herwaarden, Noortje; van den Hoogen, Frank Hj; van Vollenhoven, Ronald F; Bijlsma, Johannes Wj; van den Bemt, Bart Jf; van der Maas, Aatke; den Broeder, Alfons A

2016-11-01

A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be non-inferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, open-label, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost-effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of -€12 280 (95 percentile -€10 502; -€14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of -0.02 (-0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was €390 493 (€5 085 184; dominant) of savings per QALY lost. The mean iNMB was €10 467 (€6553-€14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. Disease activity-guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. NTR3216; Post-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review.

PubMed

Maneiro, Jose Ramon; Salgado, Eva; Gomez-Reino, Juan J; Carmona, Loreto

2012-08-01

To evaluate the safety, efficacy, and effectiveness of TNF antagonists in patients with sarcoidosis. A descriptive study of a case series registered in BIOBADASER and a systematic review was performed. The search strategy of articles published between 1998 and July 2011 in Medline, Embase, and the Cochrane Library included synonyms of sarcoidosis and synonyms of TNF antagonists. Seven patients treated with infliximab (IFX) and 1 with etanercept (ETN) switched to IFX for inefficacy were registered in BIOBADASER 2.0. In 3, treatment is still ongoing. Reasons for discontinuation were serious adverse events in 2 cases, inefficacy in 2 cases, and complete clinical response in 2 cases. Eight serious adverse events were reported. In the selected 69 of 2262 reports and 1 abstract of the review, 232 patients (89.9%) were treated with IFX and 26 (10.0%) were treated with ETN. In 2 randomized clinical trials, favorable response of the lung disease was reported with IFX. In other randomized clinical trials, no improvement of ocular manifestations was reported with ETN. In the cases series, results were diverse. Mean weighted rates of adverse events, infections, serious infections, and malignancy were 39.9, 22.1, 5.9, and 1.0 per 100 patient-years, respectively. There is insufficient evidence to ensure the efficacy of TNF antagonists in sarcoidosis. Nevertheless, IFX may be effective in selected manifestations of the disease. Before starting treatment of sarcoidosis with IFX, a careful evaluation of the benefit/risk ratio must be considered on an individual basis. Copyright © 2012 Elsevier Inc. All rights reserved.

Current treatment of juvenile rheumatoid arthritis.

PubMed

Ilowite, Norman T

2002-01-01

Prognostic factors in juvenile rheumatoid arthritis (JRA) include polyarticular onset, polyarticular disease course, and rheumatoid factor positivity; in the systemic onset subtype, persistence of systemic features at 6 months after onset confers a worse prognosis. Timely diagnosis and appropriate aggressive treatment of patients with poor prognostic features improve quality of life and outcome. After nonsteroidal anti-inflammatory drugs, methotrexate is the most commonly used second-line agent. However, approximately one third of patients do not respond to methotrexate adequately. Randomized, placebo-controlled, clinical trials in patients with JRA are few, but one such trial with the tumor necrosis factor inhibitor etanercept shows that this drug is effective and well-tolerated. Other recently approved agents for rheumatoid arthritis, including infliximab, leflunomide, celecoxib, and rofecoxib, have not been adequately studied in pediatric patients, and the role of these agents in children with JRA remains to be determined.

Herpes zoster: Risk and prevention during immunomodulating therapy.

PubMed

Tran, Cong Tri; Ducancelle, Alexandra; Masson, Charles; Lunel-Fabiani, Françoise

2017-01-01

Herpes zoster can be serious or incapacitating, particularly in patients whose immune system is compromised by a disease or treatment. Immunomodulating drugs can increase the risk of infection. Well-established risk factors include advanced age and glucocorticoid therapy. The data are somewhat conflicting for medications such as methotrexate, tofacitinib, TNFα antagonists (infliximab, adalimumab, etanercept, certolizumab, and golimumab), abatacept, tocilizumab, and rituximab. Nevertheless, the risk of herpes zoster is increased in patients taking biological agents, because of the underlying diseases and/or effects of the drugs. A live attenuated herpes zoster vaccine has been proven effective and safe in immunocompetent individuals. At present, however, it is not recommended for patients with immunodeficiencies, including those taking biological drugs, as no studies have assessed its risk/benefit ratio in this population. This situation may change in the near future, as recent data support the effectiveness and safety of the herpes zoster vaccine in patients who take biotherapies or have other causes of immunodeficiency. Alternative approaches designed to protect these patients from herpes zoster and its complications are also under evaluation. There is a need to define the indications of the herpes zoster vaccine in terms of the target population, timing, modalities, and frequency, according to the underlying chronic systemic disease, age group, varicella-zoster virus status, and exposure to therapeutic agents. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

The Efficacy and Safety of Mainstream Medications for Patients With cDMARD-Naïve Rheumatoid Arthritis: A Network Meta-Analysis.

PubMed

Cai, Weiyan; Gu, Youyi; Cui, Huanqin; Cao, Yinyin; Wang, Xiaoliang; Yao, Yi; Wang, Mingyu

2018-01-01

Background: The mainstream medications for rheumatoid arthritis (RA) include conventional disease-modifying antirheumatic drugs (cDMARDs), which mostly are methotrexate (MTX), and biologic agents such as adalimumab (ADA), certolizumab (CZP), etanercept (ETN), golimumab (GOL), infliximab (IFX), and tocilizumab (TCZ). This network meta-analysis was aimed at evaluating the efficacy and safety of the medications above and interventions combining cDMARDs and biologic agents for patients with RA. Methods: PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched systematically for eligible randomized controlled trials (RCTs). Outcomes concerning efficacy and safety were evaluated utilizing odds ratios (ORs) and 95% credible intervals ( CrI ). The outcomes of efficacy would be evaluated through remission and American College of Rheumatology (ACR) scores. The surface under the cumulative ranking curve (SUCRA) was calculated to rank each treatment on each index. Results: A total of 20 RCTs with 9,047 patients were included, and the efficacy and safety of the concerning interventions for RA were evaluated. Compared with cDMARDs alone, TCZ+MTX, ETN+MTX, IFX+MTX, TCZ, and ADA+MTX showed significant statistical advantage on ACR20, ACR50, and ACR70. Apart from that, as for remission, TCZ+MTX, IFX+MTX, TCZ, and CZP+MTX performed better compared to cDMARDs alone. The SUCRA ranking also indicated that TCZ+MTX was the intervention with best ranking in the entire four efficacy indexes followed by ETX+MTX and IFX+MTX. However, there was no obvious difference among these medications compared with cDMARDs when it comes to safety, which need more specific studies on that. Conclusion: TCZ+MTX was potentially the most recommended combination of medications for RA due to its good performance in all outcomes of efficacy. ETX+MTX and IFX+MTX, which also performed well, could be introduced as alternative treatments. However, considering the adverse events, the treatments concerning should be introduced with caution.

Open-label observation of addition of etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active rheumatoid arthritis despite methotrexate therapy in the Latin American region.

PubMed

Machado, Daniel A; Guzman, Renato M; Xavier, Ricardo M; Simon, J Abraham; Mele, Linda; Pedersen, Ronald; Ferdousi, Tahmina; Koenig, Andrew S; Kotak, Sameer; Vlahos, Bonnie

2014-01-01

Previous global studies examined etanercept (ETN) + methotrexate (MTX) for treatment of rheumatoid arthritis (RA), but included few subjects from Latin America. The objective of this study was to compare the safety and efficacy of ETN + MTX versus a standard-of-care disease-modifying antirheumatic drug (DMARD) + MTX in Latin American subjects with moderate to severe active RA despite MTX therapy. This open-label, active-comparator study (NCT00848354) randomized subjects 2:1 to ETN 50 mg/wk + MTX or investigator-selected DMARD (sulfasalazine or hydroxychloroquine) + MTX (ETN + MTX, n = 281; DMARD + MTX, n = 142). The primary end point was the proportion achieving American College of Rheumatology (ACR) 50 at week 24. Secondary end points included ACR20/70, disease activity score (DAS) 28 measures, and mean change in modified total Sharp score. Patient-reported outcomes were the Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment: RA (WPAI:RA), and Caregiver Burden and Resource Utilization. Statistical analyses were stratified by country; χ test and analysis of covariance were used. Adverse events were monitored. More subjects achieved ACR50 at week 24 with ETN + MTX versus DMARD + MTX (62% vs 23%, respectively), in addition to secondary end points (P < 0.0001 for all); mean change in modified total Sharp score was lower for the ETN + MTX group (0.4 vs 1.4, respectively; P = 0.0270). Improvements in patient-reported outcomes favored ETN + MTX for Health Assessment Questionnaire, 36-item Short-Form, Hospital Anxiety and Depression Scale for depression, WPAI:RA, and Caregiver Burden and Resource Utilization emergency department visits for RA (P < 0.01). Overall, adverse events were similar between the groups (69% vs 68%,); serious adverse events were also similar (4% vs 1%). The rate of overall infections was higher with ETN + MTX (38%) than DMARD + MTX (22%, P ≤ 0.001). Consistent with published global data among RA patients with inadequate response to MTX, adding ETN to MTX demonstrated better efficacy than adding one other conventional DMARD to MTX. No new safety issues were observed. ETN + MTX provided favorable benefit-risk profile among RA patients from LA region.

Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-alpha on this pathway.

PubMed

Pitidhammabhorn, Dhanesh; Kantachuvesiri, Surasak; Totemchokchyakarn, Kitti; Kitiyanant, Yindee; Ubol, Sukathida

2006-09-01

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiation in Vitro.

PubMed

Jeffery, Louisa; Fisk, Helena L; Calder, Philip C; Filer, Andrew; Raza, Karim; Buckley, Christopher D; McInnes, Iain; Taylor, Peter C; Fisher, Benjamin A

2017-06-01

To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF-driven Th17 cell differentiation. Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25- T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry. Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (-0.51, p = 0.007 and -0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro . Physiological concentrations of EPA, but not LA, prevented this. EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro . EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

The efficiency of biologic therapy in a group of patients with rheumatoid arthritis.

PubMed

Gavrilă, B I; Ciofu, C; Stoica, V; Panaitescu, E

2015-01-01

The following study aims to evaluate the monotherapy with biologic agents: Infliximab (IFX), Etanercept (ETA), Adalimumab (ADA) and Rituximab (RTX) in patients diagnosed with rheumatoid arthritis (RA). To achieve these objectives, the database of "Dr. I. Cantacuzino" Clinical Hospital, Department of Internal Medicine and Rheumatology, was used. The study was retrospective and descriptive, covering 168 patients with RA, followed for 12 months, from January 2012 to January 2013. Admission criteria for the study were the following: patients diagnosed with RA according to ACR 1987/ EULAR 2010 criteria, disease activity score (DAS 28)> 5.1, positive inflammation tests, presence of RA refractory to classic remitting treatment administered at least 6 months prior to the initiation of biological therapy, on patients treated with RTX. They were considered non-responders after 6 months of treatment with anti tumor necrosis factor alpha (anti-TNF) and decided to switch agents with anti CD-20. Comparing values between any two points in time (baseline - 6 months -12 months) for any type of therapy, there were significant decreases in the values of erythrocyte sedimentation rate (ESR), reactive C protein (CRP) and disease activity score (DAS 28). There were no significant differences between therapies regarding ESR at 6 months (p = 0.070, ANOVA) and 12 months (p = 0.375, Kruskal-Wallis), significant differences were regarding CRP at 6 and 12 months (p = 0.000, Kruskal-Wallis) and DAS 28 at 6 months (p = 0.000, Kruskal- Wallis) and 12 months (p = 0.018, Kruskal-Wallis). All 4 therapies have proven efficient, prognostic markers decreasing gradually at 6 and 12 months.

Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα

PubMed Central

Aschar-Sobbi, Roozbeh; Izaddoustdar, Farzad; Korogyi, Adam S.; Wang, Qiongling; Farman, Gerrie P.; Yang, FengHua; Yang, Wallace; Dorian, David; Simpson, Jeremy A.; Tuomi, Jari M.; Jones, Douglas L.; Nanthakumar, Kumaraswamy; Cox, Brian; Wehrens, Xander H.T.; Dorian, Paul; Backx, Peter H.

2015-01-01

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF. PMID:25598495

Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis

PubMed Central

Semeraro, Francesco; Arcidiacono, Barbara; Nascimbeni, Giuseppe; Angi, Martina; Parolini, Barbara; Costagliola, Ciro

2014-01-01

Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds. PMID:24711694

Anti-TNF therapy for juvenile idiopathic arthritis-related uveitis.

PubMed

Semeraro, Francesco; Arcidiacono, Barbara; Nascimbeni, Giuseppe; Angi, Martina; Parolini, Barbara; Costagliola, Ciro

2014-01-01

Juvenile idiopathic arthritis-related uveitis is the most common type of uveitis in childhood and one of the main causes of visual impairment in children. The introduction of biological treatment has widened the range of therapeutic options for children with uveitis refractory to standard nonbiologic immunosuppressants. Data from clinical trials suggest that both adalimumab and infliximab have demonstrated effectiveness and safety in open-label studies, although no large, randomized, controlled trials have been reported so far. The role of etanercept in treating juvenile idiopathic arthritis-related uveitis is not yet well defined. In our experience, anti-tumor necrosis factor therapy has been shown to be more effective than steroids and/or methotrexate in treating uveitis. Up to now, tumor necrosis factor blocking compounds have been reserved for the treatment of the most severe cases of refractory uveitis, and larger prospective clinical trials are required in order to better assess the safety of these new compounds.

Cost-effectiveness analysis of secukinumab for the treatment of active psoriatic arthritis: a Canadian perspective.

PubMed

Goeree, Ron; Chiva-Razavi, Sima; Gunda, Praveen; Graham, Christopher N; Miles, LaStella; Nikoglou, Efthalia; Jugl, Steffen M; Gladman, Dafna D

2018-02-01

The study evaluates the cost-effectiveness of secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A, vs currently licensed biologic treatments in patients with active psoriatic arthritis (PsA) from a Canadian healthcare system perspective. A decision analytic semi-Markov model evaluated the cost-effectiveness of secukinumab 150 mg and 300 mg compared to subcutaneous biologics adalimumab, certolizumab pegol, etanercept, golimumab, and ustekinumab, and intravenous biologics infliximab and infliximab biosimilar in biologic-naive and biologic-experienced patients over a lifetime horizon. The response to treatments was evaluated after 12 weeks by PsA Response Criteria (PsARC) response rates. Non-responders or patients discontinuing initial-line of biologic treatment were allowed to switch to subsequent-line biologics. Model input parameters (Psoriasis Area Severity Index [PASI], Health Assessment Questionnaire [HAQ], withdrawal rates, costs, and resource use) were collected from clinical trials, published literature, and other Canadian sources. Benefits were expressed as quality-adjusted life years (QALYs). An annual discount rate of 5% was applied to costs and benefits. The robustness of the study findings were evaluated via sensitivity analyses. Biologic-naive patients treated with secukinumab achieved the highest number of QALYs (8.54) at the lowest cost (CAD 925,387) over a lifetime horizon vs all comparators. Secukinumab dominated all treatments, except for infliximab and its biosimilar, which achieved minimally more QALYs (8.58). However, infliximab and its biosimilar incurred more costs than secukinumab (infliximab: CAD 1,015,437; infliximab biosimilar: CAD 941,004), resulting in higher cost-effectiveness estimates relative to secukinumab. In the biologic-experienced population, secukinumab dominated all treatments as it generated more QALYs (8.89) at lower costs (CAD 954,692). Deterministic sensitivity analyses indicated the results were most sensitive to variation in PsARC response rates, change in HAQ, and utility values in both populations. Secukinumab is either dominant or cost-effective vs all licensed biologics for the treatment of active PsA in biologic-naive and biologic-experienced populations in Canada.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis and Treatment With a Biologic: A Case Report.

PubMed

Chong, Ian; Chao, Alice

2017-01-01

One of the most dangerous dermatologic emergencies is Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). Although a rare disease, it can often lead to significant mortality. In this case report, we present a 77-year-old man who developed a sloughing rash that was secondary to a nonsteroidal anti-inflammatory drug. In addition to the recommended supportive care, the patient was treated with etanercept, a new, less commonly used intervention. We provide a brief review of SJS/TEN. Nonsteroidal anti-inflammatory drugs are a rare cause of SJS/TEN, and additionally, the use of biologics is a novel treatment modality for SJS/TEN.

Treatment of experimental adjuvant arthritis with a novel folate receptor-targeted folic acid-aminopterin conjugate

PubMed Central

2011-01-01

Introduction Folate receptor (FR)-expressing macrophages have been shown to accumulate at sites of inflammation, where they promote development of inflammatory symptoms. To target such a macrophage population, we designed and evaluated the biologic activity of EC0746, a novel folic acid conjugate of the highly potent antifolate, aminopterin. Methods Using a FR-positive subclone of murine macrophage-derived RAW264.7 cells and rat thioglycollate-elicited macrophages, we studied the effect of EC0746 on dihydrofolate reductase activity, cell proliferation, and cellular response towards bacterial lipopolysaccharide as well as IFNγ activation. The EC0746 anti-inflammatory activity, pharmacokinetics, and toxicity were also evaluated in normal rats or in rats with adjuvant-induced arthritis; that is, a FR-positive macrophage model that closely resembles rheumatoid arthritis in humans. Results EC0746 suppresses the proliferation of RAW264.7 cells and prevents the ability of nonproliferating rat macrophages to respond to inflammatory stimuli. In the macrophage-rich rat arthritis model, brief treatment with subcutaneously administered EC0746 is shown to mediate an FR-specific anti-inflammatory response that is more potent than either orally administered methotrexate or subcutaneously delivered etanercept. More importantly, EC0746 therapy is also shown to be ~40-fold less toxic than unmodified aminopterin, with fewer bone marrow and gastrointestinal problems. Conclusions EC0746 is the first high FR-binding dihydrofolate reductase inhibitor that demonstrates FR-specific anti-inflammatory activities both in vitro and in vivo. Our data reveal that a relatively toxic anti-inflammatory drug, such as aminopterin, can be targeted with folic acid to inflammatory macrophages and thereby relieve inflammatory symptoms with greatly reduced toxicity. PMID:21463515

Biosimilars: a regulatory perspective from America

PubMed Central

2011-01-01

Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product. This paper reviews the processes for approval of biosimilars in the US and the European Union and highlights recent changes in federal regulations governing the approval of biosimilars in the US. PMID:21586106

Biosimilars: a regulatory perspective from America.

PubMed

Kay, Jonathan

2011-05-12

Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product. This paper reviews the processes for approval of biosimilars in the US and the European Union and highlights recent changes in federal regulations governing the approval of biosimilars in the US.

Listeriosis in patients receiving biologic therapies.

PubMed

Bodro, M; Paterson, D L

2013-09-01

The evolution of inflammatory diseases has radically changed since the introduction of biologic therapies, such as tumour necrosis factor alpha inhibitors (anti-TNFα). They, therefore, represent a widely used therapeutic modality. Nevertheless, post-marketing studies reveal an increased risk of infection in patients taking these drugs, especially granulomatous infections such as listeriosis. We aimed to evaluate the reported cases of listeriosis in patients treated with biologic treatments. We used the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) from 2004 to 2011. We also perform a literature review of previously reported cases of listeriosis in patients taking biologic therapies. We identified 266 cases of Listeria monocytogenes infection associated with biologic therapies. The majority of patients were receiving infliximab (77.1 %), followed by etanercept (11.7 %), adalimumab (9.8 %), rituximab (4.1 %), abatacept (0.4 %) and golimumab (0.4 %). Indications for the use of biologics were as follows: 47.7 % for rheumatologic diseases, 38 % for inflammatory bowel diseases, 3.4 % for haematological diseases and 10.5 % for other indications. Seventy-three percent of the patients were receiving concomitant immunosuppressant drugs, especially steroids (56 %) and methotrexate (31.6 %). The median time to the onset of infection was 184 days. Mortality rates range from 11.1 % in adalimumab-treated patients to 27.3 % in rituximab-treated patients (p = 0.7). Listeriosis is common in biologics-treated patients, especially related to infliximab use given concomitantly with other immunosuppressive therapies. Infections after treatment with biologics mostly occurred in the first year after initiating treatment.

Impact of TNF-α antagonists on the quality of life in selected skin diseases.

PubMed

Gisondi, P; Girolomoni, G

2013-06-01

Aim of the study was to investigate the impact of TNF-α antagonists on health-related quality of life (HRQoL) in selected skin diseases, i.e. chronic plaque psoriasis, Behçet's disease (BD), hidradenitis suppurativa (HS) and pyoderma gangrenosum (PG). We have carried out a systematic literature search of Medline (2000 to April 2013) using the Cochrane highly sensitive and specific search strategy. Citations were screened for randomized, controlled trials of TNF-α antagonists (adalimumab, etanercept and infliximab) versus placebo in adults with psoriasis, BD, HS or PG. From the literature it is evident that skin diseases can affect physical, psychological, social and occupational aspects of everyday life. TNF-α antagonists induced consistent benefits across health outcomes in psoriasis, but only monoclonal antibodies, infliximab and adalimumab were effective in improving QoL in patients with BD, HS and PG. Dermatology Life Quality Index was the most common used tool for investigating HRQoL. For the majority of patients with skin diseases, the most important negative impacts on QoL were appearance related. Generally, the burden on QoL was correlated to the severity of skin disease and the improvement in QoL achieved by TNF-α blockers was proportional to the degree of disease remission. HRQoL issues are becoming even more important in evaluating medical care, including treatment of skin diseases. In general, achieving the highest clearing of skin disease with anti-TNF-α agents is required for optimal improvement in QoL.

An update on pharmacogenomics in rheumatoid arthritis with a focus on TNF-blocking agents.

PubMed

Ranganathan, Prabha

2008-12-01

TNFalpha is a proinflammatory cytokine, which is crucial in the pathogenesis of rheumatoid arthritis (RA). In recent years, biological therapies which block the damaging effects of TNFalpha on synovium and cartilage have been developed. TNF antagonists, such as etanercept, infliximab and adalimumab, although highly effective in RA, are expensive, totaling several thousand US dollars in yearly costs. In addition, only approximately 60% of patients respond to these agents. This has led to the need to prospectively identify patients most likely to respond to these agents, which can be achieved by pharmacogenomics approaches. Polymorphisms in genes encoding for TNFalpha, the MHC region, and the Fcgamma receptor IIIA, as well as their ability to predict disease progression in RA and response to anti-TNF therapies, have been the focus of a number of studies, which are discussed in this review. There is no consensus at present as to whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA. Large, prospective, multicenter studies are needed to replicate and validate the results of the studies outlined in this review.

Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

PubMed Central

Lu, Yingjuan; Parker, Nikki; Kleindl, Paul J; Cross, Vicky A; Wollak, Kristin; Westrick, Elaine; Stinnette, Torian W; Gehrke, Mark A; Wang, Kevin; Santhapuram, Hari Krishna R; You, Fei; Hahn, Spencer J; Vaughn, Jeremy F; Klein, Patrick J; Vlahov, Iontcho R; Low, Philip S; Leamon, Christopher P

2015-01-01

Folate receptor (FR)-β has been identified as a promising target for antimacrophage and antiinflammatory therapies. In the present study, we investigated EC0565, a folic acid–derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Because of its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture and FR-binding specificity. Using FR-expressing macrophages, the effect of EC0565 on mTOR signaling and cellular proliferation was studied. The pharmacokinetics, metabolism and bioavailability of EC0565 were studied in normal rats. The in vivo activity of EC0565 was assessed in rats with adjuvant arthritis, a “macrophage-rich” model with close resemblance to rheumatoid arthritis. EC0565 forms micellar aggregates in physiological buffers and demonstrates good water solubility as well as strong multivalent FR-binding capacity. EC0565 inhibited mTOR signaling in rat macrophages at nanomolar concentrations and induced G0/G1 cell cycle arrest in serum-starved RAW264.7 cells. Subcutaneously administered EC0565 in rats displayed good bioavailability and a relatively long half-life (~12 h). When given at 250 nmol/kg, EC0565 selectively inhibited proliferating cell nuclear antigen expression in thioglycollate-stimulated rat peritoneal cells. With limited dosing regimens, the antiarthritic activity of EC0565 was found superior to that of etanercept, everolimus and a nontargeted everolimus analog. The in vivo activity of EC0565 was also comparable to that of a folate-targeted aminopterin. Folate-targeted mTOR inhibition may be an effective way of suppressing activated macrophages in sites of inflammation, especially in nutrient-deprived conditions, such as in the arthritic joints. Further investigation and improvement upon the physical and biochemical properties of EC0565 are warranted. PMID:26181632

S3 Guideline for the treatment of psoriasis vulgaris, update - Short version part 1 - Systemic treatment.

PubMed

Nast, Alexander; Amelunxen, Lasse; Augustin, Matthias; Boehncke, Wolf-Henning; Dressler, Corinna; Gaskins, Matthew; Härle, Peter; Hoffstadt, Bernd; Klaus, Joachim; Koza, Joachim; Mrowietz, Ulrich; Ockenfels, Hans-Michael; Philipp, Sandra; Reich, Kristian; Rosenbach, Thomas; Rzany, Berthold; Schlaeger, Martin; Schmid-Ott, Gerhard; Sebastian, Michael; von Kiedrowski, Ralph; Weberschock, Tobias

2018-05-01

The German guideline for the treatment of psoriasis vulgaris was updated using GRADE methodology. The guideline is based on a systematic literature review completed on December 1, 2016, and on a formal consensus and approval process. The first section of this short version of the guideline covers systemic treatment options considered relevant by the expert panel and approved in Germany at the time of the consensus conference (acitretin, adalimumab, apremilast, cyclosporine, etanercept, fumaric acid esters, infliximab, methotrexate, secukinumab and ustekinumab). Detailed information is provided on the management and monitoring of the included treatment options. © 2018 The Authors | Journal compilation © Blackwell Verlag GmbH, Berlin.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis and Treatment With a Biologic: A Case Report

PubMed Central

Chong, Ian; Chao, Alice

2017-01-01

Introduction One of the most dangerous dermatologic emergencies is Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). Although a rare disease, it can often lead to significant mortality. Case Presentation In this case report, we present a 77-year-old man who developed a sloughing rash that was secondary to a nonsteroidal anti-inflammatory drug. In addition to the recommended supportive care, the patient was treated with etanercept, a new, less commonly used intervention. Discussion We provide a brief review of SJS/TEN. Nonsteroidal anti-inflammatory drugs are a rare cause of SJS/TEN, and additionally, the use of biologics is a novel treatment modality for SJS/TEN. PMID:28488978

Complications and adverse reactions in the use of newer biologic agents.

PubMed

Callen, Jeffrey P

2007-03-01

New developments in genetic engineering and biotechnology have allowed the creation of bioengineered molecules that target specific steps in the pathogenesis of several immune-mediated disorders, including Crohn's disease, rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, pemphigus, and B-cell lymphoma. These drugs work by eliminating pathogenic T cells (alefacept), blocking T-cell activation and/or inhibiting the trafficking of T cells (efalizumab), changing the immune profile from Th1 to Th2, blocking cytokines (eg, tumor necrosis factor alpha antagonists including etanercept, infliximab and adalimumab, or interleukin-1-receptor antagonists [anakinra]), or eliminating pathogenic B cells (rituximab). This article reviews the complications and adverse reactions associated with these medications.

Etanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant

ClinicalTrials.gov

2017-09-01

Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Juvenile Myelomonocytic Leukemia; Previously Treated Childhood Rhabdomyosarcoma; Previously Treated Myelodysplastic Syndromes; Pulmonary Complications; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Recurrent/Refractory Childhood Hodgkin Lymphoma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Atlantoaxial Instability in a Patient with Neck Pain and Ankylosing Spondylitis.

PubMed

Lyons, Christian; Ross, Michael; Elliott, Ryan; Tall, Michael

2018-03-26

The purpose of this report is to describe the evaluation and treatment of a patient with neck pain and ankylosing spondylitis who had underlying atlantoaxial instability. The patient was a 31-yr-old man diagnosed with ankylosing spondylitis 1 yr prior who was referred to a physical therapist for the treatment of chronic, worsening low back and hip pain. He also had secondary complaints of neck, upper back, and shoulder pain. The patient worked as a military pilot. As part of the patient's physical examination, a Sharp-Purser test was performed, which was positive for excessive motion. Diagnostic imaging confirmed the atlantoaxial instability; it was also determined that the patient's atlanto-occipital joints were fused. Despite evidence of atlantoaxial instability, it was determined the patient would be managed through nonsurgical interventions. The patient was prescribed etanercept by his rheumatologist and the physical therapist developed a comprehensive rehabilitation program that addressed relevant impairments of the spine, hips, and shoulders. At 3 yr following his initial evaluation with the physical therapist, the patient continued to report minimal bodily pain and no limitations in his functional capabilities. Additionally, the patient had earned a high profile flying position with an aggressive flying schedule and he successfully completed his first running marathon. It is important for clinicians to have an understanding of the clinical findings associated with atlantoaxial instability, as these findings provide guidance for diagnostic imaging and specialist referral prior to initiating conservative management strategies, such as physical therapy.

Health economic analyses of psoriasis management: a systematic literature search.

PubMed

Gutknecht, Mandy; Krensel, Magdalene; Augustin, Matthias

2016-11-01

In the course of the chronic skin disease psoriasis, where a variety of treatment interventions is available, a strong growth of health economic studies comparing treatment costs and benefits can be noticed. The objective was to identify health economic evaluations of psoriasis treatments that have been published to date. Of particular interest were the mostly used analysis and outcome parameters, the compared treatments, and the question, if available health economic studies may be used to perform a meta-analysis of qualitative findings. A systematic literature search using PubMed Medline, Ovid Medline, and Cochrane Library was performed for articles, published and available until mid of January 2016. Among the key words were the terms "psoriasis" and "cost-effectiveness". The search resulted in 318 articles without duplicates. Thereof 60 health economic analyses in psoriasis management were identified. Most of these are cost-effectiveness evaluations (45). The clinical parameter PASI (Psoriasis Area Severity Index) is the most often used cost-effectiveness outcome (33) followed by the Dermatology Life Quality Index (DLQI) (6). In case of cost-utility analyses, QALYs (quality-adjusted life-years) were mostly generated with the help of EuroQol five dimensions questionnaire (EQ-5D) (12), which was partly based on PASI and DLQI values. The majority of health economic studies is focusing on the direct medical and non-medical costs without consideration of productivity losses. Almost 70 % of 60 publications were conducted in Europe. Overall, most considered systemic treatments were the biological agents etanercept (36), adalimumab (27), and infliximab (26) followed by ustekinumab (17) and phototherapy (incl. UV-B, PUVA/psoralen combined with UV-A) (14). Comparisons including only topical treatments mostly focused on vitamin D treatment (14), corticosteroids (13), and coal tar products (6) followed by dithranol (5) and tazarotene (4). Given the setting, compared treatments, and study conditions, different results can be found for medical decision-making. Thereby, it can be noted that there are no standards on methods and outcomes measures available. This leads to a very limited comparability of health economic studies and presents no comfortable basis to examine a meta-analysis of health economic results. The presented systematic review shows the need for nationwide data and interpretation.

Cost-Effectiveness of TNF-Blocker Injection Spacing for Patients with Established Rheumatoid Arthritis in Remission: An Economic Evaluation from the Spacing of TNF-Blocker Injections in Rheumatoid Arthritis Trial.

PubMed

Vanier, Antoine; Mariette, Xavier; Tubach, Florence; Fautrel, Bruno

2017-04-01

In patients with rheumatoid arthritis in remission, a disease activity-driven tapering of adalimumab or etanercept relying on progressive injection spacing has not been shown to be equivalent to a maintenance strategy at full dose in terms of disease activity in the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS) trial. To evaluate the cost-effectiveness of such a spacing strategy based on the data of the STRASS trial. This is a cost-utility analysis of the STRASS trial, a French multicenter 18-month equivalence randomized open-label controlled trial that included patients at stable dose for at least 1 year, in remission for at least 6 months. Effectiveness was assessed in quality-adjusted life-years (QALYs). Costs involved in the study period were assessed from a payer perspective. The decremental cost-effectiveness ratio (DCER) was calculated in the complete cases sample (n = 98). Several sensitivity analyses were conducted and the impact of missing data on DCER estimate was investigated. An acceptability analysis was performed. In the spacing arm, TNF-blockers were stopped for 34.1% of the patients, tapered for 43.2%, and maintained at full dose for 18.2%. The spacing strategy was associated with less QALYs gain (mean difference of -0.158; 95% confidence interval [CI] -0.085 to -0.232) and reduced costs (mean difference of -€8,440; 95% CI -6,507 to -10,212). The estimated DCER of the spacing strategy over the maintenance at full dose was €53,417 saved per QALY lost (95% CI 32,230 to 104,700). The spacing strategy appears cost-effective, but the acceptability of such a QALY loss reported to the cost avoided remains to be evaluated, because no consensual threshold has been determined for willingness to accept as compared with willingness to pay. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

The Effect of Reduced or Withdrawn Etanercept-methotrexate Therapy on Patient-reported Outcomes in Patients with Early Rheumatoid Arthritis.

PubMed

Wiland, Piotr; Dudler, Jean; Veale, Douglas; Tahir, Hasan; Pedersen, Ron; Bukowski, Jack; Vlahos, Bonnie; Williams, Theresa; Gaylord, Stefanie; Kotak, Sameer

2016-07-01

An analysis of a clinical trial to assess the effects of treatment reduction and withdrawal on patient-reported outcomes (PRO) in patients with early, moderate to severe rheumatoid arthritis (RA) who achieved 28-joint Disease Activity Score (DAS28) low disease activity (LDA) or remission with etanercept (ETN) plus methotrexate (MTX) therapy. During treatment induction, patients received open-label ETN 50 mg weekly plus MTX for 52 weeks. In the reduced-treatment phase, patients with DAS28-erythrocyte sedimentation rate (ESR) ≤ 3.2 at Week 39 and DAS28-ESR < 2.6 at Week 52 in the open-label phase were randomized to double-blind treatment with ETN 25 mg plus MTX, MTX, or placebo (PBO) for 39 weeks (weeks 0-39). In the third phase, patients who achieved DAS28 remission (DAS28-ESR < 2.6) or LDA (2.6 ≤ DAS28-ESR ≤ 3.2) at Week 39 in the double-blind phase had all treatment withdrawn and were observed for an additional 26 weeks (weeks 39-65). Of the 306 patients enrolled, 193 were randomized in the double-blind phase and 131 participated in the treatment-withdrawal phase. After reduction or withdrawal of ETN 50 mg/MTX, patients reduced to ETN 25 mg/MTX experienced slight, nonsignificant declines in the majority of PRO measures, whereas switching to PBO or MTX alone caused significant declines. Presenteeism and activity impairment scores were significantly better in the ETN reduced-dose group versus MTX monotherapy and PBO at Week 39 (p ≤ 0.05). In patients with early RA who achieved remission while receiving full-dose ETN/MTX, continuing combination therapy at a lower dose did not cause a significant worsening of PRO response, but switching to MTX alone or PBO did. ClinicalTrials.gov identifier: NCT00913458.

Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.

PubMed

Zhang, Qian; Cao, De-Li; Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

2016-07-11

Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation. CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

Treatment of severe psoriasis in children: recommendations of an Italian expert group.

PubMed

Fortina, Anna Belloni; Bardazzi, Federico; Berti, Samantha; Carnevale, Claudia; Di Lernia, Vito; El Hachem, Maya; Neri, Iria; Gelmetti, Carlo Mario; Lora, Viviana; Mazzatenta, Carlo; Milioto, Mirella; Moretta, Gaia; Patrizi, Annalisa; Peris, Ketty; Villani, Alberto

2017-10-01

This article provides comprehensive recommendations for the systemic treatment of severe pediatric psoriasis based on evidence obtained from a systematic review of the literature and the consensus opinion of expert dermatologists and pediatricians. For each systemic treatment, the grade of recommendation (A, B, C) based on the treatment's approval by the European Medicines Agency for childhood psoriasis and the experts' opinions is discussed. The grade of recommendation for narrow-band-ultraviolet B phototherapy, cyclosporine, and retinoids is C, while that for methotrexate is C/B. The use of adalimumab, etanercept, and ustekinumab has a grade A recommendation. No conventional systemic treatments are approved for pediatric psoriasis. Adalimumab is approved by the European Medicines Agency as a first-line treatment for severe chronic plaque psoriasis in children (≥ 4 years old) and adolescents. Etanercept and ustekinumab are approved as second-line therapy in children ≥ 6 and ≥ 12 years, respectively. A treatment algorithm as well as practical tools (i.e., tabular summaries of differential diagnoses, treatment mechanism of actions, dosing regimens, control parameters) are provided to assist in therapeutic reasoning and decision-making for individual patients. These treatment recommendations are endorsed by major Italian Pediatric and Dermatology Societies. What is Known: • Guidelines for the treatment of severe pediatric psoriasis are lacking and most traditional systemic treatments are not approved for use in young patients. Although there has been decades of experience with some of the traditional agents such as phototherapy, acitretin, and cyclosporine in children, there are no RCTs on their pediatric use while RCTs investigating new biologic agents have been performed. What is New: • In this manuscript, an Italian multidisciplinary team of experts focused on treatment recommendations for severe forms of psoriasis in children based on an up-to-date review of the literature and experts' opinions.

Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA).

PubMed

Klotsche, Jens; Niewerth, Martina; Haas, Johannes-Peter; Huppertz, Hans-Iko; Zink, Angela; Horneff, Gerd; Minden, Kirsten

2016-05-01

Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited. To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment. Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation. We calculated the relative risks of SAE and ESI for ETA and ADA compared with methotrexate (MTX). Among the 1414 patients treated with ETA (n=1414; 4461 exposure years (EY)) and ADA (n=320; 493 EY), significantly more SAE, infections and medically important infections were observed (ETA: 4.5, 5.7, 0.9; ADA: 4.7, 11.4, 0.4 per 100 EY) compared with those treated with MTX alone (n=1455; 2.907 EY; 2.6, 5.5, 0.5 per 100 EY). The risk for malignancies was not significantly increased for ETA and ADA compared with MTX (0.09, 0.27 and 0.07/100 person-years). Patients under ETA monotherapy developed more frequently incident inflammatory bowel disease (IBD) and incident uveitis (0.5 and 0.8/100 EY) than patients treated by ETA in combination with MTX (0.1 and 0.2/100 EY) or MTX alone (0.03 and 0.1/100 EY). Our data confirm the acceptable long-term tolerability of ETA and ADA in pJIA. However, whether the onset of IBD and uveitis during ETA monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Therapies for peripheral joint disease in psoriatic arthritis. A systematic review.

PubMed

Soriano, Enrique R; McHugh, Neil J

2006-07-01

Traditional drug treatments for psoriatic arthritis (PsA) include nonsteroidal antiinflammatory agents (NSAID) and disease modifying antirheumatic drugs (DMARD), although the evidence base for their effectiveness is not well established. This review was compiled from a comprehensive literature search of electronic bibliographic databases for all English publications that were systematic reviews, metaanalyses, randomized controlled trials, controlled trials, and observational studies. The evidence supports NSAID for symptom relief, although data are lacking for COX-2-specific agents. No evidence exists to support systemic corticosteroids or corticosteroids by intraarticular injection, although the latter are commonly used in clinical practice. Among traditional DMARD, grade 1B evidence supports sulfasalazine, cyclosporine, and leflunomide for symptom relief, with lower-grade evidence for methotrexate. None of them slows radiographic progression. Grade 1B evidence supports improvement in symptoms, physical function, quality of life, and radiographic progression with anti-TNF antagonists (etanercept, infliximab, and adalimumab). The relative lack of evidence poses challenges in developing algorithms for treatment of peripheral arthritis in PsA.

[Medical treatment of juvenile idiopathic arthritis].

PubMed

Horneff, Gerd; Augustin, Sankt

2008-09-01

Juvenile idiopathic arthritis is the most common chronic autoimmune disease. The outcome of this inflammatory disease is uncertain. Patients may suffer from severe joint damage leading to mutilations as well as from extraarticular manifestations. The prognosis is variable and depends in part on the number of affected joints and the occurrence of extraarticular manifestations. Pharmacomedical treatment has changed markedly in the last decade. It consists of a combination therapy including nonsteroidal antirheumatics, glucocorticoids either systemic or intraarticular, classical disease modifying drugs like sulfasalazine and methotrexate as well as leflunomide and biologicals. These new therapeutic strategies have effected dramatic improvements also in patients with severe, so far intractable disease. The TNF inhibitors etanercept and adalimumab have succeeded in double blind controlled trials, while infliximab failed to show significant superiority over placebo. Further treatment options include inhibitors of interleukin 1 (anakinra and rilonacept), interleukin 6 (tocilizumab) and inhibitors of T-cell activation (abatacept). This review will summarize the pharmacotherapeutic options based on studies published in the literature.

Fluorescence correlation spectroscopy to study antibody binding and stoichiometry of complexes

NASA Astrophysics Data System (ADS)

Swift, Kerry M.; Matayoshi, Edmund D.

2008-02-01

FCS (fluorescence correlation spectroscopy) was used to study the association at the single molecule level of tumor necrosis factor alpha (TNF-α) and two of its protein antagonists Humira (TM) (adalimumab), a fully humanized monoclonal antibody, and Enbrel (TM) (etanercept), a soluble form of the TNF receptor. Single molecule approaches potentially have the advantage not only of enhanced sensitivity, but also of observing at equilibrium the details that would otherwise be lost in classical ensemble experiments where heterogeneity is averaged. We prepared fluorescent conjugates of the protein drugs and their biological target, the trimeric soluble form of TNF-α. The bivalency of adalimumab and the trimeric nature of TNF-α potentially allow several forms of associative complexes that may differ in stoichiometry. Detailed knowledge of this reaction may be relevant to understanding adalimumab's pharmacological properties. Our FCS data showed that a single trimeric TNF-α can bind up to three adalimumab molecules. Under some conditions even larger complexes are formed, apparently the result of cross-linking of TNF-α trimers by adalimumab. In addition, distinct differences between Humira and Enbrel were observed in their association with TNF-α.

Severe and acute complications of biologics in psoriasis.

PubMed

Oussedik, Elias; Patel, Nupur U; Cash, Devin R; Gupta, Angela S; Feldman, Steven R

2017-12-01

Biologic therapies have revolutionized the approach to immune-mediated diseases such as psoriasis. Due to their favorable safety profiles and excellent efficacy, biologic agents are considered the gold standard for moderate-to-severe psoriasis. The aim of this paper is to saliently review the severe and acute complications of the Food and Drug Administration (FDA) approved biologic agents for psoriasis. Reviewed agents include tumor necrosis factor alpha inhibitors (etanercept, infliximab, and adalimumab), interleukin 12/23 inhibitors (ustekinumab), and interleukin 17 (IL-17) inhibitors (secukinumab and ixekizumab). While malignancies, serious infections, and major adverse cardiovascular events have been reported, their association with biologic therapy are not hypothesized as causal. However, IL-17 inhibitors appear to cause exacerbations and new cases of inflammatory bowel disease. While more long-term studies are warranted in understanding the biologic's long-term side effect profile, short-term studies have confirmed that the biologics are some of the safest treatment options for psoriasis. Nevertheless, certain populations yield higher risk to acute complications with the biologics than others - physicians must use their judgement and vigilance when monitoring and treating patients undergoing therapy with biological agents.

From the Medical Board of the National Psoriasis Foundation: Perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis.

PubMed

Choi, Young M; Debbaneh, Maya; Weinberg, Jeffrey M; Yamauchi, Paul S; Van Voorhees, Abby S; Armstrong, April W; Siegel, Michael; Wu, Jashin J

2016-10-01

Treatment with systemic immunomodulatory agents is indicated for patients with moderate to severe plaque psoriasis and psoriatic arthritis. In these patients, surgery may confer an increased risk of infectious or surgical complications. We conducted a literature review to examine studies addressing the use of methotrexate, cyclosporine, and targeted immunomodulatory agents (tumor necrosis factor-alfa inhibitors, interleukin [IL]-12/23 inhibitors, IL-17 inhibitors) in patients undergoing surgery. We examined 46 total studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. One study in patients with psoriasis and psoriatic arthritis reviewed 77 procedures and did not find an elevated risk of postoperative complications with tumor necrosis factor-alfa and IL-12/23 inhibitors even with major surgeries. Based on level III evidence, infliximab, adalimumab, etanercept, methotrexate, and cyclosporine can be safely continued through low-risk operations in patients with psoriasis and psoriatic arthritis. For moderate- and high-risk surgeries, a case-by-case approach should be taken based on the patient's individual risk factors and comorbidities. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients.

PubMed

Calvo-Río, Vanesa; Blanco, Ricardo; Santos-Gómez, Montserrat; Rubio-Romero, Esteban; Cordero-Coma, Miguel; Gallego-Flores, Adela; Veroz, Raúl; Torre, Ignacio; Hernández, Félix Francisco; Atanes, Antonio; Loricera, Javier; González-Vela, M C; Palmou, Natalia; Hernández, José L; González-Gay, Miguel A

2016-08-01

To assess the efficacy of golimumab (GLM) in refractory uveitis associated to spondyloarthritis (SpA). Multicenter study of SpA-related uveitis refractory to at least 1 immunosuppressive drug. The main outcome variables were degree of anterior and posterior chamber inflammation, visual acuity, and macular thickness. A total of 15 patients (13 men/2 women; 18 affected eyes; mean age 39 ± 6 years) were evaluated. The underlying SpA subtypes were ankylosing spondylitis (n = 8), psoriatic arthritis (n = 6) and non-radiographic axial SpA (n = 1). The ocular involvement patterns were recurrent anterior uveitis in 8 patients and chronic anterior uveitis in 7. Before GLM they have received methotrexate (n = 13), sulfasalazine (n = 6), pulses of methylprednisolone (n = 4), azathioprine (n = 3), leflunomide (n = 2), and cyclosporine (n = 1). Overall, 10 of them had also been treated with TNF-α blockers; etanercept (n = 7), adalimumab (n = 7), infliximab (n = 6), and certolizumab (n = 1). GLM was given at the standard dose (50mg/sc/monthly) as monotherapy (n = 7) or in combination with conventional immunosuppressive drugs (n = 8), mainly methotrexate. Most patients had rapid and progressive improvement of intraocular inflammation parameters. The median number of cells in the anterior chamber at 2 years [0 (0-0)] was significantly reduced compared to baseline findings [1 (0-3); p = 0.04]. The mean best corrected visual acuity value also improved (0.84 ± 0.3 at 2 years versus 0.62 ± 0.3 at baseline; p = 0.03). Only minor side effects were observed after a mean follow-up of 23 ± 7 months. Our results indicate that GLM may be a useful therapeutic option in refractory SpA-related uveitis. Copyright © 2016 Elsevier Inc. All rights reserved.

Golimumab for the treatment of psoriatic arthritis: a NICE single technology appraisal.

PubMed

Yang, Huiqin; Craig, Dawn; Epstein, David; Bojke, Laura; Light, Kate; Bruce, Ian N; Sculpher, Mark; Woolacott, Nerys

2012-04-01

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from a single phase III randomized controlled trial (GO-REVEAL) that compared golimumab with placebo for the treatment of active and progressive patients who were symptomatic despite the use of previous DMARDs or NSAIDs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 (relative risk [RR] 5.73, 95% CI 3.24, 10.56) and Psoriatic Arthritis Response Criteria (PsARC) [RR 3.45, 95% CI 2.49, 4.87], and significantly improved skin disease response as measured by Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62, 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients' functional status as measured by Health Assessment Questionnaire change from baseline at 24 weeks (-0.33; p < 0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. The ERG identified several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice. No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics. The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab was a cost-effective treatment option, the manufacturer's own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally effective, then etanercept, adalimumab and golimumab had almost equal costs and equal QALYs, and all had an ICER of about £15 000 per QALY versus palliative care, whilst infliximab, with a higher acquisition cost, was dominated by the other biologics. The Appraisal Committee altered its position between the Appraisal Consultation Document and the Final Appraisal Determination. It ultimately recommended that golimumab be provided as an option for the treatment of active and progressive PsA in adults only if (i) it is used as described for other tumour necrosis factor inhibitor treatments in 'Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis' (NICE clinical guideline 199); and (ii) the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.

Tofacitinib suppresses disease activity and febrile attacks in a patient with coexisting rheumatoid arthritis and familial Mediterranean fever.

PubMed

Gök, Kevser; Cengiz, Gizem; Erol, Kemal; Ozgocmen, Salih

2017-01-01

Familial Mediterranean fever (FMF) is the most common hereditary auto-inflammatory (periodic fever) syndrome, and usually successfully treated with colchicine. However, nearly 5-10% of FMF cases are resistant or intolerant to colchicine and treatment options are highly restricted in these cases. Biologics including anakinra, canakinumab, rilonacept, etanercept, infliximab, interferon-alpha, and tocilizumab are shown to have efficacy to control FMF attacks. Tofacitinib, a Janus kinase (JAK) inhibitor, is an orally administered non-biologic disease modifying anti-rheumatic drug for the treatment of rheumatoid arthritis (RA). Herein we report a female patient with coexisting RA and colchicine resistant FMF whose FMF attacks and disease activity were completely controlled after treatment with tofacitinib, a small-molecule JAK3 inhibitor.

[Anti-TNF alpha in dermatology].

PubMed

Mahe, E; Descamps, V

2002-12-01

The discovery of the major role of TNF alpha in the physiopathology of certain inflammatory diseases and notably in rheumatoid arthritis and Crohn's disease has led to the development of anti-TNF alpha drugs. These new therapeutic arms issued from bio-technology have rapidly demonstrated their efficacy in the treatment of these two diseases. The anti-TNF alpha arsenal is currently dominated by etanercept, a fusion protein composed of a soluble TNF alpha receptor, and infliximab, a chimeric monoclonal antibody. However, new molecules will soon enrich this arsenal. TNF alpha is a major cytokine of inflammatory diseases of the skin. Many dermatological diseases will probably benefit from these new treatments. Two studies have already demonstrated their interest in cutaneous and articular psoriasis. Encouraging sporadic results suggest other potential indications (Behcet's disease, bullous dermatitis, neutrophilic dermatitis, toxic epidermal necrolysis, systemic vascularitis,.). These promising new treatments, although expensive, and with yet unknown long term side effects, justify rigorous assessment of their efficacy and tolerance in each indication. Here again the dermatologist has a major role to play in post-marketing pharmacovigilance.

Emerging Drugs for Uveitis

PubMed Central

Larson, Theresa; Nussenblatt, Robert B.; Sen, H. Nida

2010-01-01

Importance of the Field Uveitis is a challenging disease covering both infectious and noninfectious conditions. The current treatment strategies are hampered by the paucity of randomized controlled trials (RCTs) and few trials comparing efficacy of different agents. Areas Covered in this Review This review describes the current and future treatments of uveitis. A literature search was performed in PUBMED from 1965 to 2010 on drugs treating ocular inflammation with emphasis placed on more recent, larger studies. What the Reader Will Gain Readers should gain a basic understanding of current treatment strategies beginning with corticosteroids and transitioning to steroid sparing agents. Steroid sparing agents include the antimetabolites which include methotrexate, azathioprine, and mycophenolate mofetil; the calcineurin inhibitors which include cyclosporine, tacrolimus; alkylating agents which include cyclophosphamide and chlorambucil; and biologics which include the TNF-α inhibitors infliximab, adalimumab, and etanercept; daclizumab, interferon α2a, and rituximab. Take Home Message Newer agents are typically formulated from existing drugs or developed based on new advances in immunology. Future treatment will require a better understanding of the mechanisms involved in autoimmune diseases and better delivery systems in order to provide targeted treatment with minimal side effects. PMID:21210752

Psychometric properties of sleep and coping numeric rating scales in rheumatoid arthritis: a subanalysis of an etanercept trial.

PubMed

Avila-Ribeiro, Pedro; Brault, Yves; Dougados, Maxime; Gossec, Laure

2017-01-01

In rheumatoid arthritis, quality of sleep and ability to cope are important for patients; however their usefulness as outcome measures is not well established. Post-hoc analysis of an open-label 12-week trial of etanercept in biologic-naïve rheumatoid arthritis patients with visits at screening, baseline and over 12 weeks. Outcomes measured included Disease Activity Score 28 erythrocyte sedimentation rate (DAS28), numeric rating scales for sleep, coping, patient and physician-global assessment, pain and fatigue, and modified-HAQ. Reliability between screening and baseline visits by intra-class correlation, and responsiveness between baseline and 12 weeks by standardised response means were assessed for each outcome. In 108 patients, mean age 54 (standard deviation (SD) 13) years, mean disease duration 8 (SD 7) years, 75% women; disease activity was high at baseline: mean DAS28 5.5 (SD 0.8). Reliability intra-class correlation was 0.83[95% confidence interval: 0.77;0.88] for sleep, 0.81[0.74;0.87] for modified-HAQ, 0.80[0.71;0.86] for fatigue, 0.72[0.62;0.80] for physician-global assessment, 0.66[0.54;076] for coping, 0.65[0.53;0.75] for pain and 0.63[0.50;0.73] for patient-global assessment. Responsiveness standardised response means was 1.65[1.32;2.10] for physician-global assessment, 1.37[1.09;1.73] for pain, 1.36[1.08;1.73] for patient-global assessment, 1.15[0.95;1.41] for fatigue, 0.96[0.70;1.28] for coping, 0.92[0.73;1.15] for sleep and 0.86[0.69;1.07] for modified-HAQ. Numeric rating scales assessing sleep and coping were found to be generally as reliable as 'usual' outcomes in rheumatoid arthritis. Responsiveness was less high, indicating these domains of health may be less accessible to biologic treatment. When assessing the patient's perspective on treatment, it is feasible and valid to measure sleep and coping by numeric rating scales.

The impact of biologic therapy in chronic plaque psoriasis from a societal perspective: an analysis based on Italian actual clinical practice.

PubMed

Polistena, B; Calzavara-Pinton, P; Altomare, G; Berardesca, E; Girolomoni, G; Martini, P; Peserico, A; Puglisi Guerra, A; Spandonaro, F; Vena Gino, A; Chimenti, S; Ayala, F

2015-12-01

Psoriasis is one of the most common forms of chronic dermatitis, affecting 2-3% of the worldwide population. It has a serious effect on the way patients perceive themselves and others, thereby prejudicing their quality of life and giving rise to a significant deterioration in their psycho-physical well-being; it also poses greater difficulties for them in leading a normal social life, including their ability to conduct a normal working life. All the above-mentioned issues imply a cost for the society. This study proposes to evaluate the impact on societal costs for the treatment of chronic plaque psoriasis with biologics (etanercept, infliximab and adalimumab) in the Italian clinical practice. A prospective observational study has been conducted in 12 specialized centres of the Psocare network, located throughout Italy. Direct and indirect costs (as well as the health-related quality of life of patients with plaque psoriasis undergoing biologic treatments) have been estimated, while the societal impact has been determined using a cost-utility approach. Non-medical and indirect costs account for as much as 44.97% of the total cost prior to treatment and to 6.59% after treatment, with an overall 71.38% decrease. Adopting a societal perspective in the actual clinical practice of the Italian participating centres, the ICER of biologic therapies for treating plaque psoriasis amounted to €18634.40 per QALY gained--a value far from the €28656.30 obtained by adopting a third-party payer perspective. Our study confirms that chronic psoriasis subjects patients to a considerable burden, together with their families and caregivers, stressing how important it is to take the societal perspective into consideration during the appraisal process. Besides, using data derived from Italian actual practice, treatment with biologics shows a noteworthy benefit in social terms. © 2015 European Academy of Dermatology and Venereology.

Long-term changes in the quality of life of patients with rheumatoid arthritis treated with biological therapies.

PubMed

Ortega-Valín, Luis; Mayorga-Bajo, Isabel; Prieto-Fernández, Carolina; Del Pozo-Ruiz, Javier; Gutiérrez-Gutiérrez, Esperanza; Pérez-Sandoval, Trinidad

2017-02-27

To analyze the changes in health-related quality of life (HRQoL) of patients with rheumatoid arthritis (RA) treated with biological therapies. Observational prospective study performed from October 2006 to May 2011. The inclusion criteria were adult patients, diagnosed with RA, treated for at least one year with anti-tumor necrosis factor therapy (infliximab or etanercept), who had not received other biological treatments previously. A total of 41 patients who completed the study undertook the specific and validated questionnaire QoL-RA Scale 3 times: E1 (September 2006-February 2007), E2 (April 2008-January 2009) and E3 (July 2010- May 2011). Data analysis was conducted using Epi-Info version 3.3 2004 for Windows® and Excel 2007; mean comparisons were evaluated by Student's t-test and the relationship between the 3 outcomes for each patient by lineal regression. Overall results show a downward trend which was not statistically significant: 7.09 (standard deviation [SD]=1.15) in E1; 6.90 (SD=1.60) in E2; and 6.52 (SD=1.59) in E3. Items with higher scores were those related to psychosocial aspects (help from family, interaction with family and friends), whereas the physical dimension was valued more poorly (physical ability, arthritis pain, arthritis). Between E2 and E3 there was a significant increase in help from family (P=.0008), whereas level of tension (P=.0119) and mood (P=.0451) decreased significantly. In all, HRQoL reported by patients is good and has remained unchanged after approximately 6 years of study. The stability of HRQoL is probably partly attributable to treatment. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Economic evaluation of tocilizumab monotherapy compared to adalimumab monotherapy in the treatment of severe active rheumatoid arthritis.

PubMed

Carlson, Josh J; Ogale, Sarika; Dejonckheere, Fred; Sullivan, Sean D

2015-03-01

To estimate the cost-effectiveness of tocilizumab (TCZ) monotherapy (Mono) versus adalimumab (ADA) Mono from the US payer perspective in patients with rheumatoid arthritis for whom methotrexate is inappropriate. We compared TCZ Mono (8 mg/kg monthly) with ADA Mono (40 mg every other week), using efficacy results from a head-to-head study, ADalimumab ACTemrA (ADACTA). We calculated the incremental cost per responder (achievement of American College of Rheumatology [ACR] 20% improvement criteria, ACR 50% improvement criteria, ACR 70% improvement criteria, or low disease activity score) for TCZ versus ADA at 6 months. A patient-level simulation was used to estimate the lifetime incremental cost per quality-adjusted life-year (QALY) of initiating treatment with TCZ Mono versus ADA Mono. Both drugs are followed by an etanercept-certolizumab-palliative care sequence. Nonresponders discontinue at 6 months; responders experience a constant probability of discontinuation. Discontinuers move to the next treatment. ACR responses produce changes in the Health Assessment Questionnaire (HAQ) score. We mapped the HAQ score to utility to estimate QALYs. Costs include those related to hospitalization and those related to treatment (drug acquisition, administration, and monitoring). Probabilistic and one-way sensitivity analyses were conducted, along with several scenario analyses. Compared with ADA, TCZ was more effective, with an estimated 6-month incremental cost ranging from $6,570 per additional low disease activity score achiever to $14,265 per additional ACR 70% improvement criteria responder. The lifetime incremental cost-effectiveness ratio was $36,944/QALY. TCZ Mono is projected to be cost-effective compared with ADA Mono in patients with severe rheumatoid arthritis for whom methotrexate is not appropriate, from a US payer perspective. Copyright © 2015. Published by Elsevier Inc.

Biological Response Modifiers in Rheumatoid Arthritis: Systematic Review and Meta-analysis of Safety

PubMed Central

Tank, Nitishkumar D.; Karelia, Bharti N.; Vegada, Bhavisha N.

2017-01-01

Objective: To analyze available evidence on the safety of different biological response modifiers which are used for a treatment of rheumatoid arthritis (RA). Materials and Methods: We searched systematically for randomized controlled clinical trials on treatment of RA with different biological response modifiers, followed by a systematic review with meta-analysis. Trials were searched from MEDLINE and Cochrane Library databases. The following safety parameters reported in the selected trials were analyzed: number of patients suffering any adverse event (AE), withdrawal due to AEs, serious AE (SAEs), infections, serious infections, infusion reactions, injection site reactions, malignancies, and overall mortality. Undesired effects were estimated using combined relative risks (RR) and number needed to harm (NNH). Heterogeneity was evaluated by Cochrane's Q and I2 statistics. Results: According to inclusion criteria, a total of 43 trials (20,504 patients) were included in this study. A total number of AEs were found more with abatacept (RR: 1.05, NNH: 21.93). Withdrawal due to AEs was found with all biologicals, highest with anakinra (RR: 3.48, NNH: 15.70). Patients receiving newer tumor necrosis factor-alpha inhibitors, golimumab, were more likely to develop SAEs (RR: 2.44, NNH: 12.72) and infection (RR: 1.25, NNH: 10.09), and in certolizumab, serious infections (RR: 2.95, NNH: 37.31) were found more. Infusion reaction develops more with rituximab (RR: 1.52, NNH: 8.47). Etanercept showed the highest risk to develop infusion site reaction (RR: 5.33, NNH: 4.65). Biologicals showed no difference to their control counterparts in malignancy and mortality risk. Conclusion: This meta-analysis helps to clarify some frequently encountered and unanswered safety questions of different biological response modifiers, a new class of drugs, in the clinical care of RA patients. PMID:29081616

Autologous Adipose-Derived Mesenchymal Stromal Cells for the Treatment of Psoriasis Vulgaris and Psoriatic Arthritis: A Case Report.

PubMed

De Jesus, Miguel M; Santiago, Jayson S; Trinidad, Camille V; See, Melvin E; Semon, Kimberly R; Fernandez, Manuel O; Chung, Francisco S

2016-11-01

Psoriasis is a dermatologic disease of immune origins with no definitive cure. We report the Makati Medical Center experience of utilizing autologous mesenchymal stromal cells (MSCs) for one patient with psoriasis vulgaris (PV) and another with psoriatic arthritis (PA). Patients were educated and gave informed consent, according to the principles of the Declaration of Helsinki. The protocol was approved by the Cellular Transplantation Ethics Committee of the Makati Medical Center. Autologous MSCs were cultured from lipoaspirate and expanded in a clean room class 100 facility (Cellular Therapeutics Center, Makati Medical Center). MSCs were infused intravenously at a dose of 0.5-3.1 million cells/kg after complying with quality control parameters. Psoriasis area and severity index (PASI) evaluations were conducted by third-party dermatologists. The PA patient, who was previously unresponsive to standard treatment modalities, demonstrated a decrease in PASI (from 21.6 to 9.0, mild state after two infusions). No improvements were noted in joint pain until further treatment with etanercept and infliximab. The PV patient, who was previously dependent on methotrexate, showed a decrease in PASI from 24.0 to 8.3 after three infusions; this clinical improvement was sustained for 292 days (9.7 months) without methotrexate. The PV patient illustrated a marginal reduction in serum tumor necrosis factor-α (TNF-α), while significant (3.5- to 5-fold) decreases in reactive oxygen species (ROS) activity were noted. The ROS levels correlated with the clinical improvement of the PV patient. No serious adverse events were noted for either patient as a result of MSC infusions. This report demonstrates safe and tolerable transplantation of autologous MSCs for the treatment of psoriasis and warrants large clinical studies to investigate the long-term safety and efficacy of this approach.

Midyear Commentary on Trends in Drug Delivery and Clinical Translational Medicine: Growth in Biosimilar (Complex Injectable Drug Formulation) Products Within Evolving Collaborative Regulatory Interagency (FDA, FTC, and DOJ) Practices and Enforcement

PubMed Central

Ho, Rodney J.Y.

2017-01-01

Before the 2009 Biologics Price Competition and Innovation Act that enabled the U.S. Federal Drug Administration (FDA) to create the 351(k) Biologic License Application–an abbreviated biosimilar approval process, FDA approved follow-on biomolecule products such as beta-interferon, glucagon, hyaluronidase, and somatropin (human growth hormone) under varying and evolving rules. With the 351(k) Biologic License Application biosimilar approval process in place, currently, there are 4 (licensed in 2015–2016) biosimilars available, namely Neupogen (filgrastim; $1 B/y), Humira (adalumumab; $14.2 B/y), Enbrel (etanercept; $8.7 B/y), and Remicade (infliximab; $6.5 B/y). With well-established product market capitalization of these and other top income producers—such as Rituxan (rituximab; $6.8 B/y), Herceptin (trastuzumab; $6.5 B/y), and Avastin (bevacizumab; $5.8 B/y), and a price differential of 15%–30% compared to branded products, there is an intense interest in development of biosimilars by established pharmaceutical companies. Currently, there are 160 biosimilar candidates in clinical studies, many of which are sponsored by large pharmaceutical companies known for product innovation. This trend will likely continue. Additional information on a biomolecule platform is presented in the Journal of Pharmaceutical Sciences Drug Delivery Clinical Trials Database (jpharmscidatabase.org). There are 44,789, 18,456, and 12,897 clinical trials registered to evaluate (1) drug delivery technology, (2) biomolecule platform, and (3) drug metabolism and pharmacokinetic-pharmacodynamic interactions; representing 19%–60% increase over the last 3 years. PMID:27876365

Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to-Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials.

PubMed

Armstrong, April W; Lynde, Charles W; McBride, Sandy R; Ståhle, Mona; Edson-Heredia, Emily; Zhu, Baojin; Amato, David; Nikaï, Enkeleida; Yang, Fan Emily; Gordon, Kenneth B

2016-06-01

Therapies that reduce psoriasis symptoms may improve work productivity. To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to-severe chronic plaque psoriasis were included. In UNCOVER-1, patients were randomized 1:1:1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50 mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. Change in work productivity from baseline as measured by WPAI-PSO scores. Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI-PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P < .001; -2.6 [0.84], P = .003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P < .001; -18.3 [1.24], P < .001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P < .001; -19.8 [1.33], P < .001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P < .001; -25.2 [1.15], P < .001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P < .001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P = .009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. Ixekizumab-treated patients reported short- and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis. clinicaltrials.gov Identifiers: NCT01474512, NCT01597245, NCT01646177.

Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection.

PubMed

Gómez-Reino, Juan J; Carmona, Loreto; Angel Descalzo, Miguel

2007-06-15

To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103-285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60-64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.

AVX-470: A Novel Oral Anti-TNF Antibody with Therapeutic Potential in Inflammatory Bowel Disease

PubMed Central

Bhol, Kailash C.; Tracey, Daniel E.; Lemos, Brenda R.; Lyng, Gregory D.; Erlich, Emma C.; Keane, David M.; Quesenberry, Michael S.; Holdorf, Amy D.; Schlehuber, Lisa D.; Clark, Shawn A.; Fox, Barbara S.

2013-01-01

Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the GI tract that is currently treated with injected monoclonal antibodies specific for tumor necrosis factor (TNF). We developed and characterized AVX-470, a novel polyclonal antibody specific for human TNF. We evaluated the oral activity of AVX-470m, a surrogate antibody specific murine TNF, in several well-accepted mouse models of IBD. Methods AVX-470 and AVX-470m were isolated from the colostrum of dairy cows that had been immunized with TNF. The potency, specificity and affinity of both AVX-470 and AVX-470m were evaluated in vitro and compared with infliximab. AVX-470m was orally administered to mice either before or after induction of colitis and activity was measured by endoscopy, histopathology, immunohistochemistry and quantitative measurement of mRNA levels. Colitis was induced using either 2,4,6-trinitrobenzene sulfonate (TNBS) or dextran sodium sulfate (DSS). Results AVX-470 and AVX-470m were shown to be functionally comparable in vitro. Moreover, the specificity, neutralizing potency and affinity of AVX-470 were comparable to infliximab. Orally administered AVX-470m effectively reduced disease severity in several mouse models of IBD. Activity was comparable to that of oral prednisolone or parenteral etanercept. The antibody penetrated the colonic mucosa and inhibited TNF-driven mucosal inflammation with minimal systemic exposure. Conclusions AVX-470 is a novel polyclonal anti-TNF antibody with an in vitro activity profile comparable to that of infliximab. Oral administration of a surrogate antibody specific for mouse TNF is effective in treating mouse models of IBD, delivering the anti-TNF to the site of inflammation with minimal systemic exposure. PMID:23949620

Mechanisms and Treatments of Heterotopic Ossification Following Spinal Cord Injuries

DTIC Science & Technology

2016-10-01

tissues  from  the  completed etanercept and GW2580 experiments are being processed for  immunohistology to  stain  for  markers of M1 and M2...a defined  area of the muscle. We observed that HO developed only if the mechanical damage was combined with  injection of  Gram ‐negative bacterial... staining  on archival sections of mouse hind limb muscles  generated prior to this award. As illustrated in Figure 4, we are able to successfully  stain

Off-Label Uses of Anti-TNF Therapy in Three Frequent Disorders: Behçet's Disease, Sarcoidosis, and Noninfectious Uveitis

PubMed Central

Sánchez-Cano, Daniel; Callejas-Rubio, José Luis; Ruiz-Villaverde, Ricardo; Ríos-Fernández, Raquel; Ortego-Centeno, Norberto

2013-01-01

Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID:23983404

Follow-up of 1887 patients receiving tumor necrosis-alpha antagonists: Tuberculin skin test conversion and tuberculosis risk.

PubMed

Cagatay, Tulin; Bingol, Zuleyha; Kıyan, Esen; Yegin, Zeynep; Okumus, Gulfer; Arseven, Orhan; Erkan, Feyza; Gulbaran, Ziya; Erelel, Mustafa; Ece, Turhan; Cagatay, Penbe; Kılıçaslan, Zeki

2018-04-01

To evaluate the characteristics of patients who developed tuberculosis while receiving tumor necrosis factor-alpha (TNF-α) antagonists and the related factors with tuberculosis. Patient's demographics, tuberculin skin test (TST), isoniazid prophylaxis and type of TNF-α antagonist were recorded. TST conversion (≥5 mm increase) was evaluated for patients who had baseline and 1-year TST. Files of 1887 patients who were receiving TNF-α antagonists between August 2005 and June 2015 were evaluated. TST significantly increased at the end of 1 year (n = 748 baseline:7.36 ± 7.2 mm vs. 1 year:9.52 ± 7.5 mm, P < 0.001). One-third of patients (31.2%) who had negative TST at baseline had positive TST at 1 year. Tuberculosis developed in 22 patients (1.16%). The annual incidence of tuberculosis was 423/100 000 patient-year. TNF-α antagonist indications were ankylosing spondylitis (n = 8), inflammatory bovel diseases (n = 7) and rheumatoid arthritis (n = 4). Ten (45.5%) patients received infliximab, six (27.3%) patients received etanercept and six (27.3%) patients received adalimumab. Nineteen (86.4%) patients were under isoniazid prophylaxis. Twelve patients had extrapulmonary tuberculosis (54.5%; four lymph node, three pleura, two periton, one pericarditis, one intestinal, one joint). Atypical mycobacterium was detected in one patient. Adalimumab treatment (9.5× increase), male sex (15.6× increase) and previous tuberculosis disease history (11.5× increase) were risk factors for active tuberculosis. Conversion of TST was not found related with tuberculosis. Despite the high proportion of isoniazid prophylaxis, the incidence of tuberculosis in our patients receiving TNF-α antagonist was higher than the literature. Adalimumab treatment, male sex and previous tuberculosis disease history were found as risk factors for tuberculosis. © 2017 John Wiley & Sons Ltd.

Short and long-term immunogenicity and safety following the 23-valent polysaccharide pneumococcal vaccine in juvenile idiopathic arthritis patients under conventional DMARDs with or without anti-TNF therapy.

PubMed

Aikawa, Nadia E; França, Ivan L A; Ribeiro, Ana C; Sallum, Adriana M E; Bonfa, Eloisa; Silva, Clovis A

2015-01-29

To assess immunogenicity and safety of the 23-valent polysaccharide pneumococcal vaccine (PPV23) in juvenile idiopathic arthritis (JIA) patients under conventional DMARDs with or without anti-TNF therapy. The influences of demographic data, disease activity and treatment on immune response and the potential deleterious effects of vaccine on disease itself were also evaluated. 17 JIA patients immediately pre-etanercept (Group 1) and 10 JIA patients on stable dose of methotrexate (Group 2) received one dose of PPV23. All patients were evaluated pre-vaccination, 2 months and 12 months post-vaccination for seven pneumoccocal serotypes. Serology was performed by enzyme immunoassay and the immunogenicity endpoints included seroprotection (SP), seroconversion (SP) and geometric mean concentration of antibodies(GMC). Clinical and laboratorial parameters of JIA were evaluated before and after vaccination. Groups 1 and 2 were comparable regarding age, gender, disease duration and other DMARDs use (p>0.05). Pre-immunization SP and GMC were alike in patients with and without anti-TNF therapy (p>0.05). The frequencies of patients achieving adequate vaccine response (seroconversion in ≥50% of all serotypes) at 2 months (53 vs. 30%, p=0.424) and 12 months (36 vs. 40%, p=1.0) were similar in JIA patients with and without anti-TNF therapy. Further comparison of patients with and without adequate response at 2 months revealed no influence of demographic, clinical and laboratorial JIA parameters (p>0.05). Serious adverse events were not observed. Anti-TNF therapy in JIA patients does not seem to have an additional deleterious effect on short/long-term PPV23 immunogenicity compared to MTX alone and no influence on disease parameters was observed with this vaccine. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effectiveness of treatment with biologic- and disease-modifying antirheumatic drugs in rheumatoid arthritis patients in Colombia.

PubMed

Machado-Alba, J E; Ruiz, A F; Machado-Duque, M E

2016-06-01

Rheumatoid arthritis (RA) is an autoimmune disease cause of disability and high costs. To determine the effectiveness of therapy with biologic- and disease-modifying antirheumatic drugs (DMARDs) in patients with RA and factors associated with the control of the disease. Retrospective cohort study of RA patients receiving treatment with DMARDs in a rheumatologic healthcare institution in five Colombian cities from December 2009 to August 2013. The effectiveness was assessed by Disease Activity Score-28 (DAS-28) and a lower value of 2.6 was considered remission. A total of 827 patients were studied for an average observation period of 17.3 ± 11.0 months, with mean age 54.3 ± 13.1 years. The most frequently used DMARDs were methotrexate, leflunomide and chloroquine. The most frequently used biological DMARDs were etanercept and abatacept. Initially, 17.8% of the patients received some biological DMARDs in comparison with 28.7% at the end of the observation period. A median DAS28 of 3.5 was found, which was reduced by the end of the observation period to 2.8 (p < 0.001), and cases of patients who were in remission increased from 30.1% to 42.9%. Treatment with leflunomide (OR: 0.47; CI 95%: 0.35-0.64, p < 0.001) or rituximab (OR: 0.37; CI 95%: 0.17-0.83, p = 0.016) was associated with a lesser probability of reaching remission. To be treated in the city of Manizales (OR: 2.56; CI 95%: 1.36-4.82, p = 0.004) was associated with a high probability of remission. Biological and DMARDs therapy for RA was effective in a relevant proportion of Colombian patients as a consequence of management with strategies set on remission aims quantified using DAS28. Cost-effectiveness of the therapy must be evaluated. © 2016 John Wiley & Sons Ltd.

Salivary dysfunction associated with systemic diseases: systematic review and clinical management recommendations.

PubMed

von Bültzingslöwen, Inger; Sollecito, Thomas P; Fox, Philip C; Daniels, Troy; Jonsson, Roland; Lockhart, Peter B; Wray, David; Brennan, Michael T; Carrozzo, Marco; Gandera, Beatrice; Fujibayashi, Takashi; Navazesh, Mahvash; Rhodus, Nelson L; Schiødt, Morten

2007-03-01

The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.

Systematic review of randomized controlled trials in the treatment of dry eye disease in Sjogren syndrome.

PubMed

Shih, Kendrick Co; Lun, Christie Nicole; Jhanji, Vishal; Thong, Bernard Yu-Hor; Tong, Louis

2017-01-01

Primary Sjögren's syndrome is an autoimmune disease characterized by dry eye and dry mouth. We systematically reviewed all the randomized controlled clinical trials published in the last 15 years that included ocular outcomes. We found 22 trials involving 9 topical, 10 oral, 2 intravenous and 1 subcutaneous modalities of treatment. Fluoromethalone eye drops over 8 weeks were more effective than topical cyclosporine in the treatment of dry eye symptoms and signs; similarly, indomethacin eye drops over 1 month were more efficacious than diclofenac eye drops. Oral pilocarpine 5 mg twice daily over 3 months was superior to use of lubricants or punctal plugs for treating dry eye, but 5% of participants had gastrointestinal adverse effects from pilocarpine, though none discontinued treatment. In contrast, etanercept, a TNF-alpha blocking antibody, administered as subcutaneous injections twice weekly, did not improve dry eye significantly compared to placebo injections. In conclusion, topical corticosteroids have been shown to be effective in dry eye associated with Sjögren's syndrome. As some topical non-steroidal anti-inflammatory drugs may be more effective than others, these should be further evaluated. Systemic secretagogues like pilocarpine have a role in Sjögren's syndrome but the adverse effects may limit their clinical use. It is disappointing that systemic cytokine therapy did not produce encouraging ocular outcomes but participants should have assessment of cytokine levels in such trials, as those with higher baseline cytokine levels may respond better. (229 words).

Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNFα Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients

PubMed Central

2015-01-01

Objective. To analyze the clinical relevance of the levels of TNFα blockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time. Methods. Clinical characteristics (disease activity, and adverse events), serum TNFα blockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFα blockers for a median of 28 months. Results. Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and nonresponders (P > 0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08–120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64–52.52)). Conclusion. Patients not responding to treatment had higher serum anti-ADA and anti-INF Ab concentrations. Anti-INF Ab formation is related to increased risk of infusion related reactions, changing to another biologic drug, and treatment discontinuation. PMID:26064930

Potential use of TNF-α inhibitors in systemic sclerosis.

PubMed

Murdaca, Giuseppe; Spanò, Francesca; Contatore, Miriam; Guastalla, Andrea; Puppo, Francesco

2014-01-01

Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-α has a central role in initial host response to infections and in the pathogenesis of various systemic immune-mediated diseases. Serum levels of TNF-α are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF-α inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-α inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc.

Cost Sharing, Family Health Care Burden, and the Use of Specialty Drugs for Rheumatoid Arthritis

PubMed Central

Karaca-Mandic, Pinar; Joyce, Geoffrey F; Goldman, Dana P; Laouri, Marianne

2010-01-01

Objectives To examine the impact of benefit generosity and household health care financial burden on the demand for specialty drugs in the treatment of rheumatoid arthritis (RA). Data Sources/Study Setting Enrollment, claims, and benefit design information for 35 large private employers during 2000–2005. Study Design We estimated multivariate models of the effects of benefit generosity and household financial burden on initiation and continuation of biologic therapies. Data Extraction Methods We defined initiation of biologic therapy as first-time use of etanercept, adalimumab, or infliximab, and we constructed an index of plan generosity based on coverage of biologic therapies in each plan. We estimated the household's burden by summing up the annual out-of-pocket (OOP) expenses of other family members. Principal Findings Benefit generosity affected both the likelihood of initiating a biologic and continuing drug therapy, although the effects were stronger for initiation. Initiation of a biologic was lower in households where other family members incurred high OOP expenses. Conclusions The use of biologic therapy for RA is sensitive to benefit generosity and household financial burden. The increasing use of coinsurance rates for specialty drugs (as under Medicare Part D) raises concern about adverse health consequences. PMID:20831715

Myasthenia gravis: an update for the clinician

PubMed Central

Sieb, J P

2014-01-01

This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term ‘myasthenia gravis’ includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte– macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective. PMID:24117026

Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication.

PubMed

Heiligenhaus, A; Mingels, A; Heinz, C; Ganser, G

2007-01-01

To study the value of methotrexate (MTX) and the requirement for additional anti-inflammatory drugs for the treatment of severe chronic iridocyclitis associated with juvenile idiopathic arthritis (JIA). Institutional study of 35 consecutive patients with JIA started on MTX as the single systemic immunosuppressive drug for the treatment of associated iridocyclitis. The clinical epidemiologic data, course of visual acuity (VA), development of complications, and the need for additional anti-inflammatory drugs were analyzed. Mean follow-up with MTX treatment was 27.6 months. Uveitic complications were present in 31 patients before MTX treatment. With MTX, quiescence of uveitis was obtained with (n=21) or without (n=4) additional topical steroids. Additional systemic immunosuppressive drugs were required in another 7 patients: cyclosporine A (n=4), azathioprine (n=1), infliximab (n=1), or etanercept (n=1). Three patients had active uveitis at the end of the follow-up period. During MTX therapy, uveitis first developed in the unaffected fellow eyes in 2 patients, and secondary glaucoma or ocular hypertension occurred in 7 patients. The VA deteriorated in 6, improved in 13, and was stable in the remaining eyes. The data suggest that MTX is very effective in controlling inflammation of uveitis in patients with JIA. However, additional topical steroids or systemic immunosuppressive drugs are often required.

Can Islamic prayers benefit spondyloarthritides? Case report of a patient with ankylosing spondylitis and increased spinal mobility after an intensive regimen of Islamic prayer.

PubMed

Badsha, Humeira; Tak, Paul P

2008-08-01

A 35-year-old Arab male had severe Ankylosing Spondylitis for 10 years with syndesmophyte formation in the lumbar spine, decreased spinal mobility (modified Schoeber's test of 0.5 cm), BASDAI of 4, and BASFI score of 6. He was initially started on non- steroidal anti-inflammatory medications (NSAID) and a regular swimming program as well as physiotherapy. Due to lack of response he was started on Etanercept monotherapy. After 1 month his modified Schober's had improved to 1 cm, BASDAI to 2, and BASFI to 1. At 5 months after starting treatment, there was no further improvement. Patient embarked on an intensive regimen of Islamic prayers during the month of Ramadan, lasting approximately 2 h daily, for 1 month. At the end of 1 month he had improved spinal mobility with a modified schober's test of 2.5 cm and stable BASFI scores. Islamic prayers consist of several postures, including stretching, bending and kneeling. Further study is needed, but Muslim patients can be easily motivated to perform long hours of Islamic prayers, and this can offer benefits, when used in conjunction with conventional treatments, for spondyloarthritis.

Human brucellosis mimicking axial spondyloarthritis: a challenge for rheumatologists when applying the 2009 ASAS criteria.

PubMed

Ye, Cong; Shen, Gui-Fen; Li, Shou-Xin; Dong, Ling-Li; Yu, Yi-Kai; Tu, Wei; Zhu, Ying-Zi; Hu, Shao-Xian

2016-06-01

Although the development of the 2009 SpA classification criteria by Assessment of SpondyloArthritis international Society (ASAS) represents an important step towards a better definition of the early disease stage particularly in axial spondyloarthritis (axSpA), the specificity of the criteria has been criticized these days. As the commonest zoonotic infection worldwide, human brucellosis can mimic a large number of diseases, including SpA. This study was performed to determine the frequency of rheumatologic manifestations in patients with brucellosis and the chance of misdiagnosing them as having axSpA in central China. The results showed that clinical manifestations of axSpA could be observed in brucellosis. Over half of patients had back pain, and one fifth of the patients with back pain were less than 45 years old at onset and had the symptom for more than 3 months. Two young males were falsely classified as suffering from axSpA according to the ASAS criteria, and one with MRI proved sacroiliitis was once given Etanercept for treatment. Therefore, differential diagnosis including human brucellosis should always be kept in mind when applying the ASAS criteria, even in traditionally non-endemic areas.

Current drug therapy for rheumatoid arthritis.

PubMed

Kawai, Shinichi

2003-01-01

The etiology of rheumatoid arthritis (RA) remains unclear at present, but advances have been made in the drug therapy for RA. Recent attention has been focused on selective cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit a subtype of cyclooxygenase. Various clinical studies have confirmed that the selective COX-2 inhibitors cause fewer severe gastrointestinal complications, although an increased incidence of myocardial infarction was suggested. Terminal enzymes of the arachidonic acid cascade, such as membrane-associated prostaglandin E synthase, might be a target for new NSAIDs in the near future. Low-dose glucocorticoid treatment for RA has been reconsidered possibly to prevent articular destruction of RA. Special attention for glucocorticoid-induced osteoporosis by concomitant administration of bisphosphonates might be necessary. Disease-modifying antirheumatic drugs should be effective in delaying the progression of joint destruction and physical disability. Methotrexate, sulfasalazine, and leflunomide have shown such an effect. Inhibition of articular destruction was also proven by administration of the biologic agents etanercept and infliximab plus methotrexate. Tuberculosis complicated with infliximab therapy is one of the most important concerns in Japan. Agents that improve the quality of life of patients with RA are still needed.

Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Xin-Ai; Jia, Lin-Lin; Cui, Wei

We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heartmore » weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of TNF-α attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of TNF-α attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of TNF-α attenuates hypertension-induced imbalance of cytokines. • PVN inhibition of TNF-α attenuates PVN NF-κB p65 activity and oxidative stress.« less

Cost-effectiveness of TNF inhibitors vs synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a Markov model study based on two longitudinal observational studies.

PubMed

Kvamme, Maria K; Lie, Elisabeth; Uhlig, Till; Moger, Tron A; Kvien, Tore K; Kristiansen, Ivar S

2015-07-01

The objective of this study was to estimate the additional costs and health benefits of adding a TNF inhibitor (TNFi) (adalimumab, certolizumab, etanercept, golimumab, infliximab) to a synthetic DMARD (sDMARD), e.g. MTX, in patients with RA. We developed the Norwegian RA model as a Markov model simulating 10 years of treatment with either TNFi plus sDMARDs (TNFi strategy) or sDMARDs alone (synthetic strategy). Patients in both strategies started in one of seven health states, based on the Short Form-6 Dimensions (SF-6D). The patients could move to better or worse health states according to transition probabilities. In the TNFi strategy, patients could stay on TNFi (including switch of TNFi), or switch to non-TNFi-biologics (abatacept, rituximab, tocilizumab), sDMARDs or no DMARD. In the synthetic strategy, patients remained on sDMARDs. Data from two observational studies were used for the assessment of resource use and utilities in the health states. Health benefits were evaluated using the EuroQol-5 Dimensions (EQ-5D) and SF-6D. The Norwegian RA model predicted that 10-year discounted health care costs totalled €124,942 (€475,266 including production losses) for the TNFi strategy and €65,584 (€436,517) for the synthetic strategy. The cost per additionally gained quality-adjusted life-year of adding a TNFi was €92,557 (€60,227 including production losses) using SF-6D and €61,285 (€39,841) using EQ-5D. Including health care costs only, the probability that TNFi treatment was cost-effective was 90% when using EQ-5D, assuming a Norwegian willingness-to-pay level of €67,300. TNFi treatment for RA is cost-effective when accounting for production losses. Excluding production losses, TNFi treatment is cost-effective using EQ-5D, but not SF-6D. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping.

PubMed

Antonazzo, Ippazio Cosimo; Raschi, Emanuel; Vignatelli, Luca; Baldin, Elisa; Riise, Trond; D'Alessandro, Roberto; De Ponti, Fabrizio; Poluzzi, Elisabetta

2017-09-01

The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis

PubMed Central

Barnabe, Cheryl; Tomlinson, George; Marshall, Deborah; Devoe, Dan; Bombardier, Claire

2016-01-01

Objective To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. Design Systematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis. Data sources Trials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews. Study selection criteria Randomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest. Main outcomes American College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. Results 158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine (“triple therapy”), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. Conclusions Triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients. PMID:27102806

Disease-modifying anti-rheumatic drug use in pregnant women with rheumatic diseases: a systematic review of the risk of congenital malformations.

PubMed

Baldwin, Corisande; Avina-Zubieta, Antonio; Rai, Sharan K; Carruthers, Erin; De Vera, Mary A

2016-01-01

Despite the high incidence of rheumatic diseases during the reproductive years, little is known about the impact of disease-modifying anti-rheumatic drug (DMARD) use during pregnancy. Our objective was to systematically review and appraise evidence in women with rheumatic disease on the use of traditional and biologic DMARDs during pregnancy and the risk of congenital malformation outcomes. We conducted a systematic search of MEDLINE, EMBASE, and INTERNATIONAL PHARMACEUTICAL ABSTRACTS databases. Inclusion criteria were: 1) study sample including women with rheumatic disease; 2) use of traditional and/or biologic DMARDs during pregnancy; and 3) congenital malformation outcome(s) reported. We extracted information on study design, data source, number of exposed pregnancies, type of DMARD, number of live births, and number of congenital malformations. Altogether, we included 79 studies; the majority were based on designs that did not involve a comparison group, including 26 case reports, 17 case series, 20 cross-sectional studies, and 4 surveys. Studies that had a comparator group included 1 case control, 10 cohort studies, and 1 controlled trial. Hydroxychloroquine and azathioprine represent the most studied traditional DMARD exposures and, among biologics, most of the reports were on infliximab and etanercept. This is the first systematic review on the use of both traditional and biologic DMARDs during pregnancy among women with rheumatic diseases and congenital malformation outcomes, with a focus on study design and quality. Findings confirm the limited number of studies, as well as the need to improve study designs.

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study.

PubMed

Ebina, Kosuke; Hashimoto, Motomu; Yamamoto, Wataru; Ohnishi, Akira; Kabata, Daijiro; Hirano, Toru; Hara, Ryota; Katayama, Masaki; Yoshida, Shuzo; Nagai, Koji; Son, Yonsu; Amuro, Hideki; Akashi, Kengo; Fujimura, Takanori; Hirao, Makoto; Yamamoto, Keiichi; Shintani, Ayumi; Kumanogoh, Atsushi; Yoshikawa, Hideki

2018-01-01

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.

Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001.

PubMed

Louis, A; Cleland, J G; Crabbe, S; Ford, S; Thackray, S; Houghton, T; Clark, A

2001-06-01

This is a synopsis of presentations made at the American College of Cardiology (ACC) in 2001 summarising recent research developments relating to heart failure. Clinical studies of particular interest to physicians with an interest in heart failure and its prevention are reviewed. The COPERNICUS trial lends further support to the use of the beta-blocker, carvedilol, in severe heart failure and the CAPRICORN trial to its use in patients with post-infarction left ventricular systolic dysfunction. The MIRACLE study reinforces the evidence from three smaller trials that cardiac resynchronisation therapy is an effective treatment for the relief of symptoms in patients with severe heart failure and cardiac dyssynchrony. The STAF trial casts further doubt on the wisdom of cardioversion as a routine strategy for the management of chronic atrial fibrillation. The RITZ-2 trial suggests that an intravenous, non-selective endothelin antagonist is effective in improving haemodynamics and symptoms and possibly in reducing morbidity in severe heart failure. Observational studies in heart failure suggest that a moderate excess of body fat and elevated blood cholesterol may be desirable in patients with heart failure, challenging the current non-evidenced-based vogue for cholesterol lowering therapy in heart failure. The RENAISSANCE and RECOVER outcome studies of etanercept, a tumour necrosis factor (TNF) receptor analogue that blocks the effect of TNF, were stopped because of lack of evidence of benefit shortly after the ACC.

Biosimilars in rheumatology: A review of the evidence and their place in the treatment algorithm

PubMed Central

Skapenko, Alla

2017-01-01

Abstract Determining biosimilarity involves a comprehensive exercise with a focus on determining the comparability of the molecular characteristics and preclinical profile of the biosimilar and reference product, such that there is less need for extensive clinical testing to assure comparability of clinical outcomes. Three anti-TNF biosimilar agents are approved for patients with rheumatic diseases in the European Union. The infliximab (Remicade®) biosimilars CT-P13 (Remsima® and Inflectra®) and SB2 (Flixabi®) and the etanercept (Enbrel®) biosimilar SB4 (Benepali®) have shown close comparability to their reference medicinal products, having undergone extensive evaluations. Guidelines on the treatment of rheumatic diseases have acknowledged that biosimilars and biologic DMARDs (bDMARDs) are interchangeable in clinical practice, except when patients experience lack of efficacy or tolerability with the reference agent. Given that cost is a barrier to effective bDMARD use, the introduction of less costly biosimilars is likely to widen access and dissipate treatment inequalities. Physicians faced with prescribing decisions should be reassured by the robust and exhaustive process that is involved in assuring comparability of biosimilars with their reference agents. De novo usage of a biosimilar and switching to a biosimilar following lack of efficacy or tolerability with a different reference biologic agent are likely to be strategies most easily adopted, although switching during successful treatment should also be considered given the potential cost implications. The introduction of biosimilar bDMARDs has the potential to improve patient access to effective biologic therapy, to better accommodate restraints within healthcare budgets and to improve overall patient outcomes. PMID:28903543

Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly.

PubMed

Galloway, James B; Hyrich, Kimme L; Mercer, Louise K; Dixon, William G; Fu, Bo; Ustianowski, Andrew P; Watson, Kath D; Lunt, Mark; Symmons, Deborah P M

2011-01-01

To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.

Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly

PubMed Central

Galloway, James B.; Hyrich, Kimme L.; Mercer, Louise K.; Dixon, William G.; Fu, Bo; Ustianowski, Andrew P.; Watson, Kath D.; Lunt, Mark

2011-01-01

Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments. PMID:20675706

Biological therapies (immunomodulatory drugs), worsening of psoriasis and rebound effect: new evidence of similitude.

PubMed

Teixeira, Marcus Zulian

2016-11-01

Employing the secondary action or adaptative reaction of the organism as therapeutic response, homeopathy uses the treatment by similitude (similia similibus curentur) administering to sick individuals the medicines that caused similar symptoms in healthy individuals. Such homeostatic or paradoxical reaction of the organism is scientifically explained through the rebound effect of drugs, which cause worsening of symptoms after withdrawal of several palliative treatments. Despite promoting an improvement in psoriasis at the beginning of the treatment, modern biological therapies provoke worsening of the psoriasis (rebound psoriasis) after discontinuation of drugs. Exploratory qualitative review of the literature on the occurrence of the rebound effect with the use of immunomodulatory drugs [T-cell modulating agents and tumor necrosis factor (TNF) inhibitors drugs] in the treatment of psoriasis. Several researches indicate the rebound effect as the mechanism of worsening of psoriasis with the use of efalizumab causing the suspension of its marketing authorization in 2009, in view of some severe cases. Other studies also have demonstrated the occurrence of rebound psoriasis with the use of alefacept, etanercept and infliximab. As well as studied in other classes of drugs, the rebound effect of biologic agents supports the principle of similitude (primary action of the drugs followed by secondary action and opposite of the organism). Copyright © 2016 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.

Secukinumab is Efficacious and Safe in Hispanic Patients with Moderate-to-Severe Plaque Psoriasis: Pooled Analysis of Four Phase 3 Trials.

PubMed

Adsit, Sandra; Zaldivar, Enrique Rivas; Sofen, Howard; Dei-Cas, Ignacio; Maldonado-García, César; Peñaranda, Elkin O; Puig, Luís; Meng, Xiangyi; Fox, Todd; Guana, Adriana

2017-06-01

There is little evidence available on the efficacy and safety of biologic therapies for the treatment of psoriasis in Hispanic patients. Secukinumab is demonstrated to be highly effective for clearing psoriasis. The aim of this study was to compare the efficacy and safety of secukinumab in Hispanic and non-Hispanic patients. Data were pooled from four phase 3 studies of secukinumab in patients with moderate-to-severe plaque psoriasis. Patients who self-identified as Hispanic were included in the Hispanic subgroup. Efficacy responses (Psoriasis Area and Severity Index [PASI] 75/90/100 and Investigator's Global Assessment 2011 modified version 0/1) for secukinumab 300 mg were greater than for etanercept at week 12 in the Hispanic and non-Hispanic patient subgroups. At week 12 with secukinumab 300 mg, PASI 90/100 responses were achieved by 70.6%/35.9% of Hispanic patients and 58.0%/28.1% of non-Hispanic patients. At week 12 with secukinumab 150 mg, PASI 90/100 responses were achieved by 59.5%/25.1% of Hispanic patients and 41.2%/13.4% of non-Hispanic patients. In both subgroups, peak efficacy responses with secukinumab were observed at week 16 and were maintained to week 52. Secukinumab is highly effective for clearing psoriasis in both Hispanic and non-Hispanic patients. Novartis Pharmaceutical Corporation.

Progress in pediatrics in 2013: choices in allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses.

PubMed

Caffarelli, Carlo; Santamaria, Francesca; Vottero, Alessandra; Dascola, Carlotta Povesi; Mirra, Virginia; Sperli, Francesco; Bernasconi, Sergio

2014-07-12

This review will provide new information related to pathophysiology and management of specific diseases that have been addressed by selected articles published in the Italian Journal of Pediatrics in 2013, focusing on allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses in children. Recommendations for interpretation of skin prick test to foods in atopic eczema, management of allergic conjunctivitis, hypertension and breastfeeding in women treated with antiepileptic drugs and healthy breakfast have been reported. Epidemiological studies have given emphasis to high incidence of autoimmune disorders in patients with Turner syndrome, increasing prevalence of celiac disease, frequency of hypertension in adolescents, incidence and risk factor for retinopathy of prematurity. Advances in prevention include elucidation of the role of probiotics in reducing occurrence of allergies and feeding intolerance, and events of foetal life that influence later onset of diseases. Mechanistic studies suggested a role for vitamin D deficiency in asthma and type 1 diabetes and for reactivation of Varicella-Zoster virus in aseptic meningitis. Regarding diagnosis, a new mean for the diagnosis of hyperbilirubinaemia in newborns, a score for recognition of impaired nutritional status and growth and criteria for early Dyke-Davidoff-Masson Syndrome have been suggested. New therapeutic approaches consist of use of etanercept for reducing insulin dose in type 1 diabetes, probiotics in atopic eczema, and melatonin in viral infections.

Progress in pediatrics in 2013: choices in allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses

PubMed Central

2014-01-01

This review will provide new information related to pathophysiology and management of specific diseases that have been addressed by selected articles published in the Italian Journal of Pediatrics in 2013, focusing on allergology, endocrinology, gastroenterology, hypertension, infectious diseases, neonatology, neurology, nutrition and respiratory tract illnesses in children. Recommendations for interpretation of skin prick test to foods in atopic eczema, management of allergic conjunctivitis, hypertension and breastfeeding in women treated with antiepileptic drugs and healthy breakfast have been reported. Epidemiological studies have given emphasis to high incidence of autoimmune disorders in patients with Turner syndrome, increasing prevalence of celiac disease, frequency of hypertension in adolescents, incidence and risk factor for retinopathy of prematurity. Advances in prevention include elucidation of the role of probiotics in reducing occurrence of allergies and feeding intolerance, and events of foetal life that influence later onset of diseases. Mechanistic studies suggested a role for vitamin D deficiency in asthma and type 1 diabetes and for reactivation of Varicella-Zoster virus in aseptic meningitis. Regarding diagnosis, a new mean for the diagnosis of hyperbilirubinaemia in newborns, a score for recognition of impaired nutritional status and growth and criteria for early Dyke-Davidoff-Masson Syndrome have been suggested. New therapeutic approaches consist of use of etanercept for reducing insulin dose in type 1 diabetes, probiotics in atopic eczema, and melatonin in viral infections. PMID:25015124

Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations

PubMed Central

Mori, Shunsuke; Fujiyama, Shigetoshi

2015-01-01

Accompanying the increased use of biological and non-biological antirheumatic drugs, a greater number of cases of hepatitis B virus (HBV) reactivation have been reported in inactive hepatitis B surface antigen (HBsAg) carriers and also in HBsAg-negative patients who have resolved HBV infection. The prevalence of resolved infection varies in rheumatic disease patients, ranging from 7.3% to 66%. Through an electronic search of the PubMed database, we found that among 712 patients with resolved infection in 17 observational cohort studies, 12 experienced HBV reactivation (1.7%) during biological antirheumatic therapy. Reactivation rates were 2.4% for etanercept therapy, 0.6% for adalimumab, 0% for infliximab, 8.6% for tocilizumab, and 3.3% for rituximab. Regarding non-biological antirheumatic drugs, HBV reactivation was observed in 10 out of 327 patients with resolved infection from five cohort studies (3.2%). Most of these patients received steroids concomitantly. Outcomes were favorable in rheumatic disease patients. A number of recommendations have been established, but most of the supporting evidence was derived from the oncology and transplantation fields. Compared with patients in these fields, rheumatic disease patients continue treatment with multiple immunosuppressants for longer periods. Optimal frequency and duration of HBV-DNA monitoring and reliable markers for discontinuation of nucleoside analogues should be clarified for rheumatic disease patients with resolved HBV infection. PMID:26420955

Reversible posterior leukoencephalopathy syndrome secondary to systemic-onset juvenile idiopathic arthritis: A case report and review of the literature.

PubMed

Zhang, Pingping; Li, Xiaofeng; Li, Yating; Wang, Jing; Zeng, Huasong; Zeng, Xiaofeng

2015-01-01

Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical syndrome based on changes in clinical imaging, and it has been reported to mainly occur in adults. However, it has been recently discovered that RPLS is also prevalent in infant patients, particularly in those using glucocorticoids, immunosuppressant medications and cytotoxic drugs. The current study presents a 5-year-old male with a previous diagnosis of systemic-onset juvenile idiopathic arthritis (SoJIA) and macrophage-activation syndrome who developed posterior reversible encephalopathy syndrome during treatment with glucocorticoids, disease-modifying antirheumatic drugs and biological agent (etanercept) therapy. After ~5 days of treatment, the patient made a complete clinical recovery; the magnetic resonance imaging reviewed 2 weeks later showed that the previous hyper-intensity signal had disappeared and the multiple lesions in the brain had been completely absorbed. The case report shows that, conforming to recent literature, SoJIA in infants should be considered a risk factor for developing RPLS. The clinical manifestations of the disease are multiple, but usually reversible, and the patients mostly have a good prognosis. Rapid diagnosis and treatment is essential as early treatment may prevent progression to irreversible brain damage. By increasing the awareness of RPLS, the patient care may improve and further insight may be gained.

Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk.

PubMed

Parakkal, Deepak; Sifuentes, Humberto; Semer, Rumi; Ehrenpreis, Eli Daniel

2011-11-01

Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. The study of biologic and immunomodulator naive patients in Crohn's disease (SONIC), advocates combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppression increases risk for HSTCL. We herein review all cases of HSTCL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors. Individual reports from the FDA Adverse Event Reporting System database for lymphomas from the biological agents - infliximab, adalimumab, certolizumab, natalizumab, and etanercept were downloaded and analyzed with Microsoft Access. Full reports for all identified HSTCL cases were obtained from the FDA. Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone. HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.

Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

PubMed Central

Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

2016-01-01

Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD. PMID:27746855

Review of the treatment of psoriatic arthritis with biological agents: choice of drug for initial therapy and switch therapy for non-responders.

PubMed

D'Angelo, Salvatore; Tramontano, Giuseppina; Gilio, Michele; Leccese, Pietro; Olivieri, Ignazio

2017-01-01

Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a broad clinical spectrum and variable course. It can involve musculoskeletal structures as well as skin, nails, eyes, and gut. The management of PsA has changed tremendously in the last decade, thanks to an earlier diagnosis, an advancement in pharmacological therapies, and a wider application of a multidisciplinary approach. The commercialization of tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) as well as interleukin (IL)-12/23 (ustekinumab) and IL-17 (secukinumab) inhibitors is representative of a revolution in the treatment of PsA. No evidence-based strategies are currently available for guiding the rheumatologist to prescribe biological drugs. Several international and national recommendation sets are currently available with the aim to help rheumatologists in everyday clinical practice management of PsA patients treated with biological therapy. Since no specific biological agent has been demonstrated to be more effective than others, the drug choice should be made according to the available safety data, the presence of extra-articular manifestations, the patient's preferences (e.g., administration route), and the drug price. However, future studies directly comparing different biological drugs and assessing the efficacy of treatment strategies specific for PsA are urgently needed.

[What's new in dermatological treatments?].

PubMed

Martin, L

2010-12-01

Although the isolated clinical cases published are sometimes helpful in individual situations in which the therapeutic options have been exhausted, this type of publication cannot be generalized. For this reason, the selection presented covering the period from November 2009 to October 2010 is to a very large extent based on controlled trials, either because they contribute important information or because they raise great hope for a significant number of patients. For the first time in cutaneous oncology, a treatment (ipilimumab) has significantly increased overall survival in patients with metastatic melanoma (phase III), although this gain remains modest (4-6 months) and adverse immunological effects are frequent (30-40%). A phase I trial with treatment specifically targeting the mutant BRAF protein has shown an objective response in 81% of the patients treated in the metastatic phase of melanoma, thus allowing its development to be pursued. Grouping two studies in a rare tumor such as dermatofibrosarcoma also gives hope with imatinib as a neoadjuvant treatment when the initial tumor is inoperable, with, however, an inconsistent response of approximately 50% and only if the tumor presents reorganization of chromosomes 17 and 22. Cutaneous inflammatory diseases are still dominated by dual therapies in psoriasis, with, notably, an effectiveness trial on etanercept at different doses not showing a difference in efficacy depending on dose for the joint component of psoriasis, but also by the publication of a direct comparison of two dual therapies, ustekinumab versus etanercept. In atopic dermatitis, a controversial article invites one to reflect upon the progress made in the management of children by clinical nurses, as in the Netherlands and in Great Britain, in an attempt to contend with the shortage of dermatologists. Since the use of biotherapies is not the prerogative of psoriasis, infliximab was assessed in a phase II trial in Verneuil disease without demonstrating significant efficacy on the main criterion, but it did show a tendency to reduce the score used. This trial suffered from a weakness both in methodology and statistical power, thus precluding any conclusion. The rarity of therapeutic trials on drug eruptions warrants their mention. A French phase II study gives a glimpse of a trend toward efficacy in terms of survival in the treatment of toxic epidermal necrolysis with cyclosporine. As for infectious dermatosis and sexually transmitted infections, a French multicenter study has shown significantly higher efficacy with ivermectin than with malathion in treating pediculosis without increasing the side effects. Today, however, this systemic treatment cannot be a first-line treatment outside of certain specific situations. A large cohort study (somewhat unsatisfactory in its methodology) has not demonstrated the teratogenicity of antiherpes treatments in 830,000 infants. In prevention of HIV transmission, no microbicidal gel had shown efficacy to date. This has now been accomplished in South Africa with a 1% tenofovir gel. The results of a preliminary trial on therapeutic vaccination against HPV16 proposed to women who are carriers of cervical intraepithelial neoplasia opens the way for wide vaccine therapy of cutaneous virus-induced neoplasia. In conclusion, several articles analyzing the dermatology literature provide an opportunity to reflect on the quality of such articles, Boutron's being absolutely in-dis-pen-sa-ble! Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Restoration of Tumor Immune Surveillance via Targeting of IL-13Receptor-α2

PubMed Central

Fichtner-Feigl, Stefan; Terabe, Masaki; Kitani, Atsushi; Young, Cheryl A.; Fuss, Ivan; Geissler, Edward K.; Schlitt, Hans-Jürgen; Berzofsky, Jay A.; Strober, Warren

2009-01-01

In previous studies we described a “counter-immunosurveillance” mechanism initiated by tumor-activated, IL-13-producing NKT cells that signal Gr-1+ cells to produce TGF-β1, a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8+ T cells. Here we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models) this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13Rα2, on Gr-1intermediate cells, since down-regulation of IL-13Rα2 expression or the AP-1 signal generated by the receptor via in vivo administration of specific siRNA or decoy oligonucleotides leads to loss of TGF-β1 production. Furthermore, acting on prior studies showing that IL-13Rα2 expression is induced (in part) by TNF-α, we show that receptor expression and TGF-β1 production is inhibited by administration of a TNF-α neutralizing substance, TNF-αR-Fc (etanercept). Taking advantage of this latter fact, we then demonstrate in the CT-26 model that counter-immunosurveillance could be inhibited, anti-CT-26-specific CD8+ cytolytic activity restored, and CT-26 metastatic tumor nodules greatly decreased by administration of TNF-αR-Fc. Corroborative data was obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity. PMID:18451175

Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease

PubMed Central

Shamim, Daniah; Laskowski, Michael

2017-01-01

Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents. PMID:28811745

Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor α Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease.

PubMed

Shamim, Daniah; Laskowski, Michael

2017-01-01

Tumor necrosis factor α (TNF-α) inhibitors have long been used as disease-modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-α inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro-inflammatory TNF-α and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and β-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-α modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents.

The effects of Euphorbia hirta on the ultrastructure of the murine liver, kidney and aorta

PubMed Central

WONG, J.Y.R.; CHEN, Y.S.; CHAKRAVARTHI, S.; JUDSON, J.P.; L., SANTHANA RAJ; ER, H.M.

2013-01-01

Euphorbia hirta is widely used in traditional remedies and has been used cross-culturally for generations against maladies such as asthma, skin ailments and hypertension. Previous studies have demonstrated that Euphorbia hirta has antibacterial activity, and have also indicated certain antimolluscidal, antimalarial and anti-inflammatory properties, the latter of which have been suggested to be more pronounced than those of the rheumatological drug, etanercept. To date, no studies have identified the anatomical effects of this herb on the organs of test animals. This study aimed to identify the effects of Euphorbia hirta on the ultrastructure of the murine liver, kidney and aorta. A total of 32 adult male Sprague-Dawley rats were divided into four groups; three groups were fed with aqueous extracts of Euphorbia hirta at doses of 1, 10 and 50 mg/kg, respectively, every alternate day for 50 days, while one group served as a control. The animals were later sacrificed and the liver, kidney and aorta harvested for examination by electron microscopy. The aorta showed no ultrastructural changes across the groups. Renal and hepatic tissue from the treated groups demonstrated dose-dependent injuries, which showed architectural damage beginning in the nuclei and spreading outwards. Taking into consideration the properties of Euphorbia hirta that have been described in previous studies, in addition to the results from the present study, it appears that the herb may exhibit similar effects to those of the quinolone group of antibiotics. Further in-depth investigations are required into the potential effects of Euphorbia hirta, deleterious and otherwise. PMID:24223653

Psoriasis in those planning a family, pregnant or breast-feeding. The Australasian Psoriasis Collaboration.

PubMed

Rademaker, Marius; Agnew, Karen; Andrews, Megan; Armour, Katherine; Baker, Chris; Foley, Peter; Frew, John; Gebauer, Kurt; Gupta, Monisha; Kennedy, Debra; Marshman, Gillian; Sullivan, John

2017-05-23

The Australasian Psoriasis Collaboration has reviewed the evidence for managing moderate to severe psoriasis in those who are pregnant or are breast-feeding, or planning a family. The severity of the psoriasis, associated comorbidities and specific anti-psoriasis treatment, along with other exposures, can have a deleterious effect on pregnancy outcomes. Psoriasis itself increases the risk of preterm and low birthweight babies, along with spontaneous and induced abortions, but no specific birth defects have been otherwise demonstrated. The baseline risk for a live born baby to have a major birth defect is 3%, and significant neuro-developmental problem is 5%. In Australia, pregnant women with psoriasis are more likely to be overweight or obese, depressed, or smoke in their first trimester, and are also less likely to take prenatal vitamins or supplements. Preconception counselling to improve maternal, pregnancy and baby health is therefore strongly encouraged. The topical and systemic therapies commonly used in psoriasis are each discussed separately, with regards to pregnancy exposure, breast-feeding and effects on male fertility and mutagenicity. The systemic therapies included are acitretin, adalimumab, apremilast, certolizumab, ciclosporin, etanercept, infliximab, ixekizumab, methotrexate, NBUVB, prednisone, PUVA, secukinumab and ustekinumab. The topical therapies include dithranol (anthralin), calcipotriol, coal tar, corticosteroids (weak, potent and super-potent), moisturisers, salicylic acid, tacrolimus, and tazarotene. As a general recommendation, effective drugs that have been widely used for years are preferable to newer alternatives with less foetal safety data. It is equally important to evaluate the risks of not treating, as severe untreated disease may negatively impact both mother and the foetus. © 2017 The Australasian College of Dermatologists.

Biologic therapies and bone loss in rheumatoid arthritis.

PubMed

Zerbini, C A F; Clark, P; Mendez-Sanchez, L; Pereira, R M R; Messina, O D; Uña, C R; Adachi, J D; Lems, W F; Cooper, C; Lane, N E

2017-02-01

Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures. Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of "small molecules of new agents." Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent's treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2002-05-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables can be retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abarelix, abciximab, acarbose, alefacept, alteplase, amisulpride, amoxicillin trihydrate, apomorphine hydrochloride, aprepitant, argatroban monohydrate, aspirin, atenolol; Betamethasone dipropionate, betamethasone valerate, bicalutamide, bleomycin sulfate; Calcium carbonate, candesartan cilexetil, celecoxib, cetirizine hydrochloride, cisplatin, clarithromycin, clavulanate potassium, clomethiazole edisilate, clopidogrel hydrogensulfate, cyclophosphamide, chorionic gonadotropin (human); Dalteparin sodium, desloratadine, dexamethasone, doxorubicin, DPC-083; Efalizumab, efavirenz, enoxaparin sodium, eprosartan mesilate, etanercept, etoposide, ezetimibe; Faropenem daloxate, fenofibrate, fluocinolone acetonide, flutamide, fluvastatin sodium, follitropin beta, fondaparinux sodium; Gabapentin, glibenclamide, goserelin, granisetron hydrochloride; Haloperidol, hydrochlorothiazide; Imiquimod, interferon beta-1a, irbesartan, iseganan hydrochloride; L-758298, lamivudine, lanoteplase, leflunomide, leuprorelin acetate, loratadine, losartan potassium; Melagatran, metformin hydrochloride, methotrexate, metronidazole, micafungin sodium, mitoxantrone hydrochloride; Nelfinavir mesilate, neutral insulin injection, nizatidine; Olopatadine hydrochloride, omeprazole, ondansetron hydrochloride; Pamidronate sodium, paracetamol, paroxetine hydrochloride, perindopril, pimecrolimus, pioglitazone hydrochloride, piroxicam, pleconaril, pralmorelin, pravastatin sodium, prednisolone, prednisone, propofol; Raloxifene hydrochloride, ranpirnase, remifentanil hydrochloride, risedronate sodium, risperidone, rofecoxib, ropinirole hydrochloride, rosuvastatin calcium; Sevoflurane, sildenafil citrate, simvastatin, somatropin; Tacrolimus, tamoxifen citrate, telmisartan, temozolomide, thiopental sodium, tinzaparin sodium, tirofiban hydrochloride, treosulfan, triamcinolone acetonide; Urokinase; Valsartan, vardenafil, vincristine; Warfarin sodium; Ximelagatran; Zidovudine.

Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis.

PubMed

Dufton, Neil P; Peghaire, Claire R; Osuna-Almagro, Lourdes; Raimondi, Claudio; Kalna, Viktoria; Chuahan, Abhishek; Webb, Gwilym; Yang, Youwen; Birdsey, Graeme M; Lalor, Patricia; Mason, Justin C; Adams, David H; Randi, Anna M

2017-10-12

The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (Erg cEC-Het ) and inducible homozygous deficient mice (Erg iEC-KO ), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL 4 )-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The transcription factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.

Beyond Psoriasis: Novel Uses for Biologic Response Modifiers in Pediatric Dermatology.

PubMed

Bellodi-Schmidt, Fernanda; Shah, Kara N

2016-01-01

Dermatologists have witnessed the increasing availability of novel biologic response modifiers for the treatment of inflammatory and autoimmune diseases in recent years. The most common dermatologic indication for the use of biologic response modifiers in adults is psoriasis, but the U.S. Food and Drug Administration has not approved any of these agents for use in any dermatologic disease in children with the exception of omalizumab, and as such, use in this population is considered off-label. In this review, we focus on the use of these agents in children to treat inflammatory skin diseases other than psoriasis, including atopic dermatitis, hidradenitis suppurativa, pemphigus vulgaris, bullous pemphigoid, and toxic epidermal necrolysis, with an emphasis on the use of etanercept, infliximab, rituximab, omalizumab, and ustekinumab. By highlighting novel uses of these agents, particularly for the treatment of dermatologic conditions for which optimal therapies are yet to be established, we hope to raise awareness of the potential use of this class of medications to treat inflammatory skin diseases in children. © 2015 Wiley Periodicals, Inc.

Fc-fusion Proteins in Therapy: An Updated View.

PubMed

Jafari, Reza; Zolbanin, Naime M; Rafatpanah, Houshang; Majidi, Jafar; Kazemi, Tohid

2017-01-01

Fc-fusion proteins are composed of Fc region of IgG antibody (Hinge-CH2-CH3) and a desired linked protein. Fc region of Fc-fusion proteins can bind to neonatal Fc receptor (FcRn) thereby rescuing it from degradation. The first therapeutic Fc-fusion protein was introduced for the treatment of AIDS. The molecular designing is the first stage in production of Fc-fusion proteins. The amino acid residues in the Fc region and linked protein are very important in the bioactivity and affinity of the fusion proteins. Although, therapeutic monoclonal antibodies are the top selling biologics but the application of therapeutic Fc-fusion proteins in clinic is in progress and among these medications Etanercept is the most effective in therapy. At present, eleven Fc-fusion proteins have been approved by FDA. There are novel Fc-fusion proteins which are in pre-clinical and clinical development. In this article, we review the molecular and biological characteristics of Fc-fusion proteins and then further discuss the features of novel therapeutic Fc-fusion proteins. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Presentation of suspected pediatric uveitis.

PubMed

Saeed, Muhammad Usman; Raza, Syed Hamid; Goyal, Sudeshna; Cleary, Gavin; Newman, William David; Chandna, Arvind

2014-01-01

Presentation of suspected pediatric uveitis: Pediatric uveitis is usually managed in specialized ophthalmic centers in the UK. Meaningful data acquisition in these clinics may be helpful in clinical governance, and healthcare planning in a specialty that is gradually changing due to changes in treatment choices. Retrospective analysis of prospectively acquired data in the Liverpool pediatric uveitis database was performed. Analysis of our data, based on 147 patients, with a mean age of 10 years, indicated a female to male ratio of 2:1. 99% of patients were Caucasian. Our data indicates 86% of all patients attending the uveitis clinic were diagnosed with juvenile idiopathic arthritis, followed by intermediate uveitis 5% and idiopathic uveitis 4%. 46% of patients required treatment. Systemic treatment included methotrexate (34%), prednisolone (14%), etanercept (6%), ciclosporin (6%), mycophenolate (3%), and infliximab (1%). Severe visual loss (defined by counting fingers or below vision) was seen in 10 eyes despite appropriately treated chronic uveitis. Our data shows uveitis-related ocular morbidity in a predominantly pediatric Caucasian population. Patients with severe and chronic uveitis may experience significant uveitis-related complications and subsequent visual loss despite aggressive treatment.

Tumor necrosis factor-alpha antagonists: differential clinical effects by different biotechnological molecules.

PubMed

Licastro, F; Chiappelli, M; Ianni, M; Porcellini, E

2009-01-01

Inhibitors of tumor necrosis factor-alpha have deeply changed the therapy of several inflammatory human diseases. For instance, clinical management of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools, such as antagonist of TNF-alpha molecule. These drugs include etanercept, a soluble TNF-alpha receptor antagonist, three anti-TNF-alpha antibodies, adalimumab, infliximab, golimumab and certolizumab a humanized Fab fragment combined with polyethylene glycol. These compounds efficiently inhibit several TNF-alpha biological-mediated effects, however, they have also shown differential clinical efficacy in several trials from different autoimmune diseases. It is of clinical relevance that non-responders to one of these drugs often positively responded to another. Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects. However, partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses. Therefore, these apparently homogeneous agents can not be considered equivalent in their clinically efficacy. Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual TNF-alpha inhibitors.

New systemic agents in dermatology with respect to fertility, pregnancy, and lactation.

PubMed

Grunewald, Sonja; Jank, Alexander

2015-04-01

With the increasing use of new, predominantly biologic drugs in dermatology, questions frequently arise in clinical practice as to their safety in women wishing to conceive as well as during pregnancy and lactation. Apart from the Summary of Product Characteristics and the Physician's Desk Reference, reliable information may be obtained from databases such as the one compiled by the Center for Pharmacovigilance and Consultation on Embryonal Toxicology at Charité University Medical Center Berlin (https://www.embryotox.de). Another source of information is researching recent publications, for example via PubMed (http://www.ncbi.nlm.nih.gov/pubmed). This article presents current knowledge from the sources mentioned above, and gives detailed information about the use of new biologic agents in women wishing to conceive as well as during pregnancy and lactation. Drugs reviewed include: infliximab, adalimumab, etanercept, metastatic for psoriasis, vemurafenib, dabrafenib, imatinib, ipilimumab for melanoma, vismodegib for basal cell carcinoma, rituximab for cutaneous lymphoma as well as omalizumab and anakinra used in the treatment of allergies. © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Delayed Treatment Acceleration in Patients with Rheumatoid Arthritis Who Have Inadequate Response to Initial Tumor Necrosis Factor Inhibitors: Data from the Corrona Registry

PubMed Central

Pappas, Dimitrios A.; Gerber, Robert A.; Litman, Heather J.; Gruben, David; Geier, Jamie; Hua, Winnie D.; Chen, Connie; Li, Youfu; Kremer, Joel M.; Andrews, John S.; Bourret, Jeffrey A.

2018-01-01

Background The implementation of treat-to-target principles in rheumatoid arthritis (RA) has not been fully investigated in patients with inadequate response to tumor necrosis factor (TNF) inhibitor treatment. Objectives To evaluate the prevalence of an inadequate response to initial TNF inhibitor treatment at 6 and 12 months among patients with RA in a real-world patient registry, as well as the delay in therapy adjustment and its impact on disease activity and patient-reported outcome (PRO) measures. Methods This analysis is based on data of patients with moderate or severe disease activity (Clinical Disease Activity Index [CDAI] score >10) who were included in the Consortium of Rheumatology Researchers of North America (Corrona) RA registry, a prospective, observational database. The patients had never received treatment with a biologic disease-modifying antirheumatic drug (DMARD) and had initiated treatment with a TNF inhibitor (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) between October 2001 and December 2014. We evaluated treatment response (CDAI score ≤10), select PRO measures, and treatment changes at 6 months. Patients who had an inadequate response to TNF inhibitor therapy at 6 months and continued to use their initial TNF inhibitor were evaluated again at 12 months. Results This retrospective analysis included 2282 patients. At 6 months, 1732 (75.9%) of the patients continued to use their initial TNF inhibitor; of these, 803 (46.4%) patients had an inadequate response to treatment. Of the 803 patients who had an inadequate response at 6 months, 488 (60.8%) continued their initial treatment at 12 months. Of these 488 patients, 315 (64.5%) had an inadequate response at 12 months, and 173 (35.5%) had a response. Numerically greater improvements in all PRO measures were observed for patients who responded to therapy compared with patients with an inadequate response. Conclusions In this real-world analysis of data from the Corrona RA registry, a considerable proportion of patients with RA had an inadequate response to the initial TNF inhibitor therapy at 6 and 12 months. Many patients continued to have moderate or high disease activity, without accelerating treatment (eg, addition or increase in the dose of concurrent conventional synthetic DMARDs or a TNF inhibitor), contrary to treat-to-target principles, thus remaining at risk for accumulating joint damage and disability. PMID:29910846

TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis

PubMed Central

Mahanty, Siddhartha; Adrianzen, M. Paz; Arroyo, Gianfranco; Calcina, Juan; Gonzalez, Armando E.; García, Héctor H.; Nash, Theodore E.

2017-01-01

Background Neurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ). Methodology/Principal findings We followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups. Conclusions/Significance Overall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modulatory molecules. Taken together, these data suggest that TNF-α blockade may provide a viable strategy to manage post-treatment pericystic inflammation that follows antiparasitic therapy for neurocysticercosis. PMID:29190292

Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis

PubMed Central

McDonald, Jay R.; Zeringue, Angelique L.; Caplan, Liron; Ranganathan, Prabha; Xian, Hong; Burroughs, Thomas E.; Fraser, Victoria J; Cunningham, Fran; Eisen, Seth A.

2009-01-01

Background Herpes zoster occurs more commonly in patients taking immunosuppressive medications, though the risk associated with different medications is poorly understood. Methods Retrospective cohort study including 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster, and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. Results The incidence of herpes zoster was 9.96 per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (p<0.001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (HR 0.62) and adalimumab (HR 0.53) were associated with lower risk of herpes zoster. There was excellent agreement between ICD-9-CM diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). Conclusions Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs’ national administrative databases can be used to study rare adverse drug events. PMID:19368499

Economical impact associated with a biological therapy prioritization protocol in patients with rheumatoid arthritis in the Hospital of Sagunto.

PubMed

Borrás-Blasco, Joaquín; Casterá, M Dolores-Elvira; Cortes, Xavier; Rosique-Robles, J Dolores; Abad, F Javier

2014-11-01

Until 2010 the cost of biological treatments in Rheumatoid Arthritis (RA) was increasing annually by 15% in our hospital. In 1st January 2011, a Hospital Commission of Biological Therapies involving rheumatology and pharmacy services was created to improve the management of biological drugs and a biological therapy prioritization protocol in RA patients was also established to improve the efficient usage of biological drugs in RA. To evaluate the economic impact associated with a biological therapy prioritization protocol for RA patients in the Hospital of Sagunto. Observational, ambispective study comparing the associated cost of RA patients treated with biological drugs in the pre-protocol (2009 - 2010) versus post-protocol periods (2011 - 2012). RA patients treated with Abatacept (ABA), Adalimumab (ADA), Etanercept (ETN) or Infliximab (IFX) for at least 6 months during the study period (2009 - 2012) were included. In 2012, Tocilizumab (TCZ) was also included in the prioritization protocol. Prioritization protocol was established based on both clinical and economical aspects and supervised case by case by our Commission. Cost savings and economic impact were calculated using Spanish official prices. In the pre-protocol period (2009 - 2010), total expenses were increasing by €110,000, up to €1,761,000 in 2010 (€11,362 pat/year). After protocol implementation, total expenses decreased by 53,676€ on the 2010 - 2011 period, and 149,200€ on the 2011 - 2012 period. On the 2010 - 2011 period the cost of biological therapy per patient-year decreased 355€ (11,007€ pat/year) and additional 653€ (up to 10,354€ pat/year) by 2012, with a cumulative effect of the protocol implementation of 1,008€ per patient-year. In the pre-protocol period (2009), the annual cost/patient was 10.812€ with ETN, 10.942€ with IFX, 12.961€ with ADA and 12.739€ with ABA. By 1st January 2013, the annual cost per patient was 9,469€ with ETN, 10,579€ with IFX, 11,117€ with ADA, 13,540€ with ABA and 14,932€ with TCZ. The creation of our Commission of Biological Therapies is key to rational management of RA patients and optimization of resources, allowing us to save 200,000€ after 2-year efficiency protocol implementation.

TNF-α inhibitors do not impair sperm quality in males with ankylosing spondylitis after short-term or long-term treatment.

PubMed

Micu, Mihaela C; Micu, Romeo; Surd, Stela; Gîrlovanu, Marinela; Bolboacă, Sorana D; Ostensen, Monika

2014-07-01

The aim of this study was to study the influence of active disease status and TNF-α antagonists on sperm quality in a group of AS patients. Twenty-three active AS patients and 42 controls were recruited. Patients' sperm samples were analysed at baseline (previous to) and at 3-6 months after TNF-α therapy (adalimumab, infliximab, etanercept) administration. Baseline assessment was made for only 20 patients, 2 of them proving to have normal fertility, 2 having a pregnant stable partner and the third having a 9-month-old child. Six patients were retested after 12 months of biologic therapy. Each patient acted as his own comparator. Results were further compared with sperm samples from age-matched controls. Sperm analysis was performed according to the World Health Organization (WHO) 1999 guidelines. Patients' baseline assessment showed normozoospermia in 91% and oligozoospermia in 9% of patients. No significant differences in sperm quality were noticed at follow-up visits compared with baseline. Comparison to controls showed no statistically significant differences in semen quality, with some exceptions: the control group presented a higher percentage of non-progressive and immobile sperm cells and higher numbers of head and tail atypias. Sperm quality in patients with active AS and after receiving short- and long-term TNF-α blocker therapy is comparable to sperm quality in healthy controls. Our study confirms that the disease process of AS does not have a major impact on sperm quality and that treatment with anti-TNF has no negative impact on sperm quality even under long-term treatment. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Agreement Between Maternal Report and Medical Records During Pregnancy: Medications for Rheumatoid Arthritis and Asthma.

PubMed

Palmsten, Kristin; Hulugalle, Avanthi; Bandoli, Gretchen; Kuo, Grace M; Ansari, Shayda; Xu, Ronghui; Chambers, Christina D

2018-01-01

There are limited data regarding the comparability of medication exposure information during pregnancy from maternal report and medical records, including for rheumatoid arthritis and asthma-related medications. This study included pregnant women with rheumatoid arthritis (n = 216) and asthma (n = 172) enrolled in the MothertoBaby Pregnancy Studies (2009-2014). Women reported types and dates of medications used through semi-structured telephone interviews up to three times during pregnancy and once after delivery, and medical records were obtained. We calculated Cohen's kappa coefficients and 95% confidence intervals (CIs) and per cent agreement for agreement between report and records. For rheumatoid arthritis, prednisone was reported most frequently (53%). During pregnancy, kappa coefficients for rheumatoid arthritis medications ranged from 0.32 (95% CI 0.15, 0.50) for ibuprofen, with 84.3% agreement, to 0.90 (95% CI 0.84, 0.96) for etanercept with 95.4% agreement, and was 0.44 (95% CI 0.33, 0.55) for prednisone, with 71.3% agreement. For asthma, albuterol was reported most frequently (77.9%). During pregnancy, kappa coefficients for asthma medications ranged from 0.21 (95% CI 0.08, 0.35), with 64.5% agreement for albuterol to 0.84 (95% CI 0.71, 0.96) for budesonide/formoterol, with 96.5% agreement. Where kappas for any use during pregnancy were less than excellent (i.e. ≤0.80), medication use was more frequently captured by report than record. Agreement was higher for medications typically used continuously than sporadically. Information on medication use from medical records alone may not be adequate when studying the impact of intermittently used medications during pregnancy on perinatal outcomes. © 2017 John Wiley & Sons Ltd.

Inflammation Is an Important Covariate for the Crosstalk of Sleep and the HPA Axis in Rheumatoid Arthritis.

PubMed

Straub, Rainer H; Detert, Jaqueline; Dziurla, René; Fietze, Ingo; Loeschmann, Peter-Andreas; Burmester, Gerd R; Buttgereit, Frank

2017-01-01

Rheumatoid arthritis (RA) patients have sleep problems, and inflammation influences sleep. We demonstrated that sleep quality improves during intensified treatment with methotrexate (MTX) or etanercept (ETA). Since the hypothalamic-pituitary-adrenal (HPA) axis is involved in sleep regulation, this study investigated the interrelation between sleep parameters, inflammation as objectified by C-reactive protein (CRP), and serum cortisol and adrenocorticotropic hormone (ACTH) levels. Thirty-one eligible patients (disease activity score, DAS28CRP ≥3.2) participated in a 16-week, open, prospective study of HPA axis outcomes. MTX was initiated in 15 patients (female-to-male ratio 9/6) and ETA in 16 patients (14/2). Clinical, laboratory (after polysomnography [PSG] between 8 and 9 a.m.), sleep (PSG), and HPA axis outcome parameters (after PSG between 8 and 9 a.m.) were recorded at baseline and week 16. Clinical characteristics of patients markedly improved throughout the study (e.g., DAS28CRP: p < 0.001; CRP: p < 0.001). Sleep efficiency and wake time after sleep onset markedly improved in the ETA group. Serum cortisol and ACTH did not change during observation. At baseline, serum cortisol levels were negatively correlated to sleep efficiency; this may depend on inflammation, because controlling for CRP eliminated this negative correlation. After ETA treatment, serum cortisol had a high positive correlation with total sleep time, sleep efficiency, and a negative correlation with wake time before and after sleep onset, which was not eliminated by controlling for CRP. In RA patients, the data indicate that inflammation is an important covariate for the crosstalk of sleep and the HPA axis. © 2017 S. Karger AG, Basel.

Anti-interleukin 6 receptor tocilizumab in refractory uveitis associated with Behçet's disease: multicentre retrospective study.

PubMed

Atienza-Mateo, Belén; Calvo-Río, Vanesa; Beltrán, Emma; Martínez-Costa, Lucía; Valls-Pascual, Elia; Hernández-Garfella, Marisa; Atanes, Antonio; Cordero-Coma, Miguel; Miquel Nolla, Joan; Carrasco-Cubero, Carmen; Loricera, Javier; González-Vela, María C; Vegas-Revenga, Nuria; Fernández-Díaz, Carlos; Demetrio-Pablo, Rosalía; Domínguez-Casas, Lucía C; Luis Martín-Varillas, José; Palmou-Fontana, Natalia; Hernández, José L; González-Gay, Miguel Á; Blanco, Ricardo

2018-05-01

To assess the efficacy of tocilizumab (TCZ) in refractory uveitis of Behçet's disease (BD). Multicentre study of patients with BD-associated uveitis. Patients were refractory to conventional and biologic immunosuppressive drugs. The main outcome measures were intraocular inflammation, macular thickness, visual acuity and corticosteroid-sparing effects. We studied 11 patients (7 men) (20 affected eyes); median age 35 years. Uveitis was bilateral in nine patients. The patterns of ocular involvement were panuveitis (n = 8, with retinal vasculitis in 4), anterior uveitis (n = 2) and posterior uveitis (n = 1). Cystoid macular oedema was present in seven patients. The clinical course was recurrent (n = 7) or chronic (n = 4). Before TCZ, patients had received systemic corticosteroids, conventional immunosuppressants and the following biologic agents: adalimumab (n = 8), infliximab (n = 4), canakimumab (n = 1), golimumab (n = 3), etanercept (n = 1). TCZ was used as monotherapy or combined with conventional immunosuppressants at 8 mg/kg/i.v./4 weeks (n = 10) or 162 mg/s.c./week (n = 1). At TCZ onset the following extraocular manifestations were present: oral and/or genital ulcers (n = 7), arthritis (n = 4), folliculitis/pseudofolliculitis (n = 4), erythema nodosum (n = 2), livedo reticularis (n = 1) and neurological involvement (n = 2). TCZ yielded rapid and maintained improvement in all ocular parameters of the patients, with complete remission in eight of them. However, this was not the case for the extraocular manifestations, since TCZ was only effective in three of them. After a mean (s.d.) follow-up of 9.5 (8.05) months, TCZ was withdrawn in two cases, due to a severe infusion reaction and arthritis impairment, respectively. TCZ could be a therapeutic option in patients with BD and refractory uveitis.

Biologics and dermatology life quality index (DLQI) in the Australasian psoriasis population.

PubMed

Norris, Diana; Photiou, Louise; Tacey, Mark; Dolianitis, Con; Varigos, George; Foley, Peter; Baker, Chris

2017-12-01

Psoriasis is a chronic condition that may require long-term treatment for disease control. This analysis utilizes data from the Australasian Psoriasis Registry with particular attention to the impact of biologic therapy on DLQI, and the differences between the biologics in terms of DLQI score change. A retrospective review of patients enrolled in the Australasian Psoriasis Registry from April 2008 to August 2016 was conducted. All subjects from the registry that had DLQI and Psoriasis Assessment Severity Index (PASI) scores recorded at a baseline time point of treatment commencement, in addition to week 12 and 24 post commencement were included in the study. A window of ±3 weeks was permitted at these time points. Multivariate linear regression analysis was undertaken to identify significant predictors associated with change in DLQI. Significant predictors of reduction in DLQI and PASI score from baseline to week 24 include use of adalimumab, infliximab, secukinumab and ustekinumab. Other therapies, including etanercept and oral systemic agents did not show significant change. Each class of biologic showed significant reductions in DLQI score, with IL-12/23 blockade showing the greatest reduction. Significant predictors of lack of reduction in DLQI score include a baseline PASI score <16, and history of diabetes, alcoholism or uveitis. Patients with moderate to severe chronic plaque psoriasis who are treated with biologics show the greatest reduction in DLQI score, compared with other treatments. Australian dermatologists are prescribing biologics when patients qualify for them in keeping with current guidelines.

TNF-alpha inhibitors in dermatology.

PubMed

Cordoro, K M; Feldman, S R

2007-09-01

To date, the US FDA has approved three tumor necrosis factor (TNF)-a inhibitors for use in dermatology. Etanercept (Enbrel, Amgen-Wyeth), a fully human fusion protein of TNF receptor II bound to the Fc component of human IgG1, is approved for use in psoriasis (2004) and psoriatic arthritis (2002). Infliximab (Remicade, Centocor) is a chimeric monoclonal antibody that is approved for use in psoriasis (2006) and psoriatic arthritis (2005), and adalimumab (Humira, Abbott Laboratories), a fully human monoclonal antibody, is approved for use in psoriatic arthritis (2005). While data regarding the efficacy and safety of these therapies is abundant, it proves nearly impossible to objectively compare and contrast agents as there are no head-to-head trials. Clinical experience and post-marketing reporting has allowed dermatologists to identify the relative strengths and limitations of each agent. The well-founded enthusiasm for these agents, because of their excellent initial efficacy and safety profile, is reasonably tempered by concerns about declining efficacy over time, the risk of infection, lymphoma and demyelinating disorders, and cost. The distinct and targeted mechanism of action of the TNF inhibitors allows dermatologists to customize therapy to match the individual needs and characteristics of patients who are candidates for systemic or phototherapy.

Adverse cutaneous reactions induced by TNF-alpha antagonist therapy.

PubMed

Borrás-Blasco, Joaquín; Navarro-Ruiz, Andrés; Borrás, Consuelo; Casterá, Elvira

2009-11-01

To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-alpha) antagonist therapy. A literature search was performed using PubMed (1996-March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. Since the introduction of TNF-alpha antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-alpha antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-alpha antagonists for a variety of rheumatologic conditions. TNF-alpha antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-alpha antagonists. As the use of TNF-alpha antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-alpha antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

[Proteins support stem cells - use of protein therapeutics in hematopoietic stem cell transplantation].

PubMed

Meyer, Sara Christina; Stern, Martin

2011-11-01

Hematopoietic stem cell transplantation (HSCT) has evolved from a largely experimental therapeutic approach three decades ago to a well-established therapy today for many malignant and non-malignant disorders of the hematopoietic and the immune system. Although it is per se a therapy by transmission of cells, protein therapeutics such as growth factors and antibodies are relevant in all phases of a HSCT and substantially contribute to the success of this often only curative treatment. This review discusses HSCT with a particular focus on the protein therapeutics involved. Granulocyte colony stimulating factor (G-CSF) for mobilization of stem cells to the peripheral blood, the polyclonal anti-T-cell globulin (ATG) and the monoclonal antibodies alemtuzumab and etanercept for prophylaxis and therapy of graft versus host disease (GvHD) are highlighted. Also rituximab, palivizumab and polyclonal intravenous immunoglobulins for treating infections in post-transplant patients are discussed. Since our understanding of cell surface receptors, cytokine and signaling pathways is increasing, there will emerge new targets for directed therapy by proteins in the future. They may have the potential to further improve the success and to widen theapplication of HSCT.

Biosimilars in psoriasis: what can we expect?

PubMed

Radtke, Marc Alexander; Augustin, Matthias

2014-04-01

Biosimilars are biotechnologically processed drugs whose amino acid sequence is identical to the original biopharmaceutical. They are of considerable clinical, economical, and health care interest. As patents for biologicals used to treat psoriasis expire, biosimilars will become more and more important within the field of dermatology. The patents for the two top-selling drugs (adalimumab and etanercept) will terminate in the next few years. Applications for biosimilars will presumably be submitted to the EMA and the FDA for all patent-free biologicals. Both regulatory bodies have issued guidelines on the assessment of bioequivalence, as well as the benefits and risks of biosimilars. While the preclinical requirements of the FDA and EMA are largely comparable, the formal requirements for clinical bioequivalence, including clinical efficacy and safety, differ markedly. Therefore, from a medical and health care perspective before biosimilars enter the market, specific evidence-based regulatory conditions need to be created and fulfilled. Only then biosimilars can be a less expensive option for a large number of patients, providing them with substances of the same value. Adequate, unequivocal proof of their bioequivalence, quality, and related patient safety should have priority over any ostensible economic benefits. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Rheumatoid arthritis in a military aviator.

PubMed

Moszyk, Danielle J; Sulit, Daryl J

2007-01-01

Rheumatoid arthritis is a chronic inflammatory condition whose pathogenesis is determined partially by genetic and environmental factors. Without treatment, 20 to 30% of individuals with this condition will become permanently disabled in a few years. Rheumatoid arthritis and its potential complications can cause significant disability and could seriously affect the performance of an aviator. Traditionally, disease-modifying anti-rheumatic drugs (DMARD) and biologics have not been used until disease progression occurs, but they recently have been added earlier in the course of disease for a more aggressive approach to treatment. It has been shown to significantly reduce the number of affected joints, pain, and disability. This newer treatment regimen has helped a military pilot continue his aviation career. We present the case of an experienced designated military pilot who was diagnosed with rheumatoid arthritis. He was initially treated early with a DMARD and biologic medication. He has remained in remission and currently only uses etanercept (biologic medication) and a non-steriodal anti-inflammatory drug to control his disease. He has responded favorably to therapy and has few limitations. Due to his positive response to treatment, the aviator was granted military aeromedical waivers for rheumatoid arthritis and chronic medication use.

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

PubMed

Ibrahim, Fowzia; Lorente-Cánovas, Beatriz; Doré, Caroline J; Bosworth, Ailsa; Ma, Margaret H; Galloway, James B; Cope, Andrew P; Pande, Ira; Walker, David; Scott, David L

2017-11-01

RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis—a proof of principle and exploratory trial: is dose tapering practical in good responders?

PubMed Central

Lorente-Cánovas, Beatriz; Doré, Caroline J; Bosworth, Ailsa; Ma, Margaret H; Galloway, James B; Cope, Andrew P; Pande, Ira; Walker, David; Scott, David L

2017-01-01

Abstract Objectives RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. Methods We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0–6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6–12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Results Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0–6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6–12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Conclusion Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. Trail registration EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701 PMID:28968858

Estimation of cost savings between 2011 and 2014 attributed to infliximab biosimilar in the South Korean healthcare market: real-world evidence using a nationwide database.

PubMed

Kim, Jiyoun; Ha, Dongmun; Song, Inmyung; Park, Haesun; Lee, Sang-Won; Lee, Eui-Kyung; Shin, Ju-Young

2018-06-01

The introduction of biosimilars is expected to reduce the cost of biologic drugs, but the actual cost savings have not yet been quantified in Korea. The aim of this study was to estimate the annual cost savings attributed to the introduction of infliximab biosimilar. We conducted a retrospective analysis using data from the Health Insurance Review and Assessment Service-National Patients Sample (HIRA-NPS) between 2011 and 2014. The study subjects were patients who were treated with infliximab, adalimumab or etanercept. We compared the drug costs before and after the introduction of infliximab biosimilar in December 2012 (2011-2012 and 2013-2014) to estimate the annual drug cost savings attributed to this and the number of patients who could additionally benefit from the biosimilar in 2013 and 2014. A total of 10 986 prescriptions were identified: 2620 for infliximab. The cost savings were estimated at $262 270 for 133 patients in 2013 and $395 220 for 174 patients in 2014. Among the patients who underwent a 1-year maintenance course of infliximab therapy, the annual expenditure on infliximab was lower in 2014 than in 2011. If the cost savings were used to treat additional patients, 13.3%-38.6% more patients per year could be treated by indication. The introduction of infliximab biosimilar reduced direct medical costs for both patients and the payer, which could then be used to increase patient access to biologic medicines. The entry of infliximab biosimilar could result in further reductions in healthcare costs. © 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs.

PubMed

Pedard, Martin; Quirié, Aurore; Totoson, Perle; Verhoeven, Frank; Garnier, Philippe; Tessier, Anne; Demougeot, Céline; Marie, Christine

2018-05-02

In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkB tyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis. Copyright © 2018 Elsevier B.V. All rights reserved.

Patient Satisfaction with Treatments for Moderate-to-Severe Plaque Psoriasis in Clinical Practice

PubMed Central

Takeshita, J.; Krueger, G.G.; Robertson, A.D.; Troxel, A.B.; Shin, D.B.; Van Voorhees, A.S.; Gelfand, J.M.

2014-01-01

Background Treatment satisfaction among moderate-to-severe psoriasis patients has not been studied and compared across treatments using a validated instrument. Objectives To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality of life measures. Methods Cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the United States. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics, or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. Results Median unadjusted Overall Satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared to patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy, or adalimumab with methotrexate had significantly higher median Overall Satisfaction scores by 7.2 to 8.3 points, while those receiving topical therapies only had significantly lower Overall Satisfaction by 8.9 points. Adjusted Convenience scores were the lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between Overall Satisfaction and Psoriasis Area and Severity Index (ρ = −0.36, p < 0.001) and Dermatology Life Quality Index (−0.47, p < 0.001). Conclusions Discernable differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development. PMID:24266717

Assessment of the Item Selection and Weighting in the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis

PubMed Central

MAHR, ALFRED D.; NEOGI, TUHINA; LAVALLEY, MICHAEL P.; DAVIS, JOHN C.; HOFFMAN, GARY S.; MCCUNE, W. JOSEPH; SPECKS, ULRICH; SPIERA, ROBERT F.; ST.CLAIR, E. WILLIAM; STONE, JOHN H.; MERKEL, PETER A.

2013-01-01

Objective To assess the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) with respect to its selection and weighting of items. Methods This study used the BVAS/WG data from the Wegener's Granulomatosis Etanercept Trial. The scoring frequencies of the 34 predefined items and any “other” items added by clinicians were calculated. Using linear regression with generalized estimating equations in which the physician global assessment (PGA) of disease activity was the dependent variable, we computed weights for all predefined items. We also created variables for clinical manifestations frequently added as other items, and computed weights for these as well. We searched for the model that included the items and their generated weights yielding an activity score with the highest R2 to predict the PGA. Results We analyzed 2,044 BVAS/WG assessments from 180 patients; 734 assessments were scored during active disease. The highest R2 with the PGA was obtained by scoring WG activity based on the following items: the 25 predefined items rated on ≥5 visits, the 2 newly created fatigue and weight loss variables, the remaining minor other and major other items, and a variable that signified whether new or worse items were present at a specific visit. The weights assigned to the items ranged from 1 to 21. Compared with the original BVAS/WG, this modified score correlated significantly more strongly with the PGA. Conclusion This study suggests possibilities to enhance the item selection and weighting of the BVAS/WG. These changes may increase this instrument's ability to capture the continuum of disease activity in WG. PMID:18512722

Assessment of Health Related Quality of Life as an Outcome Measure in Granulomatosis with Polyangiitis (Wegener's)

PubMed Central

Tomasson, Gunnar; Boers, Maarten; Walsh, Michael; LaValley, Michael; Cuthbertson, David; Carette, Simon; Davis, John C.; Hoffman, Gary S.; Khalidi, Nader A.; Langford, Carol A.; McAlear, Carol A.; McCune, W. Joseph; Monach, Paul A.; Seo, Philip; Specks, Ulrich; Spiera, Robert; St. Clair, E. William; Stone, John H.; Ytterberg, Steven R.; Merkel, Peter A.

2011-01-01

Objective Assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's, GPA) Methods Subjects were participants in the Wegener’s Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 Health Survey (SF-36) that includes physical and mental component summary scores (PCS and MCS). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG). Results Data from 180 subjects in the WGET (median follow-up = 2.3 years, mean number of visits = 10) and 237 subjects in the VCRC-LS (median follow-up = 2.0 years, mean number of visits = 8) were analyzed. One unit increase in BVAS/WG corresponded to a 1.15 unit (95%CI: 1.02; 1.29) decrease in PCS and a 0.93 (95%CI: 0.78; 1.07) decrease in MCS in the WGET and by 1.16 for PCS (95%CI: 0.94; 1.39) and 0.79 for MCS (95%CI: 0.51; 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per three months), but worsened slightly (0.03 decrease in PCS per three months) among patients not achieving sustained remission (p = 0.005). Conclusion HRQOL, as measured by SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA. PMID:21954229

Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases

PubMed Central

Nomura, Kaori; Takahashi, Kunihiko; Hinomura, Yasushi; Kawaguchi, Genta; Matsushita, Yasuyuki; Marui, Hiroko; Anzai, Tatsuhiko; Hashiguchi, Masayuki; Mochizuki, Mayumi

2015-01-01

Background The use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection. Methods Two AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug-event combinations for three substances frequently recorded in both systems. Results The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37) in the JP and 3.3±3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected. Conclusion The FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data. PMID:26109846

Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor α-mediated neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, Dong Hwan, E-mail: ethan2887@gmail.com; Seol, Wongi; Eun, Jin Hwan

Leucine-rich repeat kinase (LRRK2), a major causal gene of Parkinson's disease (PD), functions as a kinase. The most prevalent mutation of LRRK2 is G2019S. It exhibits increased kinase activity compared to the wildtype LRRK2. Previous studies have shown that LRRK2 can phosphorylate p53 at T304 and T377 of threonine-X-arginine (TXR) motif in neurons. Reduction of LRRK2 expression or inhibition of LRRK2 kinase activity has been shown to be able to alleviate LPS-induced neuroinflammation in microglia cells. In this study, we found that LRRK2 could also phosphorylate p53 in microglia model BV2 cells. Transfection of BV2 with phosphomimetic p53 T304/377D significantlymore » increased the secretion of pro-inflammatory cytokine TNFα compared to BV2 transfected with p53 wild type after LPS treatment. In addition, conditioned media from these transfected cells increased the death of dopaminergic neuronal SN4741 cells. Moreover, such neurotoxic effect was rescued by co-treatment with the conditioned media and etanercept, a TNFα blocking antibody. Furthermore, TNFα secretion was significantly increased in primary microglia derived from G2019S transgenic mice treated with LPS compared to that in cells derived from their littermates. These results suggest that LRRK2 kinase activity in microglia can contribute to neuroinflammation in PD via phosphorylating p53 at T304 and T377 site. - Highlights: • LPS stimulates LRRK2-mediated p53 phosphorylation and its nuclear localization. • Phosphorylation of p53 by LRRK2 in microglia enhances TNFα expression. • Microglial TNFα via LRRK2-induced p53 phosphorylation decreases neuronal survival.« less

Biologic interventions for fatigue in rheumatoid arthritis.

PubMed

Almeida, Celia; Choy, Ernest H S; Hewlett, Sarah; Kirwan, John R; Cramp, Fiona; Chalder, Trudie; Pollock, Jon; Christensen, Robin

2016-06-06

Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage. To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis. We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors. We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure. Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model. We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue. Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.

Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis

PubMed Central

2011-01-01

Introduction There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα). In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. Methods The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column. The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex. Results The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rβ chain. The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells. The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment. Conclusions The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA. PMID:21435242

[Kidney involvement in rheumatoid arthritis].

PubMed

Icardi, A; Araghi, P; Ciabattoni, M; Romano, U; Lazzarini, P; Bianchi, G

2003-01-01

Rheumatoid Arthritis (RA) is a widespread disease and its renal involvement, relatively common, is clinically significant because worsens course and mortality of the primary disease. There is still no agreement on the prevalence of renal disorders in RA: data analysis originates from different sources, as death certificates, autopsies, clinical and laboratory findings and kidney biopsies, each with its limitations. Histoimmunological studies on bioptical specimens of patients with RA and kidney damage, led to clarify prevalent pathologies. In order of frequency: glomerulonephritis and amyloidosis (60-65% and 20-30% respectively), followed by acute or chronic interstitial nephritis. Kidney injury during RA includes secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs and nephropathies as extra-articular manifestations (rheumatoid nephropathy). Amyloidosis affects survival, increases morbidity and is the main cause of end stage renal disease in patients with RA and nephropathy. Strong association between RA activity and amyloidosis needs the use of immunosuppressive and combined therapies, to prevent this complication and reduce risk of dialysis. Long-lasting and combined RA pharmacotherapy involves various renal side effects. In this review we describe NSAIDs and DMARDs (Disease-Modifying Antirheumatic Drugs) nephrotoxicity, particularly by gold compounds, D-penicillamine, cyclosporine A and methotrexate. Rare cases of IgA glomerulonephritis during immunomodulating therapy with leflunomide and TNF blocking receptor (etanercept) are reported; real clinical significance of this drug-related nephropathy will be established by development of RA treatment. In RA nephropathies, mesangial glomerulonephritis is the most frequent histological lesion (35-60 % out of biopsies from patients with urinary abnormalities and/or kidney impairment), followed by minimal change glomerulopathy (3-14%) and p-ANCA positive necrotizing crescentic glomerulonephritis.

Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors*

PubMed Central

Pontejo, Sergio M.; Alejo, Ali; Alcami, Antonio

2015-01-01

The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. PMID:25940088

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

PubMed Central

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

2007-01-01

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis. PMID:17888176

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats.

PubMed

Yago, Toru; Nanke, Yuki; Kawamoto, Manabu; Furuya, Takefumi; Kobashigawa, Tsuyoshi; Kamatani, Naoyuki; Kotake, Shigeru

2007-01-01

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

Clinical improvement of renal amyloidosis in a patient with systemic-onset juvenile idiopathic arthritis who received tocilizumab treatment: a case report and literature review.

PubMed

Chantarogh, Songkiat; Vilaiyuk, Soamarat; Tim-Aroon, Thipwimol; Worawichawong, Suchin

2017-05-12

Juvenile idiopathic arthritis (JIA) is a common rheumatic disease in children and adolescents. Although JIA may cause secondary amyloidosis, this is a rare complication in patients with JIA and other rheumatic diseases. Many previous studies have revealed that common heterozygous or homozygous mutations in the MEFV gene are associated with systemic-onset JIA (SJIA). We herein report a case involving a 19-year-old female patient with difficult-to-control SJIA. She developed progressive proteinuria without clinical signs or symptoms of edema. Renal amyloidosis was diagnosed by renal pathologic examination, which demonstrated deposition of eosinophilic amorphous material in the interlobular arteries, arterioles, and interstitium. Electron microscopy showed fibrillary material deposits with a diameter of 8 to 10 nm. A heterozygous E148Q mutation in the MEFV gene was identified. Conventional disease-modifying anti-rheumatic drugs and etanercept had been used to treat the SJIA, but the disease could not be controlled. Therefore, we decided to start tocilizumab to control the disease activity. However, the patient was unable to receive a standard dose of tocilizumab in the early period of treatment because of socioeconomic limitations. Her disease course was still active, and proteinuria was found. Therefore, tocilizumab was increased to a dose of 8 mg/kg every 2 weeks (standard dose of SJIA), and the patient exhibited a clinical response within 3 months. Refractory SJIA associated with renal amyloidosis is an uncommon cause of proteinuria in adolescents. Tocilizumab may be a beneficial treatment for renal amyloidosis in patients with SJIA.

Antitumor Necrosis Factor-α Therapy Associated with Inflammatory Bowel Disease: Three Cases and a Systematic Literature Review.

PubMed

Bieber, Amir; Fawaz, Abdallah; Novofastovski, Irina; Mader, Reuven

2017-07-01

Antitumor necrosis factor-α (anti-TNF-α) therapy is the most prescribed biologic agent therapy in rheumatology and gastroenterology. However, a number of serious side effects have been reported with these drugs. Only a handful of cases of new-onset inflammatory bowel disease (IBD), mostly in children diagnosed with juvenile idiopathic arthritis (JIA), have been reported during anti-TNF-α therapy. We present 3 cases of adult IBD following anti-TNF-α therapy and a literature review on this topic. We searched PubMed MESH for all relevant terms, papers were reviewed, and patient-specific data were extracted. Relevant clinical data were calculated and presented. The PubMed search resulted in 137 articles, of which 11 articles and 4 cited publications were included in our analysis. We found 53 cases of IBD after anti-TNF-α therapy reported in the literature; most of them were case series collected retrospectively from national databases or studies. Almost all the patients developed IBD after the introduction of etanercept (ETN); 2 patients with rheumatoid arthritis were also included. The average age at IBD onset was 17.3 years and the average time from ETN introduction to IBD onset was 27 months (± 24). Gastrointestinal symptoms have been reported as improving or subsiding in most of the patients after discontinuing ETN. Although this manifestation is not common, it should be taken into consideration as an adverse effect of ETN. Rheumatologists, and in particular rheumatologists treating adult patients, should be aware of this possible complication. Further investigation about the pathogenic process underlying this phenomenon is warranted.

Analysis of the data on pregnancy and lactation provided by patient information leaflets of anti-rheumatic drugs in Argentina.

PubMed

Sabando, Miguel Ormaza; Saavedra, Maira Arias; Sequeira, Gabriel; Kerzberg, Eduardo

2018-04-01

To analyse the level of consistency and updating of the information on pregnancy and lactation provided by patient information leaflets (PILs) of the antirheumatic drugs approved in Argentina. Inconsistencies between the 2016 EULAR Task Force recommendations on the use of anti-rheumatic drugs during pregnancy and lactation and the information provided by PILs of the same drugs approved in Argentina were analysed along with inconsistencies within the PILs of different registered trademarks of these drugs. Eighty-eight PILs of 32 drugs were analysed. Out of the 88 PILs, 50% presented information inconsistencies as to pregnancy. Medications comprised in this group were: hydroxychloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs (during the first two trimesters), celecoxib, some glucocorticoids, colchicine, and some anti-TNF drugs (etanercept, adalimumab and infliximab) during part of the pregnancy. As for lactation, 56% had information inconsistencies. Medications encompassed in this group were: hydroxychloroquine, chloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs, celecoxib, meprednisone, prednisone, colchicine, and anti-TNF drugs. Out of 17 drugs that had more than one registered trademark, information inconsistencies on pregnancy were found in the PILs of sulfasalazine, diclofenac, ibuprofen and methylprednisolone. Concerning lactation, inconsistencies were present in the PILs of hydroxychloroquine, sulfasalazine, diclofenac, ibuprofen, meprednisone, and colchicine. At least half of the PILs of anti-rheumatic drugs analysed in this study had information inconsistencies on pregnancy and lactation. This is a serious state of affairs because the consensual decision-making process between patient and professional may be compromised, which, in turn, may give rise to medical-legal issues.

Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases.

PubMed

Van Rompaey, Luc; Galien, René; van der Aar, Ellen M; Clement-Lacroix, Philippe; Nelles, Luc; Smets, Bart; Lepescheux, Liên; Christophe, Thierry; Conrath, Katja; Vandeghinste, Nick; Vayssiere, Béatrice; De Vos, Steve; Fletcher, Stephen; Brys, Reginald; van 't Klooster, Gerben; Feyen, Jean H M; Menet, Christel

2013-10-01

The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.

Systemic Inflammatory Response Syndrome After Administration of Unmodified T Lymphocytes

PubMed Central

Papadopoulou, Anastasia; Krance, Robert A; Allen, Carl E; Lee, Daniel; Rooney, Cliona M; Brenner, Malcolm K; Leen, Ann M; Heslop, Helen E

2014-01-01

Systemic inflammatory response syndrome (SIRS) is a rare systemic inflammatory response associated with fever, tachycardia, profound hypotension, and respiratory distress, which has been reported in cancer patients receiving T cells genetically modified with chimeric antigen receptors to retarget their specificity to tumor-associated antigens. The syndrome usually occurs following significant in vivo expansion of the infused cells and has been associated with tumor destruction/lysis. Analysis of patient plasma has shown elevated cytokine levels, and resolution of symptoms has been reported after administration of steroids and/or antibodies (such as anti–tumor necrosis factor and anti-interleukin (IL)-6 receptor antibodies) that interfere with cytokine responses.To date, SIRS has not been reported in subjects receiving genetically unmodified T cells with native receptors directed against tumor antigens, in which greater physiological control of T-cell activation and expansion may occur. Here, however, we report a patient with bulky refractory Epstein-Barr virus (EBV)–associated lymphoma, who developed this syndrome 2 weeks after receiving T cells directed against EBV antigens through their native receptors. She was treated with steroids and etanercept, with rapid resolution of symptoms. SIRS may therefore occur even when T cells recognize antigens physiologically through their “wild-type” native receptors and should be acknowledged as a potential complication of this therapy. PMID:24651135

Subacute lupus erythematosus during treatment with golimumab for seronegative rheumatoid arthritis.

PubMed

Brunasso, A M G; Aberer, W; Massone, C

2014-02-01

We report on a 52-year-old woman with a history of severe seronegative rheumatoid arthritis. Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful. In 2010 she was given golimumab subcutaneously at a monthly dose of 50 mg. She had a negative ANA titre. After 16 months of uninterrupted therapy and sustained response, she developed skin lesions on the upper trunk, back and upper extremities, which worsened on exposure to the sun. The skin biopsy was compatible with subacute lupus erythematosus. Laboratory findings included an ANA titre 1:640, negative anti-Ro/SSA and anti-DNA antibodies. Topical corticosteroid therapy proved inadequate. The patient's condition improved only after discontinuation of golimumab. The causal relationship between subacute cutaneous lupus erythematosus and golimumab is not dose-related and occurs with some delay (a typical feature of immunological adverse reactions). The association is likely, but not confirmed (because re-challenge was not performed). However, a clear improvement was noted after withdrawal. Based on this case, we hypothesized the aetiological role of golimumab-associated immunogenicity. TNF-α antagonist-induced lupus-like syndrome (TAILS) is a well-known side effect of this class of substances. The British Society of Rheumatology recommends discontinuation of the causal anti-TNF-α treatment in patients with TAILS.

Fluorescence optical imaging and musculoskeletal ultrasonography in juvenile idiopathic polyarticular disease before and during antirheumatic treatment - a multicenter non-interventional diagnostic evaluation.

PubMed

Klein, Ariane; Just, Georg Werner; Werner, Stephanie Gabriele; Oommen, Prasad T; Minden, Kirsten; Becker, Ingrid; Langer, Hans-Eckhard; Klee, Dirk; Horneff, Gerd

2017-06-30

Valid detection of inflamed joints is essential for correct classification, therapeutic decisions, prognosis and assessment of treatment efficacy in juvenile idiopathic arthritis (JIA). Fluorescence optical imaging (FOI) enables visualization of inflammation in arthritis of finger and hand joints and might be used for monitoring. A 24-week observational study in polyarticular JIA patients newly starting treatment with methotrexate or an approved biologic was performed in three centers. Patients were evaluated clinically, by gray-scale ultrasonography (GSUS), power-Doppler ultrasonography (PDUS) and FOI at baseline, week 12 and week 24. Of 37 patients enrolled, 24 patients started methotrexate and 13 patients a biologic for the first time (etanercept n = 11, adalimumab and tocilizumab n = 1 each). Mean JADAS 10 decreased significantly from 17.7 at baseline to 12.2 and 7.2 at week 12 and 24 respectively. PedACR 30/50/70/100 response rates at week 24 were 85%/73%/50%/27%. The total number of clinically active joints in hand and fingers at baseline/week 12/week 24 was 262 (23.6%)/162 (16.4%)/162 (9.0%). By GSUS, at baseline/week 12/week 24, 192 (19.4%)/135 (16.1%)/83 (11.5%) joints showed effusions and 186 (18.8%)/107 (12.7%)/69 (9.6%) showed synovial thickening, and by PDUS 68 (6.9%)/15 (1.8%)/36 (5%) joints showed hyperperfusion. Any sign of arthritis was detected by US in a total of 243 joints (24.5%) at baseline, 161 joints (19.2%) at week 12 and 123 joints (17%) at week 24. By FOI at baseline/week 12/week 24, 430 (38.7%)/280 (29.2%)/215 (27.6%) showed a signal enhancement in at least one phase. Summarizing all three points of time, the highest numbers of signals were detected by FOI with 32% of joints, especially in phase 2, while by US 20.7% and by clinical examination 17.5% of joints were active. A high number of joints (21.1%) had FOI signals but were inactive by clinical examination. A total 20.1% of joints with signals in FOI did not show effusion, synovial thickening or hyperperfusion by US. Because of the high number of negative results, specificity of FOI compared with clinical examination/US/PD was high (84-95%), and sensitivity was only moderate. FOI and US could detect clinical but also subclinical inflammation. FOI detected subclinical inflammation to a higher extent than US. Improvement upon treatment with either methotrexate or a biologic can be visualized by FOI and US. Deutsches Register Klinischer Studien DRKS00011579 . Registered 10 January 2017.

Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy

PubMed Central

Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

2013-01-01

Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Results Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99). Conclusion Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections. PMID:20309874

The efficacy of inhibiting tumour necrosis factor alpha and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons.

PubMed

Nixon, R; Bansback, N; Brennan, A

2007-07-01

New treatments that inhibit the cytokines tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1) in the treatment of rheumatoid arthritis have proven clinical effect against placebo and methotrexate (MTX) in several clinical trials in early and late-stage disease and different severity groups. Since there are no head-to-head randomized controlled trials directly comparing the currently available treatments, etanercept, adalimumab, infliximab or anakinra, we perform a meta-analysis that adjusts for differences between study characteristics, and allows indirect comparisons between treatments. Thirteen trials of cytokine antagonists were included from a systematic review of the literature. They reported the primary outcome of American College of Rheumatology (ACR) response criteria at 6 months or beyond. Meta-analytical methods are used to quantify relative treatment effects, using the log odds ratio of an ACR20 or ACR50 response at 6 months, whilst adjusting for study-level variables. In each of the trials, cytokine treatment was efficacious in comparison with placebo or MTX. For each treatment, the inclusion of MTX in combination improved the response. After adjustment for study-level variables, we found TNFalpha antagonists to be more efficacious compared with anakinra (P < 0.05). Indirect comparisons between the three TNFalpha antagonists indicated no difference in efficacy. Sensitivity analysis using a different statistical model structure confirmed these results. When the outcome of interest is the probability of an ACR20 or ACR50 response at 6 months we found: (i) treatment with the IL-1 antagonist anakinra is better than placebo; (ii) for each treatment, the use of combination MTX improves the probability of response; (iii) treatment with any of the TNFalpha antagonists is better than with the IL-1 antagonist anakinra; and (iv) all drugs in the TNFalpha antagonist class are no different from each other.

Association between anti-TNF-α therapy and all-cause mortality.

PubMed

Herrinton, Lisa J; Liu, Liyan; Chen, Lang; Harrold, Leslie R; Raebel, Marsha A; Curtis, Jeffrey R; Griffin, Marie R; Solomon, Daniel H; Saag, Kenneth G; Lewis, James D

2012-12-01

To compare mortality among patients with selected autoimmune diseases treated with anti-tumor necrosis factor alpha (TNF-α) agents with similar patients treated with non-biologic therapies. Cohort study set within several large health care programs, 1998-2007. Autoimmune disease patients were identified using diagnoses from computerized healthcare data. Use of anti-TNF-α agents and comparison of non-biologic therapies were identified from pharmacy data, and mortality was identified from vital records and other sources. We compared new users of anti-TNF-α agents to new users of non-biologic therapies using propensity scores and Cox proportional hazards analysis to adjust for baseline differences. We also made head-to-head comparisons among anti-TNF-α agents. Among the 46 424 persons included in the analysis, 2924 (6.3%) had died by the end of follow-up, including 1754 (6.1%) of the 28 941 with a dispensing of anti-TNF-α agent and 1170 (6.7%) of the 17 483 who used non-biologic treatment alone. Compared to use of non-biologic therapies, use of anti-TNF-α therapy was not associated with an increased mortality in patients with rheumatoid arthritis (adjusted hazard ratio [aHR] 0.93 with 95% confidence intervals (CI) 0.85-1.03); psoriasis, psoriatic arthritis, or ankylosing spondylitis (combined aHR 0.81 with CI 0.61-1.06; or inflammatory bowel disease (aHR 1.12 with CI 0.85-1.46). Mortality rates did not differ to an important degree between patients treated with etanercept, adalimumab, or infliximab. Anti-TNF-α therapy was not associated with increased mortality among patients with autoimmune diseases. Copyright © 2012 John Wiley & Sons, Ltd.

Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors.

PubMed

Wallace, Carol A; Giannini, Edward H; Spalding, Steven J; Hashkes, Philip J; O'Neil, Kathleen M; Zeft, Andrew S; Szer, Ilona S; Ringold, Sarah; Brunner, Hermine I; Schanberg, Laura E; Sundel, Robert P; Milojevic, Diana S; Punaro, Marilynn G; Chira, Peter; Gottlieb, Beth S; Higgins, Gloria C; Ilowite, Norman T; Kimura, Yukiko; Johnson, Anne; Huang, Bin; Lovell, Daniel J

2014-06-01

To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.

Effects of Biologic Agents in Patients with Rheumatoid Arthritis and Amyloidosis Treated with Hemodialysis.

PubMed

Kuroda, Takeshi; Tanabe, Naohito; Nozawa, Yukiko; Sato, Hiroe; Nakatsue, Takeshi; Kobayashi, Daisuke; Wada, Yoko; Saeki, Takako; Nakano, Masaaki; Narita, Ichiei

Objective Our objective was to examine the safety and effects of therapy with biologics on the prognosis of rheumatoid arthritis (RA) patients with reactive amyloid A (AA) amyloidosis on hemodialysis (HD). Methods Twenty-eight patients with an established diagnosis of reactive AA amyloidosis participated in the study. The survival was calculated from the date of HD initiation until the time of death, or up to end of June 2015 for the patients who were still alive. HD initiation was according to the program of HD initiation for systemic amyloidosis patients associated with RA. Results Ten patients had been treated with biologics before HD initiation for a mean of 28.2 months (biologic group), while 18 had not (non-biologic group). HD was initiated in patients with similar characteristics except for the tender joint count, swollen joint count, and disease activity score (DAS)28-C-reactive protein (CRP). History of biologics showed that etanercept was frequently used for 8 patients as the first biologic. There was no significant difference in the mortality rate according to a Kaplan-Meier analysis (p=0.939) and or associated risk of death in an age-adjusted Cox proportional hazards model (p=0.758) between both groups. Infections were significantly more frequent causes of death in the biologic group than in the non-biologic group (p=0.021). However, treatment with biologics improved the DAS28-CRP score (p=0.004). Conclusion Under the limited conditions of AA amyloidosis treated with HD, the use of biologics might affect infection and thus may not improve the prognosis. Strict infection control is necessary for the use of biologics with HD to improve the prognosis.

Effects of Biologic Agents in Patients with Rheumatoid Arthritis and Amyloidosis Treated with Hemodialysis

PubMed Central

Kuroda, Takeshi; Tanabe, Naohito; Nozawa, Yukiko; Sato, Hiroe; Nakatsue, Takeshi; Kobayashi, Daisuke; Wada, Yoko; Saeki, Takako; Nakano, Masaaki; Narita, Ichiei

2016-01-01

Objective Our objective was to examine the safety and effects of therapy with biologics on the prognosis of rheumatoid arthritis (RA) patients with reactive amyloid A (AA) amyloidosis on hemodialysis (HD). Methods Twenty-eight patients with an established diagnosis of reactive AA amyloidosis participated in the study. The survival was calculated from the date of HD initiation until the time of death, or up to end of June 2015 for the patients who were still alive. HD initiation was according to the program of HD initiation for systemic amyloidosis patients associated with RA. Results Ten patients had been treated with biologics before HD initiation for a mean of 28.2 months (biologic group), while 18 had not (non-biologic group). HD was initiated in patients with similar characteristics except for the tender joint count, swollen joint count, and disease activity score (DAS)28-C-reactive protein (CRP). History of biologics showed that etanercept was frequently used for 8 patients as the first biologic. There was no significant difference in the mortality rate according to a Kaplan-Meier analysis (p=0.939) and or associated risk of death in an age-adjusted Cox proportional hazards model (p=0.758) between both groups. Infections were significantly more frequent causes of death in the biologic group than in the non-biologic group (p=0.021). However, treatment with biologics improved the DAS28-CRP score (p=0.004). Conclusion Under the limited conditions of AA amyloidosis treated with HD, the use of biologics might affect infection and thus may not improve the prognosis. Strict infection control is necessary for the use of biologics with HD to improve the prognosis. PMID:27725536

Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR).

PubMed

Dixon, W G; Hyrich, K L; Watson, K D; Lunt, M; Galloway, J; Ustianowski, A; Symmons, D P M

2010-03-01

The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity. Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs. To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100,000 person-years) and INF (136/100,000 person-years) than for ETA (39/100,000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy. The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.

Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database.

PubMed

Scirè, Carlo A; Caporali, Roberto; Sarzi-Puttini, Piercarlo; Frediani, Bruno; Di Franco, Manuela; Tincani, Angela; Sinigaglia, Luigi; Sfriso, Paolo; Tirri, Rosella; Bellis, Emanuela; Delsante, Giovanni; Porru, Giovanni; Salaffi, Fausto; Giuggioli, Dilia; Rossini, Maurizio; Todoerti, Monica; Bazzichi, Laura; Govoni, Marcello; Gerli, Roberto; Raschetti, Roberto; Minisola, Giovanni; Montecucco, Carlomaurizio; Todesco, Silvano

2013-01-01

To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

Estimated cost efficacy of systemic treatments that are approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis.

PubMed

D'Souza, Logan S; Payette, Michael J

2015-04-01

Newer psoriasis treatments tout higher efficacy but are generally more expensive. We sought to estimate the cost efficacy of systemic psoriasis treatments that have been approved by the US Food and Drug Administration (FDA). A literature review of systemic psoriasis treatments that have been approved by the FDA was performed for the primary end point of a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75). Medication cost was referenced by wholesale acquisition cost (WAC), laboratory fees were obtained from the American Medical Association, and office visit fees are standard at our university. Total expenses were standardized by calculating cost per month of treatment considering the number needed to treat (NNT) to achieve PASI 75. Methotrexate ($794.05-1502.51) and cyclosporine ($1410.14-1843.55) had the lowest monthly costs per NNT to achieve PASI 75. The most costly therapies were infliximab ($8704.68-15,235.52) and ustekinumab 90 mg ($12,505.26-14,256.75). Monthly costs per NNT to achieve PASI 75 for other therapies were as follows: narrowband ultraviolet B light phototherapy ($2924.73), adalimumab ($3974.61-7678.78), acitretin ($4137.71-14,148.53), ustekinumab 45 mg ($7177.89-7263.99), psoralen plus ultraviolet A light phototherapy ($7499.46-8834.98), and etanercept ($8284.71-10,674.89). Drug rebates and incentives, potential adverse effects, comorbidity risk reduction, ambassador programs, and combination therapies were excluded. Our study provides meaningful cost efficacy data that may influence psoriasis treatment selection. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors.

PubMed

Pontejo, Sergio M; Alejo, Ali; Alcami, Antonio

2015-06-26

The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

PubMed

Walters, Edgar T

2014-08-01

Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain. Copyright © 2014 Elsevier Inc. All rights reserved.

Transferability of results of cost utility analyses for biologicals in inflammatory conditions for Central and Eastern European countries.

PubMed

Gulácsi, László; Rencz, Fanni; Péntek, Márta; Brodszky, Valentin; Lopert, Ruth; Hevér, Noémi V; Baji, Petra

2014-05-01

Several Central and Eastern European (CEE) countries require cost-utility analyses (CUAs) to support reimbursement formulary listing. However, CUAs informed by local evidence are often unavailable, and the cost-effectiveness of the several currently reimbursed biologicals is unclear. To estimate the cost-effectiveness as multiples of per capita GDP/quality adjusted life years (QALY) of four biologicals (infliximab, etanercept, adalimumab, golimumab) currently reimbursed in six CEE countries in six inflammatory rheumatoid and bowel disease conditions. Systematic literature review of published cost-utility analyses in the selected conditions, using the United Kingdom (UK) as reference country and with study selection criteria set to optimize the transfer of results to the CEEs. Prices in each CEE country were pro-rated against UK prices using purchasing power parity (PPP)-adjusted per capita GDP, and local GDP per capita/QALY ratios estimated. Central and Eastern European countries list prices were 144-333% higher than pro rata prices. Out of 85 CUAs identified by previous systematic literature reviews, 15 were selected as a convenience sample for estimating the cost-effectiveness of biologicals in the CEE countries in terms of per capita GDP/QALY. Per capita GDP/QALY values varied from 0.42 to 6.4 across countries and conditions (Bulgaria: 0.97-6.38; Czech Republic: 0.42-2.76; Hungary: 0.54-3.54; Poland: 0.59-3.90; Romania: 0.77-5.07; Slovakia: 0.55-3.61). While results must be interpreted with caution, calculating pro rata (cost-effective) prices and per capita GDP/QALY ratios based on CUAs can aid reimbursement decision-making in the absence of analyses using local data.

Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period

PubMed Central

Gomez-Reino, Juan J; Carmona, Loreto

2006-01-01

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34–0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97–2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13–4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. PMID:16507128

Enhanced M1/M2 macrophage ratio promotes orthodontic root resorption.

PubMed

He, D; Kou, X; Luo, Q; Yang, R; Liu, D; Wang, X; Song, Y; Cao, H; Zeng, M; Gan, Y; Zhou, Y

2015-01-01

Mechanical force-induced orthodontic root resorption is a major clinical challenge in orthodontic treatment. Macrophages play an important role in orthodontic root resorption, but the underlying mechanism remains unclear. In this study, we examined the mechanism by which the ratio of M1 to M2 macrophage polarization affects root resorption during orthodontic tooth movement. Root resorption occurred when nickel-titanium coil springs were applied on the upper first molars of rats for 3 to 14 d. Positively stained odontoclasts or osteoclasts with tartrate-resistant acid phosphatase were found in resorption areas. Meanwhile, M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) persistently accumulated on the compression side of periodontal tissues. In addition, the expressions of the M1 activator interferon-γ and the M1-associated pro-inflammatory cytokine tumor necrosis factor (TNF)-α were upregulated on the compression side of periodontal tissues. When the coil springs were removed at the 14th day after orthodontic force application, root resorption was partially rescued. The number of CD68(+)CD163(+) M2-like macrophages gradually increased on the compression side of periodontal tissues. The levels of M2 activator interleukin (IL)-4 and the M2-associated anti-inflammatory cytokine IL-10 also increased. Systemic injection of the TNF-α inhibitor etanercept or IL-4 attenuated the severity of root resorption and decreased the ratio of M1 to M2 macrophages. These data imply that the balance between M1 and M2 macrophages affects orthodontic root resorption. Root resorption was aggravated by an enhanced M1/M2 ratio but was partially rescued by a reduced M1/M2 ratio. © International & American Associations for Dental Research 2014.

Pharmacokinetics and brain uptake of an IgG-TNF decoy receptor fusion protein following intravenous, intraperitoneal, and subcutaneous administration in mice.

PubMed

Sumbria, Rachita K; Zhou, Qing-Hui; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang; Boado, Ruben J; Pardridge, William M

2013-04-01

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine active in the brain. Etanercept, the TNF decoy receptor (TNFR), does not cross the blood-brain barrier (BBB). The TNFR was re-engineered for BBB penetration as a fusion protein with a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-TNFR. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse and mediates transport via the endogenous BBB TfR. To support future chronic treatment of mouse models of neural disease with daily administration of the cTfRMAb-TNFR fusion protein, a series of pharmacokinetics and brain uptake studies in the mouse was performed. The cTfRMAb-TNFR fusion protein was radiolabeled and injected into mice via the intravenous, intraperitoneal (IP), or subcutaneous (SQ) routes of administration at doses ranging from 0.35 to 10 mg/kg. The distribution of the fusion protein into plasma following the IP or SQ routes was enhanced by increasing the injection dose from 3 to 10 mg/kg. The fusion protein demonstrated long circulation times with high metabolic stability following the IP or SQ routes of injection. The IP or SQ routes produced concentrations of the cTfRMAb-TNFR fusion protein in the brain that exceed by 20- to 50-fold the concentration of TNFα in pathologic conditions of the brain. The SQ injection is the preferred route of administration, as the level of cTfRMAb fusion protein produced in the brain is comparable to that generated with intravenous injection, and at a much lower plasma area under the concentration curve of the fusion protein as compared to IP administration.

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway.

PubMed

Cathomas, Flurin; Fuertig, Rene; Sigrist, Hannes; Newman, Gregory N; Hoop, Vanessa; Bizzozzero, Manuela; Mueller, Andreas; Luippold, Andreas; Ceci, Angelo; Hengerer, Bastian; Seifritz, Erich; Fontana, Adriano; Pryce, Christopher R

2015-11-01

The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. Copyright © 2015 Elsevier Inc. All rights reserved.

Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses.

PubMed

Matsuwaki, Takashi; Shionoya, Kiseko; Ihnatko, Robert; Eskilsson, Anna; Kakuta, Shigeru; Dufour, Sylvie; Schwaninger, Markus; Waisman, Ari; Müller, Werner; Pinteaux, Emmanuel; Engblom, David; Blomqvist, Anders

2017-11-01

Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (KO) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120µg/kg; HPA-axis: 120µg/kg), but showed attenuated but not extinguished fever (120µg/kg). Brain PGE 2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-α (TNFα) inhibitor etanercept nor the IL-6 receptor antibody tocilizumab abolished the LPS induced fever in IL-1R1 KO mice. Deletion of IL-1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFα, but by some yet unidentified pyrogenic factor. Copyright © 2017 Elsevier Inc. All rights reserved.

Biologic Therapy in Inflammatory and Immunomediated Arthritis: Safety Profile.

PubMed

Luchetti, Michele Maria; Balloni, Andrea; Gabrielli, Armando

2016-01-01

The increasing insights into the pathogenetic mechanisms of inflammatory autoimmune arthritis and the development of innovative systems of industrial production have led to discover molecules that are able to target/block other molecules that play a critical role in the immune system functioning, and that have been introduced in clinical practice alone and/or in addiction with other "old" disease-modifying anti-rheumatic drugs. For this reason, such drugs are currently known as "biological drugs" and include molecules that induce the immunosuppression acting on several immune pathways. However, though the biological drugs have been employed from more than a decade, there still exist some drawbacks of their use, in particular about the high costs of this therapy and their overall safety, including the route of administration for the intravenous use. In this review we provide an update on the correct use and current therapeutic indications of such drugs, including some of the new biologic therapies that will be soon available for the clinical use, focusing on these biological drugs: • Tumor necrosis factor-alpha (TNF-alpha) inhibitors (adalimumab, certolizumab-pegol, etanercept, golimumab and infliximab); • The T cell co-stimulation inhibitor, abatacept; • The anti-CD20 receptor monoclonal B cell agent, rituximab; • The interlukin-6 (IL-6) receptor-blocking monoclonal antibody, tocilizumab; • The interlukin-1 (IL-1) inhibitor, anakinra; • The interlukin-IL17 (IL-17) pathway inhibitors (ustekinumab, secukinumab, brodalumab).

Advances in the treatment of rheumatoid arthritis: old versus new therapies.

PubMed

Saravanan, Vadivelu; Hamilton, Jennifer

2002-07-01

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.

Renal Tumor Necrosis Factor α Contributes to Hypertension in Dahl Salt-Sensitive Rats

PubMed Central

Huang, Baorui; Cheng, Yuan; Usa, Kristie; Liu, Yong; Baker, Maria Angeles; Mattson, David L.; He, Yongcheng; Wang, Niansong; Liang, Mingyu

2016-01-01

Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13BN26 rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13BN26 rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7–8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats. PMID:26916681

Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis.

PubMed

Maneiro, José Ramón; Souto, Alejandro; Gomez-Reino, Juan J

2017-10-01

To summarize and compare the risks of malignancies accompanying biologic DMARDs (b-DMARDs) and tofacitinib in rheumatoid arthritis (RA) in randomized clinical trials (RCTs) and long-term extension studies (LTEs). Articles in Medline, Embase, Cochrane Library, and the Web of Science dated from 2000 to February 2015. Selection criteria were as follows: (1) focus on RCTs or LTEs in RA; (2) treatment with b-DMARDs or tofacitinib; (3) data on malignancies; and (4) a minimum follow-up of 12 weeks. Data included publication details, study design, risk of bias, number and types of malignancies, and patient characteristics and treatments. Of 113 articles and one updated report that were meta-analyzed, overall malignancies in RCTs showed odds ratio (95% confidence intervals) of 1.01 (0.72, 1.42) for all TNF antagonists, 1.12 (0.33, 3.81) for abatacept, 0.54 (0.20, 1.50) for rituximab, 0.70 (0.20, 2.41) for tocilizumab, and 2.39 (0.50, 11.5) for tofacitinib. Network meta-analysis of overall malignancies showed odds ratio (95% predictive intervals) of 1.68 (0.48-5.92) for infliximab, 0.79 (0.44-1.40) for etanercept, 0.93 (0.43-2.03) for adalimumab, 0.87 (0.28-2.75) for certolizumab, 0.87 (0.39-1.95) for golimumab, 1.04 (0.32-3.32) for abatacept, 0.58 (0.21-1.56) for rituximab, 0.60 (0.16-2.28) for tocilizumab, and 1.15 (0.24-5.47) for tofacitinib. Marginal numerical differences in the incidence rate of solid and hematological malignancies and non-melanoma skin cancers appeared in LTEs. In RCTs, treatment of RA with b-DMARDs or tofacitinib does not increase the risk for malignancies. Generalizability of the differences in the rate of specific malignancies encountered in LTEs requires continuous pharmacovigilance of real-world patients. Copyright © 2017. Published by Elsevier Inc.

A Single Aspiration of Rod-like Carbon Nanotubes Induces Asbestos-like Pulmonary Inflammation Mediated in Part by the IL-1 Receptor.

PubMed

Rydman, Elina M; Ilves, Marit; Vanhala, Esa; Vippola, Minnamari; Lehto, Maili; Kinaret, Pia A S; Pylkkänen, Lea; Happo, Mikko; Hirvonen, Maija-Riitta; Greco, Dario; Savolainen, Kai; Wolff, Henrik; Alenius, Harri

2015-09-01

Carbon nanotubes (CNT) have been eagerly studied because of their multiple applications in product development and potential risks on health. We investigated the difference of two different CNT and asbestos in inducing proinflammatory reactions in C57BL/6 mice after single pharyngeal aspiration exposure. We used long tangled and long rod-like CNT, as well as crocidolite asbestos at a dose of 10 or 40 µg/mouse. The mice were sacrificed 4 and 16 h or 7, 14, and 28 days after the exposure. To find out the importance of a major inflammatory marker IL-1β in CNT-induced pulmonary inflammation, we used etanercept and anakinra as antagonists as well as Interleukin 1 (IL-1) receptor (IL-1R-/-) mice. The results showed that rod-like CNT, and asbestos in lesser extent, induced strong pulmonary neutrophilia accompanied by the proinflammatory cytokines and chemokines 16 h after the exposure. Seven days after the exposure, neutrophilia had essentially disappeared but strong pulmonary eosinophilia peaked in rod-like CNT and asbestos-exposed groups. After 28 days, pulmonary granulomas, goblet cell hyperplasia, and Charcot-Leyden-like crystals containing acidophilic macrophages were observed especially in rod-like CNT-exposed mice. IL-1R-/- mice and antagonists-treated mice exhibited a significant decrease in neutrophilia and messenger ribonucleic acid (mRNA) levels of proinflammatory cytokines at 16 h. However, rod-like CNT-induced Th2-type inflammation evidenced by the expression of IL-13 and mucus production was unaffected in IL-1R-/- mice at 28 days. This study provides knowledge about the pulmonary effects induced by a single exposure to the CNT and contributes to hazard assessment of carbon nanomaterials on airway exposure. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Persistence with anti-tumour necrosis factor therapies in patients with psoriatic arthritis: observational study from the British Society of Rheumatology Biologics Register.

PubMed

Saad, Amr A; Ashcroft, Darren M; Watson, Kath D; Hyrich, Kimme L; Noyce, Peter R; Symmons, Deborah P M

2009-01-01

Anti-TNF therapies represent a breakthrough in the treatment of severe psoriatic arthritis. However, little is known about long-term drug persistence with these treatments in patients with psoriatic arthritis in routine clinical practice. The aim of this study was to assess persistence with first-course and second-course treatment with anti-TNF agents in a prospective cohort of psoriatic arthritis patients and to identify factors associated with and reasons for drug discontinuation. A total of 566 patients with psoriatic arthritis were registered with the British Society for Rheumatology Biologics Register (first anti-TNF agent: etanercept, n = 316; infliximab, n = 162; and adalimumab, n = 88). Treating physicians completed 6-monthly follow-up questionnaires detailing changes to anti-TNF therapies. Persistence with treatment was examined using Kaplan-Meier survival analysis. Reasons for withdrawal were classified as due to inefficacy, adverse events or other reasons. Univariate and multivariate Cox proportional hazard models were developed to examine potential predictors of withdrawals due to inefficacy or adverse events, using a range of demographic, baseline disease-specific and therapeutic variables. At baseline, the mean (standard deviation) age of patients was 45.7 (11.1) years, 53% were female and the mean disease duration was 12.4 (8.7) years. Persistence data were available for a mean (standard deviation) follow-up of 2.3 (0.9) person-years. In total, 422 patients had completed at least 12 months of follow-up, 75.5% of whom remained on their first anti-TNF drug while 9.5% discontinued due to inefficacy, 10.0% due to adverse events and 5.0% due to other reasons. During the period of follow-up, 178 patients received a second anti-TNF therapy. The survivor function on second anti-TNF for switchers was 74% at 12 months. Psoriatic arthritis patients show high persistence rates with both initial and second anti-TNF therapies.

Matching-adjusted indirect comparison of efficacy in patients with moderate-to-severe plaque psoriasis treated with ixekizumab vs. secukinumab.

PubMed

Warren, R B; Brnabic, A; Saure, D; Langley, R G; See, K; Wu, J J; Schacht, A; Mallbris, L; Nast, A

2018-05-01

Head-to-head randomized studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available. To assess efficacy and quality of life using matching-adjusted indirect comparisons for treatment with ixekizumab vs. secukinumab. Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 90% and 100% and Dermatology Life Quality Index (DLQI) 0/1 response rates for approved dosages of ixekizumab (160 mg at Week 0, then 80 mg every two weeks for the first 12 weeks) and secukinumab (300 mg at Weeks 0, 1, 2, 3 and 4, then 300 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo-controlled studies. Comparisons were made using the Bucher (BU) method and two modified versions of the Signorovitch (SG) method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse-variance meta-analysis. In the meta-analysis of studies with active comparators, PASI 90 response rates were 12·7% [95% confidence interval (CI) 5·5-19·8, P = 0·0005], 10·0% (95% CI 2·1-18·0, P = 0·01) and 11·2% (95% CI 3·2-19·1, P = 0·006) higher and PASI 100 response rates were 11·7% (95% CI 5·9-17·5, P < 0·001), 12·7% (95% CI 6·0-19·4, P < 0·001) and 13·1% (95% CI 6·3-19·9, P < 0·001) higher for ixekizumab compared with secukinumab using BU, SG total and SG separate methods. PASI 75 results were comparable when SG methods were used and favoured ixekizumab when the BU method was used. Week 12 DLQI 0/1 response rates did not differ significantly. Ixekizumab had higher PASI 90 and PASI 100 responses at week 12 compared with secukinumab using adjusted indirect comparisons. © 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Cost-effectiveness of sequenced treatment of rheumatoid arthritis with targeted immune modulators.

PubMed

Jansen, Jeroen P; Incerti, Devin; Mutebi, Alex; Peneva, Desi; MacEwan, Joanna P; Stolshek, Bradley; Kaur, Primal; Gharaibeh, Mahdi; Strand, Vibeke

2017-07-01

To determine the cost-effectiveness of treatment sequences of biologic disease-modifying anti-rheumatic drugs or Janus kinase/STAT pathway inhibitors (collectively referred to as bDMARDs) vs conventional DMARDs (cDMARDs) from the US societal perspective for treatment of patients with moderately to severely active rheumatoid arthritis (RA) with inadequate responses to cDMARDs. An individual patient simulation model was developed that assesses the impact of treatments on disease based on clinical trial data and real-world evidence. Treatment strategies included sequences starting with etanercept, adalimumab, certolizumab, or abatacept. Each of these treatment strategies was compared with cDMARDs. Incremental cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment sequence relative to cDMARDs. The cost-effectiveness of each strategy was determined using a US willingness-to-pay (WTP) threshold of $150,000/QALY. For the base-case scenario, bDMARD treatment sequences were associated with greater treatment benefit (i.e. more QALYs), lower lost productivity costs, and greater treatment-related costs than cDMARDs. The expected ICERs for bDMARD sequences ranged from ∼$126,000 to $140,000 per QALY gained, which is below the US-specific WTP. Alternative scenarios examining the effects of homogeneous patients, dose increases, increased costs of hospitalization for severely physically impaired patients, and a lower baseline Health Assessment Questionnaire (HAQ) Disability Index score resulted in similar ICERs. bDMARD treatment sequences are cost-effective from a US societal perspective.

Profile of tofacitinib citrate and its potential in the treatment of moderate-to-severe chronic plaque psoriasis

PubMed Central

Di Lernia, V; Bardazzi, F

2016-01-01

The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by activating intracellular signaling and transcription pathways, among which there are Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) pathways. JAKs are intracellular second messengers that are crucial for transmitting extracellular cytokine signals to the cell. JAK inhibition interrupts intracellular signaling and can suppress immune cell activation and inflammation in T-cell-mediated disorders, such as psoriasis. Consequently, JAKs are the subject of intensive research activity, since they represent possible therapeutic targets. Tofacitinib is an orally available compound belonging to a novel category of nonbiologic drugs, the “JAK inhibitors”, which target JAKs. Recently, oral and topical formulations of tofacitinib have been demonstrated to be safe and effective for the treatment of plaque psoriasis in randomized clinical trials. In particular, a 10 mg bid dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly. Questions remain unresolved regarding the safety risk beyond the 5 mg bid dose. This review, assessing the available scientific literature, focuses on the profile of tofacitinib, as investigational compound in the treatment of plaque psoriasis. An overview of the efficacy and safety data from randomized clinical trials is provided. In addition, the authors highlight future potential applications of tofacitinib in other skin diseases, in particular alopecia areata and vitiligo. PMID:26889081

Resolution of Behçet's syndrome associated pulmonary arterial aneurysms with infliximab.

PubMed

Schreiber, Benjamin E; Noor, Nadim; Juli, Christoph F; Haskard, Dorian O

2011-12-01

We describe the successful treatment of pulmonary arterial aneurysms in Behçet's syndrome using a tumor necrosis factor (TNF) inhibitor. A case is reported of Behçet's syndrome complicated by pulmonary arterial aneurysms that responded to anti-TNF therapy. This is accompanied by a literature review of previously published cases. We searched the English language medical literature using the PubMed and Medline search terms: "Behçet's," "Pulmonary aneurysms," and "infliximab," "etanercept," or "adalimumab." A 43-year-old man with a 6-month history of oral and genital ulcers, weight loss, and fatigue developed arterial aneurysms in the common carotid and common iliac arteries and thromboses in a femoral vein and pulmonary arteries. Treatment with high-dose oral corticosteroids and pulsed intravenous cyclophosphamide was initiated but while on treatment he developed pulmonary arterial aneurysms with hemoptysis. His treatment was changed to intravenous infliximab with methotrexate to which he showed a good response with marked clinical improvement, reduction in his inflammatory markers, and regression of the pulmonary arterial aneurysms. The review of the literature identified 3 reported cases of treatment of pulmonary arterial aneurysms in Behçet's syndrome with anti-TNF therapy, with good outcomes in each case. Pulmonary artery aneurysms are important complications of Behçet's syndrome. Anti-TNF inhibitors should be considered in patients who do not respond to treatment with corticosteroids and cyclophosphamide. Copyright © 2011 Elsevier Inc. All rights reserved.

Pulmonary manifestations of ankylosing spondylitis.

PubMed

Kanathur, Naveen; Lee-Chiong, Teofilo

2010-09-01

Ankylosing spondylitis, a chronic multisystem inflammatory disorder, can present with articular and extra-articular features. It can affect the tracheobronchial tree and the lung parenchyma, and respiratory complications include chest wall restriction, apical fibrobullous disease with or without secondary pulmonary superinfection, spontaneous pneumothorax, and obstructive sleep apnea. Ankylosing spondylitis is a common cause of pulmonary apical fibrocystic disease; early involvement may be unilateral or asymmetrical, but most cases eventually consist of bilateral apical fibrobullous lesions, many of which are progressive with coalescence of the nodules, formation of cysts and cavities, fibrosis, and bronchiectasis. Mycobacterial or fungal superinfection of the upper lobe cysts and cavities occurs commonly. Aspergillus fumigatus is the most common pathogen isolated, followed by various species of mycobacteria. Prognosis of patients with fibrobullous apical lesions is mainly determined by the presence, extent, and severity of superinfection. Pulmonary function test results are nonspecific and generally parallel the severity of parenchymal involvement. A restrictive ventilatory impairment can develop in patients with ankylosing spondylitis because of either fusion of the costovertebral joints and ankylosis of the thoracic spine or anterior chest wall involvement. Chest radiographic findings may mirror the severity of clinical involvement. Pulmonary parenchymal disease is typically progressive, and cyst formation, cavitation, and fibrosis are seen in advanced cases. No treatment has been shown to alter the clinical course of apical fibrobullous disease. Although several antiinflammatory agents, such as infliximab, etanercept, and adalimumab, are being used to treat ankylosing spondylitis, their effects on pulmonary manifestations are unclear.

Expert Recommendations on Treating Psoriasis in Special Circumstances (Part II).

PubMed

Carrascosa, J M; Galán, M; de Lucas, R; Pérez-Ferriols, A; Ribera, M; Yanguas, I

2016-11-01

There is insufficient information on how best to treat moderate to severe psoriasis in difficult clinical circumstances. We considered 5 areas where there is conflicting or insufficient evidence: pediatric psoriasis, risk of infection in patients being treated with biologics, psoriasis in difficult locations, biologic drug survival, and impact of disease on quality of life. Following discussion of the issues by an expert panel of dermatologists specialized in the management of psoriasis, participants answered a questionnaire survey according to the Delphi method. Consensus was reached on 66 (70.9%) of the 93 items analyzed; the experts agreed with 49 statements and disagreed with 17. It was agreed that body mass index, metabolic comorbidities, and quality of life should be monitored in children with psoriasis. The experts also agreed that the most appropriate systemic treatment for this age group was methotrexate, while the most appropriate biologic treatment was etanercept. Although it was recognized that the available evidence was inconsistent and difficult to extrapolate, the panel agreed that biologic drug survival could be increased by flexible, individualized dosing regimens, continuous treatment, and combination therapies. Finally, consensus was reached on using the Dermatology Quality of Life Index to assess treatment effectiveness and aid decision-making in clinical practice. The structured opinion of experts guides decision-making regarding aspects of clinical practice for which there is incomplete or conflicting information. Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Treatment of psoriasis with interleukin-12/23 monoclonal antibody: a systematic review.

PubMed

Wu, Yan; Chen, Jing; Li, Yuan-Hong; Ma, Guo-Zhang; Chen, John Z S; Gao, Xing-Hua; Chen, Hong-Duo

2012-01-01

To systematically review the efficacy and safety of interleukin-12/23 monoclonal antibody (IL-12/23 mAb) on psoriasis. Relevant randomized controlled trials (RCTs) were identified by systematic literature searches in MEDLINE, OVID, EMBASE, Cochrane Library, and the metaRegister of Controlled Trials. The efficacy outcomes and adverse effects of included RCTs were critically assessed. A total of 3365 participants in 5 multicenter RCTs were included. The RRs of most efficacy outcomes showed significant differences between i) IL-12/23 mAb and placebo at week 12/16; ii) IL-12/23 mAb and etanercept at week 12; iii) IL-12/23 mAb in high dose and IL-12/23 mAb in low dose at week 24/28. Increasing treatment times did not obviously provide additional benefit to efficacy improvement. The adverse events of IL-12/23 mAb were similar to those of controls. Antibodies to IL-12/23 mAb were mostly undetected or shown at low titer. Treatment with IL-12/23 mAb did not influence related biochemical markers. IL-12/23 mAb was effective in the treatment of psoriasis on skin lesions, health-related quality of life and psoriatic arthritis in the short-term. The increase in treatment time points was not associated with additional efficacy and dose-dependence was observed with the ongoing treatment up to week 24/28. The adverse effects were minimal and tolerable.

Acute exacerbation of interstitial pneumonia associated with rheumatoid arthritis during the course of treatment for Pneumocystis jirovecii pneumonia: a case report.

PubMed

Kuroda, Takeshi; Takeuchi, Hiroyuki; Nozawa, Yukiko; Sato, Hiroe; Nakatsue, Takeshi; Wada, Yoko; Moriyama, Hiroshi; Nakano, Masaaki; Narita, Ichiei

2016-04-26

Pneumocystis jirovecii pneumonia (PCP) is potentially fatal infectious complication in patients with rheumatoid arthritis (RA) during immunosuppressive therapy. Hospital survival due to human immunodeficiency virus-unrelated PCP reaches to 60%. The high mortality rate results from difficulties in establishing an early diagnosis, concurrent use of prophylactic drugs, possible bacterial coinfection. We herein report a case of PCP in RA patients who developed the architectural distortions of lung in spite of combined modality therapy. A 73-year-old Japanese woman with RA was admitted with shortness of breath. Five weeks previously, she had been started on etanercept in addition to methotrexate (MTX). Chest computed tomography (CT) demonstrated diffuse ground glass opacities distributed throughout the bilateral middle to lower lung fields, and serum β-D-glucan was elevated. Bronchoalveolar lavage fluid revealed no P. jirovecii, but the organism was detected by polymerase chain reaction method. Trimethoprim/sulfamethoxazole was administered with methylprednisolone pulse therapy. However, the follow-up chest X-ray and chest CT demonstrated aggravation of the pneumonia with architectural distortions. Additional direct hemoperfusion with polymyxin B-immobilized fibers and intravenous cyclophosphamide therapy were insufficiently effective, and the patient died on day 25. The architectural distortions of lung should be considered as a cause of death of PCP. For this reason, a high suspicion of this infectious complication must be kept in mind in order to establish an early diagnosis and treatment in patients with RA managed with MTX and biologics.

Safety Profile of Anticancer and Immune-Modulating Biotech Drugs Used in a Real World Setting in Campania Region (Italy): BIO-Cam Observational Study

PubMed Central

Scavone, Cristina; Sportiello, Liberata; Sullo, Maria G.; Ferrajolo, Carmen; Ruggiero, Rosanna; Sessa, Maurizio; Berrino, Pasquale M.; di Mauro, Gabriella; Berrino, Liberato; Rossi, Francesco; Rafaniello, Concetta; Capuano, Annalisa; Valentini, G.

2017-01-01

Objectives: To investigate the occurrence of adverse events (AEs) in naïve patients receiving biotech drugs. Design: A prospective observational study. Setting: Onco-hematology, Hepato-gastroenterology, Rheumatology, Dermatology, and Neurology Units in Campania Region (Italy). Participants: 775 patients (53.81% female) with mean age 56.0 (SD 15.2). The mean follow-up/patient was 3.48 (95% confidence interval 3.13–3.84). Main outcome measures: We collected all AEs associated to biotech drugs, including serious infections and malignancies. Serious AEs were defined according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, clinical safety data management: definitions and standards for expedited reporting E2A guideline. Results: The majority of the study population was enrolled in Onco-hematology and Rheumatology Units and the most common diagnosis were hematological malignancies, followed by rheumatoid arthritis, colorectal cancer, breast cancer, and psoriatic arthritis. The most commonly prescribed biotech drugs were rituximab, bevacizumab, infliximab, trastuzumab, adalimumab, and cetuximab. Out of 775 patients, 320 experienced at least one AE. Most of patients experienced AEs to cetuximab therapy, rituximab and trastuzumab. Comparing female and male population, our findings highlighted a statistically significant difference in terms of AEs for adalimumab (35.90% vs. 7.41%, p < 0.001) and etanercept (27.59% vs. 10.00%, p = 0.023). Considering all biotech drugs, we observed a peak for all AEs occurrence at follow-up 91–180 days category. Bevacizumab, brentuximab, rituximab, trastuzumab and cetuximab were more commonly associated to serious adverse events; most of these were possibly related to biotech drugs, according to causality assessment. Three cases of serious infections occurred. Conclusions: The results of our study demonstrated that the majority of AEs were not serious and expected. Few cases of serious infections occurred, while no case of malignancy did. Overall, the safety profile of biotech drugs used in our population was similar to those observed in pivotal trials. Notwithstanding the positive results of our study, some safety concerns still remain unresolved. In order to collect more effectiveness and safety data on biotech drugs, the collection and analysis of real world data should be endorsed as well as the management of post-authorization studies. PMID:28932193

Treatment effectiveness and treatment patterns among rheumatoid arthritis patients after switching from a tumor necrosis factor inhibitor to another medication

PubMed Central

Bonafede, Machaon MK; Curtis, Jeffrey R; McMorrow, Donna; Mahajan, Puneet; Chen, Chieh-I

2016-01-01

Objectives After treatment failure with a tumor necrosis factor inhibitor (TNFi), patients with rheumatoid arthritis (RA) can switch to another TNFi (TNFi cyclers) or to a targeted disease-modifying antirheumatic drug (DMARD) with a non-TNFi mechanism of action (non-TNFi switchers). This study compared treatment patterns and treatment effectiveness between TNFi cyclers and non-TNFi switchers in patients with RA. Methods The analysis included a cohort of patients from the Truven Health Analytics MarketScan Commercial database with RA who switched from a TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) either to another TNFi or to a non-TNFi targeted DMARD (abatacept, tocilizumab, or tofacitinib) between January 1, 2010 and September 30, 2014. A claims-based algorithm was used to estimate treatment effectiveness based on six criteria (adherence, no dose increase, no new conventional therapy, no switch to another targeted DMARD, no new/increased oral glucocorticoid, and intra-articular injections on <2 days). Results The cohort included 5,020 TNFi cyclers and 1,925 non-TNFi switchers. Non-TNFi switchers were significantly less likely than TNFi cyclers to switch therapy again within 6 months (13.2% vs 19.5%; P<0.001) or within 12 months (29.7% vs 34.6%; P<0.001) and significantly more likely to be persistent on therapy at 12 months (61.8% vs 58.2%; P<0.001). Non-TNFi switchers were significantly more likely than TNFi cyclers to achieve all six of the claims-based effectiveness algorithm criteria for the 12 months after the initial switch (27% vs 24%; P=0.011). Conclusion Although the absolute differences were small, these results support switching to a non-TNFi targeted DMARD instead of TNFi cycling when patients with RA require another therapy after TNFi failure. PMID:27980429

Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: study using the Spanish registry of adverse events of biological therapies in rheumatic diseases.

PubMed

Hernández, M Victoria; Sanmartí, Raimon; Cañete, Juan D; Descalzo, Miguel A; Alsina, Mercè; Carmona, Loreto; Gomez-Reino, Juan J

2013-12-01

To analyze the incidence rate (IR) and risk factors of cutaneous adverse events (CAE) in patients with chronic inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) antagonists. We analyzed all patients from the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) registry treated with a TNF antagonist (infliximab, etanercept, or adalimumab). Data collected included age, sex, diagnosis and duration of rheumatic disease, type of TNF antagonist, and concomitant treatment. Type of CAE was classified as local or systemic cutaneous manifestation related to treatment administration (infusion reaction), infection, malignancy, or autoimmune skin disease. Time of onset of CAE and outcome were also recorded. The IRs of CAE per 1,000 patient-years of exposure with 95% confidence intervals (95% CIs) were estimated. Multivariable analysis was performed to identify potential risk factors for CAE. A total of 5,437 patients were included, representing 17,330 patient-years of exposure. A total of 920 CAE were reported; the IRs per 1,000 patient-years were 53 (95% CI 50-57) for CAE, 28 (95% CI 25-30) for infection, 15 (95% CI 13-17) for infusion reactions, 5 (95% CI 4-6) for autoimmune skin diseases, and 3 (95% CI 2-4) for skin malignancy. The mean time between starting TNF antagonist treatment and CAE was 1.78 years. In 32% of patients, CAE required TNF antagonist withdrawal. The main risk factors for CAE were female sex and treatment with infliximab, leflunomide, and glucocorticoids. The IR of CAE in patients treated with TNF antagonists is significant and should be addressed carefully, and withdrawal of therapy is required in some cases. Copyright © 2013 by the American College of Rheumatology.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures.

PubMed

Schneider, Jeremy A; Cohen, Philip R

2017-06-01

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most severe dermatologic conditions occurring in the inpatient setting. There is a lack of consensus regarding appropriate management of SJS and TEN. The scientific literature pertaining to SJS and TEN (subsequently referred to as SJS/TEN) is summarized and assessed. In addition, an interventional approach for the clinician is provided. PubMed was searched with the key words: corticosteroids, cyclosporine, etanercept, intravenous immunoglobulin, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The papers generated by the search, and their references, were reviewed. Supportive care is the most universally accepted intervention for SJS/TEN. Specific guidelines differ from the care required for patients with thermal burns. Adjuvant therapies are utilized in most severe cases, but the data are thus far underwhelming and underpowered. Using systemic corticosteroids as sole therapy is not supported. A consensus regarding combined corticosteroids and intravenous immunoglobulin (IVIG) has not been reached. Data regarding IVIG, currently the standard of care for most referral centers, is conflicting. Newer studies regarding cyclosporine and tumor necrosis factor inhibitors are promising, but not powered to provide definitive evidence of efficacy. Data regarding plasmapheresis is equivocal. Thalidomide increases mortality. Clinicians who manage SJS/TEN should seek to employ interventions with the greatest impact on their patients' condition. While supportive care measures may seem an obvious aspect of SJS/TEN patient care, providers should understand that these interventions are imperative and that they differ from the care recommended for other critically ill or burn patients. While adjuvant therapies are frequently discussed and debated for hospitalized patients with SJS/TEN, a standardized management approach is not yet clear based on the current data. Therefore, until further data are available, decisions regarding such treatments should be made on a case-by-case basis.

Anti-drug antibodies in Colombian patients with rheumatoid arthritis treated with Enbrel vs Etanar - Preliminary report.

PubMed

Reyes-Beltrán, Benjamín; Delgado, Gabriela

2017-12-01

The present study was undertaken to detect antibodies against etanercept (ETN) in a group of Colombian patients with rheumatoid arthritis (RA) and being treated with Enbrel ® vs. Etanar ® . From these patients with RA, clinical and laboratory data were collected and serum taken for anti-drug antibody (ADAb) analysis. Samples from 32 patients (16 who had been treated with Enbrel ® and 16 with Etanar ® ) were analyzed. Positive sera for ADAb were found in six of the 32 subjects (18.7%); five (31.2%) in the Enbrel ® group and one (6.25%) in the Etanar ® group. Patients under treatment with Enbrel ® registered a longer disease duration than patients being treated with Etanar ® (15.4 years vs. 10.98 years, p = 0.175) as well as a longer average treatment with the drug (45.7 vs. 23.9 months, p = 0.052). The percentage of patients with disease activity defined as a disease activity score by C-reactive protein (DAS28-CRP) scores ≥2.3 was higher in those patients with positive sera in the enzyme-linked immunosorbent assay (ELISA) (66.7%) than in those with negative sera (34.6%). A logistic regression test revealed that the higher the DAS28-CRP value, the higher the ELISA absorbance value. The results showed evidence of greater frequency of ADAb in patients treated with ETN than has been reported to date. Greater disease activity was seen in those patients in whose serum ADAb had been detected. Significant differences were found between the positive ELISA for the group of patients treated with Enbrel ® compared to those treated with Etanar ® . Some of the factors that could explain this difference are the length of the treatment time with the drug, the commercial ELISA kit used to detect ADAb, or the immunogenicity itself of each product.

Medication adherence and persistence over time with self-administered TNF-alpha inhibitors among young adult, middle-aged, and older patients with rheumatologic conditions.

PubMed

Calip, Gregory S; Adimadhyam, Sruthi; Xing, Shan; Rincon, Julian C; Lee, Wan-Ju; Anguiano, Rebekah H

2017-10-01

Self-injectable TNF inhibitors are increasingly used early in the chronic treatment of moderate to severe rheumatologic conditions. We estimated medication adherence/persistence over time following initiation in young adult and older adult patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis. We conducted a retrospective cohort study of patients aged 18+ years newly initiating etanercept, adalimumab, certolizumab pegol, or golimumab using the Truven Health MarketScan Database between 2009 and 2013. Pharmacy dispensing data were used to calculate 12-month medication possession ratios (MPR) and determine adherence (MPR ≥ 0.80) for up to 3 years after starting therapy. Persistence over each 12-month interval was defined as not having a ≥92-day treatment gap. Multivariable generalized estimating equation models were used to calculate odds ratios (OR) and robust 95% confidence intervals (CI) for associations between patient characteristics and repeated adherence/persistence measures over time. Among 53,477 new users, 14% were young adults (18-34 years), 49% middle-aged (35-54 years), and 37% older adults (55+ years). Overall, 37% of patients were adherent and 83% were persistent in the first year of therapy. The lowest adherence (17%) and persistence (70%) were observed among young adult patients by Year +3. Compared to older adults, middle-aged (OR = 0.73, 95% CI: 0.71-0.76) and young adults (OR = 0.50, 95% CI: 0.47-0.53) were less likely to be adherent. Higher Charlson comorbidity scores, hospitalizations, and emergency department visits were associated with non-adherence/non-persistence. We observed low adherence to self-administered TNF inhibitors but most patients remained persistent over time. Further efforts to improve adherence in young adults and patients with greater comorbidity are needed. Copyright © 2017 Elsevier Inc. All rights reserved.

Both anti-TNF and CTLA4 Ig treatments attenuate the disease severity of staphylococcal dermatitis in mice.

PubMed

Na, Manli; Wang, Wanzhong; Fei, Ying; Josefsson, Elisabet; Ali, Abukar; Jin, Tao

2017-01-01

RA patients being treated with biologics are known to have an increased risk of infections. We recently demonstrated that both CTLA4 Ig and anti-TNF treatment aggravate systemic Staphylococcus aureus (S. aureus) infection in mice, but with distinct clinical manifestations. However, the effects of CTLA4 Ig and anti-TNF treatments on a local S. aureus infection (e.g., skin infection) might differ from their effects on a systemic infection. The aim of this study was to examine the differential effects of anti-TNF versus CTLA4 Ig treatment on S. aureus skin infections in mice. Abatacept (CTLA4 Ig), etanercept (anti-TNF treatment) or PBS was given to NMRI mice subcutaneously inoculated with S. aureus strain SH1000. The clinical signs of dermatitis, along with histopathological changes due to skin infection, were compared between the groups. Both CTLA4 Ig and anti-TNF treatment resulted in less severe skin infections and smaller post-infectious hyperpigmentation compared with controls. Consistent with the clinical signs of dermatitis, smaller lesion size, more epithelial hyperplasia and more granulation were found in skin biopsies from mice receiving anti-TNF compared with PBS controls. However, both CTLA4 Ig and anti-TNF therapy tended to prolong the healing time, although this finding was not statistically significant. Serum MCP-1 levels were elevated in the anti-TNF group relative to the CTLA4 Ig and PBS groups, whereas IL-6 levels were higher in PBS controls than in the other two groups. Both anti-TNF and CTLA4 Ig treatments tended to down-regulate the necrosis/apoptosis ratio in the locally infected skin tissue. Importantly, no tangible difference was found in the bacterial burden among groups. Both CTLA4 Ig and anti-TNF therapies attenuate disease severity but may prolong the healing time required for S. aureus skin infections. Neither treatment has an impact on bacterial clearance in skin tissues.

Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review.

PubMed

Chen, Meng; Zhou, Shu-Yi; Fabriaga, Erlinda; Zhang, Pian-Hong; Zhou, Quan

2018-04-01

This review addressed drug interactions precipitated by fruit juices other than grapefruit juice based on randomized controlled trials (RCTs). Literature was identified by searching PubMed, Cochrane Library, Scopus and Web of Science till December 30 2017. Among 46 finally included RCTs, six RCTs simply addressed pharmacodynamic interactions and 33 RCTs studied pharmacokinetic interactions, whereas seven RCTs investigated both pharmacokinetic and pharmacodynamic interactions. Twenty-two juice-drug combinations showed potential clinical relevance. The beneficial combinations included orange juice-ferrous fumarate, lemon juice- 99m Tc-tetrofosmin, pomegranate juice-intravenous iron during hemodialysis, cranberry juice-triple therapy medications for H. pylori, blueberry juice-etanercept, lime juice-antimalarials, and wheat grass juice-chemotherapy. The potential adverse interactions included decreased drug bioavailability (apple juice-fexofenadine, atenolol, aliskiren; orange juice-aliskiren, atenolol, celiprolol, montelukast, fluoroquinolones, alendronate; pomelo juice-sildenafil; grape juice-cyclosporine), increased bioavailability (Seville orange juice-felodipine, pomelo juice-cyclosporine, orange-aluminum containing antacids). Unlike furanocoumarin-rich grapefruit juice which could primarily precipitate drug interactions by strong inhibition of cytochrome P450 3A4 isoenzyme and P-glycoprotein and thus cause deadly outcomes due to co-ingestion with some medications, other fruit juices did not precipitate severely detrimental food-drug interaction despite of sporadic case reports. The extent of a juice-drug interaction may be associated with volume of drinking juice, fruit varieties, type of fruit, time between juice drinking and drug intake, genetic polymorphism in the enzymes or transporters and anthropometric variables. Pharmacists and health professionals should properly screen for and educate patients about potential adverse juice-drug interactions and help minimize their occurrence. Much attention should be paid to adolescents and the elderly who ingest medications with drinking fruit juices or consume fresh fruits during drug treatment. Meanwhile, more researches in this interesting issue should be conducted. Copyright © 2018. Published by Elsevier B.V.

Whipple's disease mimicking rheumatoid arthritis can cause misdiagnosis and treatment failure.

PubMed

Glaser, Cornelia; Rieg, Siegbert; Wiech, Thorsten; Scholz, Christine; Endres, Dominique; Stich, Oliver; Hasselblatt, Peter; Geißdörfer, Walter; Bogdan, Christian; Serr, Annerose; Häcker, Georg; Voll, Reinhard E; Thiel, Jens; Venhoff, Nils

2017-05-25

Whipple's disease, a rare chronic infectious disorder caused by Tropheryma whipplei, may present with predominant joint manifestations mimicking rheumatoid arthritis (RA). A retrospective single-center cohort study of seven patients was performed. Clinical symptoms were assessed by review of medical charts and Whipple's disease was diagnosed by periodic-acid-Schiff-stain and/or Tropheryma whipplei-specific polymerase-chain-reaction. Median age at disease onset was 54 years, six patients were male. Median time to diagnosis was 5 years. All patients presented with polyarthritis with a predominantly symmetric pattern. Three had erosive arthritis. Affected joints were: wrists (5/7), metacarpophalangeal joints (MCPs) (5/7), knees (5/7), proximal interphalangeal joints (PIPs) (3/7), hips (2/7), elbow (2/7), shoulder (2/7). All patients had increased C-reactive-protein concentrations, while rheumatoid factor and anti-CCP-antibodies were absent, and were initially (mis)classified as RA-patients according to EULAR/ACR-criteria (median DAS28 4.3). Six patients received antirheumatic treatment consisting of prednisone with methotrexate and/or leflunomide, three were additionally treated with at least one biologic agent (abatacept, adalimumab, etanercept, rituximab, tocilizumab). Most patients showed insufficient treatment response. In all patients Tropheryma whipplei was detected in synovial fluid by polymerase-chain-reaction; in three patients the diagnosis of Whipple's disease was further ascertained by periodic-acid-Schiff-staining. Gastrointestinal symptoms and other extra-articular manifestations were absent, mild or non-specific. Treatment was initiated with trimethoprin/sulfamethoxazole in five and doxycycline/hydroxychloroquine in two patients and had to be adapted in five patients. Finally, all patients had good treatment responses with improvement of arthritis and extra-articular manifestations. Whipple's disease is rare and can mimic rheumatoid arthritis. Especially patients with seronegative rheumatoid arthritis with a prolonged disease course and insufficient treatment response should be reevaluated for Whipple's disease.

Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor α therapy: results from the British Society for Rheumatology Biologics Register

PubMed Central

Harrison, M J; Dixon, W G; Watson, K D; King, Y; Groves, R; Hyrich, K L; Symmons, D P M

2009-01-01

Background: Anti-tumour necrosis factor (TNF)α treatments improve outcome in severe rheumatoid arthritis (RA) and are efficacious in psoriasis and psoriatic arthritis. However recent case reports describe psoriasis occurring as an adverse event in patients with RA receiving anti-TNFα therapy. Objectives: We aimed to determine whether the incidence rate of psoriasis was higher in patients with RA treated with anti-TNFα therapy compared to those treated with traditional disease-modifying antirheumatic drugs (DMARDs). We also compared the incidence rates of psoriasis between the three anti-TNFα drugs licensed for RA. Methods: We studied 9826 anti-TNF-treated and 2880 DMARD-treated patients with severe RA from The British Society for Rheumatology Biologics Register (BSRBR). All patients reported with new onset psoriasis as an adverse event were included in the analysis. Incidence rates of psoriasis were calculated as events/1000 person years and compared using incidence rate ratios (IRR). Results: In all, 25 incident cases of psoriasis in patients receiving anti-TNFα therapy and none in the comparison cohort were reported between January 2001 and July 2007. The absence of any cases in the comparison cohort precluded a direct comparison; however the crude incidence rate of psoriasis in those treated with anti-TNFα therapy was elevated at 1.04 (95% CI 0.67 to 1.54) per 1000 person years compared to the rate of 0 (upper 97.5% CI 0.71) per 1000 person years in the patients treated with DMARDs. Patients treated with adalimumab had a significantly higher rate of incident psoriasis compared to patients treated with etanercept (IRR 4.6, 95% CI 1.7 to 12.1) and infliximab (IRR 3.5, 95% CI 1.3 to 9.3). Conclusions: Results from this study suggest that the incidence of psoriasis is increased in patients treated with anti-TNFα therapy. Our findings also suggest that the incidence may be higher in patients treated with adalimumab. PMID:18385277

Bruton's tyrosine kinase inhibitor BMS-986142 in experimental models of rheumatoid arthritis enhances efficacy of agents representing clinical standard-of-care.

PubMed

Gillooly, Kathleen M; Pulicicchio, Claudine; Pattoli, Mark A; Cheng, Lihong; Skala, Stacey; Heimrich, Elizabeth M; McIntyre, Kim W; Taylor, Tracy L; Kukral, Daniel W; Dudhgaonkar, Shailesh; Nagar, Jignesh; Banas, Dana; Watterson, Scott H; Tino, Joseph A; Fura, Aberra; Burke, James R

2017-01-01

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.

The Effect of Biologic and Targeted Synthetic Drugs on Work- and Productivity-related Outcomes for Patients with Psoriatic Arthritis: A Systematic Review.

PubMed

Iragorri, Nicolas; Hofmeister, Mark; Spackman, Eldon; Hazlewood, Glen S

2018-05-01

To systematically review the effects of biologic therapies for psoriatic arthritis [secukinumab, ustekinumab, adalimumab, etanercept, certolizumab pegol (CZP), apremilast, golimumab (GOL), or infliximab (IFX)] on work productivity. A systematic review of Medline, EMBASE, CENTRAL, and ClinicalTrials.gov was conducted to identify randomized controlled trials reporting on work productivity outcomes at the end of the placebo-controlled double-blind period. There were 7959 records identified. Full text of 377 records was further assessed for eligibility, of which 5 trials were included. All included trials were assessed with the Cochrane Risk of Bias Tool, and 4 out of 5 were judged to be of low risk of bias in most domains. Improvements in self-assessed work productivity were observed in 5 trials (IFX, GOL, CZP, ustekinumab, and apremilast), ranging from a mean difference of -0.9 to -1.8 on a 1-10 scale of self-assessed work productivity (negative change represents improvement), although statistical significance of the results was not reported for CZP and apremilast. Treatment with CZP resulted in a statistically significant reduction in absenteeism (200 mg) and presenteeism (200 and 400 mg). IFX and GOL reported a nonsignificant reduction of absenteeism. The Work Productivity Survey, the Work Limitations Questionnaire, and visual analog scales were used to measure work productivity. Treatment with IFX, GOL, CZP, ustekinumab, and apremilast resulted in improvements in self-reported work productivity. A pooled analysis was not possible because of the clinical heterogeneity of the trials and variability in outcome reporting.

Recommendations for incorporating biologicals into management of moderate to severe plaque psoriasis: individualized patient approaches.

PubMed

Langley, Richard G; Ho, Vincent; Lynde, Charles; Papp, Kim A; Poulin, Yves; Shear, Neil; Toole, Jack; Zip, Catherine

2006-01-01

Psoriasis is a T-cell mediated skin disease that affects approximately 2% of the population worldwide. Despite the prevalence of the disease and long-standing efforts to develop strategies to treat it, there is a need for safe and effective therapies to treat psoriasis, particularly the more severe forms. Biological agents such as alefacept, efalizumab, etanercept, and infliximab have been recognized as a class of treatment distinct from other forms of therapy in the treatment algorithm of psoriasis. Recent national and international consensus meetings have developed statements that position biological agents as an important addition to the treatment armamentarium for moderate to severe psoriasis, along with phototherapy and traditional systemic agents. There has been consensus that treatment should be individualized to each patient's needs and circumstances. Biological agents offer the hope of safe, effective, long-term management of moderate to severe psoriasis. As new agents receive approval from Health Canada, the available range of therapeutic options for treating this chronic disease will broaden. A Canadian Psoriasis Expert Panel recently convened in February 2005 to analyze, based on a series of clinical case scenarios, the indications, contraindications, and considerations for and against each of the four biological agents, derived from product labelling, where available, and from the efficacy and safety data from phase 3 and earlier clinical trials, as well as post-marketing reports. The Panel has formulated a set of recommendations for incorporating these biological agents into the current treatment paradigm of moderate to severe plaque psoriasis and has identified the preferred biological agents for each patient based on individual needs and circumstances.

Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients.

PubMed

Scheinfeld, Noah

2013-04-15

Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients' lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients.

TNFα pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and β3 integrin activation.

PubMed

Bitzan, Martin; Babayeva, Sima; Vasudevan, Anil; Goodyer, Paul; Torban, Elena

2012-12-01

In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS). Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFα) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy. Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated β3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre-incubation with antibodies against TNFα or either of the two TNFα receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFα therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely. We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and β3 integrin-mediated podocyte attachment are driven by the TNFα pathway.

Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

PubMed

Spencer, C H; Rouster-Stevens, K; Gewanter, H; Syverson, G; Modica, R; Schmidt, K; Emery, H; Wallace, C; Grevich, S; Nanda, K; Zhao, Y D; Shenoi, S; Tarvin, S; Hong, S; Lindsley, C; Weiss, J E; Passo, M; Ede, K; Brown, A; Ardalan, K; Bernal, W; Stoll, M L; Lang, B; Carrasco, R; Agaiar, C; Feller, L; Bukulmez, H; Vehe, R; Kim, H; Schmeling, H; Gerstbacher, D; Hoeltzel, M; Eberhard, B; Sundel, R; Kim, S; Huber, A M; Patwardhan, A

2017-06-13

The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

One-Year Tuberculosis Risk in Rheumatoid Arthritis Patients Starting Their First Tumor Necrosis Factor Inhibitor Therapy from 2008 to 2012 in Taiwan: A Nationwide Population-Based Cohort Study.

PubMed

Lim, Chong-Hong; Lin, Ching-Heng; Chen, Der-Yuan; Chen, Yi-Ming; Chao, Wen-Cheng; Liao, Tsai-Ling; Chen, Hsin-Hua

2016-01-01

To investigate the risk of tuberculosis (TB) among rheumatoid arthritis (RA) patients within 1 year after initiation of tumor necrosis factor inhibitor (TNFi) therapy from 2008 to 2012. We used the 2003-2013 Taiwanese National Health Insurance Research Database to identify RA patients who started any RA-related medical therapy from 2008 to 2012. Those who initiated etanercept or adalimumab therapy during 2008-2012 were selected as the TNFi group and those who never received biologic disease-modifying anti-rheumatic drug therapy were identified as the comparison group after excluding the patients who had a history of TB or human immunodeficiency virus infection/acquired immune deficiency syndrome. We used propensity score matching (1:6) for age, sex, and the year of the drug index date to re-select the TNFi group and the non-TNFi controls. After adjusting for potential confounders, hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to examine the 1-year TB risk in the TNFi group compared with the non-TNFi controls. Subgroup analyses according to the year of treatment initiation and specific TNFi therapy were conducted to assess the trend of 1-year TB risk in TNFi users from 2008 to 2012. This study identified 5,349 TNFi-treated RA patients and 32,064 matched non-TNFi-treated controls. The 1-year incidence rates of TB were 1,513 per 105 years among the TNFi group and 235 per 105 years among the non-TNFi controls (incidence rate ratio, 6.44; 95% CI, 4.69-8.33). After adjusting for age, gender, disease duration, comoridities, history of TB, and concomitant medications, TNFi users had an increased 1-year TB risk (HR, 7.19; 95% CI, 4.18-12.34) compared with the non-TNFi-treated controls. The 1-year TB risk in TNFi users increased from 2008 to 2011 and deceased in 2012 when the Food and Drug Administration in Taiwan announced the Risk Management Plan for patients scheduled to receive TNFi therapy. This study showed that the 1-year TB risk in RA patients starting TNFi therapy was significantly higher than that in non-TNFi controls in Taiwan from 2008 to 2012.

Adoption of Biosimilar Infliximab for Rheumatoid Arthritis, Ankylosing Spondylitis, and Inflammatory Bowel Diseases in the EU5: A Budget Impact Analysis Using a Delphi Panel

PubMed Central

Kanters, Tim A.; Stevanovic, Jelena; Huys, Isabelle; Vulto, Arnold G.; Simoens, Steven

2017-01-01

Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors. Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget. Results: Uptake of biosimilar infliximab was particularly expected for naïve patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to slightly increase for ankylosing spondylitis, Crohn's Disease, and ulcerative collitis. Savings in budget were expected in all countries, for all diseases, when larger price discounts on biosimilar infliximab were used. Discussion and Conclusion: This study has shown that only when price reductions are large enough (i.e., 50% or more), physicians indicated that they will prescribe biosimilars. Policy makers should ensure substantial price reductions and stimulate physicians to use biosimilar products, to obtain savings in healthcare budgets. PMID:28620302

Adoption of Biosimilar Infliximab for Rheumatoid Arthritis, Ankylosing Spondylitis, and Inflammatory Bowel Diseases in the EU5: A Budget Impact Analysis Using a Delphi Panel.

PubMed

Kanters, Tim A; Stevanovic, Jelena; Huys, Isabelle; Vulto, Arnold G; Simoens, Steven

2017-01-01

Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors. Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget. Results: Uptake of biosimilar infliximab was particularly expected for naïve patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to slightly increase for ankylosing spondylitis, Crohn's Disease, and ulcerative collitis. Savings in budget were expected in all countries, for all diseases, when larger price discounts on biosimilar infliximab were used. Discussion and Conclusion: This study has shown that only when price reductions are large enough (i.e., 50% or more), physicians indicated that they will prescribe biosimilars. Policy makers should ensure substantial price reductions and stimulate physicians to use biosimilar products, to obtain savings in healthcare budgets.

Compliance with biologic therapies for rheumatoid arthritis: do patient out-of-pocket payments matter?

PubMed

Curkendall, S; Patel, V; Gleeson, M; Campbell, R S; Zagari, M; Dubois, R

2008-10-15

To assess the impact of patient out-of-pocket (OOP) expenditures on adherence and persistence with biologics in patients with rheumatoid arthritis (RA). An inception cohort of RA patients with pharmacy claims for etanercept or adalimumab during 2002-2004 was selected from an insurance claims database of self-insured employer health plans (n=2,285) in the US. Adherence was defined as medication possession ratio (MPR): the proportion of the 365 followup days covered by days supply. Persistence was determined using a survival analysis of therapy discontinuation during followup. Patient OOP cost was measured as the patient's coinsurance and copayments per week of therapy, and as the proportion of the total medication charges paid by the patient. Multivariate linear regression models of MPR and proportional hazards models of persistence were used to estimate the impact of cost, adjusting for insurance type and demographic and clinical variables. Mean +/- SD OOP expenditures averaged $7.84+/-$14.15 per week. Most patients (92%) paid less than $20 OOP for therapy/week. The mean +/- SD MPR was 0.52+/-0.31. Adherence significantly decreased with increased weekly OOP (coeff= -0.0035, P<0.0001) and with a higher proportion of therapy costs paid by patients (coeff= -0.8794, P<0.0001), translating into approximately 1 week of therapy lost per $5.50 increase in weekly OOP. Patients whose weekly cost exceeded $50 were more likely to discontinue than patients with lower costs (hazard ratio 1.58, P<0.001). Most patients pay less than $20/week for biologics, but a small number have high OOP expenses, associated with lower medication compliance. The adverse impact of high OOP costs on adherence, persistence, and outcomes must be considered when making decisions about increasing copayments.

[Tuberculosis in rheumatic patients treated with tumour necrosis factor alpha antagonists: the Portuguese experience].

PubMed

Fonseca, João Eurico; Canhão, Helena; Silva, Cândida; Miguel, Cláudia; Mediavilla, Maria Jesus; Teixeira, Ana; Castelão, Walter; Nero, Patrícia; Bernardes, Miguel; Bernardo, Alexandra; Mariz, Eva; Godinho, Fátima; Santos, Maria José; Bogas, Mónica; Oliveira, Margarida; Saavedra, Maria João; Barcelos, Anabela; Cruz, Margarida; Santos, Rui André; Maurício, Luís; Rodrigues, Mário; Figueiredo, Guilherme; Quintal, Alberto; Patto, José Vaz; Malcata, Armando; da Silva, José Canas; Araújo, Domingos; Ventura, Francisco; Branco, Jaime; Queiroz, Mário Viana

2006-01-01

In Portugal, 13 cases of tuberculosis (TB) were reported, in the period between 1999 and 2005, in 960 patients exposed to anti-TNFalpha treatment (1.35%), 8 females and 5 males. Mean age was 46.7 +/- 13.8 years. 9 patients had rheumatoid arthritis (RA), in 639 exposed patients (1.4%), 3 had ankylosing spondylitis (AS), in 200 exposed patients (1.5%) and 1 had psoriatic arthritis (PA), in 101 exposed patients (1%). The anti-TNFa used was in 8 cases infliximab (in 456 patients exposed, 1.5%), in 4 adalimumab (in 171 patients exposed, 2.3%) and in 1 etanercept (in 333 exposed, 0.3%). Treatment with a biological agent was started 11.1 +/- 8.7 months (min 3 and max 50) before TB onset. Tuberculin skin test (TST) was performed in 9 out of the 13 patients (the other 4 had started biological therapy before 2002). In 3 cases the TST response was 0 mm, in 3 less than 10 mm, in one was 14 mm and in two 20 mm. In the 3 cases with a TST response superior to 10 mm, isoniazid treatment 300 mg/d was prescribed, during 9 months. The time between first symptoms and TB diagnosis was 2.6 +/- 2.9 months. TB involvement was pulmonary in 6 patients, lymph node disease in 2, peritoneal and pulmonary in 2, osteoarticular in one case, lymph node disease and splenic in another and miliar TB in the last case. One death was reported; all of the other cases had a good outcome after anti-TB treatment. In two cases (one treated with adalimumab and the other with infliximab), paradoxical response to treatment occurred. None of the patients has restarted biological therapy after TB treatment.

Classical to current approach for treatment of psoriasis: a review.

PubMed

Rahman, Mahfoozur; Alam, Kainat; Ahmad, Mohammad Zaki; Gupta, Gaurav; Afzal, Muhammad; Akhter, Sohail; Kazmi, Imran; Jyoti; Ahmad, Farhan Jalees; Anwar, Firoz

2012-09-01

Psoriasis is a genetic predisposition with T-cell mediated autoimmune inflammatory skin disorder, characterized by cutaneous inflammation, increased epidermal proliferation, hyperkeratosis, angiogenesis, and abnormal keratinization that affects up to 2 - 3% of the population worldwide. Common therapies that are used for the treatment of psoriasis include topical, systemic, phototherapy, combination, herbal therapy and novel molecules. Topically used agents include Vit D, calcipotriol, corticosteroids, dithranol and retinoids etc. Systemically used agents include methotrexate and cyclosporine etc. Phototherapy includes UV-B, Psoralen plus ultraviolet therapy and excimer laser etc. These therapies have a number of potential problems, such as limited in efficacy, inconvenience, organ toxicity, carcinogenic and broadband immunosuppression. In natural treatment a variety of natural agents such as methanolic extracts of duzhong (Eucommia ulmoides Oliv.), yerba mate (Ilex paraguariensis,) linseed oil, fish oil, and Indigo naturalis etc., that modulates T cell and cytokine action at various steps along with the pathogenic sequence have been developed. But till now there is no more in vivo, dose and its efficacy data has been established. Current therapy includes biologicals, small molecules inhibitor and enzyme inhibitors etc, which serve as novel therapeutic options for psoriasis treatment. All these avoid the side effects of the prebiologically developed systemic agents including hepatotoxicity, nephrotoxicity, and bone marrow suppression. Currently, Denilukin diftitox, Efalizumab, Alefacept, Ustekinumab and Etanercept are approved by the FDA, and others molecules are at clinical stage. Patents issued by the US office are also included in current psoriasis treatment scenario. In the United States, biologicals are widely used for moderate-to-severe psoriasis. But because of the high cost of medication and their availability in injection form, it remains to be seen how widely these agents will be utilized worldwide. Still, developing countries prefer conventional drugs.

The role of P2X7R/ERK signaling in dorsal root ganglia satellite glial cells in the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR).

PubMed

Song, Jingnian; Ying, Yanlu; Wang, Wei; Liu, Xianguo; Xu, Xuebing; Wei, Xuhong; Ruan, Xiangcai

2018-03-01

The mechanisms of chronic postsurgical pain remain to be elucidated. We reported here that skin/muscle incision and retraction (SMIR), a rat model of postsurgical pain, phosphorylated the extracellular regulated protein kinases (ERK) signaling components c-Raf, MEK (ERK kinase) and ERK1/2 in lumbar 3 dorsal root ganglion (L3 DRG) in rats. Intrathecal injection of ERK specific inhibitor SCH772984 suppressed the mechanical allodynia induced by SMIR. Furthermore, SMIR upregulated tumor necrosis factor alpha (TNFα) in L3 DRG, which could be inhibited by SCH772984. Intrathecal injection of TNF antagonist Etanercept could also inhibit the mechanical allodynia and the increased ERK phosphorylation in L3 DRG induced by SMIR. In addition, immunofluorescent data showed that P2X7R was located exclusively in GFAP labeled satellite glial cells and was highly colocalized with p-ERK1/2 following SMIR. Pretreatment with P2X7R antagonist Brilliant Blue G (BBG) could also block the mechanical allodynia, inhibited the phosphorylation of c-Raf, MEK, ERK1/2, and decrease the expression of TNF-α. Finally, intrathecal injection of BzATP produced mechanical allodynia and induced ERK phosphorylation in satellite glial cells in L3 DRG. Thus, P2X7R activation in satellite glial cells in L3 DRG, leading to a positive feedback between ERK pathway activation and TNF-α production, is suggested to be involved in the induction of chronic postsurgical pain following SMIR. Copyright © 2017 Elsevier Inc. All rights reserved.

PKCδ knockout mice are protected from para-methoxymethamphetamine-induced mitochondrial stress and associated neurotoxicity in the striatum of mice.

PubMed

Shin, Eun-Joo; Dang, Duy-Khanh; Tran, Hai-Quyen; Nam, Yunsung; Jeong, Ji Hoon; Lee, Young Hun; Park, Kyung Tae; Lee, Yong Sup; Jang, Choon-Gon; Hong, Jau-Shyong; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2016-11-01

Para-methoxymethamphetamine (PMMA) is a para-ring-substituted amphetamine derivative sold worldwide as an illegal psychotropic drug. Although PMMA use has been reported to lead to severe intoxication and even death, little is known about the mechanism(s) by which PMMA exerts its neurotoxic effects. Here we found that PMMA treatment resulted in phosphorylation of protein kinase Cδ (PKCδ) and subsequent mitochondrial translocation of cleaved PKCδ. PMMA-induced oxidative stress was more pronounced in mitochondria than in the cytosol. Moreover, treatment with PMMA consistently resulted in significant reductions in mitochondrial membrane potential, mitochondrial complex I activity, and mitochondrial Mn superoxide dismutase-immunoreactivity. In contrast, PMMA treatment led to a significant increase in intramitochondrial Ca 2+ level. Treatment with PMMA also significantly increased ionized calcium binding adaptor molecule 1 (Iba-1)-labeled microglial activation and upregulated tumor necrosis factor alpha (TNF-α) gene expression. PKCδ knockout attenuated these mitochondrial effects and dampened the neurotoxic effects of PMMA. Importantly, TNF-α knockout mice were significantly protected from PMMA-induced increases in phospho-PKCδ expression, mitochondrial translocation of cleaved PKCδ, and Iba-1-labeled microgliosis. Both rottlerin, a pharmacological inhibitor of PKCδ, and etanercept, a pharmacological inhibitor of TNF-α, significantly protected against PMMA-mediated induction of apoptosis, as assessed by terminal deoxynucleotidyl transferase dUDP nick end labeling (TUNEL) assays. In addition, PKCδ knockout and TNF-α knockout both resulted in decreased PMMA-mediated induction of dopaminergic loss. Therefore, our results suggest that PKCδ mediates PMMA-induced neurotoxicity by facilitating oxidative stress (mitochondria > cytosol), mitochondrial dysfunction, microglial activation, and pro-apoptotic signaling. Our results also indicate that PMMA-induced PKCδ activation requires the proinflammatory cytokine TNF-α. Copyright © 2016. Published by Elsevier Ltd.

Tumour necrosis factor inhibitor survival and predictors of response in axial spondyloarthritis-findings from a United Kingdom cohort.

PubMed

Yahya, Fariz; Gaffney, Karl; Hamilton, Louise; Lonsdale, Ellie; Leeder, Jane; Brooksby, Alan; Cavill, Charlotte; Berry-Jenkins, Joshua; Boyle, Cathal; Bond, Debbie; Sengupta, Raj

2018-04-01

To analyse long-term survival and efficacy of TNFi, reasons for switching or discontinuing, baseline predictors of response and remission in axial spondyloarthritis (axSpA) patients in a UK cohort. All patients with a physician-verified diagnosis of axSpA attending two specialist centres who fulfilled the eligibility criteria for TNFi were included. Routinely recorded patient data were reviewed retrospectively. Initial TNFi was recorded as the index drug. Six hundred and fifty-one patients (94% AS) were included; adalimumab (n = 332), etanercept (n = 205), infliximab (n = 51), golimumab (n = 40) and certolizumab pegol (n = 23) were index TNFi. The mean (s.d.) duration from symptom onset to time of diagnosis was 8.6 (8.7) years and mean (s.d.) duration from diagnosis to TNFi initiation was 12.6 (11.5) years. A total of 224 (34.4%) stopped index TNFi, and 105/224 switched to a second TNFi. Median drug survival for index and second TNFi were 10.2 years (95% CI: 8.8, 11.6 years) and 5.5 years (95% CI: 2.7, 8.3 years), respectively (P < 0.05). Survival rates were not influenced by choice of TNFi. HLA-B27 predicted BASDAI50 and/or two or more point reduction within 6 months and long-term drug survival (P < 0.05). Low disease activity was predicted by non-smoking and low baseline BASDAI (P < 0.05). We have observed good TNFi survival rates in axSpA patients treated in a real-life setting. This is best for first TNFi and not influenced by drug choice.

Interferon-γ and Tumor Necrosis Factor-α Mediate the Upregulation of Indoleamine 2,3-Dioxygenase and the Induction of Depressive-Like Behavior in Mice in Response to Bacillus Calmette-Guérin

PubMed Central

O’Connor, Jason C.; André, Caroline; Wang, Yunxia; Lawson, Marcus A.; Szegedi, Sandra S.; Lestage, Jacques; Castanon, Nathalie; Kelley, Keith W.; Dantzer, Robert

2010-01-01

Although the tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO), is a pivotal mediator of inflammation-induced depression, its mechanism of regulation has not yet been investigated in this context. Here, we demonstrate an essential role for interferon (IFN)γ and tumor necrosis factor (TNF)α in the induction of IDO and depressive-like behaviors in response to chronic immune activation. Wild-type (WT) control mice and IFNγR−/− mice were inoculated with an attenuated form of Mycobacterium bovis, bacille Calmette-Guérin (BCG). Infection with BCG induced an acute episode of sickness that was similar in WT and IFNγR−/− mice. Increased immobility during the forced swim and tail suspension tests occurred in WT mice 7 d after BCG inoculation but was entirely absent in IFNγR−/− mice. In WT mice, these indices of depressive-like behavior were associated with chronic upregulation of IFNγ, interleukin(IL)-1β, TNFα, and IDO. Proinflammatory cytokine expression was elevated in BCG-infected IFNγR−/− mice as well, but upregulation of lung and brain IDO mRNA was completely abolished. This was accompanied by an attenuation of BCG-induced TNFα mRNA and the lack of an increase in plasma kynurenine/tryptophan ratio in the BCG-inoculated IFNγR−/− mice compared with WT controls. Pretreatment of mice with the TNFα antagonist, etanercept, partially blunted BCG-induced IDO activation and depressive-like behavior. In accordance with these in vivo data, IFNγ and TNFα synergized to induce IDO in primary microglia. Together, these data demonstrate that IFNγ, with TNFα, is necessary for induction of IDO and depressive-like behavior in mice after BCG infection. PMID:19339614

Macrophage Phenotype Controls Long-Term AKI Outcomes—Kidney Regeneration versus Atrophy

PubMed Central

Gröbmayr, Regina; Ryu, Mi; Lorenz, Georg; Hartter, Ingo; Mulay, Shrikant R.; Susanti, Heni Eka; Kobayashi, Koichi S.; Flavell, Richard A.; Anders, Hans-Joachim

2014-01-01

The mechanisms that determine full recovery versus subsequent progressive CKD after AKI are largely unknown. Because macrophages regulate inflammation as well as epithelial recovery, we investigated whether macrophage activation influences AKI outcomes. IL-1 receptor–associated kinase-M (IRAK-M) is a macrophage-specific inhibitor of Toll-like receptor (TLR) and IL-1 receptor signaling that prevents polarization toward a proinflammatory phenotype. In postischemic kidneys of wild-type mice, IRAK-M expression increased for 3 weeks after AKI and declined thereafter. However, genetic depletion of IRAK-M did not affect immunopathology and renal dysfunction during early postischemic AKI. Regarding long-term outcomes, wild-type kidneys regenerated completely within 5 weeks after AKI. In contrast, IRAK-M−/− kidneys progressively lost up to two-thirds of their original mass due to tubule loss, leaving atubular glomeruli and interstitial scarring. Moreover, M1 macrophages accumulated in the renal interstitial compartment, coincident with increased expression of proinflammatory cytokines and chemokines. Injection of bacterial CpG DNA induced the same effects in wild-type mice, and TNF-α blockade with etanercept partially prevented renal atrophy in IRAK-M−/− mice. These results suggest that IRAK-M induction during the healing phase of AKI supports the resolution of M1 macrophage– and TNF-α–dependent renal inflammation, allowing structural regeneration and functional recovery of the injured kidney. Conversely, IRAK-M loss-of-function mutations or transient exposure to bacterial DNA may drive persistent inflammatory mononuclear phagocyte infiltrates, which impair kidney regeneration and promote CKD. Overall, these results support a novel role for IRAK-M in the regulation of wound healing and tissue regeneration. PMID:24309188

Prealbumin, platelet factor 4 and S100A12 combination at baseline predicts good response to TNF alpha inhibitors in Rheumatoid Arthritis.

PubMed

Nguyen, Minh Vu Chuong; Baillet, Athan; Romand, Xavier; Trocmé, Candice; Courtier, Anaïs; Marotte, Hubert; Thomas, Thierry; Soubrier, Martin; Miossec, Pierre; Tébib, Jacques; Grange, Laurent; Toussaint, Bertrand; Lequerré, Thierry; Vittecoq, Olivier; Gaudin, Philippe

2018-06-06

Tumour necrosis factor-alpha inhibitors (TNFi) are effective treatments for Rheumatoid Arthritis (RA). Responses to treatment are barely predictable. As these treatments are costly and may induce a number of side effects, we aimed at identifying a panel of protein biomarkers that could be used to predict clinical response to TNFi for RA patients. Baseline blood levels of C-reactive protein, platelet factor 4, apolipoprotein A1, prealbumin, α1-antitrypsin, haptoglobin, S100A8/A9 and S100A12 proteins in bDMARD naive patients at the time of TNFi treatment initiation were assessed in a multicentric prospective French cohort. Patients fulfilling good EULAR response at 6 months were considered as responders. Logistic regression was used to determine best biomarker set that could predict good clinical response to TNFi. A combination of biomarkers (prealbumin, platelet factor 4 and S100A12) was identified and could predict response to TNFi in RA with sensitivity of 78%, specificity of 77%, positive predictive values (PPV) of 72%, negative predictive values (NPV) of 82%, positive likelihood ratio (LR+) of 3.35 and negative likelihood ratio (LR-) of 0.28. Lower levels of prealbumin and S100A12 and higher level of platelet factor 4 than the determined cutoff at baseline in RA patients are good predictors for response to TNFi treatment globally as well as to Infliximab, Etanercept and Adalimumab individually. A multivariate model combining 3 biomarkers (prealbumin, platelet factor 4 and S100A12) accurately predicted response of RA patients to TNFi and has potential in a daily practice personalized treatment. Copyright © 2018. Published by Elsevier Masson SAS.

Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

PubMed Central

Barrett, David; Aplenc, Richard; Porter, David L.; Rheingold, Susan R.; Teachey, David T.; Chew, Anne; Hauck, Bernd; Wright, J. Fraser; Milone, Michael C.; Levine, Bruce L.; June, Carl H.

2014-01-01

Summary Chimeric antigen receptor–modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre–B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×106 to 1.2×107 CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce anti-leukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor–modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL. PMID:23527958

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.

PubMed

Grupp, Stephan A; Kalos, Michael; Barrett, David; Aplenc, Richard; Porter, David L; Rheingold, Susan R; Teachey, David T; Chew, Anne; Hauck, Bernd; Wright, J Fraser; Milone, Michael C; Levine, Bruce L; June, Carl H

2013-04-18

Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

Safety and Tolerability of Ixekizumab: Integrated Analysis of Injection-Site Reactions from 11 Clinical Trials.

PubMed

Shear, Neil H; Paul, Carle; Blauvelt, Andrew; Gooderham, Melinda; Leonardi, Craig; Reich, Kristian; Ohtsuki, Mamitaro; Pangallo, Beth; Xu, Wen; Ball, Susan; Ridenour, Terri; Torisu-Itakura, Hitoe; Agada, Noah; Mallbris, Lotus

2018-02-01

BACKGROUND: Injection-site reactions (ISRs) are reported with biologic therapies. The objective of this study was to comprehensively characterize ISRs among moderate-to-severe psoriasis patients treated with ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A.

METHODS: ISRs are presented from UNCOVER-1, UNCOVER-2, and UNCOVER-3 (12 weeks) and all ixekizumab-exposed patients in 11 controlled and uncontrolled trials (156 weeks).

RESULTS: At week 12, reported ISR frequency with 80 mg ixekizumab every 2 weeks (IXE Q2W, 16.8%) was comparable with etanercept twice weekly (16.4%); both were significantly higher than placebo (3.3%). With IXE Q2W, ISRs were mild (12.3%), moderate (3.9%), or severe (0.7%), typically reported in the first 2 weeks (median onset, 6.6 days), and most commonly characterized as nonspecified, erythema, and pain. Generally, erythema onset was delayed, whereas pain occurred around drug administration. Discontinuation from ixekizumab due to ISRs (0.4%) occurred in the first 12 weeks. After 2 weeks, ISR frequency decreased and remained stable (≤4.2%) through week 156. No ISR-related serious adverse events were reported in ixekizumab-treated patients. ISR data were solicited if patients reported injection-associated events. Since nonspecified ISR was the most commonly reported term, specific types might be underreported.

CONCLUSIONS: ISRs have been reported with ixekizumab during clinical trials. These reactions are typically tolerable, manageable, and decrease over time.

Clinicaltrials.gov: NCT01474512 (UNCOVER-1); NCT01597245 (UNCOVER-2); NCT01646177 (UNCOVER-3); NCT01777191 (UNCOVER-A); NCT01624233 (UNCOVER-J); NCT01107457 (I1F-MC-RHAJ); NCT02561806 (I1F-MC-RHBS); NCT02387801 (I1F-US-RHBO);NCT02513550 (I1F-MC-RHBP); NCT02634801 (I1F-EW-RHBZ)

J Drugs Dermatol. 2018;17(2):200-206.

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Biological drugs for the treatment of psoriasis in a public health system

PubMed Central

Lopes, Luciane Cruz; Silveira, Miriam Sanches do Nascimento; de Camargo, Iara Alves; Barberato, Silvio; Del Fiol, Fernando de Sá; Osorio-de-Castro, Claudia Garcia Serpa

2014-01-01

OBJECTIVE To analyze the access and utilization profile of biological medications for psoriasis provided by the judicial system in Brazil. METHODS This is a cross-sectional study. We interviewed a total of 203 patients with psoriasis who were on biological medications obtained by the judicial system of the State of Sao Paulo, from 2004 to 2010. Sociodemographics, medical, and political-administrative characteristics were complemented with data obtained from dispensation orders that included biological medications to treat psoriasis and the legal actions involved. The data was analyzed using an electronic data base and shown as simple variable frequencies. The prescriptions contained in the lawsuits were analyzed according to legal provisions. RESULTS A total of 190 lawsuits requesting several biological drugs (adalimumab, efalizumab, etanercept, and infliximab) were analyzed. Patients obtained these medications as a result of injunctions (59.5%) or without having ever demanded biological medication from any health institution (86.2%), i.e., public or private health services. They used the prerogative of free legal aid (72.6%), even though they were represented by private lawyers (91.1%) and treated in private facilities (69.5%). Most of the patients used a biological medication for more than 13 months (66.0%), and some patients were undergoing treatment with this medication when interviewed (44.9%). Approximately one third of the patients discontinued treatment due to worsening of their illness (26.6%), adverse drug reactions (20.5%), lack of efficacy, or because the doctor discontinued this medication (13.8%). None of the analyzed medical prescriptions matched the legal prescribing requirements. Clinical monitoring results showed that 70.3% of the patients had not undergone laboratory examinations (blood work, liver and kidney function tests) for treatment control purposes. CONCLUSIONS The plaintiffs resorted to legal action to get access to biological medications because they were either unaware or had difficulty in accessing them through institutional public health system procedures. Access by means of legal action facilitated long-term use of this type of medication through irregular prescriptions and led to a high rate of adverse drug reactions as well as inappropriate clinical monitoring. PMID:25210824

Anti-Interleukin-6 Receptor Tocilizumab for Severe Juvenile Idiopathic Arthritis-Associated Uveitis Refractory to Anti-Tumor Necrosis Factor Therapy: A Multicenter Study of Twenty-Five Patients.

PubMed

Calvo-Río, Vanesa; Santos-Gómez, Montserrat; Calvo, Inmaculada; González-Fernández, M Isabel; López-Montesinos, Berta; Mesquida, Marina; Adán, Alfredo; Hernández, María Victoria; Maíz, Olga; Atanes, Antonio; Bravo, Beatriz; Modesto, Consuelo; Díaz-Cordovés, Gisela; Palmou-Fontana, Natalia; Loricera, Javier; González-Vela, M C; Demetrio-Pablo, Rosalía; Hernández, J L; González-Gay, Miguel A; Blanco, Ricardo

2017-03-01

To assess the efficacy of tocilizumab (TCZ) for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. We conducted a multicenter study of patients with JIA-associated uveitis that was refractory to conventional immunosuppressive drugs and anti-tumor necrosis factor (anti-TNF) agents. We assessed 25 patients (21 female; 47 affected eyes) with a mean ± SD age of 18.5 ± 8.3 years. Uveitis was bilateral in 22 patients. Cystoid macular edema was present in 9 patients. Ocular sequelae found at initiation of TCZ included cataracts (n = 13), glaucoma (n = 7), synechiae (n = 10), band keratopathy (n = 12), maculopathy (n = 9), and amblyopia (n = 5). Before TCZ, patients had received corticosteroids, conventional immunosuppressive drugs, and biologic agents (median 2 [range 1-5]), including adalimumab (n = 24), etanercept (n = 8), infliximab (n = 7), abatacept (n = 6), rituximab (n = 2), anakinra (n = 1), and golimumab (n = 1). Patients received 8 mg/kg TCZ intravenously every 4 weeks in most cases. TCZ yielded rapid and maintained improvement in all ocular parameters. After 6 months of therapy, 79.2% of patients showed improvement in anterior chamber cell numbers, and 88.2% showed improvement after 1 year. Central macular thickness measured by optical coherence tomography in patients with cystoid macular edema decreased from a mean ± SD of 401.7 ± 86.8 μm to 259.1 ± 39.5 μm after 6 months of TCZ (P = 0.012). The best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (P < 0.01). After a median follow-up of 12 months, visual improvement persisted, and complete remission of uveitis was observed in 19 of 25 patients. Significant reduction in the prednisone dosage was also achieved. The main adverse effects were severe autoimmune thrombocytopenia in 1 patient, pneumonia and then autoimmune anemia and thrombocytopenia in 1 patient, and viral conjunctivitis and bullous impetigo in 1 patient. TCZ appears to be a useful therapy for severe refractory JIA-associated uveitis. © 2016, American College of Rheumatology.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-03-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulfate, abatacept, adalimumab, ademetionine, adjuvanted influenza vaccine, alefacept, alemtuzumab, amlodipine, amphotericin B, anakinra, aripiprazole, aspirin, axitinib; Betamethasone dipropionate, bevacizumab, biphasic insulin aspart, bortezomib, bosentan, botulinum toxin type B, BQ-123; Calcium folinate, canertinib dihydrochloride, carboplatin, carmustine, cetirizine hydrochloride, cetuximab, cholecalciferol, ciclesonide, ciclosporin, cinacalcet hydrochloride, cisplatin, clarithromycin, clofazimine, cold-adapted influenza vaccine trivalent, CpG-7909; Darbepoetin alfa, darifenacin hydrobromide, DB-289, desloratadine, Dexamet, dicycloverine hydrochloride, dimethyl fumarate, docetaxel, dolastatin 10, drospirenone, drospirenone/estradiol, duloxetine hydrochloride; Ecogramostim, edotecarin, efaproxiral sodium, enalapril maleate, epoetin beta, epoprostenol sodium, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, estradiol, etanercept; Fluconazole, fludarabine phosphate, fluorouracil; Gefitinib, gemcitabine, Ghrelin (human), glibenclamide, glimepiride, GTI-2040; Haloperidol, human insulin, hydrocortisone probutate; Imatinib mesylate, indisulam, influenza vaccine, inhaled insulin, insulin aspart, insulin glulisine, insulin lispro, irinotecan, ispronicline; Lamivudine, lamivudine/zidovudine/abacavir sulfate, lapatinib, letrozole, levocetirizine, lomustine, lonafarnib, lumiracoxib;Magnesium sulfate, MD-1100, melphalan, metformin hydrochloride, methotrexate, metoclopramide hydrochloride, mitiglinide calcium hydrate, monophosphoryl lipid A, montelukast sodium, motexafin gadolinium, mycophenolate mofetil, mycophenolic acid sodium salt; Nitisinone; Omalizumab, omapatrilat, ONYX-015, oxaliplatin; Paclitaxel, paclitaxel nanoparticles, panitumumab, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pertuzumab, phosphatidylcholine-rich phospholipid mixture, pimecrolimus, pioglitazone hydrochloride, pramlintide acetate, prasterone; QR-333; Ranelic acid distrontium salt, ranolazine, rasagiline mesilate, RFB4(dsFv)-PE38, ribavirin, rifabutin, risperidone, rituximab, rofecoxib, rosiglitazone maleate, rosiglitazone maleate/metformin hydrochloride, rotavirus vaccine; S-236, salmeterol xinafoate, sarizotan hydrochloride, sildenafil, sildenafil citrate, sunitinib malate; Tadalafil, tegaserod maleate, temozolomide, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipifarnib, trabectedin, treprostinil sodium; Vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, vinflunine, virosome influenza vaccine, voriconazole; Zidovudine. (c) 2006 Prous Science. All rights reserved.

Treatment of primary Sjögren syndrome: a systematic review.

PubMed

Ramos-Casals, Manuel; Tzioufas, Athanasios G; Stone, John H; Sisó, Antoni; Bosch, Xavier

2010-07-28

A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available. To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials. We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010. Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source. The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.

New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase.

PubMed

Peifer, Christian; Wagner, Gerd; Laufer, Stefan

2006-01-01

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.

Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity.

PubMed

Torri, Anna; Carpi, Donatella; Bulgheroni, Elisabetta; Crosti, Maria-Cristina; Moro, Monica; Gruarin, Paola; Rossi, Riccardo L; Rossetti, Grazisa; Di Vizio, Dolores; Hoxha, Mirjam; Bollati, Valentina; Gagliani, Cristina; Tacchetti, Carlo; Paroni, Moira; Geginat, Jens; Corti, Laura; Venegoni, Luigia; Berti, Emilio; Pagani, Massimiliano; Matarese, Giuseppe; Abrignani, Sergio; de Candia, Paola

2017-02-17

Upon T cell receptor stimulation, CD4 + T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4 + T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4 + T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4 + T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity*

PubMed Central

Torri, Anna; Carpi, Donatella; Bulgheroni, Elisabetta; Crosti, Maria-Cristina; Moro, Monica; Gruarin, Paola; Rossi, Riccardo L.; Rossetti, Grazisa; Di Vizio, Dolores; Hoxha, Mirjam; Bollati, Valentina; Gagliani, Cristina; Tacchetti, Carlo; Paroni, Moira; Geginat, Jens; Corti, Laura; Venegoni, Luigia; Berti, Emilio; Pagani, Massimiliano; Matarese, Giuseppe; Abrignani, Sergio; de Candia, Paola

2017-01-01

Upon T cell receptor stimulation, CD4+ T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4+ T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4+ T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4+ T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response. PMID:28077577

Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER

PubMed Central

Carmona, Loreto; Gómez-Reino, Juan J

2006-01-01

The aim of the present work is to compare drug survival and safety of infliximab, etanercept, and adalimumab (tumor necrosis factor [TNF] antagonists) in spondylarthritis (SpA) with those of rheumatoid arthritis (RA). To this purpose, we analysed the data in BIOBADASER (2000–2005), a drug registry launched in 2000 for long-term follow-up of the safety of these biologics in rheumatic diseases. The rates of drug discontinuation and adverse events (AEs) in SpA (n = 1,524) were estimated and compared with those of RA (n = 4,006). Cox regression analyses were used to adjust for independent factors. Total exposure to TNF antagonists for SpA was 2,430 patient-years and 7,865 for RA. Drug survival in SpA was significantly greater than in RA at 1, 2, and 3 years. The hazard ratio (HR) for discontinuation in SpA compared with RA was 0.66 (95% confidence interval [CI], 0.57–0.76) after adjustment for age, gender, and use of infliximab. The difference remained after controlling for the individual medication and its place in the sequence of treatment. There were fewer SpA patients with AEs (17%) than RA patients (26%; p < 0.001). The HR for AEs in SpA was 0.80 (95% CI, 0.70–0.91) compared with RA after adjustment for age, disease duration, and use of infliximab. In conclusion, due in part to a better safety profile, survival of TNF antagonists in SpA is better than in RA. TNF antagonists are at present a safe and effective therapeutic option for long-term treatment of patients with SpA failing to respond to traditional drugs. Because chronic therapy is necessary, continual review of this issue is necessary. PMID:16620398

Antibody-mediated delivery of interleukin 4 to the neo-vasculature reduces chronic skin inflammation.

PubMed

Hemmerle, Teresa; Zgraggen, Silvana; Matasci, Mattia; Halin, Cornelia; Detmar, Michael; Neri, Dario

2014-11-01

The antibody-mediated delivery of cytokines ("immunocytokines") to sites of pathological angiogenesis represents an attractive strategy for the development of innovative biopharmaceuticals, capable of modulating the activity of the immune system in cancer and in chronic inflammatory conditions. Recombinant IL4 has previously been shown to be therapeutically active in patients with psoriasis. The antibody-mediated delivery of this cytokine to sites of chronic skin inflammatory conditions should lead to an improved potency and selectivity, compared to non-targeted IL4. The therapeutic activity of F8-IL4, a fusion protein of the F8 antibody (specific to the alternatively-spliced EDA domain of fibronectin) with murine IL4, was investigated in three immunocompetent mouse models of skin inflammation: two induced by the TLR7/8 ligand imiquimod (in Balb/c and C57BL/6) and one mediated by the over-expression of VEGF-A. The EDA domain of fibronectin, a marker for angiogenesis, is expressed in the inflamed skin in all three models and F8-IL4 selectively localized to inflamed skin lesions following intravenous administration. The F8-IL4 fusion protein mediated a therapeutic benefit, which was superior to the one of a non-targeted version of IL4 and led to increased levels of key regulatory cytokines (including IL5, IL10, IL13, and IL27) in the inflamed skin, while IL2 levels were not affected in all treatment groups. A murine version of etanercept and a murine anti-IL17 antibody were used as positive control in the therapy experiments. Skin inflammatory lesions can be selectively targeted using anti-EDA antibody-cytokine fusion proteins and the pharmacodelivery of IL4 confers a therapeutic benefit by shifting the cytokine balance. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Nanostructured Surfaces for Drug Delivery and Anti-Fibrosis

NASA Astrophysics Data System (ADS)

Kam, Kimberly Renee

Effective and cost-efficient healthcare is at the forefront of public discussion; on both personal and policy levels, technologies that improve therapeutic efficacy without the use of painful hypodermic needle injections or the use of harsh chemicals would prove beneficial to patients. Nanostructured surfaces as structure-mediated permeability enhancers introduce a potentially revolutionary approach to the field of drug delivery. Parental administration routes have been the mainstay technologies for delivering biologics because these therapeutics are too large to permeate epithelial barriers. However, there is a significant patient dislike for hypodermic needles resulting in reduced patient compliance and poor therapeutic results. We present an alternative strategy to harness the body's naturally occurring biological processes and transport mechanisms to enhance the drug transport of biologics across the epithelium. Our strategy offers a paradigm shift from traditional biochemical drug delivery vehicles by using nanotopography to loosen the epithelial barrier. Herein, we demonstrate that nanotopographical cues can be used to enable biologics > 66 kDa to be transported across epithelial monolayers by increasing paracellular transport. When placed in contact with epithelial cells, nanostructured films significantly increase the transport of albumin, IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopographical cues to increase the transport of biologics across epithelial tissue. Furthermore, we describe current advancements in nano- and microfabrication for applications in anti-fibrosis and wound healing. Influencing cellular responses to biomaterials is crucial in the field of tissue engineering and regenerative medicine. Since cells are surrounded by extracellular matrix features that are on the nanoscale, identifying nanostructures for imparting desirable cellular function could greatly impact the field. Due to the rise in micro and nanofabrication techniques borrowed from the advances in the microelectronics industry, previously unattainable nanostructured surfaces on a variety of biomaterials can be generated. We investigated how nanostructured surfaces with varying nanofeature aspect ratios can influence fibrosis. Thus, nanostructured surfaces show substantial progress for therapeutic applications in drug delivery and wound healing.

Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety.

PubMed

Al-Mayouf, Sulaiman M; Alenazi, Abdullatif; AlJasser, Hind

2016-06-01

To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25-14) years and mean therapy duration was 14.7 (3-88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity.

PubMed

Inciarte-Mundo, José; Ramirez, Julio; Hernández, Maria Victoria; Ruiz-Esquide, Virginia; Cuervo, Andrea; Cabrera-Villalba, Sonia Raquel; Pascal, Mariona; Yagüe, Jordi; Cañete, Juan D; Sanmarti, Raimon

2016-07-08

Serum levels of calprotectin, a major S100 leucocyte protein, are associated with disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients. Higher drug trough serum levels are associated with good response in patients treated with tumour necrosis factor inhibitors (TNFi). Power Doppler ultrasound (PDUS) synovitis is predictive of flare and progression of structural damage in patients in clinical remission. The purpose of this study was to analyse the accuracy of calprotectin and TNFi trough serum levels in detecting PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity who were receiving TNFi. We conducted a cross-sectional study of 92 patients (42 with RA, 50 with PsA) receiving adalimumab (ADA), etanercept (ETN) or infliximab who were in remission or had low disease activity (28-joint Disease Activity Score based on erythrocyte sedimentation rate <3.2). Associations of calprotectin, TNFi trough serum levels and acute phase reactants with PDUS synovitis were assessed using correlation and linear regression analyses. The accuracy and discriminatory capacity in detecting PDUS synovitis was assessed using ROC curves. PDUS synovitis was found in 62.4 % of RA patients and 32 % of PsA patients. Both RA and PsA patients with PDUS synovitis had higher calprotectin levels and lower TNFi trough serum levels. Calprotectin positively correlated with ultrasound scores (all r coefficients >0.50 in RA). Calprotectin correlated with the PDUS synovitis score in patients treated with ADA and ETN. Using PDUS synovitis (yes or no) as the reference variable, calprotectin had an AUC of 0.826. The best cut-off was ≥1.66 μg/ml, with a likelihood ratio of 2.77. C-reactive protein (AUC 0.673) and erythrocyte sedimentation rate (AUC 0.731) had a lower discriminatory capacity. TNFi trough serum levels were significantly associated with PDUS synovitis (OR 0.67, 95 % CI 0.52-0.85, p < 0.001) but their accuracy (AUC <0.5) was less than that of calprotectin. TNFi trough serum levels were inversely correlated with calprotectin and PDUS synovitis in RA and PsA patients receiving ADA and ETN. Calprotectin and TNFi trough serum levels may help identify PDUS synovitis in RA and PsA patients in clinical remission or with low disease activity.

Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis.

PubMed

Chastek, Benjamin; Becker, Laura K; Chen, Chieh-I; Mahajan, Puneet; Curtis, Jeffrey R

2017-05-01

To examine treatment patterns, treatment effectiveness, and treatment costs for 1 year after patients with rheumatoid arthritis switched from a tumor necrosis factor inhibitor (TNFi) (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab), either cycling to another TNFi ("TNFi cyclers") or switching to a new mechanism of action (abatacept, tocilizumab, or tofacitinib) ("new MOA switchers"). This retrospective cohort study used administrative claims data for a national insurer. Treatment persistence (without switching again, restarting, or discontinuing), treatment effectiveness (defined below), and costs were assessed for the 12-month post-switch period. Patients were "effectively treated" if they satisfied all six criteria for a treatment effectiveness algorithm (high adherence, no dose increase, no new conventional synthetic disease-modifying anti-rheumatic drug, no subsequent switch in therapy, no new/increased oral glucocorticoids, and <2 glucocorticoid injections). Multivariable logistic models were used to adjust for baseline factors. The database included 581 new MOA switchers and 935 TNFi cyclers. New MOA switchers were 39% more likely than TNFi cyclers to persist after the switch (odds ratio [OR] = 1.39; 95% confidence interval [CI] = 1.12-1.74; p = .003) and 36% less likely to switch therapy again (OR = 0.64; 95% CI = 0.51-0.81; p < .001). New MOA switchers were 43% more likely than TNFi cyclers to be effectively treated (OR = 1.43; 95% CI = 1.11-1.85; p = .006). New MOA switchers had 16% lower drug costs than TNFi cyclers (cost ratio = 0.84; 95% CI = 0.79-0.88; p < .001) and 11% lower total costs of rheumatoid arthritis-related medical care (cost ratio = 0.89; 95% CI = 0.84-0.94; p < .001). Claims payments may not reflect rebates or other cost offsets. Medical and pharmacy claims do not include clinical end-points or reasons that lead to new MOA switching vs TNFi cycling. These results support switching to a new MOA after a patient fails treatment with a TNFi, which is consistent with recent guidelines for the pharmacologic management of established rheumatoid arthritis.

Newer biological agents in rheumatoid arthritis: impact on health-related quality of life and productivity.

PubMed

Strand, Vibeke; Singh, Jasvinder A

2010-01-01

Health-related quality of life (HR-QOL) in patients with rheumatoid arthritis (RA) is significantly impaired as a result of pain, deficits in physical function and fatigue associated with this disease. Decrements in HR-QOL are also associated with an increased probability of no longer working, absence from work due to RA-associated sickness, and reduced productivity while at work or in the home, all of which have consequences for the patient as well as society. HR-QOL and productivity are thus important components in the assessment of outcomes in RA, and assessment of HR-QOL is now recommended in clinical trials that assess the efficacy of new treatments for RA. Measures to assess HR-QOL include the Medical Outcomes Study Short Form 36 (SF-36), EuroQol (EQ-5D) and the Health Utilities Index - Mark 3 (HUI3); these measures not only provide an indication of the clinical (i.e. statistical) efficacy of a treatment, but also provide information on whether this efficacy is truly 'meaningful' from a patient's perspective. These measures have been utilized in clinical trials of biological agents in patients with RA, including tumour necrosis factor inhibitors (etanercept, infliximab, adalimumab, certolizumab pegol and golimumab), the co-stimulatory inhibitor molecule abatacept, the B-cell depletion agent rituximab and the interleukin-6 receptor antagonist tocilizumab, and have demonstrated that these agents can significantly improve HR-QOL. Assessment of work productivity in patients with RA and the impact of treatment is a practical way to measure disability from RA from individual and societal perspectives. As RA affects women three times more frequently than men, there is also a critical need for productivity assessment within the home as well as participation in family/social/leisure activities. Data from recent trials of biological agents demonstrate that these agents can reverse disease-related decrements in productivity and limitations in participation in family, social and leisure activities in patients with active RA. However, despite this recognition, several challenges in the assessment of productivity remain, including standardization of instruments. Development of additional instruments to assess HR-QOL and productivity that are easier to use in daily practice may further improve our ability to monitor the effectiveness of therapies.

Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis.

PubMed

Singh, Jasvinder A; Hossain, Alomgir; Tanjong Ghogomu, Elizabeth; Mudano, Amy S; Maxwell, Lara J; Buchbinder, Rachelle; Lopez-Olivo, Maria Angeles; Suarez-Almazor, Maria E; Tugwell, Peter; Wells, George A

2017-03-10

Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics. To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics. On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer). This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer. Tofacitinib monotherapy versus placeboThere were no published data. Tofacitinib + MTX versus active comparator (MTX)In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer. Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.

Comparative effectiveness research (CER): a summary of AHRQ's CER on therapies for rheumatoid arthritis.

PubMed

Oderda, Gary M; Balfe, Lisa M

2011-01-01

In recent years, the U.S. government has designated funding of several large-scale initiatives for comparative effectiveness research (CER) in health care. The American Recovery and Reinvestment Act (ARRA) of 2009 apportioned more than $1 billion to support CER programs administered by the Department of Health and Human Services (DHHS), the National Institutes of Health (NIH), and the Agency for Healthcare Research and Quality (AHRQ). CER is generally defined as the undertaking of original research or systematic reviews of published literature in order to compare the benefits and risks of different approaches to preventing, diagnosing, or treating diseases. These approaches may include diagnostic tests, medications, medical devices, and surgeries. The overall goals of CER are to support informed health care decisions by patients, clinicians, payers, and policy makers and to apply its evidence to ultimately improve the quality, effectiveness, and efficiency of health care. To (a) provide managed care professionals with general definitions of CER, specifically as it is administered by AHRQ; (b) discuss the importance of CER to clinical and managed care pharmacists; and (c) summarize key methods and findings from AHRQ's 2007 comparative effectiveness review on therapies for rheumatoid arthritis (RA). As supported by AHRQ, CER is conducted in order to synthesize comprehensive evidence on the comparative benefits and harms of treatment interventions. The findings from comparative effectiveness reviews can thus contribute to informing therapeutic strategies and treatment decisions. In 2007, a multitude of RA treatment options and studies motivated AHRQ to commission a systematic comparative effectiveness review. Conducted by investigators at the RTI-University of North Carolina Evidence-Based Practice Center, the review included comparisons of synthetic disease-modifying antirheumatic drugs (DMARDs), biologic agents, synthetic DMARDs versus biologic agents, and various combination therapies. Head-to-head comparisons of synthetic DMARDs generally revealed no significant differences in long-term clinical and radiographic outcomes, or in functional capacity or health-related quality of life. Two nonrandomized prospective cohort studies and 1 open-label effectiveness trial reported no differences in ACR20 and ACR50 response rates in patients treated with the tissue necrosis factor (TNF)-alpha inhibitors etanercept and infliximab. Comparisons of TNF-alpha inhibitors generally indicated no significant differences in rates of adverse events, including serious infections, and no increases in rates over time. In comparisons of a biologic agent combined with methotrexate versus a biologic agent alone, combination therapies were generally associated with better clinical response rates and better outcomes of functional capacity and quality of life. The most common adverse events observed in studies on biologic agents were diarrhea, headache, nausea, rhinitis, injection site reactions, and upper respiratory tract infections.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

PubMed

Delate, Thomas; Meyer, Roxanne; Jenkins, Daniel

2017-08-01

Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins.

Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation

PubMed Central

Johnston, Andrew; Fritz, Yi; Dawes, Sean M.; Diaconu, Doina; Al-Attar, Paul M.; Guzman, Andrew M.; Chen, Cynthia S.; Fu, Wen; Gudjonsson, Johann E.; McCormick, Thomas S.; Ward, Nicole L.

2013-01-01

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17RE/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058pg/ml vs. 8pg/ml; p<0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs) and leukocytes. ECs stimulated with IL-17C produce increased TNFα and KCs stimulated with IL-17C/TNFα produce similar inflammatory gene response patterns as those elicited by IL-17A/TNFα, including increases in IL-17C, TNFα, IL-8, IL-1α/β, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, LCN2 and PI3 (p<0.05); indicating a positive pro-inflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNFα-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey “involved” skin adjacent to areas of normal appearing “uninvolved” skin despite increased IL-17C expression in both areas (p<0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9expression (p<0.05) but no epidermal hyperplasia; whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration and upregulated TNFα, IL-1α/β, IL-17A/F, IL-23p19, VEGF, IL-6 and CCL20 (p<0.05) suggesting that IL-17C, when coupled with other pro-inflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 weeks of TNFα inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin. PMID:23359500

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.

PubMed

Smolen, Josef S; Landewé, Robert; Bijlsma, Johannes; Burmester, Gerd; Chatzidionysiou, Katerina; Dougados, Maxime; Nam, Jackie; Ramiro, Sofia; Voshaar, Marieke; van Vollenhoven, Ronald; Aletaha, Daniel; Aringer, Martin; Boers, Maarten; Buckley, Chris D; Buttgereit, Frank; Bykerk, Vivian; Cardiel, Mario; Combe, Bernard; Cutolo, Maurizio; van Eijk-Hustings, Yvonne; Emery, Paul; Finckh, Axel; Gabay, Cem; Gomez-Reino, Juan; Gossec, Laure; Gottenberg, Jacques-Eric; Hazes, Johanna M W; Huizinga, Tom; Jani, Meghna; Karateev, Dmitry; Kouloumas, Marios; Kvien, Tore; Li, Zhanguo; Mariette, Xavier; McInnes, Iain; Mysler, Eduardo; Nash, Peter; Pavelka, Karel; Poór, Gyula; Richez, Christophe; van Riel, Piet; Rubbert-Roth, Andrea; Saag, Kenneth; da Silva, Jose; Stamm, Tanja; Takeuchi, Tsutomu; Westhovens, René; de Wit, Maarten; van der Heijde, Désirée

2017-06-01

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Lowering Interleukin-12 Activity Improves Myocardial and Vascular Function Compared With Tumor Necrosis Factor-a Antagonism or Cyclosporine in Psoriasis.

PubMed

Ikonomidis, Ignatios; Papadavid, Evangelia; Makavos, George; Andreadou, Ioanna; Varoudi, Maria; Gravanis, Kostas; Theodoropoulos, Kostas; Pavlidis, George; Triantafyllidi, Helen; Moutsatsou, Paraskevi; Panagiotou, Christina; Parissis, John; Iliodromitis, Efstathios; Lekakis, John; Rigopoulos, Dimitrios

2017-09-01

Interleukin (IL)-12 activity is involved in the pathogenesis of psoriasis and acute coronary syndromes. We investigated the effects of IL-12 inhibition on vascular and left ventricular (LV) function in psoriasis. One hundred fifty psoriasis patients were randomized to receive an anti-IL-12/23 (ustekinumab, n=50), anti-tumor necrosis factor-a (TNF-α; etanercept, n=50), or cyclosporine treatment (n=50). At baseline and 4 months post-treatment, we measured (1) LV global longitudinal strain, twisting, and percent difference between peak twisting and untwisting at mitral valve opening (%untwMVO) using speckle-tracking echocardiography, (2) coronary flow reserve, (3) pulse wave velocity and augmentation index, (4) circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide), TNF-α, IL-6, IL-12, IL-17, malondialdehyde, and fetuin-a. Compared with baseline, all patients had improved global longitudinal strain (median values: -17.7% versus -19.5%), LV twisting (12.4° versus 14°), %untwMVO (27.8% versus 35%), and coronary flow reserve (2.8 versus 3.1) and reduced circulating NT-proBNP, IL-17, TNF-α, and IL-6 post-treatment ( P <0.05). Compared with anti-TNF-α and cyclosporine, anti-IL-12/23 treatment resulted in a greater improvement of global longitudinal strain (25% versus 17% versus 6%,), LV twist (27% versus 17% versus 1%), %untwMVO (31% versus 27% versus 17%), and coronary flow reserve (14% versus 11% versus 4%), as well as a greater reduction of IL-12 (-25% versus -4% versus -2%), malondialdehyde (-27% versus +5% versus +26%), and NT-proBNP(-26% versus -13.6% versus 9.1%) and increase of fetuin-a ( P <0.01). Pulse wave velocity and augmentation index were improved only after anti-IL-12/23 treatment and correlated with changes in global longitudinal strain, LV twisting-untwisting ( P <0.05). In psoriasis, IL-12/23 inhibition results in a greater improvement of coronary, arterial, and myocardial function than TNF-α inhibition or cyclosporine treatment. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02144857. © 2017 American Heart Association, Inc.

Budget impact model in moderate-to-severe psoriasis vulgaris assessing effects of calcipotriene and betamethasone dipropionate foam on per-patient standard of care costs.

PubMed

Asche, Carl V; Kim, Minchul; Feldman, Steven R; Zografos, Panagiotis; Lu, Minyi

2017-09-01

To develop a budget impact model (BIM) for estimating the financial impact of formulary adoption and uptake of calcipotriene and betamethasone dipropionate (C/BD) foam (0.005%/0.064%) on the costs of biologics for treating moderate-to-severe psoriasis vulgaris in a hypothetical US healthcare plan with 1 million members. This BIM incorporated epidemiologic data, market uptake assumptions, and drug utilization costs, simulating the treatment mix for patients who are candidates for biologics before (Scenario #1) and after (Scenario #2) the introduction of C/BD foam. Predicted outcomes were expressed in terms of the annual cost of treatment (COT) and the COT per member per month (PMPM). At year 1, C/BD foam had the lowest per-patient cost ($9,913) necessary to achieve a Psoriasis Area and Severity Index (PASI)-75 response compared with etanercept ($73,773), adalimumab ($92,871), infliximab ($34,048), ustekinumab ($83,975), secukinumab ($113,858), apremilast ($47,960), and ixekizumab ($62,707). Following addition of C/BD foam to the formulary, the annual COT for moderate-to-severe psoriasis would decrease by $36,112,572 (17.91%, from $201,621,219 to $165,508,647). The COT PMPM is expected to decrease by $3.00 (17.86%, from $16.80 to $13.80). Drug costs were based on Medi-Span reference pricing (January 21, 2016); differences in treatment costs for drug administration, laboratory monitoring, or adverse events were not accounted for. Potentially confounding were the definition of "moderate-to-severe" and the heterogeneous efficacy data. The per-patient cost for PASI-75 response at year 1 was estimated from short-term efficacy data for C/BD foam and apremilast only. The introduction of C/BD foam is expected to decrease the annual COT for moderate-to-severe psoriasis treatable with biologics by $36,112,572 for a hypothetical US healthcare plan with 1 million plan members, and to lower the COT PMPM by $3.00.

Tailored first-line biologic therapy in patients with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis.

PubMed

Cantini, Fabrizio; Niccoli, Laura; Nannini, Carlotta; Cassarà, Emanuele; Kaloudi, Olga; Giulio Favalli, Ennio; Becciolini, Andrea; Biggioggero, Martina; Benucci, Maurizio; Li Gobbi, Francesca; Grossi, Valentina; Infantino, Maria; Meacci, Francesca; Manfredi, Mariangela; Guiducci, Serena; Bellando-Randone, Silvia; Matucci-Cerinic, Marco; Foti, Rosario; Di Gangi, Marcella; Mosca, Marta; Tani, Chiara; Palmieri, Fabrizio; Goletti, Delia

2016-04-01

A multidisciplinary expert panel, the Italian board for the TAilored BIOlogic therapy (ITABIO), was constituted to formulate evidence-based decisional statements for the first-line tailored biologic therapy in patient with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictor biomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host-related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs. Some variables, including the patients' preference, the indication for anti-TNF monotherapy in potential childbearing women, and the intravenous route with dose titration in obese subjects resulted valid for all the three rheumatic conditions. Further, evidence of a better cost-effectiveness profile for etanercept (ETN) and biosimilar infliximab (IFX) in RA was found. Any biologic may be employed in absence of choice driving factors in RA. Otherwise, a high infection risk or LTBI positivity drive the choice toward abatacept (ABA), tocilizumab (TCZ), or ETN. TCZ should be the first choice if monotherapy is required. High rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) titers should drive the choice toward TCZ or ABA, while in patients at high CVD risk anti-TNF choice, with preference for ETN, seems appropriate. Presence of anterior uveitis or inflammatory bowel disease drives the choice to monoclonal antibody anti-TNFs (MoAb anti-TNFs). In PsA, ustekinumab (UTK), and to a lesser extent ETN, represents the first choice in patients at high infection and TB risk. Anti-TNFs or UTK choice is guided by skin or articular disease severity, enthesitis, and dactylitis, whereas ETN should be preferred if metabolic syndrome or high CV risk complicate PsA. Taking in account of multiple choice driving variables, first-line biologic therapy may be optimized in patients with RA, SpA, and PsA. Copyright © 2016 Elsevier Inc. All rights reserved.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

PubMed Central

Smolen, Josef S; Landewé, Robert; Breedveld, Ferdinand C; Buch, Maya; Burmester, Gerd; Dougados, Maxime; Emery, Paul; Gaujoux-Viala, Cécile; Gossec, Laure; Nam, Jackie; Ramiro, Sofia; Winthrop, Kevin; de Wit, Maarten; Aletaha, Daniel; Betteridge, Neil; Bijlsma, Johannes W J; Boers, Maarten; Buttgereit, Frank; Combe, Bernard; Cutolo, Maurizio; Damjanov, Nemanja; Hazes, Johanna M W; Kouloumas, Marios; Kvien, Tore K; Mariette, Xavier; Pavelka, Karel; van Riel, Piet L C M; Rubbert-Roth, Andrea; Scholte-Voshaar, Marieke; Scott, David L; Sokka-Isler, Tuulikki; Wong, John B; van der Heijde, Désirée

2014-01-01

In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA. PMID:24161836

Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis.

PubMed

Foster, Shonda A; Zhu, Baojin; Guo, Jiaying; Nikai, Enkeleida; Ojeh, Clement; Malatestinic, William; Goldblum, Orin; Kornberg, Lori J; Wu, Jashin J

2016-04-01

Psoriasis is a chronic, incurable, and immune-mediated skin disorder that is characterized by erythematous scaly papules and plaques. Understanding of psoriasis at the molecular level has led to the development of biologic agents that target disease-specific inflammatory mediators in psoriatic lesions. Biologic agents have become important components of the psoriasis armamentarium, but some patients become refractory to these agents over time or fail to respond to subsequent biologics. To (a) evaluate demographic and clinical characteristics of psoriasis patients who have treatment patterns suggestive of failure to a newly initiated biologic agent (treatment-regimen failures) compared with those who do not (non-treatment-regimen failures) and (b) to assess health care-related resource utilization and costs in non-treatment-regimen failures and treatment-regimen failures. In this retrospective observational cohort study, patients were selected from the MarketScan claims database of commercially insured individuals and individuals with Medicare supplemental insurance. The index event was a newly initiated biologic agent for the treatment of psoriasis (etanercept, adalimumab, ustekinumab, or infliximab) between January 2010 and December 2011. The analysis included psoriasis patients aged ≥ 18 years with ≥ 1 prescription claim for a biologic and continuous enrollment 12 months pre- and post-index date. Patients with claims for a biologic in the pre-index period were excluded. Patients were divided into treatment-regimen-failure and non-treatment-regimen-failure groups based on their treatment patterns post-index date. The treatment-regimen-failure group included patients who switched to another biologic, discontinued the biologic without restarting, increased the dose of the biologic, or augmented treatment with a nontopical psoriasis medication during the post-index period. Between-group patient characteristics and medication use were compared using analysis of variance for continuous variables and chi-square tests for categorical variables without adjustment. Cost differences were compared using the propensity score-adjusted bin bootstrapping method. Overall, 2,146 patients met the enrollment criteria. The mean age was 45.1 years. Of these patients, 41.5% were considered treatment-regimen failures. Among treatment-regimen failures, 53% were females, and among non-treatment-regimen failures, 61% were male. Patients who experienced treatment-regimen failure had higher incidences of comorbid cerebrovascular disease, hypertension, chronic pulmonary disease, depression, and anxiety in the pre-index period and were more likely to use concomitant topicals (67.0% vs. 58.4%; P < 0.001), methotrexate (20.2% vs. 7.3%; P < 0.001), and cyclosporine (3.1% vs. 1.0%; P < 0.001) in the post-index period. Mean total all-cause health care costs were higher in patients with treatment-regimen failure versus non-treatment-regimen failure during the pre-index period ($8,024 vs. $6,637; P = 0.002), but patients with non-treatment-regimen failure had higher all-cause costs ($30,759 vs. $28,012; P = 0.002) and psoriasis-related costs ($25,286 vs. $19,625; P < 0.001) during the post-index period. The results of the current study demonstrated that psoriasis patients with treatment patterns suggestive of treatment-regimen failure on an index biologic had different characteristics and incurred higher all-cause health care costs than did patients without treatment-regimen failure during the pre-index period. This study was supported by Eli Lilly and Company. Foster, Zhu, Guo, Nikai, Malatestinic, Ojeh, and Goldblum are full-time employees and stockholders of Eli Lilly and Company. Kornberg is a full-time employee of INC Research, which was contracted by Eli Lilly to assist with medical writing. Wu has received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, and Sandoz; he is a consultant for AbbVie, Amgen, Celgene, Dermira, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. Study concept was developed by Foster, Ojeh, Malatestinic, and Goldblum. Zhu and Guo, along with Foster, took the lead in data collection, and data interpretation was performed by Nikai, Wu, and Foster, with assistance from the other authors. The manuscript was primarily written by Kornberg, along with Foster, with assistance from the other authors. All of the authors were involved with manuscript revision.

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

PubMed

Alivernini, Stefano; Tolusso, Barbara; Petricca, Luca; Bui, Laura; Di Sante, Gabriele; Peluso, Giusy; Benvenuto, Roberta; Fedele, Anna Laura; Federico, Franco; Ferraccioli, Gianfranco; Gremese, Elisa

2017-07-01

To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Synovial features of patients with rheumatoid arthritis and psoriatic arthritis in clinical and ultrasound remission differ under anti-TNF therapy: a clue to interpret different chances of relapse after clinical remission?

PubMed Central

Alivernini, Stefano; Tolusso, Barbara; Petricca, Luca; Bui, Laura; Di Sante, Gabriele; Peluso, Giusy; Benvenuto, Roberta; Fedele, Anna Laura; Federico, Franco; Ferraccioli, Gianfranco; Gremese, Elisa

2017-01-01

Objective To define the synovial characteristics of patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in clinical and ultrasound remission achieved by combination therapy with methotrexate (MTX) and tumour necrosis factor (TNF) blockers. Methods Patients with RA in remission (n=25) (disease activity score (DAS)<1.6 for at least 6 months), patients with RA in low disease activity (LDA) (n=10) (1.6

Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial.

PubMed

Papp, Kim; Thaçi, Diamant; Marcoux, Danielle; Weibel, Lisa; Philipp, Sandra; Ghislain, Pierre-Dominique; Landells, Ian; Hoeger, Peter; Kotkin, Carol; Unnebrink, Kristina; Seyger, Marieke; Williams, David

2017-07-01

Adalimumab is indicated for the treatment of moderate to severe psoriasis in adults. We assessed the efficacy and safety of adalimumab in children and adolescents with severe plaque psoriasis. This randomised, double-blind, multiperiod, phase 3 trial was done at 38 clinics in 13 countries. Patients (aged ≥4 to <18 years) with severe plaque psoriasis who had not responded to topical therapy were randomly assigned with an interactive voice or web-response system (1:1:1) to receive adalimumab 0·8 mg/kg or 0·4 mg/kg subcutaneously at week 0, then every other week starting at week 1, or oral methotrexate once weekly (0·1-0·4 mg/kg) for 16 weeks. Randomisation was stratified by history of etanercept treatment, with a block size of three. Responders were withdrawn from treatment (for up to 36 weeks) and re-treated with adalimumab (for 16 weeks) if disease became uncontrolled. Ranked primary efficacy endpoints were the proportion of patients who achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75) score and clear or minimal physician global assessment (PGA) score at week 16, comparing adalimumab 0·8 mg/kg with methotrexate. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01251614, and has been completed. Between Dec 14, 2010, and Feb 5, 2015, 114 patients were randomly assigned to adalimumab 0·8 mg/kg (n=38), adalimumab 0·4 mg/kg (n=39) or methotrexate (n=37). At week 16, PASI75 was achieved in 22 (58%) of 38 patients in the adalimumab 0·8 mg/kg group compared with 12 (32%) of 37 patients in the methotrexate group (p=0·027). 23 (61%) of 38 patients in the adalimumab 0·8 mg/kg group and 15 (41%) of 37 in the methotrexate group achieved clear or minimal PGA (p=0·083). In the adalimumab 0·4 mg/kg group, 17 (44%) of 39 patients achieved PASI75 and 16 (41%) achieved clear or minimal PGA. The most frequent adverse events were infections (17 [45%] of 38 in the adalimumab 0·8 mg/kg group during initial treatment; 22 [56%] of 39 in the adalimumab 0·4 mg/kg group; 21 [57%] of 37 in the methotrexate group). Three serious adverse events were reported, all in patients in the adalimumab 0·4 mg/kg group, and were not judged to be related to study drug. Treatment with adalimumab 0·8 mg/kg in children and adolescents with severe plaque psoriasis provided significant improvements in PASI75 and a non-significant increase in the proportion of patients who achieved clear or minimal PGA compared with methotrexate. No new safety risks were identified. AbbVie. Copyright © 2017 Elsevier Ltd. All rights reserved.

Natural products against Alzheimer's disease: Pharmaco-therapeutics and biotechnological interventions.

PubMed

Dey, Abhijit; Bhattacharya, Raktim; Mukherjee, Anuradha; Pandey, Devendra Kumar

Alzheimer's disease (AD) is a severe, chronic and progressive neurodegenerative disease associated with memory and cognition impairment ultimately leading to death. It is the commonest reason of dementia in elderly populations mostly affecting beyond the age of 65. The pathogenesis is indicated by accumulation of the amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) in brain tissues and hyperphosphorylation of tau protein in neurons. The main cause is considered to be the formation of reactive oxygen species (ROS) due to oxidative stress. The current treatment provides only symptomatic relief by offering temporary palliative therapy which declines the rate of cognitive impairment associated with AD. Inhibition of the enzyme acetylcholinesterase (AChE) is considered as one of the major therapeutic strategies offering only symptomatic relief and moderate disease-modifying effect. Other non-cholinergic therapeutic approaches include antioxidant and vitamin therapy, stem cell therapy, hormonal therapy, use of antihypertensive or lipid-lowering medications and selective phosphodiesterase (PDE) inhibitors, inhibition of β-secretase and γ-secretase and Aβ aggregation, inhibition of tau hyperphosphorylation and intracellular NFT, use of nonsteroidal anti-inflammatory drugs (NSAIDs), transition metal chelators, insulin resistance drugs, etanercept, brain-derived neurotrophic factor (BDNF) etc. Medicinal plants have been reported for possible anti-AD activity in a number of preclinical and clinical trials. Ethnobotany, being popular in China and in the Far East and possibly less emphasized in Europe, plays a substantial role in the discovery of anti-AD agents from botanicals. Chinese Material Medica (CMM) involving Chinese medicinal plants has been used traditionally in China in the treatment of AD. Ayurveda has already provided numerous lead compounds in drug discovery and many of these are also undergoing clinical investigations. A number of medicinal plants either in their crude forms or as isolated compounds have exhibited to reduce the pathological features associated with AD. In this present review, an attempt has been made to elucidate the molecular mode of action of various plant extracts, phytochemicals and traditional herbal formulations investigated against AD as reported in various preclinical and clinical tests. Herbal synergism often found in polyherbal formulations were found effective to combat disease heterogeneity as found in complex pathogenesis of AD. Finally a note has been added to describe biotechnological improvement, genetic and genomic resources and mathematical and statistical techniques for empirical model building associated with anti-AD plant secondary metabolites and their source botanicals. Copyright © 2017 Elsevier Inc. All rights reserved.

Management of psoriasis patients with hepatitis B or hepatitis C virus infection.

PubMed

Bonifati, Claudio; Lora, Viviana; Graceffa, Dario; Nosotti, Lorenzo

2016-07-28

The systemic therapies available for the management of Psoriasis (PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs (cDMARDs) or biological ones (bDMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus (HBV) and hepatitis C virus (HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen (anti-HBsAg), HBsAg, and antibody to HCV (anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a (CyA) or bDMARDs (etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBsAg and transaminases dosing can be monitored every 3 mo. Concerning PsO patients with chronic HCV infection their management with immunosuppressive drugs is less problematic as compared to those infected by HBV. In fact, HCV reactivation is an extremely rare event after administration of drugs such as CyA or tumor necrosis factor-α inhibitors. As a rule, these patients can be monitored measuring HCV RNA load, and ALT, aspartate transaminase, gamma-glutamyl-transferase, bilirubin, alkaline phosphatase, albumin and platelet every 3-6 mo. The present article provides an updated overview based on more recently reported data on monitoring and managing PsO patients who need systemic antipsoriatic treatment and have HBV or HCV infection as comorbidity.

Characteristics and Medication Use of Psoriasis Patients Who May or May Not Qualify for Randomized Controlled Trials.

PubMed

Malatestinic, William; Nordstrom, Beth; Wu, Jashin J; Goldblum, Orin; Solotkin, Kathleen; Lin, Chen-Yen; Kistler, Kristin; Fraeman, Kathy; Johnston, Joseph; Hawley, Lcdr Lesley; Sicignano, Nicholas; Araujo, Andre

2017-03-01

Clinical trials impose exclusion criteria that may limit the generalizability of results. To (a) determine the percentage of real-world patients who would qualify for psoriasis randomized controlled trials; (b) ascertain differences between moderate-to-severe psoriasis patients who would be eligible, ineligible, or potentially eligible for clinical trials; and (c) compare their biologic treatment patterns. Moderate-to-severe psoriasis patients were identified from the U.S. Department of Defense health care database from January 1, 2008, to October 31, 2013. Eligibility classification for psoriasis trials was based on common trial exclusion criteria involving medical conditions and recent treatment history. Patient characteristics and treatment patterns of 4 biologics (adalimumab, etanercept, infliximab, and ustekinumab) were compared between groups. Adherence was measured by medication possession ratio and persistence as continuous time on drug with ≤ 90-day gap between supply times. Among 16,284 qualifying psoriasis patients, 4,677 (28.7%) were medically ineligible, and 8,466 (52.0%) had ineligibility-related treatments that could be stopped prior to trial entry; the latter patients were considered potentially eligible for psoriasis trials. Common reasons for medical ineligibility included malignancies and hematologic disorders; treatment ineligibilities included use of topical corticosteroids and phototherapy. Medically ineligible patients were older and had more comorbidities, while potentially eligible patients were younger and healthier than trial-eligible patients. Most treatment patterns were similar across groups, except that, compared with the trial-eligible group, medically ineligible patients had greater adherence to infliximab and potentially trial-eligible patients had greater adherence and persistence to adalimumab. This large real-world study found that patients who may be ineligible for psoriasis trials differ in important respects (e.g., comorbidities, prior treatments) from their trial-eligible counterparts. Regardless of their differences at baseline, adherence, persistence, and switching of biologic medications are largely similar, with few differences noted among groups. Financial support for this study was provided by Lilly USA. Wu has received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries, and he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries. Malatestinic, Goldblum, Solotkin, Lin, Johnston, and Araujo are employees and/or stock owners of Lilly. Nordstrom, Kistler, and Fraeman are employees of Evidera, which received funding from Lilly to conduct this study. LCDR Hawley is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia, institutional review board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. Study concept and design were contributed by Malatestinic and Araujo, along with the other authors. Nordstrom, Kistler, Fraeman, and Sicignano collected the data, and data interpretation was performed by Wu, Lin, and Hawley, along with Malatestinic, Nordstrom, Solotkin, and Araujo. The manuscript was written by Johnston, Malatestinic, Kistler, Wu, and Araujo, along with Nordstrom, Goldblum, Solotkin, Hawley, and Sicignano, and revised by Goldblum, Solotkin, Malatestinic, and Araujo, along with Nordstrom, Wu, Fraeman, Johnston, Hawley, and Sicignano.

Safety of Systemic Agents for the Treatment of Pediatric Psoriasis.

PubMed

Bronckers, Inge M G J; Seyger, Marieke M B; West, Dennis P; Lara-Corrales, Irene; Tollefson, Megha; Tom, Wynnis L; Hogeling, Marcia; Belazarian, Leah; Zachariae, Claus; Mahé, Emmanuel; Siegfried, Elaine; Philipp, Sandra; Szalai, Zsuzsanna; Vleugels, Ruth Ann; Holland, Kristen; Murphy, Ruth; Baselga, Eulalia; Cordoro, Kelly; Lambert, Jo; Alexopoulos, Alex; Mrowietz, Ulrich; Kievit, Wietske; Paller, Amy S

2017-11-01

Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P < .001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P = .003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis.

Evaluating Evaluation Systems: Policy Levers and Strategies for Studying Implementation of Educator Evaluation. Policy Snapshot

ERIC Educational Resources Information Center

Matlach, Lauren

2015-01-01

Evaluation studies can provide feedback on implementation, support continuous improvement, and increase understanding of evaluation systems' impact on teaching and learning. Despite the importance of educator evaluation studies, states often need support to prioritize and fund them. Successful studies require expertise, time, and a shared…

Educational Evaluation: The State of the Field.

ERIC Educational Resources Information Center

Wolf, Richard M., Ed.

1987-01-01

Educational evaluation is discussed. Topics include: an evaluation framework, educational objectives and study design from a 20-year perspective, a sample study, educational evaluation for local school improvement, decision-oriented evaluation studies, reporting study results, and professional standards for assuring the quality of educational…

42 CFR 456.243 - Content of medical care evaluation studies.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 4 2011-10-01 2011-10-01 false Content of medical care evaluation studies. 456.243... Ur Plan: Medical Care Evaluation Studies § 456.243 Content of medical care evaluation studies. Each medical care evaluation study must— (a) Identify and analyze medical or administrative factors related to...