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Sample records for adalimumab adefovir dipivoxil

  1. An improved reverse dot hybridization for simple and rapid detection of adefovir dipivoxil-resistant hepatitis B virus.

    PubMed

    Hu, Y; Zhang, W L; Xie, S L; Zhao, Y; Hu, J L; Cai, X F; Lai, G Q; Huang, A L

    2012-01-01

    Early detection of adefovir dipivoxil-resistant mutants during long-term treatment of chronic hepatitis B virus (HBV) infection with this drug is of great clinical importance. We developed an improved reverse dot hybridization test for simple and rapid detection of the rtA181V/T and rtN236T mutations associated with adefovir dipivoxil resistance in chronic hepatitis B patients. Probes were designed for genotypes B, C, and D of this resistance characteristic; a total of 70 clinical samples were analyzed with this improved reverse dot hybridization assay. Its usefulness was validated by comparing with sequencing data. Discordant results were confirmed by subclone sequencing. This reverse dot hybridization assay was sufficiently sensitive to detect 10(3) copies/mL; it also detected adefovir dipivoxil-resistant mutant strains when they comprised more than 5% of a mixed virus population. This reverse dot hybridization array correctly identified adefovir dipivoxil-resistant mutants; it had high concordance (98.5%) with direct sequencing data. There was no clear relationship between the HBV genotype and the development of adefovir dipivoxil-resistant mutants. This reverse dot hybridization assay proved to be simple and rapid for detection of rtA181V/T and rtN236T mutations associated with resistance to adefovir dipivoxil. PMID:22290465

  2. Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B

    PubMed Central

    Lee, Yoon-Suk; Kim, Byung-Kook; Lee, Ho-Jae

    2016-01-01

    In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID:27247753

  3. Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B.

    PubMed

    Lee, Yoon-Suk; Kim, Byung-Kook; Lee, Ho-Jae; Dan, Jinmyoung

    2016-06-01

    In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved. PMID:27247753

  4. Structures and physical properties of the cocrystals of adefovir dipivoxil with dicarboxylic acids

    NASA Astrophysics Data System (ADS)

    Jung, Sungyup; Lee, Jonghwi; Kim, Il Won

    2013-06-01

    The cocrystallization of adefovir dipivoxil (AD) with suberic acid (SUB) or succinic acid (SUC) was examined. X-ray diffraction was used to determine the structures of AD/SUB and AD/SUC cocrystals. Both cocrystals were formed via multiple hydrogen bonds between the adenine part of AD and the carboxylic acid groups of SUB or SUC. Longer SUB effectively dispersed AD molecules, and AD hydrogen-bonded only to SUB. When shorter SUC was used, AD formed hydrogen bonding with both SUC and adjacent AD. As a result, the cocrystal compositions were AD/SUB=1:1 and AD/SUC=2:1. Both cocrystals displayed superior thermal stability and increased aqueous solubility. The present study demonstrated that the adenine and similar structures of active pharmaceutical ingredients could be used to produce cocrystals of improved physical properties.

  5. Application of ionic liquid to polymorphic transformation of anti-viral/HIV drug adefovir dipivoxil.

    PubMed

    An, Ji-Hun; Jin, Feng; Kim, Hak Sung; Ryu, Hyung Chul; Kim, Jae Sun; Kim, Hyuk Min; Kiyonga, Alice Nguvoko; Min, Dong Sun; Youn, Wonno; Kim, Ki Hyun; Jung, Kiwon

    2016-05-01

    Ionic liquids (ILs) are defined as salts with a melting point below 100 °C. ILs have received increasing attention as new alternative to organic solvents because of their unique physicochemical properties. Therefore, this study was conducted in the purpose to present the efficacy of ILs as new solvents capable to control the Polymorphic transformation phenomenon. Here, the polymorphic transformation phenomenon of adefovir dipivoxil, an efficient antiviral active pharmaceutical ingredient on human immunodeficiency virus, was investigated. The phase transformation phenomenon from the metastable polymorph, new form (NF) to the stable polymorph, Form-X in 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF4) and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMImBF4) ILs solutions was observed utilizing the solvent-mediated phase transformation method The thermodynamic factors, AEImBF4/BDMImBF4 solvent composition ratio of 3:7-6:4 and the temperature in range of 25-100 °C, as well as the dynamic factor, the rational speed in range of 300-1000 rpm were parameters studied in this experiment. The thermodynamic and dynamic equations involving nucleation and mass transfer were applied for the quantitative analysis. The result of the present study confirmed the use of ILs as substitute solvent for volatile organic solvents, and demonstrated the efficacy of ILs as potential solvent-media to control the polymorphic transformation. PMID:26908332

  6. Experimental and molecular docking studies on DNA binding interaction of adefovir dipivoxil: Advances toward treatment of hepatitis B virus infections

    NASA Astrophysics Data System (ADS)

    Shahabadi, Nahid; Falsafi, Monireh

    The toxic interaction of adefovir dipivoxil with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multi-spectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove binding mode. The binding constant of UV-visible and the number of binding sites were 3.33 ± 0.2 × 104 L mol-1and 0.99, respectively. The fluorimetric studies showed that the reaction between the drug and CT-DNA is exothermic (ΔH = 34.4 kJ mol-1; ΔS = 184.32 J mol-1 K-1). Circular dichroism spectroscopy (CD) was employed to measure the conformational change of CT-DNA in the presence of adefovir dipivoxil, which verified the groove binding mode. Furthermore, the drug induces detectable changes in its viscosity. The molecular modeling results illustrated that adefovir strongly binds to groove of DNA by relative binding energy of docked structure -16.83 kJ mol-1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the toxic interaction of small molecular pollutants and drugs with bio macromolecules, which contributes to clarify the molecular mechanism of toxicity or side effect in vivo.

  7. Mechanism study on stability enhancement of adefovir dipivoxil by cocrystallization: Degradation kinetics and structure-stability correlation.

    PubMed

    Lin, Rui-Zhen; Sun, Peng-Jie; Tao, Qian; Yao, Jia; Chen, Jia-Mei; Lu, Tong-Bu

    2016-03-31

    The purpose of this study is to determine the mechanism by which cocrystallization can enhance the stability of adefovir dipivoxil (AD), a diester prodrug of adefovir with known chemical stability problem. Three multi-component crystals of AD with biologically safe coformers, including gallic acid cocrystal hydrate (1:1:1), salicylate salt (1:1), and maleate salt (1:1) were prepared and characterized by thermal analysis, infrared spectroscopy, powder and single crystal X-ray diffraction. DVS measurements and stability tests were applied to evaluate the stability. The new crystalline phases exhibit improved stability compared to pure drug in the order AD gallic acid cocrystal>AD maleate>AD salicylate>AD form I. Degradation kinetics and structure-stability correlation studies demonstrate that the stability enhancement mechanism by cocrystallization involves (1) inhibition of hydrolysis of AD by replacement of drug-drug homosynthons by stronger drug-coformer heterosynthons at adenine fragments; (2) suppression of dimerization of AD by separation of adenine fragments by inserting coformers in crystal lattices; (3) further reducing rates of hydrolysis by forming hydrogen bonds with hydrate water at phosphoryl fragments. This study has important implications for use of cocrystallization approach to some easily degradable drugs in pharmaceutical. PMID:26462447

  8. Adefovir

    MedlinePlus

    ... experience any of the following symptoms after you stop taking adefovir, call your doctor immediately: extreme tiredness, weakness, nausea, vomiting, loss of appetite, yellowing of the skin or eyes, dark-colored urine, light-colored bowel movements, and muscle or joint pain. ...

  9. Urinary β-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection.

    PubMed

    Takagi, Junko; Morita, Hiroyuki; Ito, Kiyoaki; Ohashi, Tomohiko; Hirase, Sho; Ito, Tatsuo; Morishima, Takkan; Otake, Kazuo; Yoneda, Masashi

    2016-01-01

    Adefovir dipivoxil (ADV) is effective for hepatitis B virus (HBV) infection; however, ADV may provoke renal injury resulting in osteomalacia, and this side effect is seldom recognized until bone fractures emerge. We herein present a 66-year-old woman with HBV infection who received ADV for 6 years. Although she exhibited no sign of bone fractures, her urinary β-2 microglobulin (β2MG) level increased to 83,837 μg/L and scintigraphy revealed minimal fractures of the third rib. ADV was subsequently reduced and her urinary β2MG rapidly fell to 3,637 μg/L. Conversely, her urinary N-acetyl-β-D-glucosaminidase, and serum phosphate, alkaline phosphatase levels did not respond. PMID:27301512

  10. Antiviral Effects of Lamivudine, Emtricitabine, Adefovir Dipivoxil, and Tenofovir Disoproxil Fumarate Administered Orally Alone and in Combination to Woodchucks with Chronic Woodchuck Hepatitis Virus Infection ▿

    PubMed Central

    Menne, Stephan; Butler, Scott D.; George, Andrea L.; Tochkov, Ilia A.; Zhu, Yuao; Xiong, Shelly; Gerin, John L.; Cote, Paul J.; Tennant, Bud C.

    2008-01-01

    Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log10 and 6.1 log10 genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log10 genome equivalents/ml), ADV alone (4.8 log10 genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log10 genome equivalents/ml), TDF alone (2.9 log10 genome equivalents/ml), 3TC alone (2.7 log10 genome equivalents/ml), and FTC alone (2.0 log10 genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection. PMID:18676881

  11. Prevention of de novo hepatitis B with adefovir dipivoxil in recipients of liver grafts from hepatitis B core antibody-positive donors.

    PubMed

    Chang, Matthew S; Olsen, Sonja K; Pichardo, Elsa M; Heese, Scott; Stiles, Jessica B; Abdelmessih, Rita; Verna, Elizabeth C; Guarrera, James V; Emond, Jean C; Brown, Robert S

    2012-07-01

    Lamivudine has been shown to prevent de novo hepatitis B virus (HBV) infections in liver transplantation (LT) patients receiving hepatitis B core antibody-positive (HBcAb(+)) grafts, but it may produce long-term resistance. Adefovir dipivoxil (ADV) might be effective in preventing de novo hepatitis and resistance. A single-center, prospective trial was conducted with 16 adults (10 men and 6 women, mean age = 54 ± 11 years) who underwent LT with HBcAb(+) grafts between September 2007 and October 2009. After LT, patients were given ADV [10 mg daily (adjusted for renal function)]. No hepatitis B immune globulin was administered. At LT, all graft recipients were hepatitis B surface antigen-negative (HBsAg(-)), 38% were surface antibody-positive (HBsAb(+)), and 50% were HBcAb(+). The median follow-up after LT was 1.8 years (range = 1.0-2.6 years). All recipients had undetectable HBV DNA (<40 IU/mL) after LT until the end of follow-up. One recipient (6%) who was HBsAb(-) and HBcAb(-) before LT became HBsAg(+) after 52 weeks. One recipient was switched from ADV to entecavir for chronic renal insufficiency, and 19% of the patients had renal dose adjustments. There was a nonsignificant trend of increasing creatinine levels over time (1.2 mg/dL at LT, 1.3 mg/dL 1 year after LT, and 2.0 mg/dL 2 years after LT, P = 0.27). A comparison with a control cohort of LT recipients with hepatitis C virus who did not receive ADV showed no difference in the creatinine levels at LT or 1 year after LT. In conclusion, ADV prophylaxis prevents HBV replication in recipients of HBcAb(+) livers but does not fully protect recipients from de novo HBV. Long-term follow-up is needed to better determine the risk of de novo infection. PMID:22422699

  12. Optimized combination therapies with adefovir dipivoxil (ADV) and lamivudine, telbivudine, or entecavir may be effective for chronic hepatitis B patients with a suboptimal response to ADV monotherapy

    PubMed Central

    Li, Xiangyong; Jie, Yusheng; You, Xu; Shi, Hong; Zhang, Min; Wu, Yuankai; Lin, Guoli; Li, Xinhua; Gao, Zhiliang; Chong, Yutian

    2015-01-01

    Objective: To identify high risk factors in chronic hepatitis B (CHB) patients for suboptimal response to adefovir dipivoxil (ADV) monotherapy, and to assess the efficacy of optimized therapy combining ADV with lamivudine (LAM), telbivudine (LdT), or entecavir (ETV) in patients with a suboptimal response to ADV alone. Methods: Suboptimal response to ADV monotherapy was defined as having a decline in serum hepatitis B virus (HBV) DNA level of more than 1 log compared to baseline, but with viremia still detectable (HBV DNA ≥ 100 IU/mL), after 48 weeks of therapy. All patients who received ADV monotherapy in our clinic were analyzed retrospectively. Both univariate and multivariate logistic regression models were applied for risk factor analysis. Patients who showed suboptimal response completed at least 12 months of optimized combination therapy consisting of ADV plus LAM, ADV plus LdT, ADV plus ETV, or continuous ADV monotherapy. The primary outcome measurement was complete viral suppression, indicated by a reduction of HBV DNA to undetectable levels (CVS, with HBV DNA < 100 IU/mL). Secondary outcome measures were HBeAg seroconversion for HBeAg-positive patients, HBsAg loss, alanine aminotransferase (ALT) normalization and virological breakthrough rates. Results: Of 521 patients who received ADV monotherapy, 170 showed a suboptimal response. These were grouped for continued therapy as follows: 34 in group A (continuous ADV monotherapy), 55 in group B (ADV plus LAM), 38 in group C (ADV plus LdT), and 43 in group D (ADV plus ETV). Using a logistic model, five conditions were identified as high risk factors for suboptimal response: presence of the tyrosine-methionine-aspartate-aspartate (YMDD) HBV DNA polymerase mutation; being HBeAg positive; having a high baseline level of HBV DNA; having a primary virological non-response to ADV; and [initial virological response] to ADV. After 48 weeks of ADV monotherapy, there were no withdrawn patients who had experienced side

  13. Adefovir

    MedlinePlus

    ... or bruising; yellowing of the skin or eyes; dark-colored urine; light-colored bowel movements; difficulty breathing; stomach pain or swelling; nausea; vomiting; unusual muscle pain; loss of appetite for at least a few days; lack of energy; flu-like symptoms; itching; feeling cold, especially in ...

  14. Adalimumab in psoriatic arthritis.

    PubMed

    Salvarani, Carlo; Pipitone, Nicolò; Catanoso, Mariagrazia; Chiarolanza, Ilaria; Boiardi, Luigi; Caruso, Andrea; Pazzola, Giulia; Macchioni, Pierluigi; Di Lernia, Vito; Albertini, Giuseppe

    2012-07-01

    Open prospective studies and randomized controlled trials (RCT) have shown the short-term efficacy of adalimumab (ADA) in psoriatic arthritis (PsA) and psoriasis. ADA effectively treated all varied musculoskeletal manifestations characteristic of PsA, including peripheral arthritis, spinal disease, enthesitis, and dactylitis. ADA significantly inhibited structural changes on radiographs, lessened disability, and improved quality of life in patients with active PsA. One study showed the efficacy of 24-week ADA therapy on bone marrow edema and erosions, as measured by magnetic resonance imaging. The clinical and radiographic efficacy of ADA demonstrated during short-term treatment was sustained during longterm treatment. ADA was generally well tolerated and its safety profile was similar to that reported in studies of ADA in rheumatoid arthritis. Overall, ADA has a favorable risk-benefit profile in PsA. The combination of ADA and cyclosporine seems to be more effective than ADA monotherapy in patients with active PsA and inadequate response to methotrexate; however, this observation must be confirmed in RCT. PMID:22751600

  15. Development and Validation of a Sensitive LC-MS-MS Method for the Determination of Adefovir in Human Serum and Urine: Application to a Clinical Pharmacokinetic Study.

    PubMed

    Zhang, Ye; Shen, Lu; Zhan, Ying; Xiao, Qing-Qing; Yang, Jin

    2016-04-01

    A rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of adefovir (PMEA,9-(2-phosphonylmethoxyethyl) adenine) concentration in human serum and urine. The analysis was performed on a negative ionization electrospray mass spectrometer via multiple reaction monitoring. The monitored transitions were set at m/z 272.0 → 134.0 and m/z 276.0 → 149.8 for PMEA and internal standard, respectively. After protein precipitation, samples were separated by high-performance liquid chromatography on a reversed-phase Dikma Diamonsil C18 (250 × 4.6 mm; 5 µm) column with a mobile phase of 0.1 mM ammonium formate buffer-methanol. The calibration curves were linear over the serum concentration range 0.5-1,000 ng/mL and urine concentration range 2.0-1,000 ng/mL. The intra- and interday precision values of PMEA in both serum and urine were lower than 18.16% for low quality control and 13.70% for medium and high quality control. The accuracy, recovery, matrix factor and stability were also within the acceptable limits. The developed method was successfully applied to the pharmacokinetic study of following oral administration of single dose of pradefovir mesylate (10, 30, 60, 90 and 120 mg) and adefovir dipivoxil (10 mg) to healthy Chinese volunteers. PMID:26657410

  16. Adalimumab in Patients with Active Noninfectious Uveitis.

    PubMed

    Jaffe, Glenn J; Dick, Andrew D; Brézin, Antoine P; Nguyen, Quan Dong; Thorne, Jennifer E; Kestelyn, Philippe; Barisani-Asenbauer, Talin; Franco, Pablo; Heiligenhaus, Arnd; Scales, David; Chu, David S; Camez, Anne; Kwatra, Nisha V; Song, Alexandra P; Kron, Martina; Tari, Samir; Suhler, Eric B

    2016-09-01

    Background Patients with noninfectious uveitis are at risk for long-term complications of uncontrolled inflammation, as well as for the adverse effects of long-term glucocorticoid therapy. We conducted a trial to assess the efficacy and safety of adalimumab as a glucocorticoid-sparing agent for the treatment of noninfectious uveitis. Methods This multinational phase 3 trial involved adults who had active noninfectious intermediate uveitis, posterior uveitis, or panuveitis despite having received prednisone treatment for 2 or more weeks. Investigators and patients were unaware of the study-group assignments. Patients were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. All patients received a mandatory prednisone burst followed by tapering of prednisone over the course of 15 weeks. The primary efficacy end point was the time to treatment failure occurring at or after week 6. Treatment failure was a multicomponent outcome that was based on assessment of new inflammatory lesions, best corrected visual acuity, anterior chamber cell grade, and vitreous haze grade. Nine ranked secondary efficacy end points were assessed, and adverse events were reported. Results The median time to treatment failure was 24 weeks in the adalimumab group and 13 weeks in the placebo group. Among the 217 patients in the intention-to-treat population, those receiving adalimumab were less likely than those in the placebo group to have treatment failure (hazard ratio, 0.50; 95% confidence interval, 0.36 to 0.70; P<0.001). Outcomes with regard to three secondary end points (change in anterior chamber cell grade, change in vitreous haze grade, and change in best corrected visual acuity) were significantly better in the adalimumab group than in the placebo group. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab (1052.4 vs. 971.7 adverse events

  17. Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir

    PubMed Central

    Park, Hana; Park, Jun Yong; Kim, Seung Up; Kim, Do Young; Han, Kwang-Hyub; Chon, Chae Yoon; Ahn, Sang Hoon

    2013-01-01

    AIM: To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV. METHODS: This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48. RESULTS: The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m2 in the LdT + ADV group increased from 49.1% (26/53) at

  18. Repigmentation of hair following adalimumab therapy.

    PubMed

    Tintle, Suzanne J; Dabade, Tushar S; Kalish, Robert A; Rosmarin, David M

    2015-06-01

    Repigmentation of canities, or age-related grey or white hair, is a rare occurrence. Generalized repigmentation of grey-white hair has been reported following inflammatory processes, and heterochromia (localized patches of hair repigmentation) is even more unusual, reported in association with medication use and malignancy. Tumor necrosis factor (TNF) inhibitors are increasingly utilized medications for inflammatory disorders, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Hair loss, or alopecia, has been described among the side effects of these medications, but changes in hair pigmentation in association with this class of drugs have not previously been reported. We describe a patient with hair repigmentation associated with adalimumab therapy. PMID:26158363

  19. Adalimumab (Humira™) in Ophthalmology: A Review of the Literature

    PubMed Central

    Neri, Piergiorgio; Lettieri, Marta; Fortuna, Cinzia; Zucchi, Manuela; Manoni, Mara; Celani, Silvia; Giovannini, Alfonso

    2010-01-01

    Tumor Necrosis Factor alpha (TNF-α) is a pleiotropic cytokine which plays a primary role in the induction of inflammation in autoimmune diseases. The newest anti-TNF-α agent is adalimumab (Humira, Abbott Pharmaceutical Inc.), a human-derived antibody. This review summarizes the characteristics of adalimumab, highlighting its clinical use in systemic and ocular inflammatory disorders, and the possible therapeutic strategies. Adalimumab has been successfully used for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriasis arthritis. More recently, adalimumab has shown promising qualities in controlling intraocular inflammations, even though this has been used prevalently as a rescue therapy for unresponsive cases. This biologic agent was also used in pediatric cases, showing a good safety and efficacy profile. Albeit no direct comparison with other biologics has been done, and adalimumab seems to be equivalent to the other anti-TNF-α, the switching to adalimumab can offer a better uveitic control. Adalimumab is a promising drug for the treatment of uveitis, even though further studies are needed on its application as a primary therapy in uveitis. PMID:21180427

  20. Three pharmaceuticals cocrystals of adefovir: Syntheses, structures and dissolution study

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaoming; Sun, Fuxing; Zhang, Tingting; Jia, Jiangtao; Su, Hongmin; Wang, Chenhui; Zhu, Guangshan

    2015-11-01

    We report here three novel cocrystals, which are composed of adefovir as the API (Active Pharmaceutical Ingredient) with p-aminobenzoic acid (1, 2C8H12N5O4P·C7H6NO2·3H2O), 3,5-dihydroxybenzoic acid (2, C8H12N5O4P·C7H6O4·H2O) and 2,6-pyridinedicarboxlic acid (3, C8H12N5O4P·C7H5NO4) as CCFs (cocrystal formers) respectively by crystal engineering strategy. Their structures were characterized by single crystal X-ray diffraction, powder X-ray diffraction (PXRD) analysis, thermogravimetric analyses (TGA), elemental analysis (EA) and infrared spectral analysis (IR). The analysis of single crystal X-ray diffraction demonstrate that cocrystal 1 and 2 form a strong hydrogen-bonded assembly through the phosphoric acids of API with water in the lattice and carboxylic acids of CCF respectively. Cocrystal 3 is formed in which the phosphoric acid groups of API are also held by the carboxylic acid groups of CCF. The PXRD results indicate their high purity of as-synthesized samples. The TGA, EA, IR and dissolution study of API and the cocrystals were also measured and discussed.

  1. Humira: the impending patent battles over adalimumab biosimilars.

    PubMed

    Norman, Peter

    2016-05-01

    The world's top selling drug, adalimumab (AbbVie's Humira), generated sales in excess of US$13 billion in 2015. The primary product patent expires in 2016 in the USA and 2018 in Europe. This has resulted in a rush by companies to develop adalimumab biosimilars and Amgen submitted regulatory filings for its product ABP-501 in late 2015 in both the USA and Europe. AbbVie has claimed its patent portfolio provides product protection until 2022, but an increasing number of patent challenges are being made and the filings for approval of biosimilars will see more challenges made over the next few years. PMID:27087201

  2. Adalimumab Treatment in Pediatric-Onset Crohn's Disease Patients after Infliximab Failure: A Single Center Study

    PubMed Central

    Song, Won Jae; Kang, Ben; Choi, So Yoon

    2016-01-01

    Purpose We aimed to investigate the efficacy and safety of adalimumab in pediatric-onset Crohn's disease patients who had failed treatment with infliximab. Methods In this retrospective study, patients included were those who had been diagnosed with Crohn's disease before 18 years old, and had received treatment with adalimumab after infliximab failure. The efficacy of adalimumab treatment was investigated at 1 month and 1 year, and adverse events that had occurred during treatment with adalimumab were explored. Results Ten patients were included in this study. The median duration from diagnosis to adalimumab treatment was 5.5 years (range: 2.4-7.9 years). At 1 month after adalimumab initiation, 80% (8/10) of patients showed clinical response, and 40% (4/10) achieved clinical remission. At 1 year, 71% (5/7) of patients showed clinical response, and 43% (3/7) were under clinical remission. Among the total included patients, 5 patients (50%) showed clinical response at 1 year. Primary non-response to adalimumab was observed in 2 patients (20%), and secondary failure to adalimumab was observed in 3 patients (30%) during 1 year treatment with adalimumab. No serious adverse event had occurred during adalimumab treatment. Conclusion Adalimumab was effective for 1 year without serious adverse events in half of pediatric-onset Crohn's disease patients who had failed treatment with infliximab. PMID:27437188

  3. Refractory dissecting Cellulitis of the Scalp Successfully controlled with Adalimumab.

    PubMed

    Martin-García, Rafael F; Rullán, Jennifer M

    2015-06-01

    Dissecting cellulitis of the scalp (DCS) is an uncommon inflammatory disease that often results in scarring alopecia. Numerous therapies have either proved ineffective or only temporarily effective in the management of this condition. Recent reports show adequate responses to tumor necrosis factor (TNF) inhibitors in cases of DCS. We report a case of severe recalcitrant DCS successfully treated with adalimumab. PMID:26061062

  4. Adalimumab: Another Medication Related to Osteonecrosis of the Jaws?

    PubMed

    Cassoni, Andrea; Romeo, Umberto; Terenzi, Valentina; Della Monaca, Marco; Rajabtork Zadeh, Oriana; Raponi, Ingrid; Fadda, Maria Teresa; Polimeni, Antonella; Valentini, Valentino

    2016-01-01

    Objective. The acronym MRONJ has been created in order to identify "Medication-Related Osteonecrosis of the Jaw," observed after the use of Bisphosphonates, RANK ligand inhibitor, and antiangiogenic medications. Only a case of osteonecrosis of the jaw in a Chron's disease patient following a course of Bisphosphonate and Adalimumab therapy has been recently described, so that it has been supposed that also this medication could promote manifestation of osteonecrosis. Clinical Case. On August, 2014, a 63-year-old female with a history of idiopathic arthritis treated with medical treatment with Adalimumab from 2010 to 2013 presented referring pain in the right mandible. Results. This patient presented with nonexposed osteonecrosis of the jaw after placement, on September, 2010, of four titanium fixtures in the mandible. Conclusions. The authors suggest that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity of the bone. PMID:27088019

  5. Adalimumab: Another Medication Related to Osteonecrosis of the Jaws?

    PubMed Central

    Cassoni, Andrea; Romeo, Umberto; Terenzi, Valentina; Della Monaca, Marco; Rajabtork Zadeh, Oriana; Raponi, Ingrid; Fadda, Maria Teresa; Polimeni, Antonella; Valentini, Valentino

    2016-01-01

    Objective. The acronym MRONJ has been created in order to identify “Medication-Related Osteonecrosis of the Jaw,” observed after the use of Bisphosphonates, RANK ligand inhibitor, and antiangiogenic medications. Only a case of osteonecrosis of the jaw in a Chron's disease patient following a course of Bisphosphonate and Adalimumab therapy has been recently described, so that it has been supposed that also this medication could promote manifestation of osteonecrosis. Clinical Case. On August, 2014, a 63-year-old female with a history of idiopathic arthritis treated with medical treatment with Adalimumab from 2010 to 2013 presented referring pain in the right mandible. Results. This patient presented with nonexposed osteonecrosis of the jaw after placement, on September, 2010, of four titanium fixtures in the mandible. Conclusions. The authors suggest that the biologic therapy with an anti-TNF-α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity of the bone. PMID:27088019

  6. Refractory dissecting cellulitis of the scalp treated with adalimumab.

    PubMed

    Sukhatme, Smita V; Lenzy, Yolanda M; Gottlieb, Alice B

    2008-10-01

    Dissecting cellulitis of the scalp (DCS) is a suppurative, neutrophillic dermatosis. Therapies typically provide short-term improvement and include antibiotics, prednisone, and isotretinoin, as well as radiation, surgical excision, and laser ablation. The authors report the use of the tumor necrosis factor (TNF) blocker, adalimumab, to successfully treat a 39-year-old male with a long-standing history of DCS. PMID:19112766

  7. Acrodermatitis Continua of Hallopeau Successfully Treated with Adalimumab

    PubMed Central

    Anetakis Poulos, Georgann; Wong, Henry K.

    2012-01-01

    Acrodermatitis continua of Hallopeau, first described by Hallopeau in 1890, is an uncommon variant of pustular psoriasis. Acrodermatitis continua of Hallopeau presents as sterile pustules on the hands and feet. It has a relapsing course. Although acrodermatitis continua of Hallopeau is a pustular psoriasis variant, the condition is not easily treated with antipsoriatic medications. In the following case, the authors report a case of acrodermatitis continua of Hallopeau successfully treated with adalimumab. In addition, the cases of acrodermatitis continua of Hallopeau treated with tumor necrosis-alpha inhibitors are summarized. PMID:22468174

  8. Rapid high-performance liquid chromatographic method for determination of adefovir in plasma using UV detection: application to pharmacokinetic studies.

    PubMed

    Foroutan, Seyed Mohsen; Zarghi, Afshin; Shafaati, Alireza; Movahed, Hooman; Khoddam, Arash

    2011-01-01

    A rapid, sensitive and reproducible HPLC method was developed and validated for the analysis of adefovir (CAS 106941-25-7) in human plasma. The separation was achieved on a monolithic silica column (Chromolith Performance RP-18e, 100 x 4.6 mm) using acetonitrile-ammonium dihydrogen phosphate buffer (6:94, v/v), pH 5.2, as the mobile phase at a flow rate of 1.5 ml min(-1). The wavelength was set at 260 nm. The assay enables the measurement of adefovir for therapeutic drug monitoring with a minimum quantification limit of 1 ng ml(-1). The method involves a simple protein precipitation procedure. Analytical recovery was complete. The calibration curve was linear over the concentration range 1-40 ng ml(-1). The coefficients of variation for inter-day and intra-day assay were found to be less than 5%. The method was applied to the determination of adefovir in plasma from 12 subjects dosed with adefovir 2 x 10 mg tablets and pharmacokinetic parameters were evaluated. PMID:21950152

  9. Efficacy of Adalimumab in a Girl with Refractory Intestinal Behcet's Disease

    PubMed Central

    Kaji, Mariko; Kishi, Takayuki; Miyamae, Takako; Nagata, Satoru; Yamanaka, Hisashi; Fujikawa, Satoshi

    2015-01-01

    We describe our experience with a juvenile patient who had refractory intestinal Behcet's disease that responded to adalimumab, a fully humanized antibody against soluble TNF-α and its receptor. The patient, a 13-year-old girl, presented with oral aphthous ulcers, vulvar pain, and rashes on the lower extremities. She gradually developed a low-grade fever, abdominal pain, diarrhea, and hematochezia. Lower gastrointestinal endoscopy revealed ulcers in the terminal ileum, consistent with intestinal Behcet's disease. Methylprednisolone pulse therapy was initiated, after which the symptoms transiently improved, but, during the corticosteroid taper, the abdominal pain recurred. The symptoms resolved soon after the administration of adalimumab. Of importance, the dose of corticosteroids was successfully reduced without exacerbation during 8 months of observation. This is the first reported case in which adalimumab was used for pediatric gastrointestinal Behcet's disease. Adalimumab is a good choice for intestinal Behcet's disease refractory to conventional treatment. PMID:26609459

  10. Adalimumab for the treatment of pediatric Crohn's disease.

    PubMed

    Nuti, Federica; Fiorino, Gionata; Danese, Silvio

    2015-01-01

    Inflammatory bowel diseases are characterized by a chronic relapsing course, high morbidity and impaired quality of life. Their incidence is rising, and about 25% of cases are diagnosed in pediatric age. Anti-TNF-α antibodies, such as infliximab and adalimumab (ADA), are usually administered in patients refractory to conventional therapies. However, increasing evidence suggests that they can be introduced earlier in the course of the disease, especially in patients with aggressive and extensive disease since diagnosis. ADA is a fully human anti-TNF-α antibody recently approved for pediatric Crohn's disease not only in patients unresponsive to infliximab, but also as a first-line anti-TNF-α therapy. In this review, we aim to summarize the current knowledge on the use of ADA in pediatric Crohn's disease and to discuss open issues regarding safety as well as future perspectives. PMID:26211396

  11. Adalimumab induction and maintenance therapy achieve clinical remission and response in Chinese patients with Crohn's disease

    PubMed Central

    Ran, Zhi Hua; Gao, Xiang; Chen, Minhu; Zhong, Jie; Sheng, Jian-Qiu; Kamm, Michael A; Travis, Simon; Wallace, Kori; Mostafa, Nael M; Shapiro, Marisa; Li, Yao; Thakkar, Roopal B; Robinson, Anne M

    2016-01-01

    Background/Aims This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). Methods Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220–450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8–26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI <150), response (decrease in CDAI ≥70 points from baseline), and change from baseline in hs-CRP were assessed through week 26. Nonresponder imputation was used for missing categorical data and last observation carried forward for missing hs-CRP/FC values. No formal hypothesis was tested. Adverse events were monitored. Results Mean adalimumab serum concentrations during the induction phase were 13.9–18.1 µg/mL (160/80 mg group) and 7.5−9.5 µg/mL (80/40 mg group). During the double-blind period, higher remission/response rates and greater reductions from baseline in hs-CRP and FC were observed with adalimumab 160/80 mg compared to that with 80/40 mg. Adverse event rates were similar among all treatment groups. Conclusions Adalimumab serum concentrations in Chinese patients with CD were comparable to those observed previously in Western and Japanese patients. Clinically meaningful remission rates and improvement in inflammatory markers were achieved with both dosing regimens; changes occurred rapidly with adalimumab 160/80 mg induction therapy. No new safety signals were reported. PMID:27175116

  12. Adalimumab and methotrexate is more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6‐month longitudinal, observational, multicentre study

    PubMed Central

    Heiberg, M S; Rødevand, E; Mikkelsen, K; Kaufmann, C; Didriksen, A; Mowinckel, P; Kvien, T K

    2006-01-01

    Objectives To compare the effectiveness of adalimumab monotherapy and adalimumab and methotrexate (MTX) combination therapy in patients with established rheumatoid arthritis. Methods Data from an ongoing longitudinal observational study in Norway were used to compare response to treatment with two different adalimumab regimens (monotherapy, n = 84; combination with MTX, n = 99). Patients were assessed with measures of disease activity, health status and utility scores. Within‐group changes were analysed from baseline to follow‐up at 3 and 6 months and the changes were compared between groups after adjustment for the propensity score. The groups were also compared for the proportions of patients achieving European League Against Rheumatism (EULAR) good response, Disease Activity Score (DAS)28 remission and treatment terminations. Results The improvement from baseline was significant for all measures in the adalimumab and MTX group, but only for DAS28, joint counts, two Short‐form Health Survey with 36 questions (SF‐36) dimensions and patient's and investigator's global assessment in the monotherapy group. All between‐group differences were numerically in favour of combination therapy and significant for C reactive protein, joint counts, DAS28, Modified Health Assessment Questionnaire, investigator's global assessment, four SF‐36 dimensions and Short Form 6D at 6 months. More patients in the combination therapy group reached EULAR good response (p<0.001) and remission (p = 0.07). At 6 months, 80.8% of the patients in the combination therapy group and 59.5% in the monotherapy group remained on treatment (p = 0.002). More withdrawals in the monotherapy group were due to adverse events. Conclusions Our results were consistent across several categories of end points and suggest that adalimumab combined with MTX is effective in patients with rheumatoid arthritis treated in daily clinical practice and is superior to adalimumab monotherapy

  13. Acute liver graft failure due to emergence of lamivudine resistant hepatitis B virus: rapid resolution during treatment with adefovir

    PubMed Central

    Mutimer, D; Feraz-Neto, B; Harrison, R; O'Donnell, K; Shaw, J; Cane, P; Pillay, D

    2001-01-01

    BACKGROUND—Strategies for prevention of liver graft reinfection by hepatitis B virus (HBV) have been developed during recent years. Initially, passive immunoprophylaxis with high titre HBV immunoglobulin (HBIg), followed by lamivudine prophylaxis, and then the combination of lamivudine and HBIg have been employed. However, suboptimal use of the combination may be associated with failure of prophylaxis reflected by the emergence of HBV species with genetic changes that confer resistance to lamivudine and HBIg. Reinfection of the graft by HBV can be associated with rapid development of liver failure.
CASE REPORT—A 43 year old HBV infected man received lamivudine before transplantation, and lamivudine and HBIg after transplantation. Despite prophylaxis, graft reinfection and severe hepatitis were observed. The observed serological evolution and genetic sequencing of the emergent HBV species suggested selection of lamivudine resistant and surface antigen escape mutants consecutively. Adefovir treatment began after the devlopment of graft failure.
OUTCOME—A rapid exponential decline in serum HBV titre was observed. Liver function tests normalised and signs of liver failure resolved.
CONCLUSION—The use of HBIg and lamivudine permits prevention of graft reinfection by HBV for the majority of patients. Adefovir, a potent inhibitor of lamivudine resistant HBV, should be used when failure of prophylaxis is associated with graft hepatitis.


Keywords: hepatitis B virus; adefovir; liver graft; lamivudine PMID:11709523

  14. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial

    PubMed Central

    Sandborn, W J; Hanauer, S B; Rutgeerts, P; Fedorak, R N; Lukas, M; MacIntosh, D G; Panaccione, R; Wolf, D; Kent, J D; Bittle, B; Li, J; Pollack, P F

    2007-01-01

    Background Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial. Objective To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow‐on randomised controlled trial (CLASSIC II). Methods In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open‐label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re‐randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open‐label arm and received adalimumab 40 mg every other week. With non‐response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non‐response or disease flare could switch to open‐label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56. Results Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open‐label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well‐tolerated in all patients. Conclusions Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti‐TNF treatment. PMID:17299059

  15. Water-compatible molecularly imprinted polymer as a sorbent for the selective extraction and purification of adefovir from human serum and urine.

    PubMed

    Pourfarzib, Mojgan; Dinarvand, Rasoul; Akbari-Adergani, Behrouz; Mehramizi, Ali; Rastegar, Hossein; Shekarchi, Maryam

    2015-05-01

    A molecularly imprinted polymer has been synthesized to specifically extract adefovir, an antiviral drug, from serum and urine by dispersive solid-phase extraction before high-performance liquid chromatography with UV analysis. The imprinted polymers were prepared by bulk polymerization by a noncovalent imprinting method that involved the use of adefovir (template molecule) and functional monomer (methacrylic acid) complex prior to polymerization, ethylene glycol dimethacrylate as cross-linker, and chloroform as porogen. Molecular recognition properties, binding capacity, and selectivity of the molecularly imprinted polymers were evaluated and the results show that the obtained polymers have high specific retention and enrichment for adefovir in aqueous medium. The new imprinted polymer was utilized as a molecular sorbent for the separation of adefovir from human serum and urine. The serum and urine extraction of adefovir by the molecularly imprinted polymer followed by high-performance liquid chromatography showed a linear calibration curve in the range of 20-100 μg/L with excellent precisions (2.5 and 2.8% for 50 μg/L), respectively. The limit of detection and limit of quantization were determined in serum (7.62 and 15.1 μg/L), and urine (5.45 and 16 μg/L). The recoveries for serum and urine samples were found to be 88.2-93.5 and 84.3-90.2%, respectively. PMID:25763883

  16. Mycobacterium chelonae infection under adalimumab therapy for spondylarthritis.

    PubMed

    Kluger, N; Cohen, P; Fallet-Bianco, C; Guillevin, L

    2010-01-01

    Tumour necrosis factor (TNF)-alpha antagonists have been prescribed increasingly over the past few years to manage various inflammatory diseases. This widespread use was quickly followed by the heightened frequency of opportunistic mycobacterial infections including environmental non-tuberculous mycobacterial infections (ENTM). We describe a 66-year-old man taking adalimumab for spondyloarthropathy who developed an inflammatory infiltration in his right index finger. A non-necrotising granuloma with epitheloid and giant cells in the dermis and eosinophilic acid-fast bacilli, identified by using Ziehl-Neelsen staining suggested a mycobacterial infection. Cultures for mycobacteria grew positive on Loewenstein-Jensen medium and molecular identification confirmed M. chelonae infection. The outcome was favourable after five months of clarythromycin. In this context of more frequent ENTM infections, chronic non-specific cutaneous lesions of the extremities should evoke systematically cutaneous ENTM infections. Skin biopsy with histological examination and oriented microbiological cultures and molecular identification are mandatory to confirm the diagnosis. PMID:20346249

  17. A Case Report of Majocchi's Granuloma Associated with Combined Therapy of Topical Steroids and Adalimumab

    PubMed Central

    Chou, Wan-Yi; Hsu, Chih-Jung

    2016-01-01

    Abstract Currently, tumor necrosis factor alpha (TNF-alpha) inhibitors are widely used for many autoimmune disorders. However, they cause an immunocompromised status that sometimes leads to many cutaneous side effects including atypical infections. Herein, we report the first case of adalimumab-related Majocchi's granuloma. A 43-year-old Taiwanese male patient with chronic plaque-type psoriasis developed numerous tender nodules 1 month after adalimumab injection. The nodules responded poorly to bacterial folliculitis treatment. After repeated skin biopsies for pathology and tissue fungal culture, Majocchi's granuloma was confirmed. Adalimumab was withheld, and 12 weeks of terbinafine treatment was given. On completion of treatment, the nodular skin lesions and dystrophic nail lesions improved dramatically. The information, including time span, clinical features, histological findings, and improvement following withdrawal of adalimumab and treatment with an oral antifungal agent, indicates that Majocchi's granuloma was adalimumab-related. Psoriasis patients are more susceptible to dermatophyte infection due to local and systemic immunosuppressant therapy. It is important to perform a thorough examination for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment. When atypical presentation together with treatment failure is noted in psoriasis patients prescribed biologics, clinicians should investigate evidence of dermatophyte infection and provide proper treatment. Sometimes, multiple skin biopsies and tissue fungal cultures are required to establish a correct diagnosis. PMID:26765401

  18. Targeted treatment of psoriasis with adalimumab: a critical appraisal based on a systematic review of the literature.

    PubMed

    Schmitt, Jochen; Wozel, Gottfried

    2009-01-01

    Psoriasis is a chronic inflammatory disease affecting 2% to 3% of the population in Western countries. Psoriasis is associated with limited quality of life, cardiovascular disease, and depression. The approval of injectable biological agents has revolutionized the management of moderate to severe psoriasis. Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF) alpha approved for moderate-to-severe plaque-type psoriasis and psoriatic arthritis (PsA). This systematic review summarizes the evidence concerning the efficacy, clinical effectiveness, safety, and cost-effectiveness of adalimumab in the treatment of psoriasis. Five randomized controlled trials demonstrated the efficacy of adalimumab in moderate-to-severe plaque-type psoriasis and PsA with PASI-75 response rates of 53% to 80% and ACR-20 response rates of 39% to 58% after 12 to 16 weeks of treatment. In clinical practice patients who have not responded to one TNF antagonist may respond to another TNF antagonist. Adalimumab has similar or better cost-effectiveness than other biologics, but is less efficient than methotrexate and cyclosporine. Adalimumab is generally well tolerated. Patients should be evaluated for active/latent tuberculosis, serious infections, and other contraindications prior to initiation of adalimumab therapy. Future studies should investigate the comparative efficacy of adalimumab and other biologic and prebiologic agents. Recently established registries will yield additional data on the effectiveness and long-term safety of adalimumab. PMID:19707417

  19. Risk Factor Analysis for the Immunogenicity of Adalimumab Associated with Decreased Clinical Response in Chinese Patients with Psoriasis.

    PubMed

    Chiu, Hsien-Yi; Wang, Ting-Shun; Chan, Chih-Chieh; Lin, Sung-Jan; Tsai, Tsen-Fang

    2015-07-01

    Although anti-drug antibodies against biologics have been associated with decreased clinical efficacy, the immunogenicity of biologics seems to vary between drugs, diseases and ethnicities. This study aims to investigate the predictors for the formation of anti-adalimumab antibodies (AAA) and the clinical consequences of AAA formation. In 53 Chinese psoriatic patients treated with adalimumab, AAA was detected in 50.9%. Differences in Psoriasis Area and Severity Index 75 (PASI75) response rates among patients with and without AAA were significant (44.4% vs. 88.5%; p = 0.001). Patients with AAA had significantly lower trough concentrations of adalimumab than those without AAA. Risk factor analysis showed that treatment interruption, low trough adalimumab concentration, absence of concomitant methotrexate use and biologics switching were associated with a higher AAA titre. The treatment pattern of biologics influences the risk of AAA formation, thereby leading to reduced efficacy of adalimumab. PMID:25673333

  20. Bilateral diaphragmatic paralysis associated with the use of the tumor necrosis factor-alpha inhibitor adalimumab

    PubMed Central

    Martin, Alan William; Rosenblatt, Randall Lee

    2014-01-01

    A 51-year-old woman was referred for evaluation of progressive dyspnea of 3 months— duration. She had received 3 doses of adalimumab for treatment of rheumatoid arthritis prior to the onset of her dyspnea. Her chest examination revealed absent diaphragmatic movement with inspiration. Spirometry showed a severe restrictive defect. Radiologic studies confirmed the diagnosis of bilateral diaphragmatic paralysis. Laboratory and radiologic workup excluded other possible causes of the diagnosis. Adalimumab was discontinued, and she was treated with bilevel positive airway pressure ventilation and intravenous immunoglobulin. Three months later, the diaphragmatic paralysis persisted. This is the second reported case of bilateral diaphragmatic paralysis occurring in a patient who had received adalimumab. Acute neuropathies are rare side effects of tumor necrosis factor-alpha inhibitors. PMID:24688191

  1. Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab)

    PubMed Central

    Tebbey, Paul W; Varga, Amy; Naill, Michael; Clewell, Jerry; Venema, Jaap

    2015-01-01

    Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody (mAb) glycoprotein consisting of 1330 amino acids that is specific for human tumor necrosis factor (TNF). The biological activity and clinical profile of mAb therapeutics, including adalimumab, is influenced by their protein structure and glycosylation patterns, which can be affected by the expression system, cell culture conditions and purification process methodology. While clinical outcome cannot yet be attributed to many of the individual structural features that constitute a mAb, it is evident that detailed structural attribute analysis is necessary if structural contributions to function are to be comprehensively defined. Adalimumab product quality data generated from over a decade of manufacturing across multiple production sites and through a series of manufacturing scale changes are presented here. These data reveal a consistent and tightly controlled profile for the product. PMID:26230301

  2. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion

    PubMed Central

    Oberoi, Raghav; Schuett, Jutta; Schuett, Harald; Koch, Ann-Kathrin; Luchtefeld, Maren

    2016-01-01

    Objective It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab–which is approved for several inflammatory disorders–on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. Methods and Results Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice. Conclusion Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. PMID:27467817

  3. Effectiveness of Adalimumab in Non-radiographic Axial Spondyloarthritis

    PubMed Central

    Cantarini, Luca; Fabbroni, Marta; Talarico, Rosaria; Costa, Luisa; Caso, Francesco; Cuneo, Gian Luca; Frediani, Bruno; Faralli, Gabriele; Vitale, Antonio; Brizi, Maria Giuseppina; Sabadini, Luciano; Galeazzi, Mauro

    2015-01-01

    Abstract The primary aim of the study was to evaluate the long-term effectiveness of adalimumab (ADA) in a cohort of non-radiographic axial spondyloarthritis (nr-axSpA), and the secondary aims were to identify predictive factors of response and evaluate radiological progression. We evaluated 37 patients (male/female: 12/25; mean age 49 ± 14; mean disease duration: 6.3 ± 5.8) with active nr-axSpA (Assessment of SpondyloArthritis International Society criteria), despite the treatment with ≥1 nonsteroidal anti-inflammatory drug for at least 3 months, initiating the treatment with ADA 40 mg every other week. Patients were treated for 24 months, and evaluated at baseline, 6, 12, and 24 months. Outcome measures included Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index. Radiograph of the spine and sacroiliac joints and magnetic resonance of the sacroiliac joints were performed at baseline and according to the standard of assessment for the disease. The proportion of patients that achieved a BASDAI50 response at 6, 12 and 24 months was 51.3%, 70.3%, and 76.8%, respectively. Treatment was well tolerated with no unexpected adverse events and/or serious adverse events. All patients remained on treatment for 2 years, with a good compliance. We did not identify any predictive factor of response to therapy. Moreover, modified Stoke Ankylosing Spondylitis Spine Score and Spondyloarthritis Research Consortium of Canada scores showed a trend of improvement during the study period. ADA was effective on clinical and radiological outcomes at 2-year follow-up; thus, early treatment with ADA may prevent radiographic damage and be associated with low disease activity or remission. Moreover, data from this cohort study have confirmed safety and tolerability profile of ADA in nr-axSpA in the long term. PMID:26222847

  4. Adefovir- or Lamivudine-Induced Renal Tubular Dysfunction after Liver Transplantation.

    PubMed

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2015-09-01

    To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral nucleoside/nucleotide analogs (NUCs); however, proximal renal tubular dysfunction (RTD) that was induced by NUCs in liver recipients was rarely reported. Here, we analyzed RTD and renal impairment (RI) following adefovir (ADV) and lamivudine (LAM) treatment in liver recipients. We retrospectively reviewed medical records of patients treated with HBIG alone (group 1, n = 42) or combined with ADV or LAM (group 2, n = 21) after LT. We compared RTD and RI incidence during the 12 months after LT. An RTD diagnosis required manifestation of at least 3 of the following features: hypophosphatemia, RI, hypouricemia, proteinuria, or glucosuria. No significant differences were observed regarding sex, age, donor type, model of end-stage liver score, and estimated glomerular filtration rate at pre-LT between the 2 groups. Hepatitis B virus recurrence within 12 months was 4.8% in both groups (P = 1.000); however, the RTD incidence was 0% in group 1 and 19.0% in group 2 (P = 0.010). RI occurrence did not differ between the groups. The only risk factor for RI was HBIG administration combined with both LAM and ADV (odds ratio 11.27, 95% confidence interval 1.13-112.07, P = 0.039, vs HBIG alone). RTD occurred more frequently in patients treated with HBIG combined with LAM or ADV compared with HBIG alone. Thus, LAM or ADV therapy can induce RTD after LT, and when administered, liver recipients should be monitored. PMID:26402818

  5. Adefovir- or Lamivudine-Induced Renal Tubular Dysfunction after Liver Transplantation

    PubMed Central

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2015-01-01

    Abstract To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral nucleoside/nucleotide analogs (NUCs); however, proximal renal tubular dysfunction (RTD) that was induced by NUCs in liver recipients was rarely reported. Here, we analyzed RTD and renal impairment (RI) following adefovir (ADV) and lamivudine (LAM) treatment in liver recipients. We retrospectively reviewed medical records of patients treated with HBIG alone (group 1, n = 42) or combined with ADV or LAM (group 2, n = 21) after LT. We compared RTD and RI incidence during the 12 months after LT. An RTD diagnosis required manifestation of at least 3 of the following features: hypophosphatemia, RI, hypouricemia, proteinuria, or glucosuria. No significant differences were observed regarding sex, age, donor type, model of end-stage liver score, and estimated glomerular filtration rate at pre-LT between the 2 groups. Hepatitis B virus recurrence within 12 months was 4.8% in both groups (P = 1.000); however, the RTD incidence was 0% in group 1 and 19.0% in group 2 (P = 0.010). RI occurrence did not differ between the groups. The only risk factor for RI was HBIG administration combined with both LAM and ADV (odds ratio 11.27, 95% confidence interval 1.13–112.07, P = 0.039, vs HBIG alone). RTD occurred more frequently in patients treated with HBIG combined with LAM or ADV compared with HBIG alone. Thus, LAM or ADV therapy can induce RTD after LT, and when administered, liver recipients should be monitored. PMID:26402818

  6. Adalimumab for the treatment of immune-mediated diseases: an update on old and recent indications.

    PubMed

    Murdaca, G; Colombo, B M; Puppo, F

    2011-04-01

    Ongoing progress in understanding the pathogenic mechanisms regulating various immune-mediated and inflammatory diseases, as well as the availability of innovative biotechnological approaches, have lead to the development of new drugs that add to conventional treatments. Among these, tumor necrosis factor (TNF)-α inhibitors such as infliximab, adalimumab, etanercept, golimumab and certolizumab pegol, are now available for clinical use. Adalimumab is a fully recombinant human immunoglobulin G1 monoclonal antibody that specifically binds with high affinity to human TNF-α and inhibits its binding to TNF receptors. Adalimumab was approved by the U.S. FDA in 2002 and was granted approval from the European Medicines Agency in September 2003 for the treatment of moderate to severe rheumatoid arthritis and subsequently for the treatment of ankylosing spondylitis, chronic plaque psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and Crohn's disease. In this paper, we will briefly review the structure and biological effects of TNF-α, the old and recent indications of adalimumab, the pretreatment considerations, the reported adverse events and finally, the recommendations for its use in pregnancy. PMID:21573251

  7. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration

    PubMed Central

    Martínez-Fernández de la Cámara, Cristina; Hernández-Pinto, Alberto M.; Olivares-González, Lorena; Cuevas-Martín, Carmen; Sánchez-Aragó, María; Hervás, David; Salom, David; Cuezva, José M.; de la Rosa, Enrique J.; Millán, José M; Rodrigo, Regina

    2015-01-01

    Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18. Adalimumab reduced photoreceptor cell death, as determined by scoring the number of TUNEL-positive cells. In addition, nuclear poly (ADP) ribose (PAR) content, an indirect measure of PAR polymerase (PARP) activity, was also reduced after treatment. The blockade of TNFα ameliorated reactive gliosis, as visualized by decreased GFAP and IBA1 immunolabelling (Müller cell and microglial markers, respectively) and decreased up-regulation of TNFα gene expression. Adalimumab also improved antioxidant response by restoring total antioxidant capacity and superoxide dismutase activity. Finally, we observed that Adalimumab normalized energetic and metabolic pattern in rd10 mouse retinas. Our study suggests that the TNFα blockade could be a successful therapeutic approach to increase photoreceptor survival during the progression of RP. Further studies are needed to characterize its effect along the progression of the disease. PMID:26170250

  8. Randomized Controlled Trial of Adalimumab in Patients With Nonpsoriatic Peripheral Spondyloarthritis

    PubMed Central

    Mease, Philip; Sieper, Joachim; Van den Bosch, Filip; Rahman, Proton; Karunaratne, P Mahinda; Pangan, Aileen L

    2015-01-01

    Objective To evaluate the efficacy and safety of adalimumab in patients with active nonpsoriatic peripheral spondyloarthritis (SpA). Methods ABILITY-2 is an ongoing phase III, multicenter study of adalimumab treatment. Eligible patients age ≥18 years fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for peripheral SpA, did not have a prior diagnosis of psoriasis, psoriatic arthritis (PsA), or ankylosing spondylitis (AS), and had an inadequate response or intolerance to nonsteroidal antiinflammatory drugs (NSAIDs). Patients were randomized 1:1 to receive adalimumab 40 mg every other week or matching placebo for 12 weeks, followed by a 144-week open-label period. The primary end point was the proportion of patients achieving 40% improvement in disease activity according to the Peripheral SpA Response Criteria (PSpARC40) at week 12. This was defined as ≥40% improvement from baseline (≥20-mm absolute improvement on a visual analog scale) in patient's global assessments of disease activity and pain, and ≥40% improvement in at least one of the following features: swollen joint and tender joint counts, total enthesitis count, or dactylitis count. Adverse events were recorded throughout the study. Results In total, 165 patients were randomized to a treatment group, of whom 81 were randomized to receive placebo and 84 to receive adalimumab. Baseline demographics and disease characteristics were generally similar between the 2 groups. At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups. Conclusion Treatment with adalimumab ameliorated the signs and symptoms of disease and improved physical function in patients with active nonpsoriatic

  9. Adalimumab-Induced Cutaneous Lupus Erythematosus in a 16-Year-Old Girl with Juvenile Idiopathic Arthritis.

    PubMed

    West, Emily S; Nanda, Kabita; Ofodile, Ope; Rutledge, Joe; Brandling-Bennett, Heather A

    2015-01-01

    Tumor necrosis factor α (TNF-α) antagonists are used in the treatment of numerous autoimmune conditions. Adalimumab is the first monoclonal antibody to TNF-α and is used to treat juvenile idiopathic arthritis. A growing body of literature associates anti-TNF-α therapies with several adverse dermatologic manifestations, including drug-induced lupus erythematosus (LE). We describe a case of cutaneous LE in a 16-year-old girl treated with adalimumab for juvenile idiopathic arthritis. The temporal association between her presenting symptoms and adalimumab initiation and gradual improvement after stopping biologic therapy suggest adalimumab-induced cutaneous LE. With increasing use of anti-TNF therapies in children, the potential for drug-induced LE should not be overlooked. PMID:25845414

  10. Safety of Adalimumab and Predictors of Adverse Events in 1693 Japanese Patients with Crohn’s Disease

    PubMed Central

    Watanabe, Mamoru; Matsui, Toshiyuki; Hase, Hidenori; Okayasu, Motohiro; Tsuchiya, Tsuyoshi; Shinmura, Yasuhiko; Hibi, Toshifumi

    2016-01-01

    Background and Aims: Data from an all-cases post-marketing study were used to evaluate the safety and effectiveness of adalimumab in Japanese patients with Crohn’s disease [CD]. Methods: Patients received adalimumab for 24 weeks. Data from all patients [n = 1693] were used for the safety assessment. Data from patients with CD activity index [CDAI] ≥ 150 at baseline were used for the effectiveness assessment. Results: The most frequent serious adverse drug reaction [ADR] was infection and infestations [6.6 events/100 patient-years]. The risk of serious infections increased in patients who had a history of malignancy and those with concomitant corticosteroid use. Of 415 patients who had switched from another anti-tumour necrosis factor alpha [TNFα] agent to adalimumab due to ADRs, 7.2% discontinued due to ADRs to adalimumab. Ten of 13 patients with a history of tuberculosis [TB] received prophylactic medication, and none developed TB. TB developed in one patient with no history of TB or anti-TB prophylaxis. Remission rates were 41.3% and 32.4% at 4 and 24 weeks, respectively. Remission rates did not differ between patients with and without concomitant use of immunomodulators. Predictive variables for increased effectiveness were CDAI ≤ 220 and disease duration of ≤ 2 years. Perianal lesions and loss of response to previous anti-TNFα agents affected effectiveness. Conclusions: The most frequent serious ADR was infection. Adalimumab significantly reduced disease activity, without any unexpected ADRs. Development of active TB during adalimumab therapy can be prevented through TB screening and prophylaxis. In patients who switched from another anti-TNFα agent to adalimumab due to ADRs, adalimumab was well tolerated. PMID:26961546

  11. Asthma-like symptoms in a patient with rheumatoid arthritis and Adalimumab treatment.

    PubMed

    Mărgineanu, Ioana; Crişan, Radu; Mihăescu, Traian

    2015-01-01

    After the introduction of anti-TNFα medication for treatment of autoimmune conditions, clinicians have investigated not only other possible uses for the drugs, but also less common side-effects and interactions with other pathologies. Despite some succes registered with Adalimumab as an antiinflammatory agent in severe asthma, there have been case reports of patients developing asthma or asthma-like symptoms following anti-TNFα therapy. The case presents a patient without previous family or personal history of respiratory or atopic conditions that developed bronchospasm immediately after the initiation of Adalimumab and Methotrexate treatment for rheumatoid arthritis. Despite the patient presenting asthma characteristics (expiratory wheezing, dry cough, partial reversibility at post bronchodilator test) and asthma medication alleviating simtomathology, biological markers (eosenophil granulocytes in sputum, serum IgE) for asthma are absent. The relationship between bronchospasm and medication and other possible causes for her respiratory symptoms are discussed. PMID:27451592

  12. Adalimumab-induced acute interstitial lung disease in a patient with rheumatoid arthritis*

    PubMed Central

    Dias, Olívia Meira; Pereira, Daniel Antunes Silva; Baldi, Bruno Guedes; Costa, André Nathan; Athanazio, Rodrigo Abensur; Kairalla, Ronaldo Adib; Carvalho, Carlos Roberto Ribeiro

    2014-01-01

    The use of immunobiological agents for the treatment of autoimmune diseases is increasing in medical practice. Anti-TNF therapies have been increasingly used in refractory autoimmune diseases, especially rheumatoid arthritis, with promising results. However, the use of such therapies has been associated with an increased risk of developing other autoimmune diseases. In addition, the use of anti-TNF agents can cause pulmonary complications, such as reactivation of mycobacterial and fungal infections, as well as sarcoidosis and other interstitial lung diseases (ILDs). There is evidence of an association between ILD and the use of anti-TNF agents, etanercept and infliximab in particular. Adalimumab is the newest drug in this class, and some authors have suggested that its use might induce or exacerbate preexisting ILDs. In this study, we report the first case of acute ILD secondary to the use of adalimumab in Brazil, in a patient with rheumatoid arthritis and without a history of ILD. PMID:24626274

  13. FDG PET/CT Evidence of Effective Treatment of Cardiac Sarcoidosis With Adalimumab.

    PubMed

    Miller, Christina T; Sweiss, Nadera J; Lu, Yang

    2016-05-01

    A 53-year-old man with mediastinal lymph node biopsy and cardiac MRI-proven cardiac sarcoidosis (CS) received treatment with pacemaker and steroids. FDG PET/CT showed active CS despite treatment with prednisone and methotrexate. Addition of weekly adalimumab (Humira) injections was introduced for 3 months. Follow-up FDG PET/CT showed complete resolution of CS as well as improvement of other sarcoid lesions in the thoracic lymph nodes. PMID:26828145

  14. Serious infection during etanercept, infliximab and adalimumab therapy for rheumatoid arthritis: A literature review.

    PubMed

    Downey, Colum

    2016-06-01

    The purpose of this review is to establish whether there is a significantly increased incidence of serious infections during treatment for rheumatoid arthritis (RA) with etanercept, infliximab or adalimumab, to determine the background risk of serious infection in RA patients without treatment with any biological therapy and to ascertain which organisms are involved in serious infections in RA patients while being treated with etanercept, infliximab or adalimumab. Randomised controlled trials (RCTs), meta-analyses of RCTs, Cochrane reviews, national registry articles and case reports were identified using PubMed/MEDLINE, The Cochrane Library and Google Scholar. The medical subject heading "rheumatoid arthritis" was combined with "serious infection" or "infection" or "adverse drug events" with each of the three reference biological therapies separately: etanercept, infliximab and adalimumab. These electronic searches were limited to human studies, adult studies, those published in the last 10 years (2004-14) and in the English language. Studies which involved the tumor necrosis factor-α inhibitors certolizumab pegol or golimumab were excluded. The background risk of serious infection appears to be approximately two-fold more than non-RA patients before any treatment with biological therapy. The national registries, which may represent the typical RA patient more accurately than clinical trials, suggest a small but significantly increased incidence of serious infection ranging 1.2-2.78 times that of control (treatment with methotrexate). Mycobacteria spp., Staphyloccus aureus, Listeria monocytogenes, Varicella zoster virus and Leishmania species (spp.) repeatedly appear in the case report literature and should be in the mind of the clinician faced with a serious infection in a RA patient with an unknown pathogen who is being treated with either etanercept, infliximab or adalimumab. PMID:26200188

  15. Comparative Effectiveness of Etanercept and Adalimumab in Patient Reported Outcomes and Injection-Related Tolerability

    PubMed Central

    Navarro-Millán, Iris; Herrinton, Lisa J.; Chen, Lang; Harrold, Leslie; Liu, Liyan; Curtis, Jeffrey R.

    2016-01-01

    Objective To describe patient preferences in selecting specific biologics and compare clinical response using patient reported outcomes (PROs) among patients with rheumatoid arthritis (RA) started on different anti-tumor necrosis factor (TNF) therapies. Methods Participants were enrollees in Kaiser Permanente Northern California. Patients with RA who had at least two provider visits and started a new anti-TNF therapy from 10/2010–8/2011, were eligible for participation in this longitudinal study. Using a telephone survey, patient preferences in biologic selection and RAPID3, MDHAQ, and SF-12 scores were collected at baseline and at 6 months. Patient scores rating injection/infusion-site burning and stinging (ISBS) were collected at 6 months. Results In all, 267 patients with RA responded to the baseline survey, of whom 57% preferred an injectable biologic, 22% preferred an infused biologic, and 21% had no preference. Motivation for injectable biologics was convenience (92%) and for infusion therapy was dislike or lack of self-efficacy for self-injection (16%). After 6 months of treatment with anti-TNF, 70% of the 177 patients who answered the ISBS question reported ISBS with the last dose; on a scale of 1 (none) to 10 (worst), 41% of these reported a score of 2–5; and 29% reported a score of 6–10. Adalimumab users experienced 3.2 times (95% confidence interval 1.2–8.6) the level of ISBS that etanercept users experienced. There were no significant differences in RAPID3, MDHAQ, or SF-12 scores between etanercept or adalimumab initiators. Conclusion Convenience and fear of self-injection were important considerations to patients selecting a biologic drug. Although more convenient, adalimumab associated with more ISBS than did etanercept, and this rate was higher than reported in clinical trials. At 6 months, PROs did not differ between etanercept and adalimumab users. PMID:27007811

  16. Management of difficult-to-treat patients with ulcerative colitis: focus on adalimumab

    PubMed Central

    Armuzzi, Alessandro; Pugliese, Daniela; Nardone, Olga Maria; Guidi, Luisa

    2013-01-01

    The treatment of ulcerative colitis has changed over the last decade, with the introduction of biological drugs. This article reviews the currently available therapies for ulcerative colitis and the specific use of these therapies in the management of patients in different settings, particularly the difficult-to-treat patients. The focus of this review is on adalimumab, which has recently obtained approval by the European Medicines Agency and the US Food and Drug Administration, for use in treating adult patients with moderate-to-severe, active ulcerative colitis, who are refractory, intolerant, or who have contraindications to conventional therapy, including corticosteroids and thiopurines. Since the results emerging from the pivotal trials have been subject to some debate, the aim of this review was to summarize all available data on the use of adalimumab in ulcerative colitis, focusing also on a retrospective series of real-life experiences. Taken together, the current evidence indicates that adalimumab is effective for the treatment of patients with different types of ulcerative colitis, including biologically naïve and difficult-to-treat patients. PMID:23630414

  17. Efficacy and Safety of Escalation of Adalimumab Therapy to Weekly Dosing in Pediatric Patients with Crohn's Disease

    PubMed Central

    Rosh, Joel; Faubion, William A.; Kierkus, Jaroslaw; Ruemmele, Frank; Hyams, Jeffrey S.; Eichner, Samantha; Li, Yao; Huang, Bidan; Mostafa, Nael M.; Lazar, Andreas; Thakkar, Roopal B.

    2016-01-01

    Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ≥40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing. Results: Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab. Conclusions: Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing. PMID:26950307

  18. Adalimumab (TNFα Inhibitor) Therapy Exacerbates IgA Glomerulonephritis Acute Renal Injury and Induces Lupus Autoantibodies in a Psoriasis Patient

    PubMed Central

    Wei, S. S.; Sinniah, R.

    2013-01-01

    Adalimumab (Humira) is a tumour necrosis factor α (TNFα) inhibitor that is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, and juvenile idiopathic arthritis (Sullivan and Preda (2009), Klinkhoff (2004), and Medicare Australia). Use of TNFα inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, and sarcoidosis or sarcoid-like granulomas) (Ramos-Casals et al. (2010)). We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab. He has renal biopsy proven IgA nephritis instead. Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure. He made a remarkable recovery after adalimumab cessation and steroid treatment. To our knowledge, this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab. PMID:24558628

  19. Possible macrophage activation syndrome following initiation of adalimumab in a patient with adult-onset Still's disease.

    PubMed

    Souabni, Leila; Dridi, Leila; Ben Abdelghani, Kawther; Kassab, Selma; Chekili, Selma; Laater, Ahmed; Zakraoui, Leith

    2014-01-01

    Macrophage activation syndrome (MAS) has been rarely reported in the course of adult-onset Still's disease (AOSD) and in the majority of cases, it was triggered by an infection. Here, we report, to our knowledge, the first case of MAS occurring after adalimumab treatment initiation and not triggered by an infection. A 26-yearold woman with classical features of AOSD developed persistent fever, severe bicytopenia associated with extreme hyperferritinemia, hyponatremia and abnormal liver function tow months after the initiation of adalimumab treatment. The diagnosis of MAS was made without histological proof. The patient was treated with methylprednisolone pulse therapy and her condition improved. During the disease course, extensive studies could not identify any viral infection or other known underlying etiology for the reactive MAS. The adalimumab was incriminated in this complication. Currently, the patient is in remission on tocilizumab and low-dose prednisolone. PMID:25018831

  20. Successful treatment with adalimumab in a patient with coexisting Behçet's disease and ankylosing spondylitis.

    PubMed

    Yildiz, Necmettin; Alkan, Hakan; Ardic, Fusun; Topuz, Oya

    2010-09-01

    The objective is to report a patient with concomitant ankylosing spondylitis (AS) and Behçet's disease (BD) successfully treated with adalimumab. A 44-year-old male diagnosed as AS applied to our outpatient clinic with complaints of morning stiffness, pain and limitation of motion at spine, concurrence of oral and genital ulcerated lesions. He was on sulfasalazine together with different NSAIDs for the past 1 year. According to the criteria of International Study Group, he was diagnosed as BD. The patient was considered as refractory to current treatment and adalimumab treatment was started. During follow-up, not only AS was in remission, but also no new oral and genital ulcerations appeared. There were no complications related to the use of anti-TNFalpha therapy. In our case it was observed that anti-TNFalpha therapy, specifically adalimumab, was effective for symptoms of both AS and BD. PMID:19705123

  1. Cost effectiveness of adalimumab in the treatment of patients with moderate to severe rheumatoid arthritis in Sweden

    PubMed Central

    Bansback, N; Brennan, A; Ghatnekar, O

    2005-01-01

    Background: Societal decision makers increasingly emphasise their need for evidence based economic analyses to make reimbursement decisions. Objective: To analyse the cost utility of adalimumab, on both incremental cost and incremental quality adjusted life years (QALYs), versus traditional disease modifying antirheumatic drugs and the other tumour necrosis factor (TNF) antagonists suitable for submission to the Swedish LFN (Pharmaceutical Benefit Board). Methods: Swedish unit costs and treatment guidelines from a lifetime perspective were implemented. A mathematical model, incorporating data from seven trials, simulated the experiences of 10 000 hypothetical patients with moderate to severe rheumatoid arthritis (RA). The primary outcome measure—QALYs—was derived from utility values calculated from a relationship between the Health Assessment Questionnaire (HAQ) Disability Index (DI) and Health Utility Index-III (HUI-3) from adalimumab trial results. The model followed the progression of HAQ-DI through a number of treatments in a sequence accounting for mortality, drug and monitoring costs, and other direct costs. Results: When using ACR50 as a response threshold for determining successful treatment, adalimumab plus methotrexate showed the greatest number of QALYs gained (2.3 from one study and 2.1 from the pooled results of two trials). The etanercept plus methotrexate strategy yielded QALY gains similar to the pooled adalimumab results. Except for the infliximab strategy, the costs results were between €35 000 and €42 000, a range normally considered cost effective in other European countries. Conclusion: Adalimumab appears to be cost effective for the treatment of moderate to severe RA. The results suggest that adalimumab is at least as cost effective as other TNF antagonists. PMID:15550533

  2. Effectiveness of adalimumab in treating patients with ankylosing spondylitis associated with enthesitis and peripheral arthritis

    PubMed Central

    2010-01-01

    Introduction The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS). Methods Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20). Results Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both. Conclusions Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS. Trial registration ClinicalTrials.gov NCT00478660. PMID:20230622

  3. Lymphomatoid papulosis in a patient treated with adalimumab for juvenile rheumatoid arthritis.

    PubMed

    Park, Ji-Hye; Lee, Jun; Lee, Jae Hyung; Lee, Dong-Youn; Koh, Eun-Mi

    2012-01-01

    Anti-tumor necrosis factor (TNF) agents are now well regarded as highly effective treatment modalities for multiple immunologically mediated diseases, including rheumatoid arthritis, Crohn's disease and psoriasis. The mechanism of action for this particular class of medications involves the blockade of multiple intracellular signaling pathways originating from TNF-α, ultimately inducing a generalized immunosuppressed state. In fact, several cases of lymphomas have been reported in patients treated with anti-TNF-α agents, though it has been difficult to prove any degree of causality. Herein, we described a patient who developed lymphomatoid papulosis after being treated with adalimumab, whereby a clear causality could be established. PMID:23257839

  4. Dramatic improvement of severe cryptococcosis-induced immune reconstitution syndrome with adalimumab in a renal transplant recipient.

    PubMed

    Scemla, A; Gerber, S; Duquesne, A; Parize, P; Martinez, F; Anglicheau, D; Snanoudj, R; Zuber, M; Bougnoux, M-E; Legendre, C; Lortholary, O

    2015-02-01

    In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report the case of a renal transplant recipient who developed severe cryptococcal meningitis-associated IRIS 1 week after immunosuppression reduction. High-dose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor-α (TNF-α) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation. PMID:25611999

  5. The efficacy of tenofovir-based therapy in patients showing suboptimal response to entecavir-adefovir combination therapy

    PubMed Central

    Kim, Jeong Han; Ahn, Sung Hyun; Ko, Soon Young; Choe, Won Hyeok; Kim, Kyun-Hwan; Kwon, So Young

    2016-01-01

    Background/Aims: Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination. Methods: We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy. Results: The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy. Conclusions: The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases. PMID:27304549

  6. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1)

    PubMed Central

    Sieper, Joachim; van der Heijde, Désirée; Dougados, Maxime; Mease, Philip J; Maksymowych, Walter P; Brown, Matthew A; Arora, Vipin; Pangan, Aileen L

    2013-01-01

    Purpose To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Methods Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index. Results Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases. Conclusions In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit–risk profile

  7. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study

    PubMed Central

    Rudwaleit, M; Rødevand, E; Holck, P; Vanhoof, J; Kron, M; Kary, S; Kupper, H

    2009-01-01

    Objective: To evaluate the effect of adalimumab on the frequency of anterior uveitis (AU) flares in patients with active ankylosing spondylitis (AS). Methods: We determined the history of ophthalmologist-diagnosed AU in 1250 patients with active AS who were enrolled in a multinational, open-label, uncontrolled clinical study of treatment with adalimumab, 40 mg every other week for up to 20 weeks. All AU flares were documented throughout the adalimumab treatment period plus 70 days. We compared the rates of AU flares per 100 patient years (PYs) reported during the year before adalimumab treatment with rates during adalimumab treatment, in total and by patient subgroups. Results: The AU flare rates before adalimumab treatment were 15/100 PYs in all patients (n = 1250), 68.4/100 PYs in 274 patients with a history of AU flares, 176.9/100 PYs in 106 patients with a recent history of AU flares, 192.9/100 PYs in 28 patients with symptomatic AU at baseline and 129.1/100 PYs in 43 patients with a history of chronic uveitis. During adalimumab treatment, the rate of AU flares was reduced by 51% in all patients, by 58% in 274 patients with a history of AU, by 68% in 106 patients with a recent history of AU, by 50% in 28 patients with symptomatic AU at baseline and by 45% in 43 patients with chronic uveitis. AU flares during adalimumab treatment were predominantly mild. Two patients with periods of high AS disease activity had new-onset AU during the treatment period. Conclusions: Results of this prospective open-label study suggest that adalimumab had a substantial preventive effect on AU flares in patients with active AS, including patients with a recent history of AU flares. Clinical trials: ClinicalTrials.gov Identifier: NCT00478660. PMID:18662932

  8. Association of Trabecular Bone Score with Inflammation and Adiposity in Patients with Psoriasis: Effect of Adalimumab Therapy.

    PubMed

    Hernández, José L; López-Mejías, Raquel; Blanco, Ricardo; Pina, Trinitario; Ruiz, Sheila; Sierra, Isabel; Ubilla, Begoña; Mijares, Verónica; González-López, Marcos A; Armesto, Susana; Corrales, Alfonso; Pons, Enar; Fuentevilla, Patricia; González-Vela, Carmen; González-Gay, Miguel Á

    2016-01-01

    Studies on trabecular bone score (TBS) in psoriasis are lacking. We aim to assess the association between TBS and inflammation, metabolic syndrome features, and serum adipokines in 29 nondiabetic patients with psoriasis without arthritis, before and after 6-month adalimumab therapy. For that purpose, adjusted partial correlations and stepwise multivariable linear regression analysis were performed. No correlation was found between TBS and disease severity. TBS was negatively associated with weight, BMI, waist perimeter, fat percentage, and systolic and diastolic blood pressure before and after adalimumab. After 6 months of therapy, a negative correlation between TBS and insulin resistance (p = 0.02) and leptin (p = 0.01) and a positive correlation with adiponectin were found (p = 0.01). The best set of predictors for TBS values at baseline were female sex (p = 0.015), age (p = 0.05), and BMI (p = 0.001). The best set of predictors for TBS following 6 months of biologic therapy were age (p = 0.001), BMI (p < 0.0001), and serum adiponectin levels (p = 0.027). In conclusion, in nondiabetic patients with moderate-to-severe psoriasis, TBS correlates with metabolic syndrome features and inflammation. This association is still present after 6 months of adalimumab therapy. Moreover, serum adiponectin levels seem to be an independent variable related to TBS values, after adalimumab therapy. PMID:27293954

  9. Association of Trabecular Bone Score with Inflammation and Adiposity in Patients with Psoriasis: Effect of Adalimumab Therapy

    PubMed Central

    Hernández, José L.; López-Mejías, Raquel; Blanco, Ricardo; Pina, Trinitario; Ruiz, Sheila; Sierra, Isabel; Ubilla, Begoña; Mijares, Verónica; González-López, Marcos A.; Armesto, Susana; Corrales, Alfonso; Pons, Enar; Fuentevilla, Patricia; González-Vela, Carmen; González-Gay, Miguel Á.

    2016-01-01

    Studies on trabecular bone score (TBS) in psoriasis are lacking. We aim to assess the association between TBS and inflammation, metabolic syndrome features, and serum adipokines in 29 nondiabetic patients with psoriasis without arthritis, before and after 6-month adalimumab therapy. For that purpose, adjusted partial correlations and stepwise multivariable linear regression analysis were performed. No correlation was found between TBS and disease severity. TBS was negatively associated with weight, BMI, waist perimeter, fat percentage, and systolic and diastolic blood pressure before and after adalimumab. After 6 months of therapy, a negative correlation between TBS and insulin resistance (p = 0.02) and leptin (p = 0.01) and a positive correlation with adiponectin were found (p = 0.01). The best set of predictors for TBS values at baseline were female sex (p = 0.015), age (p = 0.05), and BMI (p = 0.001). The best set of predictors for TBS following 6 months of biologic therapy were age (p = 0.001), BMI (p < 0.0001), and serum adiponectin levels (p = 0.027). In conclusion, in nondiabetic patients with moderate-to-severe psoriasis, TBS correlates with metabolic syndrome features and inflammation. This association is still present after 6 months of adalimumab therapy. Moreover, serum adiponectin levels seem to be an independent variable related to TBS values, after adalimumab therapy. PMID:27293954

  10. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-11-01

    Abacavir sulfate/lamivudine, Adalimumab, AdCD40L, Adefovir, Adefovir dipivoxil, Ambrisentan, Amlodipine, Amlodipine besylate/olmesartan medoxomil, AN-2728, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride, Atrasentan, Azacitidine, Bevacizumab, Blinatumomab, Bortezomib, Bosentan, Carfilzomib, Caspofungin acetate, Cediranib, Cetuximab, Choriogonadotropin alfa, Clevudine, Clindamycin phosphate/benzoyl peroxide, Clofarabine, Daidzeol, Darunavir, Dasatinib, Decitabine, Deferasirox, Deforolimus, Degarelix acetate, Denenicokin, Dexlansoprazole, Duloxetine hydrochloride, Elacytarabine, Enfuvirtide, Enoxaparin, Entecavir, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Ezetimibe/simvastatin, Forodesine hydrochloride, Fosamprenavir calcium, Gefitinib, Gemtuzumab ozogamicin, Golimumab, Imatinib mesylate, Imetelstat, Insulin gl'argine, Insulin glulisine, Interferon alfa-2b XL, Ivabradine hydrochloride, Lacosamide, Lenalidomide, Lintuzumab, Liposomal adriamycin, Liposomal belotecan, Liposome-encapsulated fentanyl, Lopinavir/ritonavir, Lutropin alfa, LY-207320, Maraviroc, Mecasermin, MKC-253, MP-470, NGR-TNF, Nilotinib hydrochloride monohydrate, Ofatumumab, Olmesartan medoxomil, Omacetaxine mepesuccinate, PAN-811, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perospirone hydrochloride, PF-734200, Phentermine/topiramate, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Pregabalin, Raltegravir potassium, Ramelteon, Ranibizumab, Recombinant Bet V1, Recombinant human insulin, Regadenoson, rhITF, Romidepsin, Rosuvastatin calcium, Ruboxistaurin hydrochloride, Rufinamide, Sapropterin dihydrochloride Saracatinib, SB-73, SC-599, Seliciclib, Sirolimus-eluting stent, Sorafenib, Sunitinib malate, Tadalafil, Tanespimycin, Tapentadol hydrochloride, Tegaserod maleate, Telbivudine, Tenofovir

  11. Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis

    PubMed Central

    Strand, Vibeke; van Vollenhoven, Ronald F.; Lee, Eun Bong; Fleischmann, Roy; Zwillich, Samuel H.; Gruben, David; Koncz, Tamas; Wilkinson, Bethanie

    2016-01-01

    Objective. To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX. Methods. In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep). Results. At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab. Conclusion. Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo. PMID:26929445

  12. Tenofovir disoproxil fumarate is superior to lamivudine plus adefovir in lamivudine-resistant chronic hepatitis B patients

    PubMed Central

    Yang, Dan-Hong; Xie, Yuan-Jun; Zhao, Nian-Feng; Pan, Hong-Ying; Li, Ming-Wei; Huang, Hai-Jun

    2015-01-01

    AIM: To assess the efficacy of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM)-resistant patients with a suboptimal response to LAM plus adefovir (ADV). METHODS: We retrospectively analyzed the efficacy of switching to tenofovir disoproxil fumarate in suboptimal responders to lamivudine plus adefovir. Charts were reviewed for LAM-resistant chronic hepatitis B (CHB) patients who visited the Zhejiang Province People’s Hospital and The First Affiliated Hospital, College of Medicine, Zhejiang University, from June 2009 to May 2013. Patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM plus ADV combination therapy were included. Patients with a suboptimal response to LAM plus ADV were randomized to switch to TDF monotherapy (300 mg/d orally; TDF group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally; LAM plus ADV group) and were followed for 48 wk. Serum HBV DNA was determined at baseline and weeks 4, 12, 24, 36, and 48. HBV serological markers and biochemistry were assessed at baseline and weeks 12, 24, and 48. Resistance surveillance and side effects were monitored during therapy. RESULTS: Fifty-nine patient were randomized to switch to TDF (n = 28) or continuation with LAM plus ADV (n = 31). No significant differences were found between the groups at baseline. Prior to TDF therapy, all patients had been exposed to LAM plus ADV for a median of 11 mo (range: 6-24 mo). No difference was seen in baseline serum HBV DNA between the two groups [5.13 ± 1.08 log10 copies/mL (TDF) vs 5.04 ± 31.16 log10 copies/mL (LAM + ADV), P = 0.639]. There was no significant difference in the rates of achieving complete virological response (CVR) at week 4 between the TDF and LAM + ADV groups (17.86% vs 6.45%, P = 0.24). The rate of achieving CVR in the TDF and LAM plus ADV groups was 75% vs 16.13% at week 12, 82.14% vs 22.58% at week 24, 89.29% vs 25.81% at week 36, and 96.43% vs 29.03% at week 48, respectively

  13. Long-Term Clinical Remission in Biologically Naïve Crohn's Disease Patients with Adalimumab Therapy, Including Analyses of Switch from Adalimumab to Infliximab

    PubMed Central

    Mizoshita, Tsutomu; Tanida, Satoshi; Ozeki, Keiji; Katano, Takahito; Shimura, Takaya; Mori, Yoshinori; Kubota, Eiji; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

    2016-01-01

    There is little evidence regarding the maintenance of long-term clinical remission by adalimumab (ADA) therapy in Crohn's disease (CD) patients naïve to anti-tumor necrosis factor treatment (naïve CD patients), since most CD patients are treated with ADA after infliximab (IFX) therapy. The long-term clinical response to ADA was retrospectively analyzed in 17 naïve CD patients for at least 24 months, and the serum trough IFX levels were evaluated in patients switching from ADA to IFX. Of the 17 naïve CD patients, 14 (82.4%) maintained long-term clinical remission with ADA therapy for at least 24 months, without serious adverse events. The clinical condition of 7 patients was observed for more than 36 months, and 3, 1, 1, and 2 cases maintained remission at months 42, 48, 54, and 60 after ADA therapy, respectively. Three patients (17.6%) switched from ADA to IFX less than 24 months after the start of ADA therapy, and they had remission, retaining trough levels of IFX higher than 1 μg/ml, occasionally by dose escalation. In conclusion, maintenance ADA therapy achieves long-term clinical remission in naïve CD patients. Switching from ADA to IFX is an important therapeutic option in CD patients showing loss of response to ADA, occasionally with dose escalation, based on the analysis of serum IFX trough levels.

  14. Adalimumab Injection

    MedlinePlus

    ... scales on the skin), chronic plaque psoriasis (a skin disease in which red, scaly patches form on some ... as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this ...

  15. Adalimumab Injection

    MedlinePlus

    ... attacks its own joints, causing pain, swelling, and loss of function), juvenile idiopathic arthritis (JIA; a condition ... body attacks its own joints, causing pain, swelling, loss of function, and delays in growth and development), ...

  16. Development of a Universal Anti-Adalimumab Antibody Standard for Interlaboratory Harmonization

    PubMed Central

    Vande Casteele, Niels; Poppe, Raf; Van de Wouwer, Marlies; Compernolle, Griet; Peeters, Miet; Brouwers, Els; Vermeire, Séverine; Geukens, Nick; Declerck, Paul J.

    2014-01-01

    Background: Therapeutic drug monitoring of adalimumab (ADM) has been introduced recently. When no detectable ADM serum concentrations can be found, the formation of antidrug antibodies (ADA) should be investigated. A variety of assays to measure the occurrence of ADA have been developed. Results are expressed as arbitrary units or as a titration value. The aim was to develop a monoclonal antibody (MA) that could serve as a universal calibrator to quantify the amount of ADA in ADM-treated patients. Methods: Hybridoma technology was used to generate a MA toward ADM. The functionality of the MA was tested in a bridging enzyme linked immunosorbent assay (ELISA) setup and in a cell-based assay. Sera from 25 anti–tumor necrosis factor naive patients with inflammatory bowel disease were used to determine the cutoff values. Sera from 9 ADM-treated patients with inflammatory bowel disease, with undetectable serum concentrations of ADM were used to quantify the ADA response. Results: In this study, MA-ADM6A10, an IgG1 that can be used as a calibrator in both an ELISA to quantify the amount of binding antibodies and in a cell-based assay to quantify the amount of neutralizing antibodies, was generated. Combining the results of both assays showed that the sera with high concentrations of anti-ADM binding antibodies also had the highest neutralizing capacity. Conclusions: The availability of a universal calibrator could facilitate the interlaboratory harmonization of antibody titers in patients who develop anti-adalimumab antibodies. PMID:24906181

  17. Cimicifuga foetida L. plus adefovir effectively inhibits the replication of hepatitis B virus in patients with chronic hepatitis B

    PubMed Central

    DAI, XIUFANG; YI, XIANFU; SUN, ZEQUN; RUAN, PENG

    2016-01-01

    The aim of the present study was to assess the anti-hepatitis B virus (HBV) effect of Cimicifuga foetida L. (C. foetida) in the patients with chronic hepatitis B (CHB). A total of 60 randomly selected patients with CHB were recruited and divided into groups I and II. The patients in group I received a monotherapy of adefovir (ADV), and the patients in group II received a combination therapy of ADV and C. foetida for >48 weeks. Intrahepatic (IH) HBV covalently closed circular DNA (cccDNA), serum HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase levels and serum interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) levels were quantified during the test. Following the treatment, a significant reduction of the median IH cccDNA level was identified in group II (P=0.017), but not in group I (P=0.05, and P=0.01 between the 2 groups), and a significant reduction of log10 HBsAg was identified in groups I (P=0.012) and II (P<0.0001, and P=0.20 between the 2 groups). A significant increase of the median serum IFN-γ level was found in group II (P=0.0005), but not in group I (P=0.06, and P=0.004 between the 2 groups), and a significant reduction of the median TGF-β level was identified in groups I (P<0.0001) and II (P<0.0001, and P=0.002 between the 2 groups). A total of 24 patients in group I, and 27 patients in group II achieved a sustained virological response (P=0.0386), and 20 patients in group I and 24 in group II achieved hepatitis B e antigen seroclearance (P=0.0442). In conclusion, C. foetida can effectively inhibit HBV transcription and replication in the patients by stimulating the release of the inflammatory cytokines, such as IFN-γ. PMID:27073640

  18. An extraordinary form of the Melkersson-Rosenthal syndrome successfully treated with the tumour necrosis factor-α blocker adalimumab

    PubMed Central

    Stein, Juergen; Paulke, Alexander; Schacher, Beate; Noehte, Matthias

    2014-01-01

    Melkersson-Rosenthal syndrome (MRS) is a rare granulomatous inflammatory disease characterised by the triad of orofacial oedema, facial nerve palsy and furrowed tongue. We describe the case of a 29-year-old patient suffering from an oligosymptomatic form of the disease with orofacial oedema, cobblestone pattern on the buccal mucosa and swelling of the tongue, accompanied by intermittent fatigue, influenza-like symptoms, intermittent tinnitus and acute hearing loss. An increase of several autoimmune-associated antibodies was also detected. Treatment with prednisolone, azathioprine or methotrexate failed to adequately control all symptoms in the long term. In the absence of a specific and well-established therapy for MRS, treatment with adalimumab was administered. Under adalimumab, total remission of all symptoms was achieved, indicating that tumour necrosis factor-α blockers are a promising therapeutic option for patients with Melkersson-Rosenthal syndrome. PMID:24827666

  19. Cholestatic Liver Disease after Rituximab and Adalimumab and the Possible Role of Cross-Reacting Antibodies to Fab 2 Fragments

    PubMed Central

    Koetter, Ina; Schwab, Matthias; Fritz, Peter; Kimmel, Martin; Alscher, M. Dominik; Braun, Niko

    2013-01-01

    Background Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. Methods Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. Results Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients’ sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. Conclusion This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug

  20. Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study

    PubMed Central

    Ortea, Ignacio; Roschitzki, Bernd; López-Rodríguez, Rosario; Tomero, Eva G.; Ovalles, Juan G.; López-Longo, Javier; de la Torre, Inmaculada; González-Alvaro, Isidoro; Gómez-Reino, Juan J.; González, Antonio

    2016-01-01

    Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (rs = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (rs = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they

  1. Contribution of renal and non-renal clearance on increased total clearance of adalimumab in glomerular disease.

    PubMed

    Roberts, Brittney V; Susano, Isidro; Gipson, Debbie S; Trachtman, Howard; Joy, Melanie S

    2013-09-01

    The contribution of renal and non-renal clearance toward targeted concentrations and/or effects of therapeutic proteins in nephrotic patients are unknown. This study dissected the contribution of clearance pathways to adalimumab elimination in patients with focal segmental glomerulosclerosis (FSGS). Urine was collected from seven patients treated with adalimumab. Renal clearance (ClR ) was measured and non-renal clearance (ClNR ) was calculated as the difference between total clearance and ClR . Differences in cumulative amount in urine, ClR, and ClNR between study weeks 1 and 16 and relationships between proteinuria (protein:creatinine ratio (Up/c)), and ClR and ClNR were evaluated. Up to 13% of the adalimumab dose was lost in urine. ClNR contributed more than ClR to enhanced total clearance. There was a nonlinear relationship between Up/c and ClR (R(2) 0.7059); an increase in ClR beginning at Up/c of 12 mg/mg [slope 1.755, (C.I. -7.825 to 11.34)]. There was a linear relationship between Up/c and ClNR (R(2) 0.5039); for every one unit increase in Up/c, ClNR would increase by 3.5 mL/hr (P = 0.01). Both ClR and ClNR contribute to enhanced total clearance of adalimumab in glomerular disease secondary to FSGS. Additional research is needed to identify mechanisms for the increased ClNR pathways. PMID:23813330

  2. Retinal Function and Morphology in the Rabbit Eye after Intravitreal Injection of the TNF Alpha Inhibitor Adalimumab

    PubMed Central

    Ghosh, Fredrik; Andréasson, Sten; Ponjavic, Vesna

    2014-01-01

    Aim To study the effects of the tumor necrosis factor alpha inhibitor adalimumab on rabbit retina after injection into the vitreous body. Methods Forty-eight rabbits of mixed strain (9–12 months old, weighing ≈ 3.5 kg) were randomized into four groups. Adalimumab was injected at one of two concentrations (1.25 mg or 2.5 mg) into the eyes of two groups, and balanced salt solution into the eyes of the third group. The fourth group acted as controls. Full-field electroretinography (ffERG) was performed before injection and 1 and 6 weeks post-injection. At 6 weeks post-injection the rabbits were euthanized and the sectioned retinas were studied. Retinal histology was studied with hematoxylin–eosin staining. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells. Results No significant difference in ffERG amplitudes or implicit times was observed between the four groups at any time point. Histological and immunohistochemical findings were similar in all groups. Conclusions Injection of adalimumab into the vitreous body of healthy rabbits, at doses up to 2.5 mg, does not appear to be toxic to the rabbit retina. PMID:24897597

  3. Refractory polymyalgia rheumatica as presenting manifestation of large-vessel vasculitis associated to sarcoidosis. Successful response to adalimumab.

    PubMed

    Bejerano, Carmen; Blanco, Ricardo; González-Vela, Carmen; Agüero, Ramón; Carril, José M; González-Gay, Miguel A

    2012-01-01

    Sarcoidosis may present with musculoskeletal features or mimic rheumatic diseases. We report on a patient who had been initially diagnosed as having polymyalgia rheumatica. Because of refractory disease associated to atypical features such as severe inflammatory low back pain, dull and achy pain in the thighs, claudication of the lower limbs and bad response to corticosteroids and methotrexate (MTX), an 18F-fluorodeoxyglucosepositron emission tomography with CT (FDG PET/CT) was performed. This technique disclosed data suggestive of arteritis of large vessels involving the ascending, arch and descending aorta as well as high FDG uptake in the femoral and posterior tibial arteries of both lower extremities. Also, increased FDG uptake was observed in the right paratracheal, retrotracheal, subcarinal, gastrohepatic ligament, coeliac and right renal hilar lymph nodes. Four lymph nodes, taken during mediastinoscopy, confirmed a diagnosis of sarcoidosis. Treatment with adalimumab (40 mg every 2 weeks subcutaneously) along with prednisone and MTX was initiated yielding progressive improvement of symptoms and normalisation of laboratory abnormalities. Five months after the onset of adalimumab a new FDG PET/CT showed complete absence of uptake of lymph nodes as well as decrease of vascular FDG uptake. To our knowledge, this is the first patient treated with adalimumab because of a large-vessel vasculitis in the setting of sarcoidosis refractory to conventional therapy. This case reinforces the claim that sarcoidosis should be considered a diagnostic challenge in the assessment of patients presenting with inflammatory musculoskeletal symptoms. PMID:22410180

  4. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial

    PubMed Central

    Schiff, Michael; Weinblatt, Michael E; Valente, Robert; van der Heijde, Désirée; Citera, Gustavo; Elegbe, Ayanbola; Maldonado, Michael; Fleischmann, Roy

    2014-01-01

    Objectives To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA). Methods AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX. Results Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results. The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%). Conclusions Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes. Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept. ClinicalTrials.gov Identifier NCT00929864. PMID:23962455

  5. Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study

    PubMed Central

    Takeuchi, Tsutomu; Yamanaka, Hisashi; Ishiguro, Naoki; Miyasaka, Nobuyuki; Mukai, Masaya; Matsubara, Tsukasa; Uchida, Shoji; Akama, Hideto; Kupper, Hartmut; Arora, Vipin; Tanaka, Yoshiya

    2014-01-01

    Objectives To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics. Methods This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6–8 mg every week versus MTX 6–8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26. Results A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed. Conclusions Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity. PMID:23316080

  6. Generation and characterization of a unique panel of anti-adalimumab specific antibodies and their application in therapeutic drug monitoring assays.

    PubMed

    Bian, Sumin; Stappen, Thomas Van; Baert, Filip; Compernolle, Griet; Brouwers, Els; Tops, Sophie; Vries, Annick de; Rispens, Theo; Lammertyn, Jeroen; Vermeire, Séverine; Gils, Ann

    2016-06-01

    A number of assays are currently available to support therapeutic drug monitoring of adalimumab. A complete characterization of the assays and comparison of different assays has not been performed. The aim of this study, therefore, is to generate and characterize of a panel of monoclonal antibodies towards adalimumab (MA-ADM); to use this panel to develop novel assays to determine adalimumab concentrations; to assess the impact of tumor necrosis factor (TNF) and (non-)neutralizing antibodies on adalimumab detection and to compare the performance of assays. In total, ten specific MA-ADM were generated of which four revealed a neutralizing potency of >78%. At least six different clusters were identified using principal component analysis. MA-ADM40D8 was selected as detecting antibody to determine adalimumab in the TNF-coated ELISA (A) and the MA-ADM28B8/MA-ADM40D8 antibody pair was chosen for use in the MA-coated ELISA (B). The impact of TNF and (non-) neutralizing antibodies was similar in both ELISAs. Finally, serum samples of adalimumab-treated Crohn's disease patients were collected and used for an external validation using the assay of Sanquin (C) and the apDia kit (D). All adalimumab assays showed excellent Pearson correlation: r=0.96 for A versus B, 0.96 for A versus C, 0.94 for A versus D, 0.97 for B versus C, 0.95 for B versus D and 0.94 for C and D. The excellent agreement with the two commercially available ELISAs allows harmonization of treatment algorithms in and between different hospitals/infusion centers. PMID:27003121

  7. A prospective, randomised, placebo-controlled study to identify biomarkers associated with active treatment in psoriatic arthritis: effects of adalimumab treatment on synovial tissue

    PubMed Central

    van Kuijk, A W R; Gerlag, D M; Vos, K; Wolbink, G; de Groot, M; de Rie, M A; Zwinderman, A H; Dijkmans, B A C; Tak, P P

    2009-01-01

    Objective: To determine which of the changes in synovial tissue correlates best with clinical response associated with effective therapy (adalimumab) to facilitate the planning of future studies with therapeutic agents for psoriatic arthritis (PsA). Methods: A total of 24 patients with active PsA were randomised to receive adalimumab (n = 12) or placebo (n = 12) for 4 weeks. Synovial biopsies were obtained before and after 4 weeks of treatment. Immunohistochemical analysis was performed to characterise the cell infiltrate, expression of cytokines and matrix metalloproteinases (MMPs) and vascularity. Sections were analysed by digital image analysis. Statistical analysis was performed using covariance analysis. Results: The mean Disease Activity Score in 28 joints (DAS28) after 4 weeks was 1.92 units lower (95% confidence interval (CI) 1.07 to 2.77) after adalimumab therapy compared with placebo. Paired pretreatment and post-treatment synovial samples were available from 19 patients. Many cell types were reduced after adalimumab treatment compared to placebo. After applying a ranked analysis of covariance (ANCOVA) model to correct for baseline imbalances, a significant effect of treatment was observed on CD3-positive cells: there was a median reduction of 248 cells/mm2 after adalimumab versus placebo treatment (p = 0.035). In addition, the expression of MMP13 was significantly reduced after active treatment: the integrated optical density (IOD)/mm2 was 18 190 lower after adalimumab treatment as compared to placebo (p = 0.033). Conclusion: Adalimumab therapy in PsA is associated with a marked reduction in T cell infiltration and MMP13 expression in synovial tissue, suggesting that these parameters could be used as biomarkers that are sensitive to change after active treatment in small proof of concept studies in PsA. PMID:18647851

  8. Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial

    PubMed Central

    Ishiguro, Naoki; Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Mukai, Masaya; Matsubara, Tsukasa; Uchida, Shoji; Akama, Hideto; Kupper, Hartmut; Arora, Vipin; Tanaka, Yoshiya

    2014-01-01

    Objective. The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity. Methods. Patients completing the 26-week, randomized, placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX. Patients were assessed for mean change from baseline in the 28-joint DAS with ESR (DAS28-ESR) and modified total Sharp score (mTSS), and for the proportions of patients achieving clinical, functional or radiographic remission. Results. Of 333 patients assessed, 278 (137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups) completed the 52-week study. Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX. Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups, but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks (mean ΔmTSS at week 52 = 2.56 vs 3.30, P < 0.001). Conclusion. Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab. However, the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies, suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy. Trial registration. ClinicalTrials.gov (http://clinicaltrials.gov/), NCT00870467. PMID:24441150

  9. Drug-induced lupus with leukocytoclastic vasculitis: a rare expression associated with adalimumab*

    PubMed Central

    Amarante, Carolina Forte; Acedo, Livia Mendes Sabia; Rabay, Fátima Maria de Oliveira; Campos, Benedito do Espírito Santo; Lira, Márcia Lanzoni de Alvarenga; Mandelbaum, Samuel Henrique

    2015-01-01

    TNF alpha antagonist-induced lupus-like syndrome is a rare condition which predominantly affects women (4:1). The average age of onset is 46-51 years. It occurs after exposure to TNF alpha antagonist and disappears after discontinuation of such agents. The pathogenic mechanism for development of the TNF alpha antagonist-induced lupus-like syndrome is not fully defined. It is believed that the medication induces apoptosis, leading to an accumulation of nucleosomal antigens of apoptotic cells. This would cause autoantibodies to be produced by susceptible individuals. The most common cutaneous manifestations include maculopapular exanthem, malar rash, alopecia, photosensitivity and, more rarely, vasculitis. Extracutaneous manifestations include: fever, weight loss, arthritis or arthralgia, myositis and hematological abnormalities. Antinuclear antibody may be positive in 80% of cases and anti-histone antibody is considered a disease marker for TNF alpha antagonist-induced lupus-like syndrome. Treatment corresponds to drug discontinuation. We report a rare case of sub-acute cutaneous lupus erythematosus with leukocytoclastic vasculitis induced by adalimumab in a 42-year-old patient. PMID:26312693

  10. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example

    PubMed Central

    Lai, Zhihong; La Noce, Anna

    2016-01-01

    The global development of a biosimilar product is a methodologically complex affair, lined with potential design pitfalls and operational missteps to be avoided. Without careful attention to experimental design and meticulous execution, a development programme may fail to demonstrate equivalence, as would be anticipated for a biosimilar product, and not receive regulatory approval based on current guidance. In order to demonstrate similarity of a biosimilar product versus the originator (ie, the branded product), based on regulatory guidance, a stepwise approach is usually taken, starting with a comprehensive structural and functional characterisation of the new biological moiety. Given the sequential nature of the review process, the extent and nature of the non-clinical in vivo studies and the clinical studies to be performed depend on the level of evidence obtained in these previous step(s). A clinical efficacy trial is often required to further demonstrate biosimilarity of the two products (biosimilar vs branded) in terms of comparative safety and effectiveness. Owing to the focus on demonstrating biosimilarity and not safety and efficacy de novo, designing an adequate phase III (potentially pivotal) clinical efficacy study of a biosimilar may present some unique challenges. Using adalimumab as an example, we highlight design elements that may deserve special attention. PMID:26870392

  11. Allergic bronchopulmonary aspergillosis in a patient with rheumatoid arthritis under adalimumab therapy: a case report.

    PubMed

    Kawasaki, Tatsuya; Kamiya, Mari; Nakagawa, Atsushi; Takagiwa, Jun; Kawahara, Yutaka; Nonomura, Yoshinori

    2016-01-01

      A 77-year-old woman with a 15-year history of rheumatoid arthritis (RA) was admitted to our hospital because of a wet cough that persisted for 1 month. The patient had been taking methotrexate (MTX) and adalimumab (ADA) for the past 3 years, and disease activity of RA was low. Discontinuation of ADA and MTX and treatment with oral levofloxacin were not effective. On admission, laboratory examinations showed eosinophilia (2539/μL), elevated serum total immunoglobulin E (538.0 IU/ml) and Aspergillus-specific immunoglobulin E levels, and Aspergillus fumigatus serum precipitins. A chest radiograph revealed multiple bilateral pulmonary shadows, and computed tomography revealed multiple consolidations. Bronchoscopic examination showed mucous plugs. Pathological examination revealed diffuse infiltration of eosinophils and fungus in the plugs. These findings led to the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). A combination of prednisolone (0.5 mg/kg/day) and itraconazole (200 mg/day) was administered. After 3 months, the pulmonary consolidations resolved. To our knowledge, this is the first report of ABPA in a patient with RA treated with ADA. If patients treated with biologic disease-modifying antirheumatic drugs present with eosinophilia and pulmonary consolidations, clinicians should consider ABPA in the differential diagnosis. PMID:27181240

  12. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example.

    PubMed

    Lai, Zhihong; La Noce, Anna

    2016-01-01

    The global development of a biosimilar product is a methodologically complex affair, lined with potential design pitfalls and operational missteps to be avoided. Without careful attention to experimental design and meticulous execution, a development programme may fail to demonstrate equivalence, as would be anticipated for a biosimilar product, and not receive regulatory approval based on current guidance. In order to demonstrate similarity of a biosimilar product versus the originator (ie, the branded product), based on regulatory guidance, a stepwise approach is usually taken, starting with a comprehensive structural and functional characterisation of the new biological moiety. Given the sequential nature of the review process, the extent and nature of the non-clinical in vivo studies and the clinical studies to be performed depend on the level of evidence obtained in these previous step(s). A clinical efficacy trial is often required to further demonstrate biosimilarity of the two products (biosimilar vs branded) in terms of comparative safety and effectiveness. Owing to the focus on demonstrating biosimilarity and not safety and efficacy de novo, designing an adequate phase III (potentially pivotal) clinical efficacy study of a biosimilar may present some unique challenges. Using adalimumab as an example, we highlight design elements that may deserve special attention. PMID:26870392

  13. Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial

    PubMed Central

    Sokolove, Jeremy; Schiff, Michael; Fleischmann, Roy; Weinblatt, Michael E; Connolly, Sean E; Johnsen, Alyssa; Zhu, Jin; Maldonado, Michael A; Patel, Salil; Robinson, William H

    2016-01-01

    Objectives To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study. Methods In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1–Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates. Results Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1–Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group. Conclusions In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab. Trial registration number NCT00929864. PMID:26359449

  14. Phase 1 Trial of Adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) Study Group

    PubMed Central

    Joy, Melanie S.; Gipson, Debbie S.; Powell, Leslie; MacHardy, Jacqueline; Jennette, J. Charles; Vento, Suzanne; Pan, Cynthia; Savin, Virginia; Eddy, Allison; Fogo, Agnes B.; Kopp, Jeffrey B.; Cattran, Daniel; Trachtman, Howard

    2009-01-01

    Background Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end stage kidney disease. Antifibrotic agents, such as tumor necrosis factor α (TNF-α) antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data. Study Design Phase I clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to TNF-α. Setting and Participants Ten patients (4 male and 6 female), age 16.8±9.0 yr, and estimated GFR 105±50 mL/min/1.73 m2, were studied as out-patients Intervention Adalimumab, 24 mg/m2 every 14 days for 16 weeks (total 9 doses) Outcomes Pharmacokinetic assessment, tolerability, and safety Measurements Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state Results Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P<0.001) and clearance was increased by 160% (P<0.01) in patients with resistant FSGS compared to healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria declined by ≥50% in 4 of 10 treated patients. Limitations Insufficient power to assess safety or efficacy of adalimumab therapy for patients with resistant FSGS Conclusions Pharmacokinetic assessment demonstrated increased clearance of adalimumab in patients with resistant primary FSGS and validated the need for evaluating the disposition of novel therapies in this disease to define appropriate dosing regimens. The study provides a rationale to evaluate efficacy of adalimumab as an antifibrotic agent for resistant FSGS in Phase II/III clinical trials. PMID:19932542

  15. An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo

    PubMed Central

    Yu, Feifan; Gudmundsdotter, Lindvi; Akal, Anastassja; Gunneriusson, Elin; Frejd, Fredrik; Nygren, Per-Åke

    2014-01-01

    In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor α (sIL-6Rα) and IL-6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, ZIL-6_13 with an affinity (KD) for IL-6 of ∼500 pM, showed the best performance. To construct fusion proteins (“AffiMabs”) with dual cytokine specificities, ZIL-6_13 was fused to either the N- or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira®). One AffiMab construct with ZIL-6_13 positioned at the N-terminus of the heavy chain, denoted ZIL-6_13-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the ZIL-6_13-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit. PMID:25484067

  16. Follow-up of phase I trial of adalimumab and rosiglitazone in FSGS: III. Report of the FONT study group

    PubMed Central

    2010-01-01

    Background Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V. Antifibrotic agents may slow or halt this process. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Methods 21 patients -- 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m2 -- received adalimumab (n = 10), 24 mg/m2 every 14 days or rosiglitazone (n = 11), 3 mg/m2 per day for 16 weeks. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. Results 19 patients completed the 16-week FONT treatment phase. The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). Conclusion Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments. PMID:20113498

  17. [Neurologic appearence of Behçet disease in 14-year old boy treated with adalimumab with good result].

    PubMed

    Iwańczak, Barbara; Reich, Adam; Kofla-Dłubacz, Anna; Kazanowska, Bernarda; Ruczka, Małgorzata

    2016-02-01

    Behçet disease is a multiorgan inflammatory vessel disorder of unknown etiology which only occasionally occurs in children. Here, we demonstrate a 14-year-old boy with Behçet disease diagnosed based on recurrent aphthous stomatitis, acneiform facial lesions, subpreputial erosions and extensive thrombosis involving sigmoid sinus, transverse sinus and right internal cervical vein. Treatment with low molecular weight heparins, systemic corticosteroids, and azathioprine only resulted in partial remission of clinical symptoms. Addition of adalimumab led to complete resolution of clinical and biochemical abnormalities and disappearance of thrombosis in central nervous system. PMID:27000816

  18. The use of adalimumab, etanercept, golimumab and infliximab in rheumatic pathologies: variation between label dosage and real-world use.

    PubMed

    Martinez-Cutillas, Julio; Alerany-Pardo, Carme; Borrás-Blasco, Joaquín; Broto-Sumalla, Antonio; Burgos-SanJosé, Amparo; Climent-Bolta, Consuelo; Escudero-Vilaplana, Vicente; Fernández-Fuente, María Anunciación; Ferrit-Martin, Mónica; Gómez-Germá, Pilar; Martínez-Sesmero, José Manuel; Mayorga-Pérez, Jesús; Menchén-Viso, Belén; Merino-Alonso, Javier; Polache-Vengud, Josefa; Sánchez-Guerrero, Amelia

    2015-01-01

    Rheumatoid arthritis (AR), psoriatic arthritis (PSA) and ankylosing spondylitis (AS) are autoimmune systemic diseases characterized by inflammation, pain and joint degeneration. The objective of this study is to evaluate, under the actual conditions of use, dosing patterns of adalimumab, etanercept, golimumab and infliximab in these pathologies, and compare them with the label regimens recommended, as well as evaluating the financial implications of these regimen modifications. The study population included all adult patients diagnosed with RA, PSA or AS who had been treated with adalimumab, etanercept, golimumab and infliximab for at least 6 months between 1 January 2011 and 31 December 2013. The main variable of this study was to assess the dose dispensed for drugs administered subcutaneously and the dose prepared/administered for drugs administered intravenously, and the annual costs of the treatment. A total of 5,428 episodes were included. The mean weekly dose was lower than the standard dose in the three pathologies studied in the patients treated with adalimumab and etanercept (84.3% vs 81.2% for RA, 85.0% vs 78.0% for PSA and 87.8% vs 81.6% for AS). The drugs with highest dose optimization in RA are etanercept (46.3%) followed by adalimumab (46%); however, the highest percentage of patients with major dose optimization corresponds to etanercept (11.6%). Both in the PA and the AS group, we also observed that etanercept is the drug more optimized, corresponding to 53.9 and 43% of patients, respectively. By contrast, 48.5% of patients with RA treated with infliximab required dose intensification; however, infliximab dose intensification in PSA and AS is not so pronounced. The practice of optimization of dose regimens in patients with rheumatic diseases under treatment with anti-TNFα is spreading among professionals, resulting in annual cost reduction in the treatment of rheumatic arthropathies. However, long term follow-up will be necessary to assess the

  19. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

    PubMed Central

    van de Putte, L B A; Atkins, C; Malaise, M; Sany, J; Russell, A; van Riel, P L C M; Settas, L; Bijlsma, J; Todesco, S; Dougados, M; Nash, P; Emery, P; Walter, N; Kaul, M; Fischkoff, S; Kupper, H

    2004-01-01

    Objective: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. Methods: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was ≥20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). Results: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p⩽0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p⩽0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p⩽0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p⩽0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (–0.29, –0.39, –0.38, –0.49 v –0.07; p⩽0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p⩽0.05). Conclusion: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated. PMID:15082480

  20. Diffuse Autoimmune Enteropathy and Colopathy in an Adult Patient Successfully Treated With Adalimumab and a Review of the Literature.

    PubMed

    Hasan, Syed Shafae; Siddiqui, Nauman Saleem; Chaitanya Arudra, Sri Krishna; de Las Casas, Luis; Akpunonu, Basil; Nawras, Ali

    2016-01-01

    Autoimmune enteropathy (AIE) is a rare disease that causes intractable diarrhea not responsive to a gluten free diet and must be distinguished from refractory sprue. It is associated with circulating autoantibodies against goblet cells and enterocytes. AIE mainly involves the small intestines, with very few cases reported in adults. Because of the paucity of cases, the epidemiology of the disease remains unclear, and treatment is based on the cases found in the literature. Of the 35 adult cases reported, only 4 involved the colon. Because of the low number of cases, there have been no clear recommendations on treatment modalities with most reports heavily emphasizing steroids as the mainstay of treatment. We present the case of adult female patient who developed postpartum AIE and colopathy with profuse diarrhea successfully treated with adalimumab and a review of the literature. To the best of our knowledge, this case is only the fourth case of a tumor necrosis factor alpha antagonist being used in the treatment of AIE and the first case of adalimumab being used. PMID:25379737

  1. Cost-effectiveness of adalimumab, infliximab or vedolizumab as first-line biological therapy in moderate-to-severe ulcerative colitis

    PubMed Central

    Yokomizo, Lauren; Limketkai, Berkeley; Park, K T

    2016-01-01

    Background There are no head-to-head randomised controlled trials (RCTs) comparing the effectiveness of biologics in ulcerative colitis (UC). We aimed to assess the cost-effectiveness of adalimumab, infliximab and vedolizumab as first-line agents to induce clinical remission and mucosal healing (MH) in UC. Methods We constructed a decision tree based on a payer's perspective in the USA to estimate the first year costs of adalimumab, infliximab or vedolizumab to achieve clinical remission and MH in patients with moderate-to-severe UC. Transition probabilities were derived from ACT, ULTRA and GEMINI RCT data. Costs were derived from Medicare reimbursement rates and wholesale drug prices. Results Assuming a biological-naïve cohort, infliximab 5 mg/kg every 8 weeks was more cost-effective ($99 171 per MH achieved) than adalimumab 40 mg every other week ($316 378 per MH achieved) and vedolizumab every 8 weeks ($301 969 per MH achieved) at 1 year. Non-drug administration cost of infliximab exceeding $1974 per infusion would make adalimumab more cost-effective. First-line UC therapy with vedolizumab would be cost-effective if the drug acquisition price was <$2537 for each 300 mg administration during the 1-year time horizon. Conclusions If non-drug costs of infliximab administration are not excessive (<$2000), infliximab is the most cost-effective first-line biologic for moderate-to-severe UC. Exceeding this threshold infusion-related cost would make adalimumab the more cost-effective therapy. Considering its drug costs in the USA, vedolizumab appears to be appropriately used as a second-line biologic after antitumour necrosis factor failure. PMID:27195130

  2. Molecular diagnosis of opportunistic pericardial infection in a patient treated with adalimumab: the role of next-generation sequencing.

    PubMed

    Poli, Stefano; Comar, Manola; Luzzati, Roberto; Sinagra, Gianfranco

    2016-01-01

    Biological immune-modulator drugs, especially inhibitors of tumor necrosis factor-α, are frequently encountered in modern clinical practice and opportunistic infections are therefore a common concern. Infective pericarditis has been described as a complication of these treatments with possible life-threatening consequences. In similar cases cultures may isolate multiple opportunistic bacteria from the pericardial fluid without specific identification of the responsible germ, representing a problem for targeted antibiotic therapy. We present a case of acute pericarditis evolving in pericardial constriction and cardiac tamponade in a patient treated with adalimumab for psoriatic arthritis overlapping with recurrent polychondritis. Next-generation sequencing allowed the identification of a common oral pathogen as the aetiological agent confirming its role in the identification of species that can be overlooked by common microbiological techniques. PMID:27571913

  3. Role of adalimumab in the management of children and adolescents with juvenile idiopathic arthritis and other rheumatic conditions

    PubMed Central

    Marzan, Katherine Anne B

    2012-01-01

    Treatment of children and adolescents with juvenile idiopathic arthritis and other pediatric rheumatic diseases has evolved. Where once there was only a limited arsenal of medications, with significant side effects and inadequate efficacy, today, with an increased understanding of the pathogenesis of these diseases, there is a wider variety of more targeted and effective treatments. TNF-α is a cytokine involved in a number of inflammatory pathways in pediatric rheumatic diseases. The emergence of biologic modifiers that target TNF-α has been pivotal in providing the ability to deliver early and aggressive treatment. Adalimumab, a recombinant monoclonal antibody to TNF-α, is an important therapeutic option, which affords children and adolescents with chronic illnesses an improved quality of life. PMID:24600289

  4. Henoch-Schönlein Purpura with Adalimumab Therapy for Ulcerative Colitis: A Case Report and Review of the Literature.

    PubMed

    LaConti, Joseph J; Donet, Jean A; Cho-Vega, Jeong Hee; Sussman, Daniel A; Ascherman, Dana; Deshpande, Amar R

    2016-01-01

    Tumor necrosis factor-α (TNFα) inhibitor therapy has signified an important milestone in the fight against many rheumatological disorders and inflammatory bowel disease (IBD). Cutaneous adverse events caused by this class of medications are well known but relatively uncommon. Most reactions are mild and rarely warrant treatment withdrawal. Henoch-Schönlein purpura (HSP) is a disease with cutaneous vasculitis, arthritis, and gastrointestinal and renal involvement that is usually seen in children, though the worst complications are typically seen in adults. We present a case of HSP complicating adalimumab treatment in a patient with ulcerative colitis who had achieved endoscopic remission. We review similar cases reported in the literature and discuss the consequences of these autoimmune diseases. PMID:27529048

  5. Henoch-Schönlein Purpura with Adalimumab Therapy for Ulcerative Colitis: A Case Report and Review of the Literature

    PubMed Central

    Donet, Jean A.; Cho-Vega, Jeong Hee; Sussman, Daniel A.; Deshpande, Amar R.

    2016-01-01

    Tumor necrosis factor-α (TNFα) inhibitor therapy has signified an important milestone in the fight against many rheumatological disorders and inflammatory bowel disease (IBD). Cutaneous adverse events caused by this class of medications are well known but relatively uncommon. Most reactions are mild and rarely warrant treatment withdrawal. Henoch-Schönlein purpura (HSP) is a disease with cutaneous vasculitis, arthritis, and gastrointestinal and renal involvement that is usually seen in children, though the worst complications are typically seen in adults. We present a case of HSP complicating adalimumab treatment in a patient with ulcerative colitis who had achieved endoscopic remission. We review similar cases reported in the literature and discuss the consequences of these autoimmune diseases. PMID:27529048

  6. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2002-11-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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, adalimumab, adefovir dipivoxil, AdGVVEGF121.10, anastrozole, anecortave acetate, aripiprazole, asulacrine isethionate, atazanavir, ATL-962, 16-Aza-epothilone B; Bevacizumab, bicalutamide, blonanserin, BMS-188667, bosentan; Celecoxib, celmoleukin, cetuximab, cilomilast, cinacalcet hydrochloride, CNTF(Ax15), colesevelam hydrochloride; Daclizumab, delavirdine mesilate, desogestrel, desoxyepothilone B, dexmethylphenidate hydrochloride, duloxetine hydrochloride; Ecogramostim, emtricitabine, epalrestat, escitalopram oxalate, examorelin, exendin-4, ezetimibe; Fidarestat, frovatriptan; HIV-1 Immunogen; Iloperidone, insulin detemir, insulin lispro, irinotecan hydrochloride; Keratinocyte growth factor; Lasofoxifene tartrate, levetiracetam, levormeloxifene, levosimendan, lumiracoxib, LY-307161 SR; Memantine hydrochloride, MEN-10755, metformin hydrochloride, metreleptin, motexafin gadolinium; Naratriptan hydrochloride, natalizumab, nesiritide, nicotine, NN-2211, NN-414; Olanzapine, omalizumab; Pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant, pimecrolimus, pirfenidone, pramlintide acetate prasterone, pregabalin; Quetiapine fumarate; Rabeprazole sodium, raloxifene hydrochloride, raltitrexed, rDNA insulin, rFGF-2, risedronate sodium, rofecoxib, roflumilast, rosiglitazone maleate; SN-22995; Tacrolimus, tadalafil, tegaserod maleate, tiotropium bromide, tomoxetine hydrochloride, trastuzumab, trimegestone; Voglibose, Voriconazole; Ziprasidone hydrochloride. PMID:12616707

  7. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-12-01

    [Methoxy-(11)C]PD-153035, 2-Methoxyestradiol; Adalimumab, Adecatumumab, Adefovir dipivoxil, ADH-1, ADX-10059, Aflibercept, AIR-human growth hormone, Aliskiren fumarate, AMG-221, Amlodipine besylate/olmesartan medoxomil, Aprepitant; Bavituximab, Bevacizumab, Bexarotene, BIBW-2992, BMS-690514, Bortezomib, Bosentan, Briakinumab; Capecitabine, Certolizumab pegol, Cetuximab, Cholecalciferol, Choline fenofibrate, Chorionic gonadotropin (human), Cixutumumab, Clopidogrel, CP-690550 citrate; Dabigatran, Dacetuzumab, Daclizumab, Dapagliflozin, Darbepoetin alfa, Dasatinib, Denosumab; Efavirenz, Elisidepsin, Enoxaparin, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Everolimus, Exenatide; Fenobam, Figitumumab, Filibuvir, Fondaparinux sodium, Fresolimumab; Gefitinib, Golimumab, Golnerminogene pradenovec; Ifosfamide, Imatinib mesylate, Ipilimumab, Ivabradine hydrochloride, Ixabepilone; Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liposomal vincristine, Liraglutide; M-118, Masitinib mesylate, Metformin hydrochloride, Micafungin sodium, Moxifloxacin hydrochloride; Neratinib; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil; Paclitaxel nanoparticles, Palifosfamide lysine, Panobacumab, Panobinostat, Patupilone, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Piclozotan hydrochloride hydrate, Pixantrone maleate, Prasterone, Prasugrel, Prednisone, Progesterone, Prucalopride, pVGI.1 (VEGF-2); Retigabine, rhFSH, Rituximab, Rivaroxaban, Rosuvastatin calcium; Salinosporamide A, Selumetinib, Sipuleucel-T, Somatropin, Sorafenib, SSR-244738, Sunitinib malate; Tamoxifen citrate, Teduglutide, Telavancin hydrochloride, Telmisartan, Telmisartan/amlodipine, Telmisartan/hydrochlorothiazide, Temsirolimus, Tenofovir disoproxil fumarate, Tipifarnib, Tolvaptan, Trastuzumab, Trastuzumab-MCC-DM1, Travoprost, Tremelimumab; Valsartan/amlodipine besylate, Valsartan/amlodipine besylate/hydrochlorothiazide, Valsartan/hydrochlorothiazide, Vandetanib

  8. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2007-11-01

    1-Octanol, 9vPnC-MnCc; Abiraterone acetate, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Aliskiren fumarate, Aminolevulinic acid hexyl ester, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, Aripiprazole, ARRY-520, AS-1404, Asimadoline, Atazanavir sulfate, AVE-0277, Azelnidipine; Bevacizumab, Bimatoprost, Boceprevir, Bortezomib, Bosentan, Botulinum toxin type B; Certolizumab pegol, Cetuximab, Clevudine, Contusugene ladenovec, CP-751871, Crofelemer, Cypher, CYT006-AngQb; Darbepoetin alfa, Desmopressin, Dexlansoprazole, DG-041; E-5555, Ecogramostim, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Falecalcitriol, Fampridine, Fesoterodine fumarate, Fingolimod hydrochloride; Gefitinib, Ghrelin (human), GS-7904L, GV-1001; HT-1001; Insulin detemir, ISIS-112989, Istradefylline; Laquinimod sodium, Latanoprost/timolol maleate, Lenalidomide, Levobetaxolol hydrochloride, Liposomal doxorubicin, Liposomal morphine sulfate, Lubiprostone, Lumiracoxib, LY-518674; MEM-1003, Mesna disulfide, Mipomersen sodium, MM-093, Mycophenolic acid sodium salt; Naptumomab estafenatox, Natalizumab; Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide; Paclitaxel nanoparticles, Paclitaxel poliglumex, Pasireotide, Pazufloxacin mesilate, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimagedine, Pimecrolimus, Pramlintide acetate, Prasterone, Pregabalin, Prulifloxacin; QAE-397; Rec-15/2615, RFB4(dsFv)-PE38, rhGAD65, Roflumilast, Romiplostim, Rosuvastatin calcium, Rotigotine, Rupatadine fumarate; Safinamide mesilate, SIR-Spheres, Sitagliptin phosphate, Sodium phenylacetate, Sodium phenylacetate/Sodium benzoate, Sorafenib, SSR-244738; Taribavirin hydrochloride, Taxus, Teduglutide, Tegaserod maleate, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Trabectedin, Travoprost

  9. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2007-09-01

    12B75, 274150; Abacavir sulfate/lamivudine, Abatacept, Ad2/HIF-1alpha, Adalimumab, Adefovir, Adefovir dipivoxil, AGN-201904-Z, AIDSVAX, Albinterferon alfa-2b, Alemtuzumab, Aliskiren fumarate, Alvimopan hydrate, Amlodipine besylate/atorvastatin calcium, Amlodipine besylate/Olmesartan medoxomil, Ammonium tetrathiomolybdate, Amodiaquine, Apaziquone, Aprepitant, Arsenic trioxide, Artesunate/Amodiaquine, Ascorbic acid, Atazanavir sulfate, Atazanavir/ritonavir, Atomoxetine hydrochloride, Atrigel-Leuprolide, Axitinib; Bevacizumab, Binodenoson, Bortezomib, Bovine lactoferrin; Calcipotriol/betamethasone dipropionate, Carisbamate, Certolizumab pegol, Ciclesonide, Conivaptan hydrochloride, CP-690550, CP-751871, Cypher; Dapivirine, Darbepoetin alfa, Darunavir, Dasatinib, del-1 Genemedicine, Denosumab, Desloratadine, Dexlansoprazole, DiabeCell, Drospirenone/ethinylestradiol, DTaP-HepB-IPV, Duloxetine hydrochloride, Dutasteride; Eculizumab, Eldecalcitol, Eletriptan, Emtricitabine, Entecavir, Eritoran tetrasodium, Ertapenem sodium, Escitalopram oxalate, Eslicarbazepine acetate, Esomeprazole magnesium, Estradiol acetate, Eszopiclone, ETEC vaccine, Etoricoxib, Exenatide, Ezetimibe; Fluticasone furoate, Fosmidomycin, Fosmidomycin/clindamycin; Glutamine; Heat Shock Protein 10, Hepatitis B hyperimmunoglobulin, HIV vaccine, Hochuekki-to, Human Albumin, Human papillomavirus vaccine; Immune globulin subcutaneous [human], IMP-321, Interferon omega, ISIS-301012, Istaroxime; Japanese encephalitis virus vaccine; Latanoprost/timolol maleate, Lenalidomide, Linaclotide acetate, Lumiracoxib, LY-517717; Malaria vaccine, MAS-063D, Meningitis B vaccine, Mepolizumab, Methylnaltrexone bromide, Micafungin sodium, MK-0822A, Morphine glucuronide, Morphine hydrochloride, Mycophenolic acid sodium salt; Natalizumab, Nesiritide, Norelgestromin/ethinyl estradiol, NT-201; Oblimersen sodium, Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide, Omalizumab, Otamixaban; Paclitaxel nanoparticles

  10. Cost-effectiveness comparison of lamivudine plus adefovir combination treatment and nucleos(t)ide analog monotherapies in Chinese chronic hepatitis B patients

    PubMed Central

    Zhang, Chi; Ke, Weixia; Liu, Li; Gao, Yanhui; Yao, Zhenjiang; Ye, Xiaohua; Zhou, Shudong; Yang, Yi

    2016-01-01

    Background/aim Lamivudine (LAM) plus adefovir (ADV) combination therapy is clinically efficacious for treating chronic hepatitis B (CHB) patients in China, but no pharmacoeconomic evaluations of this strategy are available. The aim of this study was to examine the cost-effectiveness of LAM plus ADV combination treatment compared with five other nucleos(t)ide analog monotherapies (LAM, ADV, telbivudine [TBV], entecavir [ETV], and tenofovir [TDF]). Methods To simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for different therapy options, a Markov model that included five initial monotherapies and LAM plus ADV combination as an initial treatment was developed. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: direct use of ETV + ADV) were considered separately for treating patients refractory to initial therapy. One-way and probabilistic sensitivity analyses were used to explore model uncertainties. Results In base-case analysis, ETV had the lowest lifetime cost and served as the reference therapy. Compared to the reference, LAM, ADV, and TBV had higher costs and lower efficacy, and were completely dominated by ETV. LAM plus ADV combination therapy or TDF was more efficacious than ETV, but also more expensive. Although the incremental cost-effectiveness ratios of combination therapy or TDF were both higher than the willingness-to-pay threshold of $20,466/QALY gained for the reference treatment, in an alternative scenario analysis LAM plus ADV combination therapy would be the preferable treatment option. Conclusion ETV and LAM plus ADV combination therapy are both cost-effective strategies for treating Chinese CHB patients. PMID:27041994

  11. Blockade of Tumor Necrosis Factor-Alpha: A Role for Adalimumab in Neovascular Age-Related Macular Degeneration Refractory to Anti-Angiogenesis Therapy?

    PubMed Central

    Fernández-Vega, Beatriz; Fernández-Vega, Álvaro; Rangel, Carlos Mario; Nicieza, Javier; Villota-Deleu, Eva; Vega, José A.; Sanchez-Avila, Ronald M.

    2016-01-01

    Aims To report a case of wet age-related macular degeneration (wet-AMD) refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in a patient who showed visual and anatomical improvement and stabilization after starting a subcutaneous treatment course with adalimumab, an anti-tumor necrosis factor-alpha (TNF-α) drug, for concomitant Crohn's disease. Methods Observational case report of a female patient. Ophthalmological evaluation was performed by slit lamp and ophthalmoscopy (posterior pole and anterior segment). Best-corrected visual acuity (BCVA) was determined, and imaging was performed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT). Intravitreal therapies used and treatment with anti-TNF-α were recorded. Results A 64-year-old woman with wet-AMD was treated with fourteen intravitreal injections of ranibizumab (0.5 mg) for a period of 40 months with intervals of 1–6 months. She initially showed a good visual and anatomical response to periodic anti-VEGF treatment but during check visits, anatomical and functional responses deteriorated. At the 40-month follow-up, the patient had developed Crohn's disease, and her rheumatologist started treatment with adalimumab (40 mg subcutaneously every 2 weeks). During the 25 months of treatment with adalimumab, the patient did not require any additional intravitreal anti-VEGF treatments because her BCVA, clinical, and OCT findings improved and remained stable. Conclusions We described a case of a patient with wet-AMD refractory to anti-VEGF therapy, which clinically benefited from subcutaneous adalimumab therapy. Treatment with subcutaneous anti-TNF-α in combination with anti-VEGF therapy avoids the high cost and risks related to multiple intravitreal anti-VEGF injections with good functional and anatomic outcomes. PMID:27065854

  12. An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-naïve patients with psoriatic arthritis.

    PubMed

    Betts, Keith A; Griffith, Jenny; Friedman, Alan; Zhou, Zheng-Yi; Signorovitch, James E; Ganguli, Arijit

    2016-04-01

    Objective Apremilast was recently approved for the treatment of active psoriatic arthritis (PsA). However, no studies compare apremilast with methotrexate or biologic therapies, so its relative comparative efficacy remains unknown. This study compared the response rates and incremental costs per responder associated with methotrexate, apremilast, and biologics for the treatment of active PsA. Methods A systematic literature review was performed to identify phase 3 randomized controlled clinical trials of approved biologics, methotrexate, and apremilast in the methotrexate-naïve PsA population. Using Bayesian methods, a network meta-analysis was conducted to indirectly compare rates of achieving a ≥20% improvement in American College of Rheumatology component scores (ACR20). The number needed to treat (NNT) and the incremental costs per ACR20 responder (2014 US$) relative to placebo were estimated for each of the therapies. Results Three trials (MIPA for methotrexate, PALACE-4 for apremilast, and ADEPT for adalimumab) met all inclusion criteria. The NNTs relative to placebo were 2.63 for adalimumab, 6.69 for apremilast, and 8.31 for methotrexate. Among methotrexate-naïve PsA patients, the 16 week incremental costs per ACR20 responder were $3622 for methotrexate, $26,316 for adalimumab, and $45,808 for apremilast. The incremental costs per ACR20 responder were $222,488 for apremilast vs. methotrexate. Conclusion Among methotrexate-naive PsA patients, adalimumab was found to have the lowest NNT for one additional ACR20 response and methotrexate was found to have the lowest incremental costs per ACR20 responder. There was no statistical evidence of greater efficacy for apremilast vs. methotrexate. A head-to-head trial between apremilast and methotrexate is recommended to confirm this finding. PMID:26743448

  13. Adalimumab ameliorates OVA-induced airway inflammation in mice: Role of CD4(+) CD25(+) FOXP3(+) regulatory T-cells.

    PubMed

    Elsakkar, Mohamed G; Sharaki, Olla A; Abdallah, Dina M; Mostafa, Dalia K; Shekondali, Fadia T

    2016-09-01

    Asthma is a chronic inflammatory heterogeneous disorder initiated by a dysregulated immune response which drives disease development in susceptible individuals. Though T helper 2 (TH2) biased responses are usually linked to eosinophilic asthma, other Th cell subsets induce neutrophilic airway inflammation which provokes the most severe asthmatic phenotypes. A growing evidence highlights the role of T regulatory (Treg) cells in damping abnormal Th responses and thus inhibiting allergy and asthma. Therefore, strategies to induce or augment Treg cells hold promise for treatment and prevention of allergic airway inflammation. Recently, the link between Tumor necrosis factor-α (TNF-α) and Treg has been uncovered, and TNF-α antagonists are increasingly used in many autoimmune diseases. Yet, their benefits in allergic airway inflammation is not clarified. We investigated the effect of Adalimumab, a TNF-α antagonist, on Ovalbumin (OVA)-induced allergic airway inflammation in CD1 mice and explored its impact on Treg cells. Our results showed that Adalimumab treatment attenuated the OVA-induced increase in serum IgE, TH2 and TH1 derived inflammatory cytokines (IL-4 and IFN-γ, respectively) in bronchoalveolar lavage (BAL) fluid, suppressed recruitment of inflammatory cells in BAL fluid and lung, and inhibited BAL fluid neutrophilia. It also ameliorated goblet cell metaplasia and bronchial fibrosis. Splenocytes flow cytometry revealed increased percentage of CD4(+) CD25(+) FOXP3(+) Treg cells by Adalimumab that was associated with increase in their suppressive activity as shown by elevated BAL fluid IL-10. We conclude that the beneficial effects of Adalimumab in this CD1 neutrophilic model of allergic airway inflammation are attributed to augmentation of Treg cell number and activity. PMID:27262379

  14. Rapid Detection of Hepatitis B Virus Variants Associated with Lamivudine and Adefovir Resistance by Multiplex Ligation-Dependent Probe Amplification Combined with Real-Time PCR

    PubMed Central

    Jia, Shuangrong; Wang, Feng; Li, Fake; Chang, Kai; Yang, Shaojun; Zhang, Kejun; Jiang, Wenbin; Shang, Ya

    2014-01-01

    Drug-resistant mutations of hepatitis B virus (HBV) are the major obstacles to successful therapy for chronic hepatitis B infection. Although there are many methods for detecting the antiviral drug-resistant mutations of HBV, their applications are restricted because of their shortcomings, such as low sensitivity, the time required, and the high cost. For this study, a multiplex ligation-dependent probe real-time PCR (MLP-RT-PCR) method was developed to simultaneously detect lamivudine (LAM)- and adefovir (ADV)-resistant HBV mutants (those with the mutations rtM204V/I, rtA181V/T, and rtN236T). The new method combined the high-throughput nature of multiplex ligation-dependent probe amplification (MLPA) with the rapid and sensitive detection of real-time PCR. In this report, MLP-RT-PCR was evaluated by detecting drug-resistant mutants in 116 patients with chronic hepatitis B infection. By MLP-RT-PCR analysis, LAM-resistant mutations were detected in 41 patients (35.3%), ADV-resistant mutations were detected in 17 patients (14.7%), and LAM- and-ADV-resistant mutations were detected in 5 patients (4.3%). Based on the results of MLP-RT-PCR, the mutations rtM204V, rtM204I, rtA181T, rtA181V, and rtN236T were 95.7% (111/116 patients), 98.3% (114/116 patients), 99.1% (115/116 patients), 98.3% (114/116 patients), and 99.1% (115/116 patients) concordant, respectively, with those of direct sequencing. The MLP-RT-PCR assay was more sensitive than direct sequencing for detecting mutations with low frequencies. Four samples containing the low-frequency (<10%) mutants were identified by MLP-RT-PCR and further confirmed by clonal sequencing. MLP-RT-PCR is a rapid and sensitive method that enables the detection of multidrug-resistant HBV mutations in clinical practice. PMID:24478474

  15. The Efficacy of Add-on Telbivudine Versus Switching to Pegylated Interferon Alfa-2a in Chronic Hepatitis B Patients With Poor Responses to Adefovir

    PubMed Central

    Wei, Xin; Fan, Chao; Zhou, Yun; Kang, Wenzhen; Wang, Jiuping; Sun, Li; Wang, Linxu; Peng, Meijuan; Lian, Jianqi; Jia, Zhansheng; Hao, Chunqiu

    2016-01-01

    Background: There are limited options for chronic hepatitis B (CHB) patients who have poor responses to adefovir (ADV). Objectives: The aim of this study is to evaluate the effects of adding on telbivudine (LdT) or switching to pegylated interferon alfa-2a (PEG-IFN-α2a) as alternative rescue therapies for patients with poor responses to the initial ADV treatments. Patients and Methods: Ninety-seven CHB patients with HBV DNA > 2 log10 copies/mL 48 weeks after ADV monotherapy were included in this study. Fifty-nine of these patients were treated with a combination of LdT plus ADV (LdT + ADV) daily, while thirty-eight patients were switched to PEG-IFN-α2a subcutaneous injections weekly for 48 weeks. Results: Both rescue strategies were proven to be safe and the majority of patients tolerated the therapies well. LdT + ADV led to more rapid reductions in viral loads than PEG-IFN-α2a monotherapy, with 2.14 (LdT + ADV) and 0.98 (PEG-IFN-α2a) log10 copies/mL decreases 48 weeks after rescue treatments, respectively (P < 0.00001). The rates corresponding to virological and biochemical responses were also elevated in patients who received the LdT + ADV combination therapy at the end of the observation period (88.1 vs. 68.4% for virological response, P = 0.017; 83.3 vs. 47.2%, P = 0.00045). However, the decline in the hepatitis B surface antigen (HBsAg) was more pronounced in PEG-IFN-α2a treated patients. Moreover, the cumulative rates of serological responses were higher in patients who switched to the PEG-IFN-α2a therapy. Conclusions: Both add-on LdT and switching to PEG-IFN-α2a were satisfactory and optimal treatments for CHB patients with poor responses to ADV. Both rescue strategies resulted in significant reductions in serum viral load and ALT levels, and were associated with high rate of serological outcomes in our hospital. PMID:27110255

  16. Adalimumab improves health-related quality of life in patients with moderate to severe plaque psoriasis compared with the United States general population norms: Results from a randomized, controlled Phase III study

    PubMed Central

    Revicki, Dennis A; Menter, Alan; Feldman, Steven; Kimel, Miriam; Harnam, Neesha; Willian, Mary K

    2008-01-01

    Objective To evaluate the impact of adalimumab on health-related quality of life (HRQOL) for patients with moderate to severe plaque psoriasis. Background Psoriasis is a chronic, inflammatory, immune-mediated disease that has a significant impact on patients' HRQOL. Adalimumab is a fully human monoclonal antibody that blocks tumor necrosis factor, a pro-inflammatory cytokine, and is effective and well-tolerated for patients with moderate to severe psoriasis. Methods Data were obtained for a secondary analysis of patients in a randomized, controlled Phase III trial evaluating the effect of adalimumab in patients with psoriasis (N = 1,205). Patients with moderate to severe psoriasis were randomized in a 2:1 ratio to adalimumab 80 mg (two 40 mg injections administered subcutaneously at baseline followed by one 40 mg injection every other week from Week 1 to Week 15) or placebo. Short Form-36 (SF-36) Health Survey scores of psoriasis patients were used to assess HRQOL and were compared with United States (US) population norms at baseline and Week 16. Results Baseline Physical Component Summary (PCS) scores for the placebo and adalimumab groups were similar to the general US population. Baseline mean Mental Component Summary (MCS) scores were significantly lower for the adalimumab and placebo groups compared with the general population (47.4, 47.7, and 50.8 points, respectively; p < 0.0001). PCS scores at Week 16 for patients receiving adalimumab had improved and were significantly greater than scores for the general US population (52.7 vs 48.9; p < 0.001). Compared with the general US population, MCS scores at Week 16 were similar for patients receiving adalimumab (51.2 vs 50.8; p = 1.000) and lower for patients receiving placebo (50.8 vs 48.7; p < 0.0001). Conclusion Psoriasis has a broad impact on patient functioning and well-being. Improvement in skin lesions and joint symptoms associated with adalimumab treatment was accompanied by improvements in HRQOL to levels

  17. Long-Term Efficacy of Adalimumab in Patients With Intestinal Behcet’s Disease: Eight Consecutive Cases

    PubMed Central

    Tanida, Satoshi; Mizoshita, Tsutomu; Nishie, Hirotada; Ozeki, Keiji; Katano, Takahito; Shimura, Takaya; Kubota, Eiji; Kataoka, Hiromi; Kamiya, Takeshi; Joh, Takashi

    2016-01-01

    The long-term efficacy and safety of adalimumab (ADA) for the treatment of intestinal Behcet’s disease (BD) in the clinical setting have not been evaluated previously. This retrospective study evaluated the 52-week efficacy of ADA in BD patients. A total of eight patients who were refractory to conventional therapy were given ADA (160/80/40 mg every other week). Marked improvement (MI) was achieved by 10 weeks in five patients (62.5%), and by 52 weeks in six patients (75%). In addition, complete remission was obtained in two patients (25%) at both 10 and 52 weeks. Improvement of global gastrointestinal (GI) symptoms to score 0 was observed in three patients (37.5%) at 10 weeks and four patients (50%) at 52 weeks. Moreover, improvement of endoscopic assessment to score 0 was also seen in four patients (50%) at both 10 and 52 weeks. No adverse events were observed in any patients during the 52 weeks. In conclusion, ADA offers an effective, well-tolerated treatment for intestinal BD in patients who are refractory to conventional therapy. PMID:26985255

  18. TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis.

    PubMed

    Liu, Jing; Dong, Zheng; Zhu, Qi; He, Dongyi; Ma, Yanyun; Du, Aiping; He, Fan; Zhao, Dongbao; Xu, Xia; Zhang, Hui; Jin, Li; Wang, Jiucun

    2016-01-01

    While previous studies have researched in association analyses between TNFα promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNFα promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNFα -308 G allele and the -238 G allele predicted a good response to TNF blockers (OR = 2.64 [1.48-4.73]; 2.52 [1.46-4.37]). However, G alleles of TNFα -308 and -238 could predict the response to etanercept (OR = 4.02 [2.24-7.23]; 5.17 [2.29-11.67]) much more powerfully than the response to infiliximab/adalimumab (OR = 1.68 [1.02-2.78]; 1.28 [0.57-2.86]). TNFα -857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNFα -308 A/G and -238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response. PMID:27578555

  19. Adalimumab discontinuation in patients with early rheumatoid arthritis who were initially treated with methotrexate alone or in combination with adalimumab: 1 year outcomes of the HOPEFUL-2 study

    PubMed Central

    Tanaka, Yoshiya; Yamanaka, Hisashi; Ishiguro, Naoki; Miyasaka, Nobuyuki; Kawana, Katsuyoshi; Hiramatsu, Katsutoshi; Takeuchi, Tsutomu

    2016-01-01

    Objectives To evaluate the impact of discontinuation of adalimumab (ADA) for 1 year in Japanese patients with early rheumatoid arthritis (RA). Methods This 52-week postmarketing study, HOPEFUL-2, enrolled patients who had completed HOPEFUL-1 for early RA, in which patients received either ADA + methotrexate (MTX) or MTX alone in a 26-week randomised phase, followed by ADA+MTX in a 26-week open-label phase. Results A total of 220 patients (ADA discontinuation: 114 patients vs ADA continuation: 106 patients) were enrolled in this study. The proportion of patients with sustained low disease activity (LDA) in the ADA discontinuation group was significantly lower than that in the continuation group (80% (64/80 patients) vs 97% (71/73 patients); p=0.001); however, most patients sustained LDA in both groups. In patients with 28-joint disease activity score (DAS28)-C reactive protein ≤2.0 at week 52, the proportion of patients who achieved sustained LDA at week 104 was 93%, suggesting that DAS28 remission may be a predictor to indicate biological-free disease control in patients with early RA. The incidence of adverse events (AE) was significantly lower in the ADA discontinuation group than in the continuation group (34.2% (39/114 patients) vs 48.1% (51/106 patients); p=0.04), most notably for infection (14.9% vs 27.4%, p=0.031). Conclusions Although ADA discontinuation was associated with an increase in disease activity, a large proportion of patients maintained LDA with MTX monotherapy after ADA discontinuation. Since ADA discontinuation was associated with a lower AE incidence, physicians should weigh the risks and benefits of ADA discontinuation. Trial registration number NCT01163292. PMID:26925252

  20. Adalimumab (tumor necrosis factor-blocker) reduces the expression of glial fibrillary acidic protein immunoreactivity increased by exogenous tumor necrosis factor alpha in an organotypic culture of porcine neuroretina

    PubMed Central

    Garcia-Gutierrez, M.T.; Srivastava, G.K.; Gayoso, M.J.; Gonzalo-Orden, J.M.; Pastor, J.C.

    2013-01-01

    Purpose To determine if exogenous addition of tumor necrosis factor alpha (TNFα) exacerbates retinal reactive gliosis in an organotypic culture of porcine neuroretina and to evaluate if concomitant adalimumab, a TNF-blocker, diminishes it. Methods Porcine retinal explants from 20 eyeballs were cultured. Cultures with 100 pg/ml TNFα, 10 µg/ml adalimumab, 100 pg/ml TNFα plus 10 µg/ml adalimumab, or controls without additives were maintained for 9 days. Freshly detached retinas were processed in parallel. TNFα levels in control culture supernatants were quantified with enzyme-linked immunosorbent assay. Cryostat sections were doubly immunostained for glial fibrillary acidic protein (GFAP), a marker for reactive gliosis, and cellular retinaldehyde-binding protein (CRALBP), a marker for Müller cells. Sections were also labeled with the isolectin IB4, a label for microglia/macrophages. Results TNFα in control culture supernatants was detected only at day 1. Compared to the fresh neuroretinal samples, upregulation of GFAP and downregulation of CRALBP occurred during the 9 days of culture. Exogenous TNFα stimulated glial cells to upregulate GFAP and downregulate CRALBP immunoreactivity. TNFα-treated cultures also initiated the growth of gliotic membranes and underwent retinal disorganization. Adalimumab inhibited the spontaneous increases in GFAP and maintained CRALBP. In combination with TNFα, adalimumab reduced GFAP expression and conserved CRALBP, with only slight retinal disorganization. No appreciable changes in IB4 labeling were observed under the different culture conditions. Conclusions In cultured porcine neuroretina, spontaneous reactive gliosis and retinal disorganization were exacerbated by exogenous TNFα. Adalimumab reduced spontaneous changes and those induced by TNFα. Therefore, inhibiting TNFα may represent a novel approach to controlling retinal fibrosis observed in some human diseases. PMID:23687426

  1. Balance of Treg versus T-effector cells during systemic treatment with adalimumab and topical treatment with calcipotriol-betamethasone dipropionate ointment.

    PubMed

    Keijsers, Romy R M C; Joosten, Irma; Hendriks, Anke G M; Koenen, Hans J P M; van Erp, Piet E J; van de Kerkhof, Peter C M

    2015-01-01

    Diminished suppressive capacity of regulatory T cells (Treg) has been demonstrated in blood and in lesional skin of psoriatic patients. Treatment with anti-TNFα restored the number and function of circulating Treg in psoriasis. We aimed to study Treg in the skin of psoriatic patients undergoing topical treatment with calcipotriol-betamethasone dipropionate (CBD) ointment (n = 12) or systemic treatment with anti-TNFα agent adalimumab (n = 10). Skin biopsies were collected from patients with chronic plaque psoriasis who responded to the above-mentioned treatments with a SUM-score improvement of at least 50% (at the end of treatment). Biopsies were processed for immunohistochemistry. As Treg function is associated with a numerical balance between Treg and effector T cells, Foxp3/CD4 ratios were calculated. It appeared that both treatments cause a significant decrease in the presence of Foxp3+ cells. However, in patients that were treated with CBD ointment, we observed lower Foxp3/CD4 ratios after 8 weeks of treatment compared to baseline (t = 0: 0.41 ± 0.08; t = 8: 0.22 ± 0.04, P = 0.033), whereas in patients who were treated with adalimumab we observed an increase of the Foxp3/CD4 ratios after 1.5 and 16 weeks of treatment compared to baseline (t = 0: 0.25 ± 0.04; t = 1.5: 0.32 ± 0.06; t = 16: 0.49 ± 0.10, P = 0.15). Based on Foxp3/CD4 ratios, we can conclude that adalimumab treated skin differs from CBD treated skin with regard to the anti-inflammatory/inflammatory balance. We suggest that, in contrast to CBD ointment, adalimumab favours local Treg function in the skin. PMID:25355140

  2. TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis

    PubMed Central

    Liu, Jing; Dong, Zheng; Zhu, Qi; He, Dongyi; Ma, Yanyun; Du, Aiping; He, Fan; Zhao, Dongbao; Xu, Xia; Zhang, Hui; jin, Li; Wang, Jiucun

    2016-01-01

    While previous studies have researched in association analyses between TNFα promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNFα promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNFα −308 G allele and the −238 G allele predicted a good response to TNF blockers (OR = 2.64 [1.48–4.73]; 2.52 [1.46–4.37]). However, G alleles of TNFα −308 and −238 could predict the response to etanercept (OR = 4.02 [2.24–7.23]; 5.17 [2.29–11.67]) much more powerfully than the response to infiliximab/adalimumab (OR = 1.68 [1.02–2.78]; 1.28 [0.57–2.86]). TNFα −857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNFα −308 A/G and −238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response. PMID:27578555

  3. Is drug discontinuation risk of adalimumab compared with etanercept affected by concomitant methotrexate dose in patients with rheumatoid arthritis?

    PubMed Central

    Chen, Hsin-Hua; Chen, Der-Yuan; Chen, Yi-Ming; Tang, Chao-Hsiun

    2016-01-01

    Objective To compare drug discontinuation risk between adalimumab (ADA) and etanercept (ETN) treatment among anti-tumor necrosis factor (anti-TNF)-naïve rheumatoid arthritis (RA) patients, in particular the influence of concomitant dose of methotrexate (MTX). Methods This retrospective nationwide population-based cohort study identified 4,592 anti-TNF-naïve RA patients in whom ETN (n=2,609) or ADA (n=1,983) was initiated using National Health Insurance claims data. After adjustment for prior medication, concomitant medication, and baseline demographic data, the relative risk of drug discontinuation in ADA users compared with ETN users was quantified by calculating adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox proportional hazard regression analyses, stratified by the follow-up time (≤1 year, >1 year) and/or concomitant MTX dose (≤10 mg/wk, >10 mg/wk). Results ADA users had a higher risk of drug discontinuation compared with ETN users during the first year of follow-up (aHR, 1.13; 95% CI, 1.01–1.27), but not during all treatment periods (aHR, 1.06; 95% CI, 0.98–1.16) or after 1 year (aHR, 0.99; 95% CI, 0.87–1.13). However, ADA users had a significantly higher risk of drug discontinuation compared with ETN users among patients on concomitant MTX >10 mg/wk during all treatment periods (aHR, 1.27; 95% CI, 1.10–1.47), during the first year of follow-up (aHR, 1.48; 95% CI, 1.22–1.78), or after 1 year (aHR, 1.42; 95% CI, 1.06–1.90), but not among patients on concomitant MTX 0–10 mg/wk. Conclusion This population-based cohort study demonstrated a modification effect of concomitant MTX dose on the relative risk of anti-TNF discontinuation for ADA compared with ETN among anti-TNF-naïve RA patients. However, the lack of exact cause of anti-TNF discontinuation limited causal inference of such a concomitant MTX dose-related modification effect. PMID:26917952

  4. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2007-12-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide

  5. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2004-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, adalimumab, adefovir dipivoxil, alefacept, alemtuzumab, 3-AP, AP-12009, APC-8015, L-Arginine hydrochloride, aripiprazole, arundic acid, avasimibe; Bevacizumab, bivatuzumab, BMS-181176, BMS-184476, BMS-188797, bortezomib, bosentan, botulinum toxin type B, BQ-123, BRL-55730, bryostatin 1; CEP-1347, cetuximab, cinacalcet hydrochloride, CP-461, CpG-7909; D-003, dabuzalgron hydrochloride, darbepoetin alfa, desloratadine, desoxyepothilone B, dexmethylphenidate hydrochloride, DHA-paclitaxel, diflomotecan, DN-101, DP-b99, drotrecogin alfa (activated), duloxetine hydrochloride, duramycin; Eculizumab, Efalizumab, EKB-569, elcometrine, enfuvirtide, eplerenone, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, exatecan mesilate, ezetimibe; Fenretinide, fosamprenavir calcium, frovatriptan; GD2L-KLH conjugate vaccine, gefitinib, glufosfamide, GTI-2040; Hexyl insulin M2, human insulin, hydroquinone, gamma-Hydroxybutyrate sodium; IL-4(38-37)-PE38KDEL, imatinib mesylate, indisulam, inhaled insulin, ixabepilone; KRN-5500; LY-544344; MDX-210, melatonin, mepolizumab, motexafin gadolinium; Natalizumab, NSC-330507, NSC-683864; 1-Octanol, omalizumab, ortataxel; Pagoclone, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, phenoxodiol, pimecrolimus, plevitrexed, polyphenon E, pramlintide acetate, prasterone, pregabalin, PX-12; QS-21; Ragaglitazar, ranelic acid distrontium salt, RDP-58, recombinant glucagon-like peptide-1 (7-36) amide, repinotan hydrochloride, rhEndostatin, rh-Lactoferrin, (R)-roscovitine; S-8184, semaxanib, sitafloxacin hydrate, sitaxsentan sodium, sorafenib, synthadotin

  6. Gateways to clinical trials. July-August 2008.

    PubMed

    Tomillero, A; Moral, M A

    2008-01-01

    (-)-Epigallocatechin gallate, 501516, 89-12; Abatacept, Adalimumab, Adefovir dipivoxil, AG-701, Agatolimod sodium, Alefacept, Aliskiren fumarate, Apixaban, Atazanavir sulfate, Atrasentan, Axitinib; BI-1744-CL, BIBF-1120, BIBW-2992, Bortezomib; Carboxyamidotriazole, Caspofungin acetate, CBP-501, Cediranib, Ceftobiprole, Certolizumab pegol, Cetuximab, Cholesteryl hydrophobized polysaccharide-Her2 protein complex, CHP-NY-ESO-1, Cypher; Dalbavancin, Dalcetrapib, Daptomycin, Darapladib, Deferasirox, Deforolimus, Denosumab, DNA-HIV-C, Dovitinib, DR-5001, Dronedarone hydrochloride, DT388IL3; E75, EC-17/EC-90, Ecogramostim, Efungumab, Entecavir, EP HIV-1090, EP-2101, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Faropenem daloxate, Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium, Fulvestrant; Golimumab, GSK-089, GW-590735; HO/03/03, hTERT572, hTERT572Y; Iloperidone; Immunoglobulin intravenous (human), Ispinesib mesylate, Istradefylline, Ixabepilone; JR-031, JX-594; KLH; Laropiprant, Lecozotan hydrochloride, Lenalidomide, Lestaurtinib, Linezolid; MGCD-0103, MK-0646, MVA-BN Measles; NI-0401, Niacin/laropiprant, NSC-719239, NYVAC-C; Ospemifene; Paliperidone palmitate, PAN-811, PCV7, Pegfilgrastim, Peginterferon alfa-2a, PEGirinotecan, Perifosine, Pertuzumab, PF-00299804, Picoplatin, Pimavanserin tartrate, Pitavastatin calcium, Pomalidomide, Prasterone, Pratosartan, Prucalopride, PSMA27/pDOM, Pyridoxal phosphate; QS-21, Quercetin; Rebimastat, Rimonabant, Rolofylline, Romidepsin, Rosuvastatin calcium, RTS,S/SBAS2; SCH-530348, SN-29244, Soblidotin, Sodium dichloroacetate, Solifenacin succinate, Sorafenib, Spheramine, SU-6668, Succinobucol; Taranabant, Taxus, Telaprevir, Telavancin hydrochloride, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Tocilizumab, Triphendiol; UC-781, Udenafil, UNIL-025; V-5 Immunitor, Valsartan/amlodipine besylate, Varenicline tartrate, Velafermin, Vernakalant hydrochloride, Vinflunine, Vitespen, Vorinostat

  7. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-06-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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: 101M; Adalimumab, adefovir dipivoxil, adenosine triphosphate, albumin interferon alfa, alefacept, alemtuzumab, aminolevulinic acid hexyl ester, autologous renal tumor vaccine, azimilide hydrochloride; Bortezomib, bosentan, BR-1; C340, cantuzumab mertansine, caspofungin acetate, CGP-36742, CHAMPION everolimus-eluting coronary stent, cypher; Dalbavancin, darbepoetin alfa, desloratadine, duloxetine hydrochloride, dutasteride; Efalizumab, emtricitabine, enfuvirtide, erlosamide, ertapenem sodium, everolimus, ezetimibe; Flesinoxan hydrochloride, fosamprenavir calcium, FR-901228, frovatriptan; Gadofosveset sodium, gadomer-17, galiximab, gamma-hydroxybutyrate sodium, gefitinib; HuOKT3gamma1(Ala234-Ala235); IDN-6556, imatinib mesylate, iodine (I131) tositumomab, iseganan hydrochloride, ixabepilone; Keratinocyte growth factor; LB-80380, levocetirizine, liposomal doxorubicin, LMB-9, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Mecasermin, midostaurin, morphine hydrochloride; Natalizumab, nelfinavir, nesiritide, niacin/lovastatin; Olcegepant, omalizumab, oregovomab; Parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, perospirone hydrochloride, pexelizumab, pimecrolimus, prinomastat; Resiquimod, rhIGFBP-3, rhIGF-I/rhIGFBP-3, ritanserin, ro-31-7453, rosuvastatin calcium; SCIO-469, SDZ-SID-791, SU-11248, suberanilohydroxamic acid; Tadalafil, taxus, telithromycin, tenofovir disoproxil fumarate, TER-286, tezosentan disodium, TH-9507, tipifarnib, tipranavir, tolvaptan, tramadol hydrochloride/acetaminophen, travoprost, treprostinil sodium, tucaresol

  8. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-04-01

    (+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin

  9. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-10-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables 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: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b

  10. Lamivudine-resistant rtL180M and rtM204I/V are persistently dominant during combination rescue therapy with entecavir and adefovir for hepatitis B

    PubMed Central

    WANG, YANG; LIU, SHUANG; CHEN, YU; ZHENG, SUJUN; ZHOU, LI; LU, FENGMIN; DUAN, ZHONGPING

    2016-01-01

    Adefovir (ADV) sequential monotherapy was included in the 2005 Asia-Pacific guidelines for the management of patients with lamivudine (LAM) resistance. However, following the development of ADV resistance, the proportion of resistant variants during combined rescue therapy with ADV and entecavir (ETV) were unknown. The present study characterized the dynamics of resistant variants in patients with chronic hepatitis B (CHB) and LAM-resistant variants during antiviral therapy consisting of ADV monotherapy followed by ADV-ETV combination therapy. A total of 3 patients were selected from a cohort of 55 patients with CHB due to developing ADV resistance. The patients had been previously treated with LAM (100 mg daily) for 21–24 months. At the initiation of sequential monotherapy with ADV, LAM-resistant variants (rtM204V/I and rtL180M) were detected in the three patients. These patients developed ADV resistance during 19–30 months of ADV sequential monotherapy, and then switched their antiviral regimen to ADV-ETV combination therapy. During ADV monotherapy and ADV-ETV combination therapy, the patients were monitored every 3 months for the first year of therapy, and then every 6 months thereafter. A total of 30 serum samples were collected from the patients throughout the monitoring period. In total, 10 mutants that were associated with commonly-used antiviral drugs were detected by pyrosequencing. During ADV sequential monotherapy, LAM-resistant variants were gradually decreased, whereas ADV-resistant rtA181V/T and rtN236T variants gradually increased in the viral population. During 30–41 months of ADV-ETV combination therapy, viral load reduction was 2.59–3.28 log10 copies/ml; ADV-resistant variants rtA181T/V and rtN236T were undetectable following 11–24 months of combination therapy; and rtL180M and rtM204I/V remained dominant in the viral population. In conclusion, the results of the present study suggested that, in patients with LAM and ADV

  11. The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation.

    PubMed Central

    Shepherd, Jonathan; Cooper, Keith; Harris, Petra; Picot, Joanna; Rose, Micah

    2016-01-01

    BACKGROUND Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and a limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated. OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of four biologic DMARDs [etanercept (Enbrel(®), Pfizer), abatacept (Orencia(®), Bristol-Myers Squibb), adalimumab (Humira(®), AbbVie) and tocilizumab (RoActemra(®), Roche) - with or without methotrexate where indicated] for the treatment of JIA (systemic or oligoarticular JIA are excluded). DATA SOURCES Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and the Database of Abstracts of Reviews of Effects were searched for published studies from inception to May 2015 for English-language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence. REVIEW METHODS Systematic reviews of clinical effectiveness, health-related quality of life and cost-effectiveness were undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision-analytic model was developed to compare the estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base-case time horizon was 30 years and the model took a NHS perspective, with costs and benefits discounted at 3.5%. RESULTS Four placebo-controlled randomised controlled trials (RCTs) met the inclusion criteria for the clinical effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi)-30 response to open-label lead-in treatment in order to be

  12. A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission

    PubMed Central

    Chatzidionysiou, Katerina; Turesson, Carl; Teleman, Annika; Knight, Ann; Lindqvist, Elisabet; Larsson, Per; Cöster, Lars; Forslind, Kristina; van Vollenhoven, Ronald; Heimbürger, Mikael

    2016-01-01

    Objectives Treatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of discontinuing treatment with adalimumab (ADA) while maintaining remission in patients with RA with established disease in stable remission on combination therapy with ADA and methotrexate (MTX). Methods In a randomised, controlled, open-label pilot study of patients with RA in stable remission treated with ADA+MTX, patients were randomised in a 1:1 ratio to continue with ADA plus MTX (arm AM) or MTX monotherapy (arm M) for 52 weeks. Flare was defined as Disease Activity Score (DAS28) ≥2.6 or a change in DAS28 (ΔDAS28) of >1.2 from baseline at any time. Patients in arm M with a flare restarted ADA. The primary end point was the proportion of patients in remission at week 28. Results 31 patients were enrolled in the study and randomised to arm AM (n=16) or arm M (n=15). At 28 weeks, 15/16 patients (94%) and 5/15 patients (33%) in arms AM and M, respectively, were in remission (p=0.001). During the first 28 weeks, 50% (8/16) in the AM arm and 80% (12/15) in the M arm had a flare (p=0.08). The number of patients in the AM and M arms with ≥1 ΔDAS28 >1.2 during the first 28 weeks was 1/16 (6%) and 8/15 (53%), respectively (p=0.005). Conclusions In this study, remission was rarely maintained in patients with long-standing disease who discontinued ADA. Discontinuation may be feasible in only a minority of patients with established RA in stable clinical remission. Trial registration number NCT00808509. PMID:26819752

  13. Efficacy and Safety of Adalimumab in Moderately to Severely Active Cases of Ulcerative Colitis: A Meta-Analysis of Published Placebo-Controlled Trials

    PubMed Central

    Zhang, Zong Mei; Li, Wei; Jiang, Xue Liang

    2016-01-01

    Background/Aims To evaluate the efficacy and safety of adalimumab (ADA) in moderately to severely active ulcerative colitis (UC) patients who are unresponsive to traditional therapy. Methods Electronic databases, including the PubMed, Embase, and Cochrane databases, were searched to April 20, 2014. UC-related randomized controlled trials (RCTs) that compared ADA with placebo were eligible. Review Manager 5.1 was used for data analysis. Results This meta-analysis included three RCTs. ADA was considerably more effective compared with a placebo, and it increased the ratio of patients with clinical remission, clinical responses, mucosal healing and inflammatory bowel disease questionnaire responses in the induction and maintenance phases (p<0.05), as well as patients with steroid-free remission (p<0.05) during the maintenance phase. Clinical remission was achieved in a greater number of UC cases in the ADA 160/80/40 mg groups (0/2/4 week, every other week) compared with the placebo group at week 8 (p=0.006) and week 52 (p=0.0002), whereas the week 8 clinical remission rate was equivalent between the ADA 80/40 mg groups and the placebo group. Among the patients who received immunomodulators (IMM) at baseline, ADA was superior to the placebo in terms of inducing clinical remission (p=0.01). Between-group differences were not observed in terms of serious adverse events (p=0.61). Conclusions ADA, particularly at doses of 160/80/40 mg (0/2/4 week, every other week), is effective and safe in patients with moderate-to-severe UC who are unresponsive to traditional treatment. Concomitant IMM therapy may improve the short-term therapeutic efficacy of ADA. PMID:26780088

  14. Effectiveness of Adalimumab in Non-radiographic Axial Spondyloarthritis: Evaluation of Clinical and Magnetic Resonance Imaging Outcomes in a Monocentric Cohort.

    PubMed

    Cantarini, Luca; Fabbroni, Marta; Talarico, Rosaria; Costa, Luisa; Caso, Francesco; Cuneo, Gian Luca; Frediani, Bruno; Faralli, Gabriele; Vitale, Antonio; Brizi, Maria Giuseppina; Sabadini, Luciano; Galeazzi, Mauro

    2015-07-01

    The primary aim of the study was to evaluate the long-term effectiveness of adalimumab (ADA) in a cohort of non-radiographic axial spondyloarthritis (nr-axSpA), and the secondary aims were to identify predictive factors of response and evaluate radiological progression.We evaluated 37 patients (male/female: 12/25; mean age 49 ± 14; mean disease duration: 6.3 ± 5.8) with active nr-axSpA (Assessment of SpondyloArthritis International Society criteria), despite the treatment with ≥1 nonsteroidal anti-inflammatory drug for at least 3 months, initiating the treatment with ADA 40 mg every other week. Patients were treated for 24 months, and evaluated at baseline, 6, 12, and 24 months. Outcome measures included Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index. Radiograph of the spine and sacroiliac joints and magnetic resonance of the sacroiliac joints were performed at baseline and according to the standard of assessment for the disease.The proportion of patients that achieved a BASDAI50 response at 6, 12 and 24 months was 51.3%, 70.3%, and 76.8%, respectively. Treatment was well tolerated with no unexpected adverse events and/or serious adverse events. All patients remained on treatment for 2 years, with a good compliance. We did not identify any predictive factor of response to therapy. Moreover, modified Stoke Ankylosing Spondylitis Spine Score and Spondyloarthritis Research Consortium of Canada scores showed a trend of improvement during the study period.ADA was effective on clinical and radiological outcomes at 2-year follow-up; thus, early treatment with ADA may prevent radiographic damage and be associated with low disease activity or remission. Moreover, data from this cohort study have confirmed safety and tolerability profile of ADA in nr-axSpA in the long term. PMID:26222847

  15. Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients.

    PubMed

    Repnik, Katja; Koder, Silvo; Skok, Pavel; Ferkolj, Ivan; Potočnik, Uroš

    2016-08-01

    Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients. PMID:27115882

  16. Exfoliative cutaneous lupus erythematosus in German shorthaired pointer dogs: disease development, progression and evaluation of three immunomodulatory drugs (ciclosporin, hydroxychloroquine, and adalimumab) in a controlled environment

    PubMed Central

    Mauldin, Elizabeth A.; Morris, Daniel O.; Brown, Dorothy C.; Casal, Margret L.

    2011-01-01

    Six German shorthaired pointer dogs (two females, four males) with exfoliative cutaneous lupus erythematosus (ECLE) were studied in a controlled setting until disease progression necessitated euthanasia. During investigations into the heredity of disease, five dogs received immunomodulatory drugs to alleviate clinical signs (lameness, erythema, scaling, erosions/ulcers). One dog served as a control and received only baths and oral fatty acids. Four dogs received ciclosporin (5–10 mg/kg once daily) for 4.5 months to 2 years. Ciclosporin decreased erythema and arthralgia, but did not halt worsening of lesions. Three dogs received hydroxychloroquine (5–10 mg/kg once daily) for 8 weeks, 7 months, and 9 months, respectively, with no side effects. Hydroxychloroquine appeared to slow clinical progression in two dogs on extended treatment and normalized globulin levels in all three dogs while receiving the drug. Four dogs, including the control dog, were euthanized between 1 and 4.5 years of age. Two remaining male dogs received a tumour necrosis factor (TNF)-α antagonist, adalimumab, at 0.5 mg/kg every 2 weeks for 8 weeks then weekly for 8 weeks. Serum TNF-α levels were not significantly altered nor were quantifiable changes seen in skin lesions or lameness. Subsequently, the dogs were maintained on hydroxychloroquine for another year. This is the first study to evaluate the use of a TNF-α inhibitor for canine lupus and the first to address the safety of long-term administration of hydroxychloroquine, albeit in a small number of dogs. The study documents the progression of ECLE and generally poor response to therapy. PMID:20374572

  17. Do patients with active RA have differences in disease activity and perceptions if anti-TNF naïve versus anti-TNF experienced? Baseline results of the optimization of adalimumab trial

    PubMed Central

    Pope, Janet; Thorne, J. Carter; Haraoui, Boulos Paul; Psaradellis, Eliofotisti; Sampalis, John

    2012-01-01

    Summary Background The chance of a good response in RA is attenuated in previous anti-TNF users who start new anti-TNF therapy compared to biologic naïve patients. In active RA, those with previous anti-TNF exposure compared to anti-TNF naïve may have different baseline disease activity and patient perceptions when starting a new anti-TNF treatment that could explain the observed response differences. Material/Methods The aim of this study was a post hoc analysis of baseline characteristics of patients enrolled in the Optimization of Adalimumab study that was a treat to target vs. routine care study in patients initiating adalimumab. As per the protocol, a maximum of 20% anti-TNF experienced patients were enrolled in the 300 patient trial. Twelve (4.0%) were excluded who previously used other biologics. Baseline characteristics including age, gender, tender and swollen joint counts, disease activity (DAS28), function (HAQ-DI), patient global assessment, patient satisfaction with current treatment, and inflammatory markers (CRP, ESR), were compared between previously anti-TNF experienced [etanercept or infliximab (EXP)], and anti-TNF naïve patients (NAÏVE). Results The mean (SD) age was 54.8 (13.3) years; 81.0% were female, and 237 (79.0%) were anti-TNF naïve while 51 (17.0%) patients were anti-TNF experienced (29 with etanercept, 16 with infliximab, and 6 for both). The mean (SD) baseline in EXP versus NAÏVE groups respectively was: CRP=21.7(32.9) vs. 17.5(20.7); ESR=28.7(22.5) vs. 29.8(20.4); SJC=10.5(6.0) vs. 10.7(5.6); TJC=12.8(7.1) vs. 12.3(7.3); and DAS28=6.0(1.2) vs. 5.8(1.1). None of the between-group differences were statistically significant, however, the HAQ-DI in EXP was 1.7(0.6) compared to 1.5(0.7) for the NAÏVE (P=0.021). Additionally, EXP patients had a higher patient global score [71.3(26.1) vs. 61.9(26.2), P=0.021]. Conclusions Although anti-TNF naïve and experienced patients who initiated adalimumab were similar, with respect to several

  18. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2006-10-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data 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 issues focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (-)-gossypol, 2-deoxyglucose, 3,4-DAP, 7-monohydroxyethylrutoside; Ad5CMV-p53, adalimumab, adefovir dipivoxil, ADH-1, alemtuzumab, aliskiren fumarate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, amrubicin hydrochloride, AN-152, anakinra, anecortave acetate, antiasthma herbal medicine intervention, AP-12009, AP-23573, apaziquone, aprinocarsen sodium, AR-C126532, AR-H065522, aripiprazole, armodafinil, arzoxifene hydrochloride, atazanavir sulfate, atilmotin, atomoxetine hydrochloride, atorvastatin, avanafil, azimilide hydrochloride; Bevacizumab, biphasic insulin aspart, BMS-214662, BN-83495, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, cetuximab, chrysin, ciclesonide, clevudine, clofarabine, clopidogrel, CNF-1010, CNTO-328, CP-751871, CX-717, Cypher; Dapoxetine hydrochloride, darifenacin hydrobromide, dasatinib, deferasirox, dextofisopam, dextromethorphan/quinidine sulfate, diclofenac, dronedarone hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Edaravone, efaproxiral sodium, emtricitabine, entecavir, eplerenone, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, ezetimibe, ezetimibe/simvastatin; Finrozole, fipamezole hydrochloride, fondaparinux sodium, fulvestrant; Gabapentin enacarbil, gaboxadol, gefitinib, gestodene, ghrelin (human); Human insulin, human papillomavirus vaccine; Imatinib mesylate, immunoglobulin intravenous (human), indiplon, insulin detemir, insulin glargine, insulin glulisine, intranasal insulin, istradefylline, i.v. gamma

  19. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial)

    PubMed Central

    2014-01-01

    Background Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. Methods/design This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients <30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more

  20. Novel approaches for the treatment of HIV.

    PubMed

    Arroyo, H T

    1998-03-01

    Presentations at the Fifth Conference on Retroviruses and Opportunistic Infections focused on new and novel HIV treatments. Four new agents in advanced testing are described: abacavir (1592), efavirenz (DMP-266), adefovir dipivoxil (bis-POM PMEA), and amprenavir (141W94). Other new drugs are being developed; however, the drugs are not as far along in the testing and approval process. The new drugs include integrase inhibitors, zinc finger inhibitors, cyclams and bycyclams, fusion inhibitors, and CKR-5 gene therapy. A summary of each drug is provided. PMID:11367450

  1. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B

    SciTech Connect

    Stoop, Jeroen N. . E-mail: j.n.stoop@erasmusmc.nl; Molen, Renate G. van der . E-mail: r.vandermolen@erasmusmc.nl; Kuipers, Ernst J. . E-mail: e.j.kuipers@erasmusmc.nl; Kusters, Johannes G. . E-mail: j.g.kusters@erasmusmc.nl; Janssen, Harry L.A. . E-mail: h.janssen@erasmusmc.nl

    2007-04-25

    Regulatory T cells (Treg) play a key role in the impaired immune response that is typical for a chronic Hepatitis B virus (HBV) infection. To gain more insight in the mechanism that is responsible for this impaired immune response, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the percentages of Treg and HBV-specific T-cell responses was analyzed. Peripheral blood mononuclear cells (PBMC) of 12 patients were collected at baseline and during treatment. In parallel to the decline in viral load, we found a decline in circulating Treg, combined with an increase in HBV core antigen-specific IFN-{gamma} production and proliferation. The production of IL10 did not decrease during therapy. In conclusion, adefovir induced viral load reduction results in a decline of circulating Treg together with a partial recovery of the immune response.

  2. Simultaneous determination of pradefovir, PMEA and tenofovir in HBV patient serum using liquid chromatography-tandem mass spectrometry and application to phase 2 clinical trial.

    PubMed

    Xiao, Qingqing; Wang, Dan; Yang, Wanqiu; Chen, Lin; Ding, Yitao; Yang, Jin

    2016-06-01

    Pradefovir, a prodrug of PMEA, is under phase 2 clinical trial in China to evaluate its pharmacokinetic and pharmacodynamics after multiple-dose study, with adefovir dipivoxil and tenofovir disoproxil fumarate as positive control. A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of pradefovir, PMEA and tenofovir in HBV patient serum. Serum samples were pretreated via simple protein precipitation with methanol and entecavir was used as internal standard. Chromatographic separation was carried out on a Synergi(®) fusion-RP column (150mm×4.6mm) by gradient elution with methanol and 0.1% formic acid in water (v/v) at a flow rate of 1mL/min. The analytes were detected in multiple reaction monitoring mode with positive ion electrospray ionization at m/z 424.1/151.0, 274.1/162.2, 288.1/176.1, and 278.1/152.2for pradefovir, PMEA, tenofovir and IS, respectively. The assays were validated according to current bioanalytical guidelines including specificity, linearity (2.0-500ng/mL for pradefovir and PMEA, 4.0-1000ng/mL for tenofovir), accuracy and precision, extraction recovery, matrix effect and stability. The validated method has been successfully applied to the pharmacokinetic study of pradefovir, adefovir dipivoxil and tenofovir disoproxil fumarate in a set of HBV patients. PMID:27089519

  3. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model.

    PubMed Central

    Archer, Rachel; Tappenden, Paul; Ren, Shijie; Martyn-St James, Marrissa; Harvey, Rebecca; Basarir, Hasan; Stevens, John; Carroll, Christopher; Cantrell, Anna; Lobo, Alan; Hoque, Sami

    2016-01-01

    BACKGROUND Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. UC can have a considerable impact on patients' quality of life. The burden for the NHS is substantial. OBJECTIVES To evaluate the clinical effectiveness and safety of interventions, to evaluate the incremental cost-effectiveness of all interventions and comparators (including medical and surgical options), to estimate the expected net budget impact of each intervention, and to identify key research priorities. DATA SOURCES Peer-reviewed publications, European Public Assessment Reports and manufacturers' submissions. The following databases were searched from inception to December 2013 for clinical effectiveness searches and from inception to January 2014 for cost-effectiveness searches for published and unpublished research evidence: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and NHS Economic Evaluation Database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science and Bioscience Information Service Previews. The US Food and Drug Administration website and the European Medicines Agency website were also searched, as were research registers, conference proceedings and key journals. REVIEW METHODS A systematic review [including network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of named interventions. The health economic analysis included a review of published economic evaluations and the development of a de novo model. RESULTS Ten randomised controlled trials were included in the systematic review. The trials suggest that adult patients receiving infliximab (IFX) [Remicade(®), Merck Sharp & Dohme Ltd (MSD)], adalimumab (ADA) (Humira(®), Abb

  4. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2010-04-01

    Adefovir dipivoxil, Alemtuzumab, Aliskiren fumarate, AMA1-C1/alhydrogel, Amlodipine besylate/atorvastatin calcium, Aripiprazole, Artesunate/amodiaquine, Asenapine maleate; Bosentan, Brivaracetam; Carisbamate, Clevudine, Clofarabine, Corticorelin acetate; Dasatinib; Elinogrel potassium, Entecavir, Erlotinib hydrochloride, Eslicarbazepine acetate, Etazolate; Fampridine, Fluarix, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, GDC-0941, GI-5005, Golimumab; Imatinib mesylate, Lacosamide, Lapatinib ditosylate, Levetiracetam, Liraglutide, LOLA; Mecasermin, Morphine hydrochloride; Natalizumab, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Poly I:CLC, Pralatrexate, Pregabalin; Ranolazine, Rasagiline mesilate, Retigabine hydrochloride, Rhenium Re-186 etidronate, Rosuvastatin calcium, Rotigotine, RTL-1000, Rufinamide; Sirolimus-eluting coronary stent, Sirolimus-eluting stent, Sorafenib, Stiripentol; Tiotropium bromide; Valsartan/amlodipine besylate, Varenicline tartrate; XL-184; Zoledronic acid monohydrate. PMID:20448862

  5. Two Cases of Paradoxical Hidradenitis Suppurativa while on Adalimumab

    PubMed Central

    Harvin, Glenn; Kasarala, George

    2016-01-01

    Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by recurring abscesses, nodules, and fistulas predominantly in the groin and axillae. The association between HS and Crohn's disease (CD) has been well documented. Tumor necrosis factor (TNF) inhibitors have shown to be effective in treating both HS and CD. We report 2 patients who developed HS while on TNF inhibitor treatment for CD. PMID:27403108

  6. Mutational analysis of reverse transcriptase and surface proteins of patients with partial virological response during mono and combination antiviral therapies in genotype D chronic hepatitis B

    PubMed Central

    Mahabadi, Mostafa; Alavian, Seyed Moayed; Norouzi, Mehdi; Keyvani, Hossein; Mahmoudi, Mahmood; Jazayeri, Seyed Mohammad

    2016-01-01

    Introduction The mutational pattern of chronic Hepatitis B virus (HBV) is unclear in patients who show incomplete response to antiviral therapy. The aims of this study were 1) to determine the benefit of combination therapy with adefovir dipivoxil (ADV) and Lamivudine (LAM) versus ADV or LAM alone in maintaining virological, biochemical and histological responses and 2) to investigate the patterns of mutations in the reverse transcriptase and surface proteins of HBV with LAM and/or ADF-resistant in partially-responded chronic hepatitis B (CHB) patients. Methods The study group consisted of 186 chronic HBV carriers who were admitted to the Tehran Hepatitis Network from 2010 to 2013. We retrospectively selected 86 patients who partially responded to different nucleoside analogue regimens. After 48 weeks of therapy, five groups of patients were defined including eight Lamivudine (LAM) Group (I), 30 Adefovir (ADV) Group (II), 16 ADV add on LAM Group (III), 32 ADV+LAM Group (IV), and 100 controls (no therapy). Reverse transcriptase (RT) and surface genes were amplified and sequenced for mutational analysis. Results All groups showed differences between mean values for age, gender, alanine transaminase (ALT), aspartate transaminase (AST), and HBV DNA levels groups showed significant differences than other groups (p < 0.05). The mutation frequencies for groups were I (1.7%), II (1.39%), III (2.28%), IV (2.0%), and V (0.38%). T54N, L80I/V, I91L/V, L180M, M204I/V, Q215P/S, and F221Y/S showed the highest number of mutations in all groups with different frequencies. Four new, unreported mutations were found. Conclusion Those patients who failed to respond in the first 48 weeks, whether they were receiving mono or combination therapy, should be tested genotypically, for the early modification of treatment. PMID:27504160

  7. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-03-01

    ABT-869, Acadesine, Acetylsalicylic acid/omeprazole, Adefovir, Adefovir dipivoxil, AEG-35156, Agatolimod sodium, Albiglutide, Alemtuzumab, Alipogene tiparvovec, Alogliptin benzoate, AMG-386, Amrubicin hydrochloride, Apremilast, Aripiprazole, Asoprisnil, Atorvastatin/fenofibrate, AVN-944, Axitinib; Belinostat, Bevacizumab, BHT-3021, BI-2536, Biapenem, Bilastine, Biphasic insulin aspart, Blinatumomab, Bortezomib, Bosentan; Catumaxomab, CD-NP, Cediranib, Certolizumab pegol, Cetuximab, Choline fenofibrate, Ciclesonide, CK-1827452,Clevudine, Clofarabine, CSL-360, CYT-997; Dapagliflozin, Darinaparsin, Denosumab, Densiron 68, Desloratadine, Dulanermin; Edoxaban tosilate, Emtricitabine, Entecavir, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fidaxomicintiacumiv, Fulvestrant; G-207, GCR-8015, Gefitinib, Ghrelin (human), Glufosfamide; HPV16L1E7CVLP; Ibutamoren mesilate, Imatinib mesylate, Insulin detemir, Insulin glargine, Iodine (I131) tositumomab, Istaroxime, ITMN-191, Ixabepilone; JZP-4, Lenalidomide; Levetiracetam, Linaclotide acetate, Liposomal cytarabine/daunorubicin, Liposomal doxorubicin, Liraglutide, LY-518674; Milatuzumab, MMR-V, Motesanib diphosphate, Mycophenolic acid sodium salt; Niacin/simvastatin; Obatoclax mesylate, Odanacatib; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Pazufloxacin, PBT-2, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perampanel, PfCP2.9, Pitavastatin calcium, Poly I:CLC, Pomalidomide, Pralatrexate, Pramlintide acetate, Prucalopride; rhGAD65, Roflumilast; RTS,S/AS02D; SCH-530348, Semagacestat, Sirolimus-eluting coronary stent, Sirolimus-Eluting Stent, SIR-Spheres, Sivelestat sodium hydrate, Sorafenib, Sunitinib malate; Tadalafil, Tafluprost, Tanespimycin, Teduglutide, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tiotropium bromide, TMC-435350, Tositumomab/iodine (I131) tositumomab, Travoprost/timolol, Triciribine

  8. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-01-01

    [90Y-DOTA-Tyr3]octreotate, Abatacept, ABT-888, ACE-011, Adefovir dipivoxil, Alosetron hydrochloride, Aminolevulinic acid methyl ester, Amlodipine, Apaziquone, Aripiprazole, AS-101, Atomoxetine hydrochloride, Atrasentan, Azacitidine; Bevacizumab, Biphasic insulin aspart, Bortezomib, Bosentan, Brivanib alaninate; CERE-120, Cetuximab, Ciclesonide, Cinacalcet hydrochloride, Combretastatin A-1 phosphate, Conatumumab, CT-322; Dabigatran etexilate, Darunavir, Deforolimus, Desloratadine, Doripenem, Doxorubicin eluting beads, Duloxetine hydrochloride, Dutasteride; Escitalopram oxalate, Eszopiclone, Etravirine, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fluticasone furoate, Fondaparinux sodium; Gabapentin enacarbil, Ghrelin (human), Golimumab; IC-51, IDM-2, JX-594; Lidocaine/prilocaine, Liraglutide, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Men ACWY, MxdnG1; Naproxcinod; OBP-301, Omalizumab; Paclitaxel nanoparticles, Pasireotide, Pazopanib hydrochloride, Pegaptanib octasodium, Peginterferon alfa-2a, Pegvisomant, Pemetrexed disodium, Pimecrolimus, Prasterone, Pregabalin; Raclopride, Ranelic acid distrontium salt, Ranibizumab, RB-006, Recombinant human relaxin H2, REG1, Regadenoson, Reximmune-C, Rilonacept; Saxagliptin, SCH-697243, Solifenacin succinate, Sorafenib; Tadalafil, Tapentadol hydrochloride, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Tipifarnib, Tolvaptan; Vardenafil hydrochloride hydrate, Vicriviroc, Volociximab, Vorinostat; WB-1001; Yttrium 90 (90Y) ibritumomab tiuxetan. PMID:19798455

  9. Chronic Hepatitis B: Integrating Long-Term Treatment Data and Strategies to Improve Outcomes in Clinical Practice

    PubMed Central

    Afdhal, Nezam H.; Bacon, Bruce R.; Brown, Robert S.

    2011-01-01

    A number of agents can reduce viral replication in patients with chronic hepatitis B, but most patients do not undergo a curative response to these drugs and therefore require long-term therapy. Thus, recent studies have investigated the long-term safety, efficacy, and resistance profiles of several antiviral nucleotide/nucleoside agents: lamivudine, telbivudine, adefovir dipivoxil, entecavir, and tenofovir. The most recent data have revealed that lamivudine and telbivudine produce high rates of resistance when treatment is continued for 2–5 years; as a result, these agents are no longer preferred for first-line monotherapy. Entecavir and tenofovir, on the other hand, appear to have favorable safety and efficacy profiles when used as monotherapy, with very low rates of resistance over 5 years. In order to help clinicians incorporate these data into clinical practice, this monograph will review recently published data on hepatitis B antiviral medications, as well as explore when to consider cessation of therapy. The treatment of special patient populations and the need to screen patients for hepatocellular carcinoma will also be discussed. PMID:22557938

  10. Safe and cost-effective control of post-transplantation recurrence of hepatitis B

    PubMed Central

    Takaki, Akinobu; Yagi, Takahito; Yamamoto, Kazuhide

    2015-01-01

    A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence. PMID:24905970

  11. Safe and cost-effective control of post-transplantation recurrence of hepatitis B.

    PubMed

    Takaki, Akinobu; Yagi, Takahito; Yamamoto, Kazuhide

    2015-01-01

    A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long-term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low-dose HBIG combined with NUC or HBIG-free regimens have been developed. This article reviews recent advances in post-OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self-producing anti-HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost-effectiveness are required. This review advocates a safe and economical approach to controlling post-OLT HBV recurrence. PMID:24905970

  12. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-10-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3,4-DAP; Adefovir dipivoxil, ADL-10-0101, alefacept, alemtuzumab, alosetron hydrochloride, ALT-711, aprepitant, atazanavir sulfate, atlizumab, atvogen; Bortezomib; CETP vaccine, clevudine, crofelemer; DAC:GLP-1, darbepoetin alfa, decitabine, drotrecogin alfa (activated), DX-9065a; E-7010, edodekin alfa, emivirine, emtricitabine, entecavir, erlosamide, erlotinib hydrochloride, everolimus, exenatide; Fondaparinux sodium, frovatriptan, fulvestrant; Gemtuzumab ozogamicin, gestodene; Homoharringtonine, human insulin; Imatinib mesylate, indiplon, indium 111 (111In) ibritumomab tiuxetan, inhaled insulin, insulin detemir, insulin glargine, ivabradine hydrochloride; Lanthanum carbonate, lapatinib, LAS-34475, levetiracetam, liraglutide, lumiracoxib; Maxacalcitol, melagatran, micafungin sodium; Natalizumab, NSC-640488; Oblimersen sodium; Parecoxib sodium, PEG-filgrastim, peginterferon alfa-2(a), peginterferon alfa-2b, pexelizumab, pimecrolimus, pleconaril, pramlintide acetate, pregabalin, prucalopride; rAHF-PFM, Ranelic acid distrontium salt, ranolazine, rDNA insulin, recombinant human soluble thrombomodulin, rhGM-CSF, roxifiban acetate, RSD-1235, rubitecan, ruboxistaurin mesilate hydrate; SC-51, squalamine; Tegaserod maleate, telbivudine, tesaglitazar, testosterone gel, tezosentan disodium, tipranavir; Vatalanib succinate; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate. PMID:14671684

  13. Palmoplantar pustular psoriasis induced by adalimumab: a case report and literature review.

    PubMed

    Ibis, Nurdan; Hocaoglu, Sehriban; Cebicci, Mehtap Aykac; Sutbeyaz, Serap Tomruk; Calis, Havva Talay

    2015-01-01

    TNF-α inhibitors (anti-TNF-α) are agents increasingly used in the treatment of rheumatic diseases resistant to classical disease-modifying treatment and they provide significant improvement of disease activity. However, these agents have many cutaneous side effects including psoriasis. Numerous reports of the induction or worsening of psoriasis in patients treated with TNF antagonists indicate that this is not a rare phenomenon. In this study, we present a patient with ankylosing spondylitis who developed palmoplantar pustular psoriasis after receiving anti-TNF-α therapy for 4 months. PMID:26250408

  14. Mesenteric Fibromatosis in Crohn's Disease as a Potential Effect of Adalimumab

    PubMed Central

    Goud, Aditya; Fleisher, Albert S.

    2016-01-01

    A 36-year-old woman with no medical or surgical history was evaluated for weight loss. Abdominal computed tomography (CT) showed signs of Crohn's disease, which was later confirmed endoscopically. She was started on tumor necrosis factor-α (TNF-α) inhibitor therapy. Nine months after treatment, she experienced additional weight loss and a 7 x 8 x 8-cm mass on repeat CT. Biopsy revealed retroperitoneal fibromatosis, so TNF-α was continued. Repeat CT showed an enlarged mass. TNF-α therapy had a suspected role in mass growth, therapy was discontinued, and the mass surgically resected. One year after resection, she has regained weight with no recurrence of the mesenteric fibromatosis. PMID:27144199

  15. Hepatitis B and liver transplantation: 2008 update.

    PubMed

    Beckebaum, Susanne; Sotiropoulos, Georgios C; Gerken, Guido; Cicinnati, Vito R

    2009-01-01

    The ultimate goal of treatment is suppression of viral replication to undetectable HBV-DNA levels prior to and after liver transplantation (LT) to prevent infection of the newly transplanted liver. Most published data are available from therapy with lamivudine (LAM) in pre- and post-transplant HBV patients. Add-on therapy with adefovir dipivoxil (ADV) in pre-transplant LAM-resistant patients has been shown to represent an effective antiviral strategy leading to hepatic recompensation in many cases and, eventually, removal from the waiting list. Newer nucleos(t)ide analogues such as entecavir, tenofovir and telbivudine have shown lower resistance rates than LAM and more antiviral potency in studies in the non-transplant setting. Combined hepatitis B immune globulin (HBIG) and nucleos(t)ide analogue therapy have been widely adopted as the most effective treatment strategy against recurrent HBV disease after LT. Many programs have evaluated lower doses or a shorter duration of HBIG and intramuscular versus intravenous routes of administration. Active immunisation using recombinant HBV vaccines, including the S, pre-S1 and pre-S2 regions, and those with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and have been used in studies to replace HBIG. Furthermore, it has been shown that immune memory against HBV can be adoptively transferred from organ donors to transplant recipients. Nucleos(t)ide analogue combination therapies might provide an alternative to the current treatment paradigm with costly HBIG; however, experience with this new treatment regimen is very limited and controlled clinical studies are urgently warranted to investigate its safety and efficacy and to determine which nucleos(t)ide analogue combinations will be the most promising in the long term after LT. PMID:18816503

  16. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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: 81C6; Adefovir dipivoxil, Agalsidase alfa, AGM-1470, albumin interferon alfa, alefacept, alosetron hydrochloride, anakinra, anti-CTLA-4 Mab, aprepitant, aripiprazole, atazanavir; BAY-43-9006, BBR-3438, beta-L-Fd4C, bimatoprost, bortezomib, bosentanBR96-doxorubicin; Caspofungin acetate, ciclesonide, cilengitide, cilomilast, COL-1621, COL-3, CpG-7909, cyclosporine; DCVax-Brain, dexmethylphenidate hydrochloride, dexosome vaccine (melanoma), donepezil hydrochloride, drotrecogin alfa (activated), DTI-015, [99Tc]-DTPA-mannosyldextran, duloxetine hydrochloride; Emivirine, emtricitabine, entecavir, epothilone B, estradiol-MNP, etonogestrel/etonogestrel/ethinylestradiol, etoricoxib; Febuxostat, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GVS-111; Heparinase I, HspE7, human alpha-glucosidase, human insulin; Imatinib mesylate, INGN-241, interferon alfa B/D hybrid, interferon alfa Biphasix, ISIS-14803; Lanicemine hydrochloride, 1311-lipiodol, liposome-encapsulated mitoxantrone, lixivaptan, lumiracoxib, lupus-AHP, LY-466700; Marimastat, MEN-10755, micafungin sodium; Nitronaproxen, NSC-683864 Omalizumab, oral insulin; Palonosetron hydrochloride, peginterferon alfa-2a, pimecrolimus, pralnacasan, pramlintide acetate, pregabalin, pyrazoloacridine; R-165335, ranolazine, risperidone, RPR-109881;, RSD-1235, Satraplatin, seocalcitol, sertindole, SMART anti-interferon gamma antibody, sulfasalazine; T-138067, TAK-013, tegaserod maleate, telithromycin, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipifarnib, TP-38; Valdecoxib, vatalanib succinate, voriconazole; ZD-9331. PMID:12690708

  17. [In Process Citation].

    PubMed

    Horváth, Gábor; Gerlei, Zsuzsanna; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Rókusz, László; Szalay, Ferenc; Tornai, István; Werling, Klára; Hunyady, Béla

    2015-12-15

    Diagnosis and treatment of HBV/HDV infection means for the patient to be able to maintain working capacity, to increase quality of life, to prevent cancer, and to prolong life expectancy, while society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2016 set by a consensus meeting of physicians involved in the treatment of these diseases. The prevalence of HBV infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline stresses the importance of quick and detailed virologic evaluations, the applicability of elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous ente- cavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2015, 156(Suppl. 2) 25-36. PMID:26667112

  18. [Diagnosis and treatment of chronic hepatitis B and D. Hungarian national consensus guideline].

    PubMed

    Horváth, Gábor; Hunyady, Béla; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Szalay, Ferenc; Telegdy, László; Tornai, István

    2014-03-01

    Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2014, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. PMID:24631887

  19. [In Process Citation].

    PubMed

    Horváth, Gábor; Gerlei, Zsuzsanna; Gervain, Judit; Lengyel, Gabriella; Makara, Mihály; Pár, Alajos; Rókusz, László; Szalay, Ferenc; Telegdy, László; Tornai, István; Werling, Klára; Hunyady, Béla

    2015-03-01

    Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2015, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2015, 156(Suppl. 1), 25-35. PMID:26039414

  20. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Know- ledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, Ad.Egr.TNF.11D, adefovir dipivoxil, AdPEDF.11, AES-14, albumex, alefacept, alemtuzumab, aliskiren fumarate, alvimopan hydrate, aAminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anti-IL-12 MAb, aprepitant, atazanavir sulfate, atrasentan, avanafil; Banoxantrone, BG-12, bimatoprost, bortezomib, bosentan; Calcipotriol/betamethasone dipropionate, caspofungin acetate, CBT-1, ciclesonide, clofarabine, conivaptan hydrochloride, CpG-7909, C-Vax, Cypher; DA-8159, DAC:GLP-1, darbepoetin alfa, darifenacin, duloxetine hydrochloride; Eculizumab, efalizumab, efaproxiral sodium, EGF vaccine, eletriptan, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, ETC-642, etoricoxib, everolimus, exenatide; Gefitinib, IV gamma-globulin; Human insulin, gamma-hydroxybutyrate sodium; IDN-6556, iguratimod, imatinib mesylate, indiplon, ixabepilone; Laquinimod, LB-80380, lidocaine/prilocaineliraglutide, lopinavir, lopinavir/ritonavir, lucinactant; MAb-14.18, melatonin, MLN-591-DM1; NC-531, neridronic acid, nesiritide, neutrophil-inhibitory factor, niacin/lovastatin; Oblimersen sodium, olcegepant, oral Insulin, ORV-105; Palonosetron hydrochloride, PAmAb, pegaptanib sodium, peginterferon alfa-2a, pegvisomant, perifosine, pexelizumab, phenoxodiol, phenserine tartrate, pimecrolimus, pramlintide acetate, pregabalin, PRO-542, prostate cancer vaccine, PT-141; Ramelteon, rasagiline mesilate, rDNA insulin, reslizumab, rh-Lactoferrin, ribamidine hydrochloride, rosuvastatin calcium; S-8184l, SC-1, sorafenib, St. John's Wort extract, SU-11248; Taxus, telbivudine, tenofovir disoproxil fumarate, teriparatide

  1. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-09-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has 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: 101M, 166Ho-DOTMP, 3-AP; Abatacept, abetimus sodium, ACR-16, adefovir dipivoxil, alefacept, AMD-070, aminolevulinic acid hexyl ester, anatumomab mafenatox, anti-CTLA-4 MAb, antigastrin therapeutic vaccine, AP-12009, AP-23573, APC-8024, aripiprazole, ATL-962, atomoxetine hydrochloride; Bevacizumab, bimatoprost, bortezomib, bosentan, BR-1; Calcipotriol/betamethasone dipropionate, cinacalcet hydrochloride, clofazimine, colchicine, cold-adapted influenza vaccine trivalent, CRM197; Desloratadine, desoxyepothilone B, diethylhomospermine; Edodekin alfa, efalizumab, elcometrine, eletriptan, enfuvirtide, entecavir, EP-2101, eplerenone, erlotinib hydrochloride, etoricoxib, everolimus, exherin, ezetimibe; Febuxostat, fluorescein lisicol, fosamprenavir calcium, frovatriptan; Hemoglobin raffimer, HSPPC-96, human insulin; Imatinib mesylate, insulin detemir, insulin glargine, IRX-2, istradefylline, IV gamma-globulin, ixabepilone; Kahalalide F; L-759274, levodopa/carbidopa/entacapone, licofelone, lonafarnib, lopinavir, lurtotecan, LY-156735; MAb G250, mecasermin, melatonin, midostaurin, muraglitazar; Nesiritide, nitronaproxen; O6-Benzylguanine, olmesartan medoxomil, olmesartan medoxomil/hydrochlorothiazide, omapatrilat, oral insulin; Parecoxib sodium, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pemetrexed disodium, peptide YY3-36, PG-CPT, phenoxodiol, pimecrolimus, posaconazole; Rasagiline mesilate, rDNA insulin, RG228, rimonabant hydrochloride, rosuvastatin calcium, rotigotine hydrochloride; S-3304, safinamide mesilate, salcaprozic acid sodium salt, SDZ-SID-791, SGN-30, soblidotin

  2. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-09-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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: Abetimus sodium, adefovir dipivoxil, AGI-1067, alefacept, alemtuzumab, ALVAC-p53, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, Anti-CTLA-4 Mab, AOD-9604, apafant, aprinocarsen sodium, arsenic trioxide; Balaglitazone, BIM-23190, bimatoprost, bortezomib, bosentan, BR-1; Canertinib dihydrochloride, CDP-850, cevimeline hydrochloride, cinacalcet hydrochloride, clenoliximab, clevudine, CN-787; D-003, darusentan, deferasirox, desloratadine dexanabinol, duloxetine hydrochloride; E-5564, edaravone, efaproxiral sodium, elvucitabine emfilermin, EN-101, enfuvirtide, entecavir, epithalon, eplerenone, erlotinib hydrochloride, escitalopram oxalate, esomeprazole magnesium, eszopiclone, etilefrine pivalate hydrochloride etoricoxib, everolimus, exenatide; Fidarestat, fondaparinux sodium; Ganstigmine hydrochloride; Homoharringtonine, HuMax-IL-15, hyperimmune IVIG; Imatinib mesylate, IMC-1C11, Inhaled insulin, irofulven, iseganan hydrochloride, ISIS-14803, ISIS-5132, ivabradine hydrochloride; Keratinocyte growth factor; Lafutidine, lanthanum carbonate, LAS-34475, levocetirizine, liraglutide, LY-307161 SR; Magnesium sulfate, maribavir, melatonin, mycobacterium cell wall complex; NN-414, NO-aspirin, nociceptin, nolomirole hydrochloride; Olmesartan medoxomil oral insulin, ospemifene; PDX, perillyl alcohol, pimecrolimus, pitavastatin calcium, pramlintide acetate, prasterone, pregabalin, PRO-542, PV-701, pyrazoloacridine; R-744, ranelic acid distrontium salt, rasburicase, rDNA insulin, resiniferatoxin, reslizumab, ridogrel, riplizumab ropivacaine, rosuvastatin calcium, roxifiban acetate, ruboxistaurin mesilate

  3. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2004-10-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has 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: Abiraterone acetate, Ad5CMV-p53, adefovir dipivoxil, AE-941, ambrisentan, aripiprazole, atomoxetine hydrochloride, atrasentan; BCH-10618, bimatoprost, BMS-184476, BMS-275183, BMS-387032, botulinum toxin type B, BR-1, BR96-Doxorubicin; Capravirine, caspofungin acetate, cinacalcet hydrochloride; Darbepoetin alfa, desloratadine, dextrin sulfate, DJ-927, duloxetine hydrochloride; Elacridar, emtricitabine, eplerenone, ertapenem sodium, escitalopram oxalate, ESP-24217, etoricoxib, exenatide, ezetimibe; Ferumoxtran-10, fondaparinux sodium, fosamprenavir calcium; GS-7904L, GW-5634; HMN-214, human insulin; IC-14, imatinib mesylate, indiplon, insulin glargine, insulinotropin, iseganan hydrochloride; Lanthanum carbonate, L-Arginine hydrochloride, LEA29Y, lenalidomide, LE-SN38, lestaurtinib, L-MDAM, lometrexol, lopinavir, lopinavir/ritonavir; Magnesium sulfate, maraviroc, mepolizumab, metreleptin, milataxel, MNA-715, morphine hydrochloride; Nesiritide, neutrophil-inhibitory factor, NK-911; Olanzapine/fluoxetine hydrochloride, olmesartan medoxomil, omalizumab, ortataxel, oxycodone hydrochloride/ibuprofen; Panitumumab, patupilone, PC-515, PD-MAGE-3 Vaccine, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pemetrexed disodium, pimecrolimus, prasugrel, pregabalin, PRO-2000; Rosuvastatin calcium, RPR-113090; sabarubicin hydrochloride, safinamide mesilate, SB-715992, sitaxsentan sodium, soblidotin, synthadotin; Tadalafil, taltobulin, temsirolimus, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate/emtricitabine, testosterone gel, tigecycline, tipranavir, tirapazamine, trabectedin

  4. Design, Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives.

    PubMed

    Imoto, Shuhei; Kohgo, Satoru; Tokuda, Ryoh; Kumamoto, Hiroki; Aoki, Manabu; Amano, Masayuki; Kuwata-Higashi, Nobuyo; Mitsuya, Hiroaki; Haraguchi, Kazuhiro

    2015-01-01

    Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N(9)-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC50 value of 0.29 μM), but cytotoxicity (CC50 value of 39 μM) against the host cells was also observed. PMID:26167667

  5. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2008-09-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has 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: ABT-263, AC-2307, Aclidinium bromide, Adefovir dipivoxil, ADH-1, Agatolimod sodium, Alefacept, Aliskiren fumarate, Aminolevulinic acid methyl ester, Anakinra, Apaziquone, Aprepitant, Aripiprazole, ASM-8, Atiprimod hydrochloride, AVE-0277, AVE-1642, AVE-8062, Axitinib, Azacitidine, AZD-0530; Bazedoxifene acetate, Bevacizumab, Bexarotene, BI-2536, Biphasic insulin aspart, BMS-387032, BMS-663513, Bortezomib, BQ-123, Brivanib alaninate, BSI-201; Caspofungin acetate, CDX-110, Cetuximab, Ciclesonide, CR-011, Cypher; Daptomycin, Darbepoetin alfa, Dasatinib, Decitabine, Deferasirox, Denosumab, Dexlansoprazole, Dexmethylphenidate hydrochloride, DNA-Hsp65 vaccine, Dovitinib, Drotrecogin alfa (activated), DTaP-HBV-IPV/Hibvaccine, DTaP-IPV-HB-PRP-T, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Elacytarabine, Emtricitabine, Endothelin, Entecavir, Eplivanserin fumarate, Escitalopram oxalate, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Farletuzumab, Fesoterodine fumarate, Fibrin sealant (human), Fulvestrant; Gefitinib, Gemtuzumab ozogamicin, Glufosfamide, GSK-1562902A; Hib-TT; Imatinib mesylate, IMC-11F8, Imidazoacridinone, IMP-321, INCB-18424, Indiplon, Indisulam, INNO-406, Irinotecan hydrochloride/Floxuridine, ITF-2357, Ixabepilone; KRN-951; Lasofoxifene tartrate; Lenalidomide, LGD-4665, Lonafarnib, Lubiprostone, Lumiliximab; MDX-1100, Melan-A/MART-1/gp100/IFN-alfa, Methyl-CDDO, Metreleptin, MLN-2704, Mycophenolic acid sodium salt; Na-ASP-2, Naproxcinod, Nilotinib hydrochloride monohydrate, NPI-2358; Oblimersen sodium, Odanacatib; Paclitaxel nanoparticles, PAN-811, Panobinostat, PBI-1402, PC-515, Peginterferon alfa

  6. CONSORT: Effects of adding adefovirdipivoxil to peginterferon alfa-2a at different time points on HBeAg-positivepatients

    PubMed Central

    Zhang, Ka; Cao, Hong; Liang, Jiayi; Shu, Xin; Sun, Haixia; Li, Gang; Xu, Qihuan

    2016-01-01

    Abstract Background: The aims of this study were to compare the efficacy and safety of the addition of adefovir dipivoxil (ADV) (started at different time points) to pegylated interferon alpha-2a (PEG-INF-α2a) and PEG-INF-α2a monotherapy. This prospective, randomized study sought to evaluate the safety and efficacy of the combination of PEG-INF-α2a and ADV at different time points.120 patients were randomized into groups that received PEG-INF-α2a as monotherapy (group A) or in combination with ADV started at week 0 (group B), 12 (group C), or 24 (group D). All patients were followed for 48 weeks. Efficacy and safety analyses were performed. Methods: Patients in group a received 135 μg of PEG-INF-α2a by subcutaneous injection once weekly for 48 weeks. Patients in the ADV add-on group received 135 μg of PEG-INF-α2a subcutaneously once weekly and received 10 mg of ADV administered once daily for 48 weeks. HBV DNA, HBsAg, HBeAg, and hepatitis B e antibody levels were determined. Responses were determined at week 12 (ADV add-on), the end of treatment for PEG-INF-α2a (48weeks) and ADV (EOT) and at the end of 96 weeks of follow-up (EOF). Results: The rate of HBV DNA loss were higher in the combination groups than group A at the week 12, week 48, the EOT and EOF (P < 0.05). The rates of HBeAg seroconversion and HBsAg loss were similar among the treatment groups (P>0.05). The alanineaminotransferase (ALT) normalization rate was higher in the combination group than group A only at the EOT (P = 0.007). By the EOF, the patients with ADV added at week 12 achieved higher rates of HBV DNA loss (71.9%), HBeAg seroconversion (50.0%), HBsAg loss (15.6%), and ALT normalization (78.1%). Conclusions: PEG-INF-α2a plus ADV combination therapy is safe and superior to PEG-INF-α2amonotherapyfor decreasing serum HBV DNA and normalizing the ALT level but has no significant impact on the rate of HBeAg seroconversion and HBsAg loss. Adding ADV at week 12 may be an

  7. Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues.

    PubMed

    Rapti, Irene; Hadziyannis, Stephanos

    2015-05-18

    Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and

  8. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2010-11-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: Abatacept, Adalimumab, AdCD40L, Adefovir, Aleglitazar, Aliskiren fumarate, AM-103, Aminolevulinic acid methyl ester, Amlodipine, Anakinra, Aprepitant, Aripiprazole, Atazanavir sulfate, Axitinib; Belimumab, Bevacizumab, Bimatoprost, Bortezomib, Bupropion/naltrexone; Calcipotriol/betamethasone dipropionate, Certolizumab pegol, Ciclesonide, CYT-997; Darbepoetin alfa, Darunavir, Dasatinib, Desvenlafaxine succinate, Dexmethylphenidate hydrochloride cogramostim; Eltrombopag olamine, Emtricitabine, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus-eluting coronary stent, Exenatide, Ezetimibe; Fenretinide, Filibuvir, Fludarabine; Golimumab; Hepatitis B hyperimmunoglobulin, HEV-239, HP-802-247, HPV-16/18 AS04, HPV-6/11/16/18, Human albumin, Human gammaglobulin; Imatinib mesylate, Inotuzumab ozogamicin, Invaplex 50 vaccine; Lapatinib ditosylate, Lenalidomide, Liposomal doxorubicin, Lopinavir, Lumiliximab, LY-686017; Maraviroc, Mecasermin rinfabate; Narlaprevir; Ocrelizumab, Oral insulin, Oritavancin, Oxycodone hydrochloride/naloxone; Paclitaxel-eluting stent, Palonosetron hydrochloride, PAN-811, Paroxetine, Pazopanib hydrochloride, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Pitavastatin calcium, Posaconazole, Pregabalin, Prucalopride succinate; Raltegravir potassium, Ranibizumab, RHAMM R3 peptide, Rosuvastatin calcium; Salclobuzic acid sodium salt, SCY-635, Selenate sodium, Semapimod hydrochloride, Silodosin, Siltuximab, Silybin, Sirolimus-eluting stent, SIR-Spheres, Sunitinib malate; Tapentadol hydrochloride, Tenofovir disoproxil

  9. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2010-12-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: 17-Hydroxyprogesterone caproate; Abacavir sulfate/lamivudine, Aclidinium bromide, Adalimumab, Adefovir, Alemtuzumab, Alkaline phosphatase, Amlodipine, Apilimod mesylate, Aripiprazole, Axitinib, Azacitidine; Belotecan hydrochloride, Berberine iodide, Bevacizumab, Bortezomib, Bosentan, Bryostatin 1; Calcipotriol/hydrocortisone, Carglumic acid, Certolizumab pegol, Cetuximab, Cinacalcet hydrochloride, Cixutumumab, Coumarin, Custirsen sodium; Darbepoetin alfa, Darifenacin hydrobromide, Darunavir, Dasatinib, Denibulin hydrochloride, Denosumab, Diacetylmorphine, Dulanermin, Duloxetine hydrochloride; Ecogramostim, Enfuvirtide, Entecavir, Enzastaurin hydrochloride, Eplerenone, Escitalopram oxalate, Esomeprazole sodium, Etravirine, Everolimus, Ezetimibe; Fenofibrate/pravastatin sodium, Ferric carboxymaltose, Flavangenol, Fondaparinux sodium; Glutamine, GSK-1024850A; Hepatitis B hyperimmunoglobulin, Hib-MenC, HIV-LIPO-5; Immunoglobulin intravenous (human), Indacaterol maleate, Indibulin, Indium 111 (¹¹¹In) ibritumomab tiuxetan, Influenza A (H1N1) 2009 Monovalent vaccine, Inhalable human insulin, Insulin glulisine; Lapatinib ditosylate, Leucovorin/UFT; Maraviroc, Mecasermin, MMR-V, Morphine hydrochloride, Morphine sulfate/naltrexone hydrochloride, Mycophenolic acid sodium salt; Naproxen/esomeprazole magnesium, Natalizumab; Oncolytic HSV; Paliperidone, PAN-811, Paroxetine, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimecrolimus, Posaconazole, Pregabalin; Raltegravir potassium, Ranelic acid distrontium salt, Rasburicase, Rilpivirine

  10. Protective effects of tumor necrosis factor-α blockade by adalimumab on articular cartilage and subchondral bone in a rat model of osteoarthritis

    PubMed Central

    Ma, C.H.; Lv, Q.; Yu, Y.X.; Zhang, Y.; Kong, D.; Niu, K.R.; Yi, C.Q.

    2015-01-01

    We aimed to investigate the effects of an anti-tumor necrosis factor-α antibody (ATNF) on cartilage and subchondral bone in a rat model of osteoarthritis. Twenty-four rats were randomly divided into three groups: sham-operated group (n=8); anterior cruciate ligament transection (ACLT)+normal saline (NS) group (n=8); and ACLT+ATNF group (n=8). The rats in the ACLT+ATNF group received subcutaneous injections of ATNF (20 μg/kg) for 12 weeks, while those in the ACLT+NS group received NS at the same dose for 12 weeks. All rats were euthanized at 12 weeks after surgery and specimens from the affected knees were harvested. Hematoxylin and eosin staining, Masson's trichrome staining, and Mankin score assessment were carried out to evaluate the cartilage status and cartilage matrix degradation. Matrix metalloproteinase (MMP)-13 immunohistochemistry was performed to assess the cartilage molecular metabolism. Bone histomorphometry was used to observe the subchondral trabecular microstructure. Compared with the rats in the ACLT+NS group, histological and Mankin score analyses showed that ATNF treatment reduced the severity of the cartilage lesions and led to a lower Mankin score. Immunohistochemical and histomorphometric analyses revealed that ATNF treatment reduced the ACLT-induced destruction of the subchondral trabecular microstructure, and decreased MMP-13 expression. ATNF treatment may delay degradation of the extracellular matrix via a decrease in MMP-13 expression. ATNF treatment probably protects articular cartilage by improving the structure of the subchondral bone and reducing the degradation of the cartilage matrix. PMID:26445328

  11. Maintenance Therapy in IBD

    MedlinePlus

    ... Infliximab is given as a single-dose intravenous infusion, and many patients may be able to wait ... is recommended to wait at least for two infusions to see infliximab's effectiveness. Adalimumab Adalimumab (Humira®) is ...

  12. What's in a name?

    PubMed

    1999-01-01

    A table charts the various nomenclature of drugs used to treat HIV and AIDS. The common name, generic name, and brand name are given for several categories including NARTIs (NRTIs, "Nukes", Nucleoside analogue reverse transcriptase inhibitors), NNRTIs (Non-nucleoside reverse transcriptase inhibitors), and PIs (Protease Inhibitors). Other drugs listed are Hydroxyurea (anti-cancer drug) and preveon (Adefovir (Nucleotide)). PMID:11366757

  13. Selective Inhibition of Porcine Endogenous Retrovirus Replication in Human Cells by Acyclic Nucleoside Phosphonates▿

    PubMed Central

    Shi, Minyi; Wang, Xin; De Clercq, Erik; Takao, Sonshin; Baba, Masanori

    2007-01-01

    Several anti-human immunodeficiency virus type 1 reverse transcriptase inhibitors were evaluated for their antiviral activities against porcine endogenous retrovirus in human cells. Among the test compounds, zidovudine was found to be the most active. The order of potency was zidovudine > phosphonylmethoxyethoxydiaminopyrimidine = phosphonylmethoxypropyldiaminopurine > tenofovir ≥ adefovir > stavudine. PMID:17470654

  14. Guide for Patients Taking Nonsteroidal Immunosuppressive Drugs

    MedlinePlus

    ... taking adalimumab, etanercept, or in iximab: Check your temperature frequently, and report a fever to your physician ... Receptor Antagonists For patients taking basiliximab: Check your temperature frequently, and report a fever to your physician ...

  15. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.

    PubMed Central

    Stevenson, Matt; Archer, Rachel; Tosh, Jon; Simpson, Emma; Everson-Hock, Emma; Stevens, John; Hernandez-Alava, Monica; Paisley, Suzy; Dickinson, Kath; Scott, David; Young, Adam; Wailoo, Allan

    2016-01-01

    OBJECTIVES Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION This study is registered as PROSPERO CRD42012003386. FUNDING The National Institute for Health Research Health Technology Assessment programme. PMID:27140438

  16. High-Dose Loperamide Abuse Inducing Life-Threatening Cardiac Arrhythmias; Topiramate-Induced Diarrhea in a Breastfed Infant; Danazol-Induced Stevens–Johnson Syndrome; Asenapine-Induced Myasthenic Syndrome; Black Hairy Tongue Due to Linezolid; Adalimumab-Induced Priapism

    PubMed Central

    Mancano, Michael A.

    2015-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) Med Watch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s Med Watch program and Temple University School of Pharmacy. ISMP is an FDA Med Watch partner. PMID:26405319

  17. Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification

    PubMed Central

    Verbruggen, Gust; Wittoek, Ruth; Cruyssen, Bert Vander; Elewaut, Dirk

    2012-01-01

    Background Adalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive hand osteoarthritis (HOA) were assessed. Methods Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSSTM). Results The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab. Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients. Conclusion Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo. PMID:22128078

  18. Entecavir Interacts with Influx Transporters hOAT1, hCNT2, hCNT3, but Not with hOCT2: The Potential for Renal Transporter-Mediated Cytotoxicity and Drug–Drug Interactions

    PubMed Central

    Mandíková, Jana; Volková, Marie; Pávek, Petr; Navrátilová, Lucie; Hyršová, Lucie; Janeba, Zlatko; Pavlík, Jan; Bárta, Pavel; Trejtnar, František

    2016-01-01

    Entecavir (ETV) is one of the most potent agents for the treatment of the hepatitis B viral infection. The drug is principally eliminated by the kidney. The goal of this study was to investigate the potential of ETV to interact in vitro with the renal SLC transporters hOAT1, hOCT2, hCNT2 and hCNT3. Potential drug–drug interactions of ETV at the renal transporters with antiviral drugs known to be excreted by the kidney (adefovir, tenofovir, cidofovir) as well as transporter-dependent cytotoxicity were also examined. Interactions with the selected transporters along with cytotoxicity were studied in several transiently transfected cellular models using specific substrates and inhibitors. ETV was found to be both a substrate and inhibitor of hOAT1 (IC50 = 175.3 μM), hCNT2 (IC50 = 241.9 μM) and hCNT3 (IC50 = 278.4 μM) transporters, although it interacted with the transporters with relatively low affinities. ETV inhibited the cellular uptake of adefovir, tenofovir, and cidofovir by hOAT1; however, effective inhibition was shown at ETV concentrations exceeding therapeutic levels. In comparison with adefovir, tenofovir, and cidofovir, ETV displayed no transporter-mediated cytotoxicity in cells transfected with hOAT1, hCNT2, and hCNT3. No significant interaction of ETV with hOCT2 was detected. The study demonstrates interactions of ETV with several human renal transporters. For the first time, an interaction of ETV with the hCNTs was proved. We show that the potency of ETV to cause nephrotoxicity and/or clinically significant drug-drug interactions related to the tested transporters is considerably lower than that of adefovir, tenofovir, and cidofovir. PMID:26779022

  19. A biomimetic chitosan derivates: preparation, characterization and transdermal enhancement studies of N-arginine chitosan.

    PubMed

    Lv, Hui-Xia; Zhang, Zhen-Hai; Wang, Xiao-Pan; Cheng, Qing-Qing; Wang, Wei; Huang, Xu-Hui; Zhou, Jian-Ping; Zhang, Qiang; Hou, Lu-Lu; Huo, Wei

    2011-01-01

    A novel arginine-rich chitosan (CS) derivates mimicked cell penetration peptides; N-Arginine chitosan (N-Arg-CS) was prepared by two reaction methods involving activated L-arginine and the amine group on the chitosan. FTIR spectra showed that arginine was chemically coupled with CS. Elemental analysis estimated that the degrees of substitution (DS) of arginine in CS were 6%, 31.3% and 61.5%, respectively. The drug adefovir was chosen as model and its permeation flux across excised mice skin was investigated using a Franz diffusion cell. The results showed that the most effective enhancer was 2% (w/v) concentration of 10 kDa N-Arg-CS with 6% DS. At neutral pH, the cumulative amount of adefovir permeated after 12 hours was 2.63 ± 0.19 mg cm(-2) which was 5.83-fold more than adefovir aqueous solution. Meanwhile N-Arg-CS was 1.83, 2.22, and 2.45 times more effective than Azone, eucalyptus and peppermint, respectively. The obtained results suggest that N-Arg-CS could be a promising transdermal enhancer. PMID:21829153

  20. Novel treatment options for hepatitis B virus infection.

    PubMed

    Kumar, Rakesh; Agrawal, Babita

    2004-02-01

    Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators. PMID:15043391

  1. Case Report of Lichen Planopilaris Occurring in a Pediatric Patient Receiving a Tumor Necrosis Factor α Inhibitor and a Review of the Literature.

    PubMed

    Jayasekera, Prativa S A; Walsh, Maeve L; Hurrell, Daniel; Parslew, Richard A G

    2016-03-01

    A 12-year-old girl with extended oligoarthritis treated with adalimumab presented with a short history of a progressive cutaneous eruption involving the legs and scalp. Physical examination and histologic results were consistent with lichen planopilaris. The adalimumab was discontinued. She received treatment with topical clobetasol propionate and the majority of the lesions resolved. Residual lesions and the extended oligoarthritis were then treated with sulfasalazine. Adalimumab is a tumor necrosis factor α (TNF-α) inhibitor used for the treatment of a variety of immunologically mediated conditions, including lichen planus and lichen planopilaris. TNF-α antagonists have been associated with paradoxical psoriasiform, lichenoid, eczematous, granulomatous, and acneiform eruptions. We detail this case and review the literature of lichenoid reactions secondary to TNF-α inhibitors. PMID:26840781

  2. DISSEMINATED GRANULOMA ANNULARE: A CUTANEOUS ADVERSE EFFECT OF ANTI-TNF AGENTS

    PubMed Central

    Ratnarathorn, Mondhipa; Raychaudhuri, Siba P; Naguwa, Stanley

    2011-01-01

    Tumor necrosis factor-alpha (TNF-α) inhibitors, such as etanercept, infliximab, and adalimumab, bind to TNF-α and thereby act as anti-inflammatory agents. This group of drugs has been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spodylitis, Crohn disease, and juvenile idiopathic arthritis. We describe a 56-year-old woman who developed an erythematous pruritic rash on both arms—diagnosed as granuloma annulare by skin biopsy—approximately 22 months after initiating adalimumab for treatment of rheumatoid arthritis. On stopping adalimumab there was total clearance of the skin lesions, but a similar rash developed again when her treatment was switched to another anti-TNF agent (etanercept). This clinical observation supports a link between TNF inhibition and the development of granuloma annulare. PMID:22345789

  3. Direct Comparative Effectiveness Among 3 Anti–Tumor Necrosis Factor Biologics in a Real-Life Cohort of Patients With Rheumatoid Arthritis

    PubMed Central

    Santos-Moreno, Pedro; Sánchez, Guillermo; Gómez, Danny; Bello-Gualtero, Juan; Castro, Carlos

    2016-01-01

    Objective This study aimed to compare the clinical response at 36 months and evaluate the adverse events in a cohort of patients with rheumatoid arthritis treated with etanercept, infliximab, or adalimumab. Methods An observational retrospective cohort study was performed. Patients older than 18 years with active rheumatoid arthritis, for which the physician had initiated a treatment scheme with etanercept, infliximab, or adalimumab, were included in the study. The follow-up was conducted through at least trimestral evaluations during the course of 36 months. Outcomes evaluated included Disease Activity Score 28, level of disease activity, Health Assessment Questionnaire, and degree of disability. Results Three hundred seven subjects were included in the cohort (108 adalimumab, 107 infliximab, and 92 etanercept). The median Disease Activity Score 28 at the onset was 4.1 and 2.39 at month 36. There were no differences among the 3 medications (P = 0.51). The remission rate was of 7.4 per 100 people per month (95% confidence interval [CI], 6.6–8.3) without differences between groups. The initial Health Assessment Questionnaire median was 1.75 and 0.25 at 36 months. No differences per medicine were found (P = 0.54). The most common adverse effect was dermatitis. Eighteen cases of serious adverse effects occurred, including 11 cases of serious infectious events. The adverse events rates were as follows: infliximab, 24 per 100 people per year (95% CI, 19–29); adalimumab, 22 per 100 people per year (95% CI, 18–27); and etanercept, 12 per 100 people per year (95% CI, 8–16). Conclusions Etanercept, infliximab, and adalimumab are 3 effective therapeutic anti–tumor necrosis factor alternatives to reduce the level of severity and the degree of disability generated by rheumatoid arthritis. Etanercept presented a rate of adverse events lower than those for infliximab and adalimumab. PMID:26886438

  4. Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

    PubMed Central

    Prattichizzo, Francesco; Giuliani, Angelica; Recchioni, Rina; Bonafè, Massimiliano; Marcheselli, Fiorella; De Carolis, Sabrina; Campanati, Anna; Giuliodori, Katia; Rippo, Maria Rita; Brugè, Francesca; Tiano, Luca; Micucci, Carla; Ceriello, Antonio; Offidani, Annamaria; Procopio, Antonio Domenico; Olivieri, Fabiola

    2016-01-01

    Endothelial cell senescence is characterized by acquisition of senescence-associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-α (TNF-α), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-β-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy. TNF-α blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures. A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells. Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects. PMID:26943583

  5. Gastrointestinal stability of therapeutic anti-TNF α IgG1 monoclonal antibodies.

    PubMed

    Yadav, Vipul; Varum, Felipe; Bravo, Roberto; Furrer, Esther; Basit, Abdul W

    2016-04-11

    Monoclonal antibodies (mAbs) are highly effective therapeutic agents, administered exclusively by the parenteral route owing to their previously-documented instability in the gastrointestinal (GI) tract when delivered orally. To investigate the extent of the validity of this assumption, the stability of the tumor necrosis factor alpha (TNF-α) neutralizing IgG1 mAbs, infliximab and adalimumab, was studied in human GI conditions. In gastric fluid, infliximab and adalimumab degraded rapidly, with complete degradation occurring within 1min. In small intestinal fluid, the molecules were shown to be more stable, but nonetheless degraded within a short time frame of 30min. Investigations into the mechanisms responsible for infliximab and adalimumab instability in the small intestine revealed that the proteolytic enzyme elastase, and to a lesser extent the enzymes trypsin and chymotrypsin, was responsible for their degradation. By contrast, in the human colon, 75% and 50% of the dose of infliximab and adalimumab, respectively, were intact after 60min, with conversion of mAbs into F(ab')2 Fab and Fc fragments detected in colonic conditions. These data indicate that therapeutic IgG1 antibodies are more stable in the colon than in the upper GI tract, therefore highlighting the potential for oral delivery of anti-TNF-α mAbs targeted to the colon. PMID:26892815

  6. Retrospective cohort study of anti-tumor necrosis factor agent use in a veteran population

    PubMed Central

    Madkour, Nermeen; Kazerooni, Rashid

    2014-01-01

    Introduction. Anti-tumor necrosis factor (TNF) agents are effective for several immunologic conditions (rheumatoid arthritis (RA), Crohn’s disease (CD), and psoriasis). The purpose of this study was to evaluate the efficacy and safety of anti-TNF agents via chart review. Methods. Single-site, retrospective cohort study that evaluated the efficacy and safety of anti-TNF agents in veterans initiated between 2010 and 2011. Primary aim evaluated response at 12 months post-index date. Secondary aims evaluated initial response prior to 12 months post-index date and infection events. Results. A majority of patients were prescribed anti-TNF agents for CD (27%) and RA (24%). Patients were initiated on etanercept (41%), adalimumab (40%), and infliximab (18%) between 2010 and 2011. No differences in patient demographics were reported. Response rates were high overall. Sixty-five percent of etanercept patients, 82% of adalimumab patients, and 59% of infliximab patients were either partial or full responders, respectively. Approximately 16%, 11%, and 12% of etanercept, adalimumab, and infliximab were non-responders, respectively. Infections between the groups were non-significant. Etanercept and adalimumab patients had higher but non-significant odds of being a responder relative to infliximab. Conclusions. Most patients initiated with anti-TNF agent were responders at 12 months follow-up for all indications in a veteran population. PMID:24883246

  7. Large Nosocomial Outbreak Associated with a Norwegian Scabies Index Case Undergoing TNF-α Inhibitor Treatment: Management and Control.

    PubMed

    Belvisi, Valeria; Orsi, Giovanni Battista; Del Borgo, Cosmo; Fabietti, Paolo; Ianari, Adriana; Albertoni, Francesco; Porcelli, Patricia; Potenza, Concetta; Mastroianni, Claudio Maria

    2015-11-01

    We describe a large outbreak associated with a crusted (Norwegian) scabies case in an immunocompromised patient following treatment with TNF-α inhibitor (adalimumab) for psoriasis arthritis. The increasing use of TNF-α inhibitors should induce clinicians to consider this serious parasitic infection when evaluating skin rashes in patients receiving biologic therapies. PMID:26288185

  8. 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

  9. Circumorificial plasmacytosis/plasma cell orificial mucositis: a case series and a review of the literature.

    PubMed

    Galvin, Sheila; Bowe, Conor; O Regan, Esther M; Conlon, Niall; Flint, Stephen R; Healy, Claire M

    2016-09-01

    Circumorificial plasmacytosis is a rare plasma cell proliferative disorder of the orificial mucous membranes. The etiology is unknown, and there are no reported effective treatments to date. We report three cases of idiopathic circumorificial plasmacytosis with varying clinical presentations and responses to treatment, including a first reported case of resolution with adalimumab therapy. PMID:27544398

  10. Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-α blockers

    PubMed Central

    Laine, Juha; Jokiranta, T Sakari; Eklund, Kari K; Väkeväinen, Merja; Puolakka, Kari

    2016-01-01

    Monitoring of anti-drug antibodies (ADAbs) or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF)-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL) and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3–6 months) scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2–5 of 100 patients, a proportion which is easily exceeded in real-life clinical practice. This study indicates that routine monitoring of drug level and ADAbs is cost-beneficial in clinical practice, thereby improving the decision-making process in using TNF-α blockers. PMID:27099470

  11. Comparative Persistence of the TNF Antagonists in Rheumatoid Arthritis – A Population-Based Cohort Study

    PubMed Central

    Fisher, Anat; Bassett, Ken; Wright, James M.; Brookhart, M. Alan; Freeman, Hugh; Dormuth, Colin R.

    2014-01-01

    Objective To compare persistence with tumor necrosis factor alpha (TNF) antagonists among rheumatoid arthritis patients in British Columbia. Treatment persistence has been suggested as a proxy for real-world therapeutic benefit and harm of treatments for chronic non-curable diseases, including rheumatoid arthritis. We hypothesized that the different pharmacological characteristics of infliximab, adalimumab and etanercept cause statistically and clinically significant differences in persistence. Methods We conducted a population-based cohort study using administrative health data from the Canadian province of British Columbia. The study cohort included rheumatoid arthritis patients who initiated the first course of a TNF antagonist between 2001 and 2008. Persistence was measured as the time between first dispensing to discontinuation. Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. Persistence was estimated and compared using survival analysis. Results The study cohort included 2,923 patients, 63% treated with etanercept. Median persistence in years (95% confidence interval) with infliximab was 3.7 (2.9–4.9), with adalimumab 3.3 (2.6–4.1) and with etanercept 3.8 (3.3–4.3). Similar risk of discontinuation was observed for the three drugs: the hazard ratio (95% confidence interval) was 0.98 (0.85–1.13) comparing infliximab with etanercept, 0.95 (0.78–1.15) comparing infliximab with adalimumab and 1.04 (0.88–1.22) comparing adalimumab with etanercept. Conclusions Similar persistence was observed with infliximab, adalimumab and etanercept in rheumatoid arthritis patients during the first 9 years of use. If treatment persistence is a good proxy for the therapeutic benefit and harm of these drugs, then this finding suggests that the three drugs share an overall similar benefit-harm profile in rheumatoid arthritis patients. PMID:25141123

  12. Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice.

    PubMed

    Piccand, Matthieu; Bessa, Juliana; Schick, Eginhard; Senn, Claudia; Bourquin, Carole; Richter, Wolfgang F

    2016-03-01

    The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immune-tolerant offspring showed a slower adalimumab clearance (4.24 ± 0.32 mL/day/kg) as compared to the control group (12.09 ± 3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals. PMID:26603888

  13. Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-α blockers.

    PubMed

    Laine, Juha; Jokiranta, T Sakari; Eklund, Kari K; Väkeväinen, Merja; Puolakka, Kari

    2016-01-01

    Monitoring of anti-drug antibodies (ADAbs) or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF)-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL) and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3-6 months) scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2-5 of 100 patients, a proportion which is easily exceeded in real-life clinical practice. This study indicates that routine monitoring of drug level and ADAbs is cost-beneficial in clinical practice, thereby improving the decision-making process in using TNF-α blockers. PMID:27099470

  14. A cost-effectiveness analysis of different therapies in patients with chronic hepatitis B in Italy

    PubMed Central

    Colombo, Giorgio L; Gaeta, Giovanni B; Viganò, Mauro; Di Matteo, Sergio

    2011-01-01

    Introduction: Chronic hepatitis B (CHB) is a prevalent disease associated with high morbidity, mortality, and impact on health care costs. Antiviral therapy is aimed at reducing hepatitis B virus replication in order to limit progressive liver disease and improve the natural history of the disease. This study estimates the cost-effectiveness of lamivudine, adefovir, telbivudine, entecavir, tenofovir, and pegylated interferon in patients with CHB. Methods: A Markov model was developed to evaluate the costs and benefits of antivirals in a cohort of patients with CHB (hepatitis B e antigen [HBeAg]-positive and HBeAg-negative) and cirrhosis over a period of 10 years. Different rescue therapies were considered, according to current guidelines. Data on efficacy and changes in quality of life were derived from clinical trials and epidemiological Italian data. Direct costs were assessed from the perspective of the Italian National Health Service. Results: Tenofovir was associated with lower costs and higher efficacy compared with entecavir, telbivudine, and adefovir, as shown by their incremental cost-effectiveness ratios (ICER) per quality-adjusted life-year (QALY) gained: tenofovir €30,959, entecavir €45,971, telbivudine €62,051, and adefovir €82,824. Even following 1 year of pegylated interferon therapy, tenofovir had a more favourable ICER per QALY gained compared with the other rescue options. The analysis of patients with cirrhosis confirms the results obtained with the CHB cohort though with higher ICERs. Sensitivity analyses on the main variables confirm the results of the base case scenario. Conclusion: Within the Italian health care system, in patients with CHB, tenofovir is a cost-effective strategy compared with other available therapies. Public health care authorities would benefit from mathematical models designed to estimate the future burden of CHB infection together with the impact of treatment and drug resistance. PMID:21935331

  15. New antivirals - mechanism of action and resistance development.

    PubMed

    Balzarini, J; Naesens, L; De Clercq, E

    1998-10-01

    In recent years, several novel treatment modalities emerged for a number of virus infections, including lamivudine for hepatitis B virus, abacavir, adefovir dipivoxyl and apropovir disprometil for human immunodeficiency virus, cidofovir for cytomegalovirus, and famciclovir (the oral prodrug of penciclovir) and cidofovir for other herpesviruses (i.e. herpes simplex virus and varicella-zoster virus). For all drugs, resistance eventually develops upon prolonged administration to the infected individuals, albeit at a varying extent. In addition, new mutations related to multidrug resistance have recently been identified. PMID:10066527

  16. 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

  17. The Expression of TLR-9, CD86, and CD95 Phenotypes in Circulating B Cells of Patients with Chronic Viral Hepatitis B or C before and after Antiviral Therapy

    PubMed Central

    Zhao, Ping-wei; Ma, Liang; Ji, Hui-fan; Yu, Lei; Feng, Jun-yan; Liu, Ming-yuan; Jiang, Yan-fang

    2015-01-01

    Aims. This study aimed to assess the differential expression of specific B cell subtypes in patients with chronic viral hepatitis. Methods. The frequencies of differential expression of specific B cell subtypes in patients with chronic viral hepatitis and healthy controls were assessed by flow cytometry using monoclonal antibodies specific for CD38, CD27, CD86, CD95, TLR-9, and IgD. The effect of adefovir treatment on B cell subsets in HBV patients was determined. The values of clinical parameters in the patients were also measured. Results. The frequency of CD86+ B cells was not significantly different in chronic HBV patients but was higher in HCV patients compared with that in healthy controls. CD95 and IgD levels were lower in HBV and HCV patients than in healthy controls. A significant negative correlation occurred between the proportion of CD95+ B cells and HBV DNA viral load. The frequency of TLR-9 on the B cells in HBV and HCV patients was higher compared with that of healthy controls. After treatment with adefovir, the frequency of CD95 and IgD expressed on B cells was increased in HBV patients. Conclusions. Activated B cells and exhausted B cells homeostasis were commonly disturbed in HBV and HCV patients. PMID:25892855

  18. Orbital Relapsing Polychondritis: A Unique Presentation, Complication, and Treatment.

    PubMed

    Moore, Grant H; Rootman, Daniel B; Roybal, C Nathaniel; Goldberg, Robert A

    2016-01-01

    An 87-year-old man with a history of relapsing polychondritis presented to the emergency department after 4 days of worsening left periorbital swelling and erythema. On examination, he demonstrated clinical features consistent with orbital cellulitis and was treated with a trial of intravenous antibiotics. His condition did not improve over the next 36 hours and intravenous methylprednisolone was initiated. This led to rapid improvement in orbital symptoms and signs, and a diagnosis of specific orbital inflammation secondary to relapsing polychondritis was made. The patient was discharged on a tapering dose of prednisone. As a steroid-sparing measure, adalimumab was initiated; however, the patient developed Sweet Syndrome. Adalimumab was subsequently discontinued, steroid dose was increased, and anakinra treatment was initiated. This therapeutic course led to significant clinical improvement. Since initiating anakinra, the patient has had no recurrences of Sweet Syndrome. Anakinra may be a useful adjunct therapy for ophthalmic manifestations of relapsing polychondritis. PMID:25072220

  19. Beauty and the Biologic: Artistic Documentation of Scientific Breakthrough in Psoriasis

    PubMed Central

    Maul, Julia-Tatjana; Carraro, Sabina; Stierlin, Johanna; Geiges, Michael L.; Navarini, Alexander A.

    2015-01-01

    The making of wax moulages was an exclusive and sought-after art that was primarily used for teaching, but also to document clinical and laboratory research during the first half of the 20th century. Applying the technique of moulage-making to document a case of psoriasis improvement for posterity, a moulage of the trunk of a patient with psoriasis vulgaris was taken prior to treatment with biologics – adalimumab, a TNF-α antagonist – and again 3 month after adalimumab was first given. Our modern moulage shows in the most realistic way the science-driven improvement of psoriasis achievable nowadays with biologics. However, the real clinical picture of the disease is shrouded by showing only one detail of the patient – by accident the one with the best clinical improvement. All available techniques to document skin disease have advantages and limitations and nothing beats seeing live patients. PMID:26557072

  20. Beauty and the Biologic: Artistic Documentation of Scientific Breakthrough in Psoriasis.

    PubMed

    Maul, Julia-Tatjana; Carraro, Sabina; Stierlin, Johanna; Geiges, Michael L; Navarini, Alexander A

    2015-01-01

    The making of wax moulages was an exclusive and sought-after art that was primarily used for teaching, but also to document clinical and laboratory research during the first half of the 20th century. Applying the technique of moulage-making to document a case of psoriasis improvement for posterity, a moulage of the trunk of a patient with psoriasis vulgaris was taken prior to treatment with biologics - adalimumab, a TNF-α antagonist - and again 3 month after adalimumab was first given. Our modern moulage shows in the most realistic way the science-driven improvement of psoriasis achievable nowadays with biologics. However, the real clinical picture of the disease is shrouded by showing only one detail of the patient - by accident the one with the best clinical improvement. All available techniques to document skin disease have advantages and limitations and nothing beats seeing live patients. PMID:26557072

  1. [Autoimmune aspects of treatment with TNF-alpha inhibitors].

    PubMed

    Kolarz, Bogdan; Targońska-Stepniak, Bozena; Darmochwał-Kolarz, Dorota; Majdan, Maria

    2007-01-01

    Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of such diseases as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and juvenile chronic arthritis. Recent years have brought improvement in the understanding of the pathogeneses of these diseases, resulting in the production of new groups of biological drugs, including, among others, anti-TNF-alpha antibodies. The use of TNF inhibitors has been a great advance in the treatment of patients with these inflammatory diseases. Infliximab and adalimumab are monoclonal antibodies that bind to and neutralize the activity of TNF-alpha. Infliximab is a mouse/human chimera that joins the variable regions of a mouse antibody to the constant region of human IgG1. Adalimumab is a fully human IgG1 antibody. Etanercept is a dimeric fusion protein that joins the human p75 TNF receptor to the Fc domain of human IgG1. The beneficial effects of the anti-TNF monoclonal antibodies infliximab and adalimumab and the soluble receptor fusion protein etanercept in the treatment of rheumatoid arthritis, especially in patients resistant to other disease-modifying antirheumatic drugs (DMARDs), are discussed. We observe stoppage of articular destruction during treatment with TNF-alpha inhibitors. Soon after the introduction of this therapy it was found that these agents have a propensity for stimulating the production of autoantibodies and antibodies against themselves. In this review, recent studies analyzing the effect of TNF-alpha blockade (infliximab, etanercept, and adalimumab) on the ANA, anti-dsDNA, and anticardiolipin antibody profiles in autoimmune diseases are discussed. PMID:17786135

  2. Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis

    PubMed Central

    Baki, Enayatullah; Zwickel, Philipp; Zawierucha, Anna; Ehehalt, Robert; Gotthardt, Daniel; Stremmel, Wolfgang; Gauss, Annika

    2015-01-01

    AIM: To evaluate the outcome of anti-tumor necrosis factor alpha (anti-TNFα) therapy in outpatients with ulcerative colitis at a tertiary referral center. METHODS: All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled. Patients with a follow-up period of less than 6 mo from start of anti-TNFα therapy were excluded. Medical records of all eligible individuals were carefully reviewed. Steroid-free clinical remission of a duration of at least 3 mo, colectomy rate, duration of anti-TNFα therapy, need for anti-TNFα dose escalation, and the occurrence of adverse events were evaluated as the main outcome parameters. RESULTS: Seventy-two patients were included (35 treated with infliximab, 17 with adalimumab, 20 with both consecutively). Median follow-up was 27 mo (range: 6-87 mo). Steroid-free clinical remission was achieved by 22.2% of the patients (median duration: 21 mo until end of follow-up; range: 3-66 mo). Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission. The overall colectomy rate was 20.8%. Nearly 50% of the patients underwent anti-TNFα dose escalation during the follow-up period. For both the infliximab and the adalimumab treated patients, non-response to anti-TNFα therapy was the major reason for treatment discontinuation. 18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events. CONCLUSION: Real-life remission rates of ulcerative colitis under anti-TNFα are overall low, but some patients have a clear long-term benefit. PMID:25805935

  3. Interventions for hidradenitis suppurativa: a Cochrane systematic review incorporating GRADE assessment of evidence quality.

    PubMed

    Ingram, J R; Woo, P N; Chua, S L; Ormerod, A D; Desai, N; Kai, A C; Hood, K; Burton, T; Kerdel, F; Garner, S E; Piguet, V

    2016-05-01

    More than 50 interventions have been used to treat hidradenitis suppurativa (HS), and so therapy decisions can be challenging. Our objective was to summarize and appraise randomized controlled trial (RCT) evidence for HS interventions in adults. Searches were conducted in Medline, Embase, CENTRAL, LILACS, five trials registers and abstracts from eight dermatology conferences until 13 August 2015. Two review authors independently assessed study eligibility, extracted data and assessed methodological quality. Primary outcomes were quality of life and adverse effects of the interventions. Twelve trials, from 1983 to 2015, investigating 15 different interventions met our inclusion criteria. The median trial duration was 16 weeks and the median number of participants was 27. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) by 4·0 points, which equates to the minimal clinically important difference for the scale, compared with placebo (95% confidence interval -6·5 to -1·5 points). Evidence quality was reduced to 'moderate' because the results are based on only a single study. Adalimumab 40 mg every other week was ineffective in a meta-analysis of two studies comprising 124 participants. Infliximab 5 mg kg(-1) improved the DLQI score by 8·4 points after 8 weeks in a moderate-quality study completed by 33 of 38 participants. Etanercept 50 mg twice weekly was ineffective. Inclusion of a gentamicin sponge prior to primary closure did not improve outcomes. Other interventions, including topical and oral antibiotics, were investigated by relatively small studies, preventing treatment recommendations due to imprecision. More, larger RCTs are required to investigate most HS interventions, particularly oral treatments and surgical therapy. Moderate-quality evidence suggests that adalimumab given weekly and infliximab are effective, whereas adalimumab every other week is ineffective. PMID:26801356

  4. Etanercept-induced cystic acne.

    PubMed

    Kashat, Maria; Caretti, Katherine; Kado, Jessica

    2014-07-01

    Tumor necrosis factor α antagonists are potent biologics used to treat a variety of autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn disease, psoriasis, and psoriatic arthritis. These medications are known to have many side effects (eg, infusion reactions, cytopenia, risk for infection, heart failure); however, only a few cases of acne vulgaris have been associated with the use of these biologics, particularly infliximab and adalimumab. We report a rare case of etanercept-induced cystic acne. PMID:25101341

  5. Dose modifications of anti-TNF drugs in rheumatoid arthritis patients under real-world settings: a systematic review.

    PubMed

    Ferriols-Lisart, Rafael; Ferriols-Lisart, Francisco

    2015-07-01

    Anti-TNF dose modifications in rheumatoid arthritis have implications on healthcare resource utilization. The objective was to systematically review the dose modifications, both escalations and reductions, of currently available anti-TNF drugs (adalimumab, certolizumab, etanercept, golimumab and infliximab) in the real-world setting. We performed a systematic literature search of MEDLINE, ISI Web of Science, EMBASE, Indice Médico Español databases and American College of Rheumatology and European League Against Rheumatism annual congresses databases. PRISMA and MOOSE guidelines were followed. Only observational studies were included. Clinical trials were excluded since they do not reflect routine clinical practice. Dose escalations and reductions of the anti-TNF drug and their magnitude were collected. Thirty-four studies fulfill the inclusion criteria. Etanercept was associated with the lower percentage of patients under dose escalation (4.5 %; range 0-22 %), both in naïve (4.9 %) and non-naïve patients (1.3 %). Adalimumab and infliximab were associated with significantly higher percentages. Dose modification magnitude in those patients compared to basal dose was significantly different between treatments; 7.1 % (95 % CI 6.3-7.9 %) in etanercept, 30.4 % (95 % CI 28.3-32.5 %) in adalimumab and 21 % (95 % CI 20.3-21.7 %) in infliximab. Adalimumab and infliximab were associated with a higher risk of dose escalation relative to etanercept. There were no significant differences in the dose reduction percentages for the whole group of patients between treatments. In rheumatoid arthritis, etanercept is associated with a significantly lower percentage of dose-escalated patients and a lower magnitude of dose modification. Significant differences in the dose reduction between anti-TNF drugs evaluated were not observed. PMID:25638015

  6. Reductions in disease activity in the AMPLE trial: clinical response by baseline disease duration

    PubMed Central

    Schiff, Michael; Weinblatt, Michael E; Valente, Robert; Citera, Gustavo; Maldonado, Michael; Massarotti, Elena; Yazici, Yusuf; Fleischmann, Roy

    2016-01-01

    Objectives To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial. Methods Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated. Results A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures. Conclusions Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses. Trial registration number NCT00929864, Post-results. PMID:27110385

  7. Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF-TNF-RII binding in rheumatoid arthritis.

    PubMed

    Nguyen, Dao Xuan; Ehrenstein, Michael R

    2016-06-27

    The interplay between inflammatory and regulatory pathways orchestrates an effective immune response that provides protection from pathogens while limiting injury to host tissue. Tumor necrosis factor (TNF) is a pivotal inflammatory cytokine, but there is conflicting evidence as to whether it boosts or inhibits regulatory T cells (T reg cells). In this study, we show that the therapeutic anti-TNF antibody adalimumab, but not the soluble TNF receptor etanercept, paradoxically promoted the interaction between monocytes and T reg cells isolated from patients with rheumatoid arthritis (RA). Adalimumab bound to monocyte membrane TNF from RA patients and unexpectedly enhanced its expression and its binding to TNF-RII expressed on T reg cells. As a consequence, adalimumab expanded functional Foxp3(+) T reg cells equipped to suppress Th17 cells through an IL-2/STAT5-dependent mechanism. Our data not only highlight the beneficial effect of membrane TNF on T reg cell numbers during chronic inflammation, but in addition reveal how a therapeutic antibody that is thought to act by simply blocking its target can enhance the regulatory properties of this proinflammatory cytokine. PMID:27270893

  8. Biosimilars: a systematic review of published and ongoing clinical trials of antipsoriatics in chronic inflammatory diseases.

    PubMed

    Nast, Alexander; Rosumeck, Stefanie; Seidenschnur, Karin

    2015-04-01

    Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In-Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab - all in rheumatoid arthritis patients - were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial. PMID:25819235

  9. 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. PMID:27048267

  10. The management of chronic viral hepatitis: A Canadian consensus conference 2004

    PubMed Central

    Sherman, Morris; Bain, Vincent; Villeneuve, Jean-Pierre; Myers, Robert P; Cooper, Curtis; Martin, Steven; Lowe, Catherine

    2004-01-01

    Several government and nongovernment organizations held a consensus conference on the management of acute and chronic viral hepatitis to update previous management recommendations. The conference became necessary because of the introduction of new forms of therapy for both hepatitis B and hepatitis C. The conference issued recommendations on the investigation and management of chronic hepatitis B, including the use of lamivudine, adefovir and interferon. The treatment of hepatitis B in several special situations was also discussed. There were also recommendations on the investigation and treatment of chronic hepatitis C and hepatitis C-HIV coinfection. In addition, the document makes some recommendations about the provision of services by provincial governments to facilitate the delivery of care to patients with hepatitis virus infection. The present document is meant to be used by practitioners and other health care providers, including public health staff and others not directly involved in patient care. PMID:18159509

  11. [Anti-HIV drugs and drug delivery system].

    PubMed

    Obaru, K; Mitsuya, H

    1998-03-01

    A number of candidate drugs for therapy of HIV-1 infection which show significant activity against the virus in vitro were reported; however, many of them have been dropped from drug development due to (i) insufficient intracellular activation in certain human target cells (particularly in case of nucleoside reverse transcriptase inhibitors), (ii) poor pharmacokinetic profiles, or (iii) intolerable in vitro and/or in vivo toxicities. To circumvent some of these problems, certain drug delivery systems have been applied and several candidate drugs including two novel nucleoside reverse transcriptase inhibitors, abacavir and adefovir, have acquired favorable properties in the clinical setting. This paper reviews several avenues for developing prodrugs of anti-HIV-1 agents to overcome their inherent limitations. PMID:9549371

  12. [Chronic hepatitis B: current therapy].

    PubMed

    Buffet, Catherine

    2008-11-01

    HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication. PMID:19445377

  13. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

    PubMed

    Jones, J; Colquitt, J; Shepherd, J; Harris, P; Cooper, K

    2010-05-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B, in accordance with the licensed indication, based upon the evidence submission from Gilead to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included two international randomised controlled trials (RCTs) comparing tenofovir with adefovir, and a mixed treatment comparison (MTC) using Bayesian methodology to compare tenofovir with other nucleos(t)ide analogues using direct and indirect RCT evidence. There were no statistically significant differences between tenofovir and adefovir in overall adverse events although, in hepatitis B 'e' antigen (HBeAg)-positive patients, there was a higher incidence of mild nausea in the tenofovir treatment group. The primary outcome, 'complete response', was a composite end point defined as histology response and hepatitis B virus DNA below 400 copies/ml. For both HBeAg-positive and HBeAg-negative patients, a significantly greater proportion had a complete response after 48 weeks with tenofovir than with adefovir. There was no statistically significant difference in histological response in either group of patients compared with adefovir. The MTC could only generate results for HBeAg positive nucleos(t)ide naive patients as there was insufficient evidence for other subgroups. The probability of achieving undetectable HBV DNA with tenofovir was found to be significantly higher than that for all other treatments considered in the analysis at the 0.05 level. The analysis demonstrated that there is a 98% probability that tenofovir is the most potent nucleos(t)ide in terms of this outcome. The manufacturer's submission concluded that tenofovir is a cost-effective option as first-line treatment. For HBeAg-positive patients, tenofovir followed

  14. Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity.

    PubMed

    Giesler, Kyle E; Marengo, Jose; Liotta, Dennis C

    2016-08-11

    The therapeutic value of numerous small molecules hinges on their ability to permeate the plasma membrane. This is particularly true for tenofovir (TFV), adefovir, and other antiviral nucleosides that demonstrate potent antiviral activity but poor bioavailability. Using TFV as a model substrate, we hybridized two disparate prodrug strategies to afford novel reduction-sensitive lipid conjugates of TFV that exhibit subnanomolar activity toward HIV-1 and are stable in human plasma for more than 24 h with a therapeutic index approaching 30000. These compounds significantly rival the clinically approved formulation of TFV and revitalize the potential of disulfide-bearing prodrugs which have seen limited in vitro and in vivo success since their debut over 20 years ago. We further demonstrate the utility of these conjugates as a tool to indirectly probe the enzymatic hydrolysis of phosphonomonoesters that may further advance the development of other prodrug strategies for nucleosides, peptides, and beyond. PMID:27405794

  15. Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?

    PubMed

    Langley, R G

    2012-03-01

    The introduction of the biologic agents, adalimumab, etanercept, infliximab and ustekinumab, has provided more options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and maintain effective disease control in more patients using biologic therapies. Newly published clinical data support the introduction of novel optimization strategies to further improve outcomes in patients with psoriasis. Recent randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic agents, and biologics at specific time points. Switching from methotrexate to a tumour necrosis factor (TNF)-α antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-to-severe psoriasis, while the benefit of long-term methotrexate use remains unclear. In a separate study, psoriasis area and severity index (PASI) ≥ 75 response rates were maintained over time (>3 years for adalimumab), suggesting that long-term biologic therapy is an effective and sustainable treatment option for psoriasis. For each individual patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions. However, a benefit-risk assessment of TNF-α antagonists calculated from an integrated analysis of published literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number needed to harm and number of patient years of observation to detect an adverse event have been determined for adalimumab, etanercept and infliximab. The benefit-risk profiles generated demonstrated that, during the initial year of treatment, likelihood of success with TNF-α antagonists was several orders of magnitude greater than the likelihood of serious toxicity. PMID:22356632

  16. Update on the treatment of ankylosing spondylitis

    PubMed Central

    Maksymowych, Walter P

    2007-01-01

    Non-steroidal anti-inflammatory agents (NSAIDs) remain the mainstay of treatment for ankylosing spondylitis (AS) though one recent trial suggests that continuous as opposed to on-demand use may be superior in preventing progression of structural damage. One particular NSAID, which is a highly selective cyclo-oxygenase 2 inhibitor, etoricoxib, may be superior to standard NSAIDs for AS. Second-line agents typically used for rheumatoid arthritis appear to lack efficacy. Salazopyrin is only moderately effective in the subgroup of AS patients with concomitant peripheral arthritis and not in those with purely axial disease. A recent trial showed that there is no greater efficacy in patients presenting early in their disease course. Three anti-tumor necrosis factor alpha agents, infliximab, etanercept, and adalimumab, are now available for the treatment of AS, the latest being adalimumab. All possess similar clinical efficacy in phase III trials with response rates of about 60%. Imaging studies using magnetic resonance show substantial amelioration of inflammatory lesions in the spine and sacroiliac joints. There is as yet no evidence that any of these agents prevent progression of structural damage. One study that evaluated etanercept demonstrated no impact on damage progression. Increasing evidence points to the superiority of the two monoclonal antibodies, infliximab and adalimumab, over etanercept for the treatment of extra-articular manifestations typically seen in AS such as acute anterior uveitis and inflammatory bowel disease. All three agents can be used as monotherapy and concomitant methotrexate appears to offer no advantages although insufficient doses have been used to date. Future studies should target patients earlier in their disease course as well as those with adverse prognostic factors such as elevated serum metalloproteinase 3 levels and radiographic evidence of spinal ankylosis. PMID:18516314

  17. Adherence and resource use among patients treated with biologic drugs: findings from BEETLE study

    PubMed Central

    Degli Esposti, Luca; Sangiorgi, Diego; Perrone, Valentina; Radice, Sonia; Clementi, Emilio; Perone, Francesco; Buda, Stefano

    2014-01-01

    Objectives Systemic administration of anti-tumor necrosis factor alpha (anti-TNF alpha) leads to an anti-inflammatory and joint protective effect in pathologies such as rheumatoid arthritis, psoriasis, and Crohn’s disease. The aim of this study was to assess adherence to therapy, persistence in treatment (no switches or interruptions), and consumption of care resources (drugs, outpatient services, hospitalizations). Methods We conducted an observational retrospective cohort analysis using the administrative databases of five local health units. Patients filling at least one prescription for anti-TNF alpha between January 1, 2009 and December 31, 2011 were included and followed up for 1 year. Patients were defined as adherent if >80% of the follow-up period was covered by drugs dispensation. Results A total of 1,219 patients were analyzed (mean age 49.6±14.6, male 47%). Among enrolled patients, 36% were affected by rheumatoid arthritis, and 31% and 10% were affected by psoriasis and Crohn’s disease, respectively; other indications remained below these percentages. Thirty-four percent of patients (420) were treated with adalimumab, 51% (615) with etanercept, and 15% (184) with infliximab. Among the 94% of patients who did not switch, those treated with infliximab had a higher rate of adherence across all indications (51% overall) when compared to that observed in patients treated with etanercept (27%) or adalimumab (23%). The mean annual nonpharmacological expenditure for each patient in analysis was €988 for adherent and €1,255 for nonadherent patients. Infliximab was associated with the lowest cost for all indications as determined by the multivariate generalized linear model. Conclusions Patients treated with infliximab were associated with higher adherence and persistence in treatment and lower costs, as compared to those treated with adalimumab or etanercept. PMID:25258545

  18. Asymmetric dimethylarginine but not osteoprotegerin correlates with disease severity in patients with moderate-to-severe psoriasis undergoing anti-tumor necrosis factor-α therapy.

    PubMed

    Pina, Trinitario; Genre, Fernanda; Lopez-Mejias, Raquel; Armesto, Susana; Ubilla, Begoña; Mijares, Veronica; Dierssen-Sotos, Trinidad; Corrales, Alfonso; Gonzalez-Lopez, Marcos A; Gonzalez-Vela, Maria C; Blanco, Ricardo; Hernández, Jose L; Llorca, Javier; Gonzalez-Gay, Miguel A

    2016-04-01

    Patients with psoriasis, in particular those with severe disease, have an increased risk of cardiovascular (CV) events compared with the general population. The aim of the present study is to determine whether correlation between asymmetric dimethylarginine (ADMA) and osteoprotegerin (OPG), two biomarkers associated with CV disease, and disease severity may exist in patients with moderate-to-severe psoriasis. We also aimed to establish if baseline serum levels of these two biomarkers could correlate with the degree of change in the clinical parameters of disease severity following the use of anti-tumor necrosis factor (TNF)-α therapy in these patients. This was a prospective study on a series of consecutive non-diabetic patients with moderate-to-severe psoriasis who completed 6 months of therapy with anti-TNF-α-adalimumab. Patients with kidney disease, hypertension or body mass index of 35 kg/m(2) or more were excluded. Metabolic and clinical evaluation was performed immediately prior to the onset of treatment and at month 6. Twenty-nine patients were assessed. Unlike OPG, a significant positive correlation between ADMA and resistin serum levels was found at the onset of adalimumab and also after 6 months of biologic therapy. We also observed a positive correlation between the percent of body surface area affected (BSA) and ADMA levels obtained before the onset of adalimumab and a negative correlation between baseline ADMA levels and a 6-month BSA change compared with baseline results. In patients with moderate-to-severe psoriasis, ADMA levels correlate with clinical markers of disease severity. PMID:26364678

  19. Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan

    PubMed Central

    Chen, Yi-Ming; Chang, Chia-Li; Chen, Hsin-Hua; Chen, Der-Yuan

    2016-01-01

    Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids≧5mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics–associated TB may be efficiently reduced through increased awareness. PMID:27064275

  20. Different Risk of Tuberculosis and Efficacy of Isoniazid Prophylaxis in Rheumatoid Arthritis Patients with Biologic Therapy: A Nationwide Retrospective Cohort Study in Taiwan.

    PubMed

    Liao, Tsai-Ling; Lin, Ching-Heng; Chen, Yi-Ming; Chang, Chia-Li; Chen, Hsin-Hua; Chen, Der-Yuan

    2016-01-01

    Increasing evidence indicates an increased risk of tuberculosis (TB) for rheumatoid arthritis (RA) patients receiving biologic therapy, and the effectiveness of isoniazid prophylaxis (INHP) in TB prevention. We aimed to examine 1) the incidence rate (IR) and risk factors for TB among RA patients receiving different therapies; 2) INHP effectiveness for TB prevention; 3) mortality rates after TB diagnosis in patients receiving different therapies. This retrospective study was conducted using a nationwide database: 168,720 non-RA subjects and a total of 42,180 RA patients including 36,162 csDMARDs-exposed, 3,577 etanercept-exposed, 1,678 adalimumab-exposed and 763 rituximab-exposed patients. TB risk was 2.7-fold higher in RA cohort compared with non-RA group, with an adjusted hazard ratio (aHR) of 2.58. Advanced age, male, the use of corticosteroids ≧ 5 mg/day, and the presence of diabetes mellitus (DM), chronic obstructive pulmonary disease and chronic kidney disease were risk factors for developing TB. Using csDMARDs-exposed group as reference, aHR of TB was the highest with adalimumab treatment (1.52), followed by etanercept (1.16), and the lowest with rituximab (0.08). INHP could effectively reduce TB risk in biologics-exposed patients. Mortality rates after TB diagnosis were higher in RA patients, particularly the elderly and those with DM, with lower rates in adalimumab-exposed patients compared with csDMARDs-exposed patients. In conclusion, TB risk was increased in patients receiving TNF-α inhibitors, but the risk associated with rituximab therapy was relatively low. With the effectiveness of INHP shown in the prevention of biologics-associated TB, stricter implementation of INHP should be beneficial. The mortality from biologics-associated TB may be efficiently reduced through increased awareness. PMID:27064275

  1. Tumor necrosis factor inhibitors – state of knowledge

    PubMed Central

    Lis, Krzysztof; Kuzawińska, Olga

    2014-01-01

    Tumor necrosis factor (TNF) is considered a major proinflammatory cytokine, affecting various aspects of the immune reaction. All five TNF inhibitors currently available on the market (i.e., etanercept, infliximab, adalimumab, certolizumab and golimumab) are top sellers, although indicated only in autoimmune diseases, including rheumatoid arthritis, Crohn's disease and psoriasis. This article briefly discusses the background and place for TNF inhibitors in modern therapy. The main safety aspects of TNF inhibitor administration are described in particular, with special consideration of the available meta-analyses. Finally, perspectives on the next-generation TNF inhibitors and their use in the clinic are given. PMID:25624856

  2. Golimumab: clinical update on its use for ulcerative colitis.

    PubMed

    Gilardi, D; Fiorino, G; Allocca, M; Bravatà, I; Danese, S

    2015-03-01

    Monoclonal antibodies directed against tumor necrosis factor alpha (anti-TNF-α agents) have dramatically changed the therapeutical approach to inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. A new anti-TNF drug, golimumab, has recently been approved for patients with moderate to severe ulcerative colitis. Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti-TNF agents, such as infliximab and adalimumab. This review gives an overview on golimumab in the treatment of moderate to severe ulcerative colitis. PMID:25876561

  3. Biologic Safety in Psoriasis

    PubMed Central

    Mansouri, Yasaman

    2015-01-01

    The development of targeted biologic agents has revolutionized the treatment of psoriasis. In this review, the authors focus on the published long-term (≥ one year) safety data for the use of tumor necrosis factor-α antagonists etanercept, infliximab, and adalimumab, as well as the IL-12/IL-23 antagonist ustekinumab, in adult patients with moderate-to-severe psoriasis. The efficacy of these currently available biologic therapies has been demonstrated in several studies, and their safety profiles are also reassuring. PMID:25741401

  4. Drug usage analysis and health care resources consumption in naïve patients with rheumatoid arthritis

    PubMed Central

    Sangiorgi, Diego; Benucci, Maurizio; Nappi, Carmela; Perrone, Valentina; Buda, Stefano; Degli Esposti, Luca

    2015-01-01

    Objectives The use of biologic agents has revolutionized the management of rheumatoid arthritis (RA) in the past 2 decades. These biologic agents directly target molecules and cells involved in the pathogenesis of RA. The purpose of this study was to assess the usage of biologic agents in terms of persistence to treatment, dose escalation, and consumption of health care resources (hospitalizations, drugs, and outpatients service) in the real clinical practice in naïve patients with RA. Methods We conducted a real-world, retrospective, observational cohort study based on data obtained from administrative databases of three Local Health Units in Italy. The population included adults diagnosed with RA who had at least one prescription between January 1, 2009 and December 31, 2011, for a biologic that was approved for treatment of RA. The patients were followed for 12 months after enrollment. The clinical characteristics of the patients enrolled in this study were also investigated in the 1-year period before the index date. The main and secondary endpoints were evaluated only in biologic-naïve patients without switches. The overall health care costs for patients were evaluated. Results A total of 594 patients met the study criteria (mean age 53.5±13.5, female:male ratio =3:1). Thirty-nine percent received etanercept, 25% adalimumab, 14% infliximab, 10% abatacept, 9% tocilizumab, and 3% golimumab. After 1 year of observation, patients showed similar use of other RA-related medication. For the naïve patients without switches, the persistence levels were: 78% for etanercept, 72% for tocilizumab, 71% for adalimumab, 69% for infliximab, and 64% for abatacept. For all agents, dose escalation was 21.4% for infliximab, 11.5% for adalimumab, 5.6% for abatacept, 4% for tocilizumab, and 3.8% for etanercept. The annual costs per treated patients were €12,803 for adalimumab, €11,924 for etanercept, €11,830 for tocilizumab, €11,201 for infliximab, and €10,943 for

  5. Invasive Salmonellosis by the Very Rare Salmonella choleraesuis in a Returning Traveler on a Tumor Necrosis Factor-α Inhibitor

    PubMed Central

    Eke, Uzoamaka A.; Conte, Harry; Anderson, Paula; Lyons, Robert W.

    2014-01-01

    Salmonella choleraesuis is one of the least commonly reported nontyphoidal salmonellae in the United States, accounting for only 0.08% and ranking lower than 20th place among all human source salmonellosis reported to the CDC in 2009. In the state of Connecticut, only 12 cases have been reported since 1998 and our case is the only case since 2008. We report a case of invasive Salmonellosis caused by Salmonella choleraesuis in a patient on an antitumor necrosis factor-α agent (adalimumab) who recently returned from a trip to the Dominican Republic. PMID:24715927

  6. Organizing Pneumonia in a Patient with Quiescent Crohn's Disease

    PubMed Central

    Ozeki, Keiji; Katano, Takahito; Shimura, Takaya; Mori, Yoshinori; Joh, Takashi

    2016-01-01

    A 64-year-old man with Crohn's disease (CD) was admitted to our hospital due to moderate risk of pneumonia while receiving scheduled adalimumab maintenance therapy. Symptoms remained virtually unchanged following administration of antibiotics. A final diagnosis of organizing pneumonia (OP) was made based on findings of intra-alveolar buds of granulation tissue and fibrous thickening of the alveolar walls on pathological examination and patchy consolidations and ground glass opacities on computed tomography. Immediate administration of prednisolone provided rapid, sustained improvement. Although a rare complication, OP is a pulmonary manifestation that requires attention in CD patients. PMID:27413560

  7. Surgical Management and Reconstruction of Hoffman's Disease (Dissecting Cellulitis of the Scalp).

    PubMed

    Hintze, Justin M; Howard, Brittany E; Donald, Carrlene B; Hayden, Richard E

    2016-01-01

    Dissecting cellulitis of the scalp, or Hoffman's disease, is a rare dermatologic condition characterized by recurrent pustules and sinus tract formation leading to scarring and alopecia. Medical management includes the use of corticosteroids, antibiotics, isotretinoin, and adalimumab. In cases where the disease is severe, refractory, and intractable, surgery is an option. We report two cases of Hoffman's disease, where medical management failed to achieve remission. Surgical treatment was undertaken with complete resection of the affected scalp in staged procedures with subsequent split-thickness skin grafting for reconstruction. Surgery achieved both disease remission and excellent aesthetic outcomes in both patients. PMID:26966606

  8. Surgical Management and Reconstruction of Hoffman's Disease (Dissecting Cellulitis of the Scalp)

    PubMed Central

    Hintze, Justin M.; Howard, Brittany E.; Donald, Carrlene B.; Hayden, Richard E.

    2016-01-01

    Dissecting cellulitis of the scalp, or Hoffman's disease, is a rare dermatologic condition characterized by recurrent pustules and sinus tract formation leading to scarring and alopecia. Medical management includes the use of corticosteroids, antibiotics, isotretinoin, and adalimumab. In cases where the disease is severe, refractory, and intractable, surgery is an option. We report two cases of Hoffman's disease, where medical management failed to achieve remission. Surgical treatment was undertaken with complete resection of the affected scalp in staged procedures with subsequent split-thickness skin grafting for reconstruction. Surgery achieved both disease remission and excellent aesthetic outcomes in both patients. PMID:26966606

  9. Management of inflammatory bowel disease in poor responders to infliximab

    PubMed Central

    Guerra, Iván; Bermejo, Fernando

    2014-01-01

    Infliximab (IFX) is an effective treatment for inducing and maintaining response in Crohn’s disease and ulcerative colitis patients. Some patients present lack of response or loss of response to IFX during maintenance therapy. Empirical management with combination therapy with an immunomodulator, IFX dose escalation, or switching IFX for another antitumor necrosis factor-α drug, mainly adalimumab, is common in clinical practice. Selecting the best choice with the help of serum drug concentrations and trough IFX antibody concentrations could be a very interesting approach. In addition to surgery, a broad spectrum of new drugs has been tested and could expand treatment options in the near future. PMID:25258548

  10. Recurrent Pneumothorax after Etanercept Therapy in a Rheumatoid Arthritis Patient: A Case Report

    PubMed Central

    Kim, Sang Hoon; Seo, Young Ho; Kim, Ji Hyoung; Jeong, Il Woo; Sohn, Sung Birm

    2014-01-01

    The use of anti-tumor necrosis factor (anti-TNF) agents for rheumatoid arthritis (RA) patients who are refractory to disease-modifying anti-rheumatic drugs is gradually increasing. Etanercept is the first anti-TNF agent to be approved for RA treatment and is also the most widely used. However, aggravation of interstitial lung disease after etanercept treatment in RA patients has been reported recently. We report the first case of recurrent spontaneous pneumothorax with progression of interstitial lung disease after initiating etanercept therapy. The withdrawal of etanercept and a change to adalimumab, a different class of TNF inhibitor, achieved clinical stabilization. PMID:25568848

  11. Interleukin 17 inhibits progenitor cells in rheumatoid arthritis cartilage.

    PubMed

    Schminke, Boris; Trautmann, Sandra; Mai, Burkhard; Miosge, Nicolai; Blaschke, Sabine

    2016-02-01

    Mesenchymal stem cells are known to exert immunomodulatory effects in inflammatory diseases. Immuneregulatory cells lead to progressive joint destruction in rheumatoid arthritis (RA). Proinflammatory cytokines, such as tumour necrosis factor α (TNF-α) and interleukins (ILs) are the main players. Here, we studied progenitor cells from RA cartilage (RA-CPCs) that are positive for IL-17 receptors to determinate the effects of inflammation on their chondrogenic potenial. IL-17A/F reduced the chondrogenic potential of these cells via the upregulation of RUNX2 protein and enhanced IL-6 protein and MMP3 mRNA levels. Blocking antibodies against IL-17 positively influenced their repair potential. Furthermore, treating the RA-CPCs with the anti-human IL-17 antibody secukinumab or the anti-TNF-α antibody adalimumab reduced the proinflammatory IL-6 protein level and positively influenced the secretion of anti-inflammatory IL-10 protein. Additionally, adalimumab and secukinumab in particular reduced RUNX2 protein to promote chondrogenesis. The amelioration of inflammation, particularly via IL-17 antagonism, might be a new therapeutic approach for enhancing intrinsic cartilage repair mechanisms in RA patients. PMID:26558442

  12. Effects of Antitumor Necrosis Factor Therapy on Osteoprotegerin, Neopterin, and sRANKL Concentrations in Patients with Rheumatoid Arthritis

    PubMed Central

    Kurz, Katharina; Herold, Manfred; Russe, Elisabeth; Klotz, Werner; Weiss, Guenter; Fuchs, Dietmar

    2015-01-01

    Background. Rheumatoid arthritis is a systemic autoimmune disease characterized by joint erosions, progressive focal bone loss, and chronic inflammation. Methods. 20 female patients with moderate-to-severe rheumatoid arthritis were treated with anti-TNF-antibody adalimumab in addition to concomitant antirheumatic therapies. Patients were assessed for overall disease activity using the DAS28 score, and neopterin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) concentrations as well as osteoprotegerin (OPG) and soluble receptor activator of NF-κB ligand (sRANKL) concentrations were determined before therapy and at week 12. Neopterin as well as OPG and sRANKL were determined by commercial ELISAs. Results. Before anti-TNF therapy patients presented with high disease activity and elevated concentrations of circulating inflammatory markers. OPG concentrations correlated with neopterin (rs = 0.494, p = 0.027), but not with DAS28. OPG concentrations and disease activity scores declined during anti-TNF-treatment (both p < 0.02). Patients who achieved remission (n = 7) or showed a good response according to EULAR criteria (n = 13) presented with initially higher baseline OPG levels, which subsequently decreased significantly during treatment (p = 0.018 for remission, p = 0.011 for good response). Conclusions. Adalimumab therapy was effective in modifying disease activity and reducing proinflammatory and bone remodelling cascades. PMID:26576067

  13. Unusual case of B cell lymphoma after immunosuppressive treatment for psoriasis.

    PubMed

    Nosotti, Lorenzo; Baiocchini, Andrea; Bonifati, Claudio; Visco-Comandini, Ubaldo; Mirisola, Concetta; Del Nonno, Franca

    2015-04-18

    Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance. PMID:25914782

  14. Modelling Cost-Effectiveness of Biologic Treatments Based on Disease Activity Scores for the Management of Rheumatoid Arthritis in Spain

    PubMed Central

    Beresniak, Ariel; Ariza-Ariza, Rafael; Garcia-Llorente, Jose Francisco; Ramirez-Arellano, Antonio; Dupont, Danielle

    2011-01-01

    Background. The objective of this simulation model was to assess the cost-effectiveness of different biological treatment strategies based on levels of disease activity in Spain, in patients with moderate to severe active RA and an insufficient response to at least one anti-TNF agent. Methods. Clinically meaningful effectiveness criteria were defined using DAS28 scores: remission and Low Disease Activity State (LDAS) thresholds. Monte-Carlo simulations were conducted to assess cost-effectiveness over 2 years of four biological sequential strategies composed of anti-TNF agents (adalimumab, infliximab), abatacept or rituximab, in patients with moderate to severe active RA and an insufficient response to etanercept as first biological agent. Results. The sequential strategy including etanercept, abatacept and adalimumab appeared more efficacious over 2 years (102 days in LDAS) compared to the same sequence including rituximab as second biological option (82 days in LDAS). Cost-effectiveness ratios showed lower costs per day in LDAS with abatacept (427 €) compared to rituximab as second biological option (508 €). All comparisons were confirmed when using remission criteria. Conclusion. Model results suggest that in patients with an insufficient response to anti-TNF agents, the biological sequences including abatacept appear more efficacious and cost-effective than similar sequences including rituximab or cycled anti-TNF agents. PMID:21785694

  15. Comparative clinical utility of once-weekly subcutaneous abatacept in the management of rheumatoid arthritis

    PubMed Central

    Rakieh, Chadi; Conaghan, Philip G

    2014-01-01

    Biologic therapies in rheumatoid arthritis are now part of standard practice for disease that proves difficult to control with conventional disease-modifying anti-rheumatic drugs. While anti-tumor necrosis factor therapies have been commonly used, other targeted biologic therapies with different mechanisms of action are becoming increasingly available. Abatacept is a recombinant fusion protein that inhibits the T-cell costimulatory molecules required for T-cell activation. Intravenous abatacept has good clinical efficacy with an acceptably low toxicity profile in rheumatoid arthritis, but the subcutaneous mode of delivery has only recently become available. In this article, we examine key efficacy and safety data for subcutaneous abatacept in rheumatoid arthritis, incorporating evidence from five large Phase III studies that included people with an inadequate response to methotrexate and an inadequate response to biologic disease-modifying anti-rheumatic drugs. The results demonstrate that subcutaneous abatacept has efficacy and safety comparable with that of intravenous abatacept and adalimumab. In addition, inhibition of radiographic progression at year 1 in relatively early rheumatoid arthritis is consistent with that of adalimumab. Subcutaneous abatacept is well tolerated, with very low rates of discontinuation in both short-term and long-term follow-up. PMID:24812514

  16. Biologics and Pediatric Generalized Pustular Psoriasis: An Emerging Therapeutic Trend

    PubMed Central

    Mattes, Monica

    2016-01-01

    Generalized pustular psoriasis (GPP) is a rare form of childhood psoriasis, often requiring systemic therapy, which is challenging as there is a paucity of randomized controlled trials and standardized guidelines. Biologic agents have been used in adults and in pediatric plaque psoriasis, but evidence regarding their efficacy in pediatric GPP has slowly become available. The objective of this study is to summarize and compare the efficacy and safety of biologic agents, such as etanercept, infliximab, and adalimumab, in the treatment of pediatric GPP. A PubMed literature review was conducted and 12 studies met the inclusion criteria for analysis. After reviewing the efficacy of these drugs in pediatric GPP patients and their safety in the use of other pediatric conditions, etanercept was identified as a possible first-line biologic agent for pediatric psoriasis, including GPP, followed by infliximab and adalimumab. In conclusion, several case reports have documented the successful use of biologic agents in refractory cases of pediatric GPP, but clinical trials are needed to gain a better understanding of the efficacy and side effect profile in this population. PMID:27462478

  17. Blockade of tumour necrosis factor α significantly alters the serum level of IgG- and IgA-rheumatoid factor in patients with rheumatoid arthritis

    PubMed Central

    Yazdani-Biuki, B; Stadlmaier, E; Mulabecirovic, A; Brezinschek, R; Tilz, G; Demel, U; Mueller, T; Brickmann, K; Graninger, W; Brezinschek, H

    2005-01-01

    Methods: 12 consecutive patients with seropositive RA treated with etanercept were studied and followed up for 9 months. Clinical efficacy of treatment was evaluated using the 28 joint count Disease Activity Score (DAS28). Serum samples were collected at baseline and after 9 months and serum immunoglobulin, RF isotypes, and anti-cyclic citrullinated peptide (aCCP), antinuclear, nucleosome, and dsDNA antibodies determined. For comparison 7 patients with seropositive RA treated with adalimumab were studied. Results: DAS28 decreased significantly after the first month and then was constant for the whole study (5.7 (0.3) v 3.8 (0.2), p⩽0.000). Serum IgA-RF and IgG-RF increased significantly after 9 months' etanercept treatment (mean (SEM) IgA-RF rose from 19.5 (4.8) to 30.5 (5.9) IU/ml, p⩽0.01; IgG-RF from 20.6 (8.1) to 33.8 (11.5) IU/ml, p⩽0.04). Serum levels of total immunoglobulin and specific autoantibodies remained unchanged during the study. In patients treated with adalimumab, no significant changes in serum levels of RF isotypes and aCCP antibodies were seen. Conclusion: Etanercept, although effective in treating the clinical symptoms of RA, seems to have a pivotal effect on RF-producing B cells either directly or indirectly. PMID:16014683

  18. Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis

    PubMed Central

    Kanakaraj, Palanisamy; Puffer, Bridget A.; Yao, Xiao-Tao; Kankanala, Spandana; Boyd, Ernest; Shah, Rutul R.; Wang, Geping; Patel, Dimki; Krishnamurthy, Rajesh; Kaithamana, Shashi; Smith, Rodger G.; LaFleur, David W.; Barbas III, Carlos F.; Hilbert, David M.; Kiener, Peter A.; Roschke, Viktor V.

    2012-01-01

    Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone. PMID:22864384

  19. Demyelinizing Neurological Disease after Treatment with Tumor Necrosis Factor-α Antagonists

    PubMed Central

    Bruè, Claudia; Mariotti, Cesare; Rossiello, Ilaria; Saitta, Andrea; Giovannini, Alfonso

    2016-01-01

    Purpose Demyelinizing neurological disease is a rare complication after treatment with tumor necrosis factor (TNF)α antagonists. We report on a case of multiple sclerosis after TNFα antagonist treatment and discuss its differential diagnosis. Methods This is an observational case study. Results A 48-year-old male was referred to Ophthalmology in January 2015 for an absolute scotoma in the superior quadrant of the visual field in his right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left. Fundus examination was unremarkable bilaterally. Spectral domain optical coherence tomography revealed a normal macular retina structure. Visual field examination revealed a superior hemianopsia in the right eye. Head magnetic resonance imaging showed findings compatible with optic neuritis. The visual evoked potentials confirmed the presence of optic neuritis. The patient had been under therapy with adalimumab since January 2014, for Crohn's disease. Suspension of adalimumab was recommended, and it was substituted with tapered deltacortene, from 1 mg/kg/day. After 1 month, the scotoma was resolved completely. Conclusions TNFα antagonists can provide benefit to patients with inflammatory autoimmune diseases. However, they can also be associated with severe adverse effects. Therefore, adequate attention should be paid to neurological abnormalities in patients treated with TNFα antagonists. PMID:27504093

  20. Therapeutic TNF Inhibitors can Differentially Stabilize Trimeric TNF by Inhibiting Monomer Exchange.

    PubMed

    van Schie, Karin A; Ooijevaar-de Heer, Pleuni; Dijk, Lisanne; Kruithof, Simone; Wolbink, Gertjan; Rispens, Theo

    2016-01-01

    Tumor necrosis factor (TNF) is a homotrimeric cytokine that is a key mediator of inflammation. It is unstable at physiological concentrations and slowly converts into an inactive form. Here, we investigated the mechanism of this process by using a Förster resonance energy transfer (FRET) assay that allowed monitoring of monomeric subunit exchange in time. We observed continuous exchange of monomeric subunits even at concentrations of TNF high enough to maintain its bioactivity. The kinetics of this process closely corresponds with the appearance of monomeric subunits and disappearance of trimeric TNF in time at ng/ml concentrations as monitored by high-performance size-exclusion chromatography (HP-SEC). Furthermore, of the five therapeutic TNF inhibitors that are currently used in the clinic, three (adalimumab, infliximab, etanercept) were found to completely inhibit the monomer exchange reaction and stabilize TNF trimers, whereas golimumab and certolizumab could not prevent monomer exchange, but did slow down the exchange process. These differences were not correlated with the affinities of the TNF inhibitors, measured with both surface plasmon resonance (SPR) and in fluid phase using fluorescence-assisted HP-SEC. The stabilizing effect of these TNF inhibitors might result in prolonged residual TNF bioactivity under conditions of incomplete blocking, as observed in vitro for adalimumab. PMID:27605058

  1. The role of interferon-gamma release assays in predicting the emergence of active tuberculosis in the setting of biological treatment: a case report and review of the literature.

    PubMed

    Scrivo, Rossana; Sauzullo, Ilaria; Mengoni, Fabio; Riccieri, Valeria; Altieri, Alfonso Maria; Cantoro, Laura; Vullo, Vincenzo; Mastroianni, Claudio Maria; Valesini, Guido

    2016-05-01

    Conversions and reversions of interferon-gamma (IFN-γ) release assays (IGRAs) were observed when these tests were repeated over time in the same individuals, including those treated with biological agents. In most studies, the variability of IFN-γ plasma levels was not paralleled by clinical change, but a few exceptions exist, in which IGRA conversion predicted the emergence of active tuberculosis (TB). We report the case of a Peruvian patient with rheumatoid arthritis (RA) and Crohn's disease scheduled for treatment with adalimumab. TB screening demonstrated latent TB infection (LTBI), and the patient was started on isoniazid (INH) for 9 months. Adalimumab was initiated after 1 month since INH. QuantiFERON-TB Gold In-Tube, one of the IGRAs currently available, was serially repeated to monitor the status of TB infection during treatment with the biological agent. The patient developed active TB preceded by progressively rising levels of released IFN-γ. We came to know that she had withdrawn INH after 2 months on her own initiative. Considering the low rate of INH completion, serial IGRAs may help in the clinical vigilance during prophylaxis as well as anti-TNF treatment, at least in patients presenting other risk factors aside from the state of immunosuppression. PMID:24827875

  2. Therapeutic TNF Inhibitors can Differentially Stabilize Trimeric TNF by Inhibiting Monomer Exchange

    PubMed Central

    van Schie, Karin A.; Ooijevaar-de Heer, Pleuni; Dijk, Lisanne; Kruithof, Simone; Wolbink, Gertjan; Rispens, Theo

    2016-01-01

    Tumor necrosis factor (TNF) is a homotrimeric cytokine that is a key mediator of inflammation. It is unstable at physiological concentrations and slowly converts into an inactive form. Here, we investigated the mechanism of this process by using a Förster resonance energy transfer (FRET) assay that allowed monitoring of monomeric subunit exchange in time. We observed continuous exchange of monomeric subunits even at concentrations of TNF high enough to maintain its bioactivity. The kinetics of this process closely corresponds with the appearance of monomeric subunits and disappearance of trimeric TNF in time at ng/ml concentrations as monitored by high-performance size-exclusion chromatography (HP-SEC). Furthermore, of the five therapeutic TNF inhibitors that are currently used in the clinic, three (adalimumab, infliximab, etanercept) were found to completely inhibit the monomer exchange reaction and stabilize TNF trimers, whereas golimumab and certolizumab could not prevent monomer exchange, but did slow down the exchange process. These differences were not correlated with the affinities of the TNF inhibitors, measured with both surface plasmon resonance (SPR) and in fluid phase using fluorescence-assisted HP-SEC. The stabilizing effect of these TNF inhibitors might result in prolonged residual TNF bioactivity under conditions of incomplete blocking, as observed in vitro for adalimumab. PMID:27605058

  3. Safety of biologics approved for treating rheumatoid arthritis: analysis of spontaneous reports of adverse events.

    PubMed

    Mendes, Diogo; Alves, Carlos; Batel Marques, Francisco

    2013-08-01

    Despite the effectiveness of biologics approved for the treatment of rheumatoid arthritis, they have been associated with serious adverse events (AEs). Biologics are used under close supervision of health care professionals. In Portugal, they are legally required to report AEs occurring during the treatment. This study aims at investigating post-marketing safety monitoring data of biologics in Portugal by comparing the frequency of spontaneously reported adverse events between 2009 and 2011 with the frequency of such events in the summary of the product characteristics of each biologic. Sales data for biologics were obtained from IMS Health and converted into defined daily doses/1,000 inhabitants/day in order to estimate a proportion of the population treated. The frequency of AEs was estimated as the percentage of patients in which an AE may have occurred. The use of each biologic was estimated for adalimumab at 1,439 patients/year, etanercept 1,944 patients/year, and infliximab 3,211 patients/year. A total of 992 AEs were reported: 207 for adalimumab, 199 for etanercept, and 586 for infliximab. Of the 515 different spontaneously reported AEs, 194 were included for comparisons with the SPCs. Of those, 31 (16 %) were similarly frequent, and 163 (84.0 %) occurred less frequently compared with SPCs' data. These results suggest an insufficient post-marketing safety monitoring of biologics in Portugal. PMID:23604594

  4. Establishment of a cell model for screening antibody drugs against rheumatoid arthritis with ADCC and CDC.

    PubMed

    Yan, Li; Hu, Rui; Tu, Song; Cheng, Wen-Jun; Zheng, Qiong; Wang, Jun-Wen; Kan, Wu-Sheng; Ren, Yi-Jun

    2015-01-01

    TNFα played a dominant role in the development and progression of rheumatoid arthritis (RA). Clinical trials proved the efficacies of anti-TNFα agents for curing RA. However, most researchers were concentrating on their abilities of neutralizing TNFα, the potencies of different anti-TNFα agents varied a lot due to the antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). For better understanding and differentiating the potentiality of various candidate anti-TNF reagents at the stage of new drug research and development, present study established a cell model expressing the transmembrane TNFα for usage in in vitro ADCC or CDC assay, meanwhile, the assay protocol described here could provide guidelines for screening macromolecular antibody drugs. A stable cell subline bearing transmembrane TNFα was first established by conventional transfection method, the expression of transmembrane TNFα was approved by flow cytometer, and the performance of the stable subline in ADCC and CDC assay was evaluated, using human peripheral blood mononuclear cells as effector cells, and Adalimumab as the anti-TNFα reagent. The stable cell subline demonstrated high level of surface expression of transmembrane TNFα, and Adalimumab exerted both ADCC and CDC effects on this cell model. In conclusion, the stable cell line we established in present research could be used in ADCC or CDC assay for screening antibody drugs, which would provide in-depth understanding of the potencies of candidate antibody drugs in addition to the traditional TNFα neutralizing assay. PMID:26884918

  5. Three Cases of Previous Smokers with Rheumatoid Arthritis Who Did Not Respond to Tumor Necrosis Factor Inhibitors Were Treated Successfully with an Anti-Interleukin-6 Receptor Antibody

    PubMed Central

    Iwata, Yasuo

    2015-01-01

    We report three cases of previous smokers who did not respond to TNF inhibitors but who responded successfully to an anti-interleukin-6 receptor antibody (tocilizumab (TCZ)). Case 1 is a 63-year-old woman whose smoking index was 200 and had been complaining of polyarthralgia since 1996. She started treatment with etanercept due to high disease activity, but her DAS28-CRP was 4.2. She was therefore switched to TCZ, which dramatically improved her symptoms; her DAS28-CRP had decreased to 2.1. Case 2 is a 64-year-old man whose smoking index was 1600 and had been complaining of polyarthralgia since 2006. Because his DAS28-CRP score increased over time to 5.9, etanercept and adalimumab were added sequentially, but he showed no response over the course of two years. The patient was therefore switched to TCZ, which dramatically improved his symptoms: his DAS28-CRP decreased to 2.7. Case 3 is a 48-year-old woman whose smoking index was 560 and had been complaining of pain in both knee joints since 2001. She was treated with adalimumab due to high disease activity but showed no response over the course of 1.5 years. The patient was therefore switched to TCZ, and her DAS28-CRP decreased to 1.8. An IL-6 blockade might be suitable for treating these 3 cases of previous smokers. PMID:25648415

  6. Coexistence of HBsAg and HBsAb in a difficult-to-treat chronic hepatitis B: loss of HBsAg with entecavir plus tenofovir combination

    PubMed Central

    2014-01-01

    Background Some reports have documented the coexistence of Hepatitis B surfage Antigen (HBsAg) and anti-HBsAg antibodies (HBsAb) in patients with chronic hepatitis B (CHB), often in the absence of amino acid substitutions in the HBsAg sequences of the Hepatitis B Virus (HBV) genome able to explain an immunological escape variant. HBV genome has a very compact coding organization, with four partially overlapping open reading frames (ORFs). Because the reverse transcriptase region (rt) of HBV polymerase overlaps the HBsAg ORF, it is possible that some mutations in the HBsAg region correspond to mutations in the rt ORF, conferring resistance to current antiviral therapies. This unique case explores the response to antiviral therapies of a CHB with concurrent HBsAg and HBsAb positivity, and analyse the clinical implications of possible mutations in rt and HBsAg ORFs. Case presentation Here we describe the case of a 59 year-old Italian man suffering from Hepatitis B envelope Antigen (HBeAg) positive CHB with concurrent HBsAb positivity. By ultra-deep pyro-sequencing (UDPS) technique, mutations conferring immunological escape or resistance to antiviral therapies were found neither in HBsAg nor in HBV rt ORFs, respectively. The patient was unsuccessfully treated with interferon, adefovir monotherapy and adefovir plus entecavir combination. Surprisingly, during entecavir plus tenofovir combination, anti-HBe seroconversion and HBsAg loss were observed, while the titer of HBsAb persisted. Conclusions Concurrent HBsAg/HBsAb positivity in active CHB is a clinical and virological dilemma. In this setting, there are not consistent data about the response to conventional therapies and the immunological balance between host and virus remains so far unexplained. This is, to our knowledge, the first case described of a CHB with HBsAg/HBsAb positivity, wild type for clinically relevant mutations in HBsAg and rt ORFs, successfully treated with a combination of nucleot(s)ide analogues

  7. A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

    PubMed Central

    Balzarini, Jan; Andrei, Graciela; Balestra, Emanuela; Huskens, Dana; Vanpouille, Christophe; Introini, Andrea; Zicari, Sonia; Liekens, Sandra; Snoeck, Robert; Holý, Antonín; Perno, Carlo-Federico; Margolis, Leonid; Schols, Dominique

    2013-01-01

    Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4+ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host

  8. TNF-α in a molecularly targeted therapy of psoriasis and psoriatic arthritis.

    PubMed

    Wcisło-Dziadecka, Dominika; Zbiciak-Nylec, Martyna; Brzezińska-Wcisło, Ligia; Mazurek, Urszula

    2016-03-01

    Psoriasis is a chronic immunological skin disease and patients with this disorder typically experience a significant decrease in their quality of life. The disease is traditionally managed with topical and systemic agents (retinoids, ciclosporin A, methotrexate), but these treatment options are often long-term and their effects can be inconsistent and not ideal. The use of biological drugs in dermatological treatment is relatively new and began in the early 2000s. It should be noted that, in most countries, in order for biological treatment to be administered, specific criteria must be met. The current treatment options for psoriasis and psoriatic arthritis include tumour necrosis factor alpha (TNF-α) blockers, interleukin (IL)-12 and IL-23 inhibitors, T cell inhibitors and B cell inhibitors. These classes of biological drugs are characterised by protein structure as well as high molecular weight and their effectiveness is evaluated based on the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) and the Dermatology Life Quality Index (DLQI). TNF-α antagonists are one such class of biological drugs which includes infliximad, etanercept and adalimumab. Infliximab is a chimeric protein that is administered via intravenous infusions as a monotherapy in psoriasis vulgaris. Etanercept is indicated for use in both psoriasis vulgaris and psoriatic arthritis and it is the only drug that can be used as a treatment for children under the age of 8 with psoriasis. The drug is administered subcutaneously. Finally, adalimumab is a fully human monoclonal antibody that neutralises both free and membrane-bound TNF-α and is used in the treatment of psoriasis vulgaris and psoriatic arthritis. This article reviews the latest research in the use of TNF-α for the treatment of moderate to severe psoriasis and psoriatic arthritis. The results of research in this field are promising and confirm the effectiveness and safety of biological drugs as dermatological treatments

  9. Similar Clinical and Surgical Outcomes Achieved with Early Compared to Late Anti-TNF Induction in Mild-to-Moderate Ulcerative Colitis: A Retrospective Cohort Study

    PubMed Central

    Fedorak, Darryl K.; Dieleman, Levinus A.; Halloran, Brendan P.

    2016-01-01

    Background. Biologic agents targeting tumor necrosis factor alpha are effective in the management of ulcerative colitis (UC), but their use is often postponed until after failure of other treatment modalities. Objectives. We aim to determine if earlier treatment with infliximab or adalimumab alters clinical and surgical outcomes in UC patients. Methods. A retrospective cohort study was conducted evaluating UC outpatients treated with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first anti-TNF exposure; early initiation was defined as starting treatment within three years of diagnosis. Primary outcomes were colectomy, UC-related hospitalization, and clinical secondary loss of response. Kaplan-Meier analysis was used to assess time to the primary outcomes. Results. 115 patients were included (78 infliximab, 37 adalimumab). Median follow-up was 175.6 weeks (IQR 72.4–228.4 weeks). Fifty-seven (49.6%) patients received early anti-TNF therapy; median time to treatment in this group was 38.1 (23.3–91.0) weeks compared to 414.0 (254.0–561.3) weeks in the late initiator cohort (p < 0.0001). Patients treated with early anti-TNF therapy had more severe endoscopic disease at induction (mean Mayo endoscopy subscore 2.46 (SD ± 0.66) versus 1.86 (±0.67), p < 0.001) and trended towards increased risk of colectomy (17.5% versus 8.6%, p = 0.16) and UC-related hospitalization (43.9% versus 27.6%, p = 0.07). In multivariate regression analysis, early anti-TNF induction was not associated with colectomy (HR 2.02 [95% CI: 0.57–7.20]), hospitalization (HR 1.66 [0.84–3.30]), or secondary loss of response (HR 0.86 [0.52–1.42]). Conclusions. Anti-TNF therapy is initiated earlier in patients with severe UC but earlier treatment does not prevent hospitalization, colectomy, or secondary loss of response. PMID:27478817

  10. Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response

    PubMed Central

    Kragstrup, Tue Wenzel; Jalilian, Babak; Keller, Kresten Krarup; Zhang, Xianwei; Laustsen, Julie Kristine; Stengaard-Pedersen, Kristian; Hetland, Merete Lund; Hørslev-Petersen, Kim; Junker, Peter; Østergaard, Mikkel; Hauge, Ellen-Margrethe; Hvid, Malene; Vorup-Jensen, Thomas; Deleuran, Bent

    2016-01-01

    Introduction In rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis. Methods The level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab. Results Plasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab. Conclusions The plasma sCD18 levels were altered

  11. Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer.

    PubMed

    Porter, Charlene; Armstrong-Fisher, Sylvia; Kopotsha, Tim; Smith, Bryan; Baker, Terry; Kevorkian, Lara; Nesbitt, Andrew

    2016-08-01

    Antibodies to tumor necrosis factor (anti-TNF) are used to treat inflammatory diseases, which often affect women of childbearing age. The active transfer of these antibodies across the placenta by binding of the Fc-region to the neonatal Fc receptor (FcRn) may result in adverse fetal or neonatal effects. In contrast to other anti-TNFs, certolizumab pegol lacks an Fc-region. The objective of this study was to determine whether the structure of certolizumab pegol limits active placental transfer. Binding affinities of certolizumab pegol, infliximab, adalimumab and etanercept to human FcRn and FcRn-mediated transcytosis were determined using in vitro assays. Human placentas were perfused ex vivo to measure transfer of certolizumab pegol and positive control anti-D IgG from the maternal to fetal circulation. FcRn binding affinity (KD) was 132nM, 225nM and 1500nM for infliximab, adalimumab and etanercept, respectively. There was no measurable certolizumab pegol binding affinity, similar to that of the negative control. FcRn-mediated transcytosis across a cell layer (mean±SD; n=3) was 249.6±25.0 (infliximab), 159.0±20.2 (adalimumab) and 81.3±13.1ng/mL (etanercept). Certolizumab pegol transcytosis (3.2±3.4ng/mL) was less than the negative control antibody (5.9±4.6ng/mL). No measurable transfer of certolizumab pegol from the maternal to the fetal circulation was observed in 5 out of 6 placentas that demonstrated positive-control IgG transport in the ex vivo perfusion model. Together these results support the hypothesis that the unique structure of certolizumab pegol limits its transfer through the placenta to the fetus and may be responsible for previously reported differences in transfer of other anti-TNFs from mother to fetus. PMID:27123565

  12. Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn's disease.

    PubMed

    Dige, Anders; Magnusson, Maria K; Öhman, Lena; Hvas, Christian Lodberg; Kelsen, Jens; Wick, Mary Jo; Agnholt, Jørgen

    2016-06-01

    Objective Anti-TNF-α treatment constitutes a mainstay in the treatment of Crohn's disease (CD), but its mechanisms of action are not fully understood. We aimed to investigate the effects of adalimumab, a human monoclonal TNF-α antibody, on macrophage (MQ) and dendritic cell (DC) subsets in mucosal biopsies and peripheral blood. Material and methods Intestinal biopsies and blood samples were obtained from 12 different CD patients both before and 4 weeks after the initiation of the induction of adalimumab treatment. Endoscopic disease activity was estimated by the Simple Endoscopic Score for Crohn's Disease. Biopsies were obtained from inflamed and non-inflamed areas. The numbers of lamina propria CD14 (+) DR(int) and CD14 (+) DR(hi) MQs, CD141(+), CD141(-) and CD103(+ )DCs subsets, and circulating monocytes and DCs were analyzed using flow cytometry. Results At baseline, we observed higher numbers of DR(int) MQs and lower numbers of CD103(+ )DCs in inflamed versus non-inflamed mucosa [843 vs. 391/10(5) lamina propria mononuclear cells (LPMCs) (p < 0.05) and 9 vs. 19 × 10(5) LPMCs (p = 0.01), respectively]. After four weeks of adalimumab treatment, the numbers of DR(int) MQs decreased [843 to 379/10(5) LPMCs (p = 0.03)], whereas the numbers of CD103(+ )DCs increased [9-20 × 10(5) LPMCs (p = 0.003)] compared with baseline. In peripheral blood, no alterations were observed in monocyte or DC numbers between baseline and week 4. Conclusions In CD, mucosal inflammation is associated with high numbers of DR(int) MQs and low numbers of CD103(+ )DCs. This composition of intestinal myeloid subsets is reversed by anti-TNF-α treatment. These results suggest that DR(int) MQs play a pivotal role in CD inflammation. PMID:26784676

  13. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry

    PubMed Central

    Tubach, Florence; Salmon, Dominique; Ravaud, Philippe; Allanore, Yannick; Goupille, Philippe; Bréban, Maxime; Pallot-Prades, Béatrice; Pouplin, Sophie; Sacchi, Antoinette; Chichemanian, Rose Marie; Bretagne, Stéphane; Emilie, Dominique; Lemann, Marc; Lorthololary, Olivier; Mariette, Xavier

    2009-01-01

    Background Tuberculosis (TB) is associated with anti-tumour necrosis factor (TNF) therapy but whether it is drug-specific remains a concern. Our objective was to describe cases of tuberculosis associated with anti-TNF therapy, identify risk factors and estimate the incidence. Methods An incidence study with the French population as reference and a case-control analysis. We collected, for 3 years, cases of TB among French patients receiving anti-TNF therapy, whatever the indication, with two controls treated with anti-TNF agents per case. Results We collected 69 cases of TB in patients treated for rheumatoid arthritis (n=40), spondylarthropathies (n=18), inflammatory colitis (n=9), psoriasis (n=1) and Behçet’s disease (n=1) treated with infliximab (n=36), adalimumab (n=28) and etanercept (n=5). None of the cases had received correct chemoprophylaxis treatment. The sex and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The SIR was 12.2 (95% confidence interval 9.7–15.5) and was higher for therapy with infliximab and adalimumab than for that with etanercept: 18.6 (13.4–25.8) and 29.3 (20.2–42.4) versus 1.8 (0.7–4.3), respectively. In the case-control analysis, the exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB: odds ratio=13.3 (2.6–69.0) and 17.1 (3.6–80.6), respectively. Other risk factors were age, the first year of anti-TNF treatment, and being born in an endemic area. Conclusions The risk of TB is higher for patients receiving monoclonal-antibody than soluble-receptor anti-TNF therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylaxis treatment favours the reactivation of latent TB. PMID:19565495

  14. Comparison between Elecsys HBsAg II and Architect HBsAg QT Assays for Quantification of Hepatitis B Surface Antigen among Patients Coinfected with HIV and Hepatitis B Virus

    PubMed Central

    Maylin, Sarah; Boyd, Anders; Delaugerre, Constance; Zoulim, Fabien; Lavocat, Fabien; Simon, François; Girard, Pierre-Marie

    2012-01-01

    Hepatitis B surface antigen (HBsAg) quantification has been steadily gaining interest as a clinical marker of therapeutic efficacy, for which two commercial assays are currently available: Architect HBsAg QT (Architect) and Elecsys HBsAg II (Elecsys). HBsAg quantification was evaluated using both assays in 126 human immunodeficiency virus (HIV) and hepatitis B virus (HBV)-coinfected patients initiating treatment with tenofovir dipivoxil fumarate. Linear regression and correlation were used to establish the relationship between the two methods. Bland-Altman analysis was performed to determine mean between-assay difference and limits of agreement (LOA) (±2 standard deviations [SD]) both overall and stratified on HBV (hepatitis B envelope antigen [HBeAg] status, replication, genotype, HBV mutants) or HIV (CD4+ cell count) cofactors. There was a significant correlation between Elecsys and Architect assays (correlation coefficient, r = 0.959; P < 0.001). HBsAg quantification using the Elecsys assay was on average 0.200 log10 IU/ml (LOA, −0.500, 0.800) higher than that using Architect, which was consistent across levels of CD4+ cell count, presence of precore and YMDD mutations, and HBeAg status. A slightly larger mean between-assay difference was observed with genotypes A and G (0.196 and 0.201, respectively) versus HBV genotypes D and E (0.036 and 0.030, respectively). Mutations on the S region at position s120/s145 were the only determinant in which the mean between-assay difference in HBsAg quantification was lower than the null value (−0.078). In conclusion, the Elecsys assay, with automatic on-board dilution, is capable of quantifying serum HBsAg levels in HIV-HBV-coinfected patients, with very high correlation with the Architect assay. PMID:22190396

  15. Comparison between Elecsys HBsAg II and architect HBsAg QT assays for quantification of hepatitis B surface antigen among patients coinfected with HIV and hepatitis B virus.

    PubMed

    Maylin, Sarah; Boyd, Anders; Delaugerre, Constance; Zoulim, Fabien; Lavocat, Fabien; Simon, François; Girard, Pierre-Marie; Lacombe, Karine

    2012-02-01

    Hepatitis B surface antigen (HBsAg) quantification has been steadily gaining interest as a clinical marker of therapeutic efficacy, for which two commercial assays are currently available: Architect HBsAg QT (Architect) and Elecsys HBsAg II (Elecsys). HBsAg quantification was evaluated using both assays in 126 human immunodeficiency virus (HIV) and hepatitis B virus (HBV)-coinfected patients initiating treatment with tenofovir dipivoxil fumarate. Linear regression and correlation were used to establish the relationship between the two methods. Bland-Altman analysis was performed to determine mean between-assay difference and limits of agreement (LOA) (±2 standard deviations [SD]) both overall and stratified on HBV (hepatitis B envelope antigen [HBeAg] status, replication, genotype, HBV mutants) or HIV (CD4(+) cell count) cofactors. There was a significant correlation between Elecsys and Architect assays (correlation coefficient, r = 0.959; P < 0.001). HBsAg quantification using the Elecsys assay was on average 0.200 log(10) IU/ml (LOA, -0.500, 0.800) higher than that using Architect, which was consistent across levels of CD4(+) cell count, presence of precore and YMDD mutations, and HBeAg status. A slightly larger mean between-assay difference was observed with genotypes A and G (0.196 and 0.201, respectively) versus HBV genotypes D and E (0.036 and 0.030, respectively). Mutations on the S region at position s120/s145 were the only determinant in which the mean between-assay difference in HBsAg quantification was lower than the null value (-0.078). In conclusion, the Elecsys assay, with automatic on-board dilution, is capable of quantifying serum HBsAg levels in HIV-HBV-coinfected patients, with very high correlation with the Architect assay. PMID:22190396

  16. Roles of hepatocyte nuclear factors in hepatitis B virus infection.

    PubMed

    Kim, Doo Hyun; Kang, Hong Seok; Kim, Kyun-Hwan

    2016-08-21

    Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB. PMID:27610013

  17. Generation of a human hepatoma cell line supporting efficient replication of a lamivudine resistant hepatitis B virus.

    PubMed

    Zhang, Yijun; Zhang, Yongmei; Kang, Yaoyue; Wang, Jinyu; Liu, Hongyan; Zhu, Haoxiang; Qin, Yanli; Mao, Richeng; Lin, Xu; Lu, Mengji; Zhang, Jiming

    2014-06-01

    Emergence of lamivudine (LAM) resistance causes treatment failure in patients with chronic hepatitis B and compromise the efficacy of subsequent salvage therapies with other nucleot(s)ide analogs (NAs). Establishment of cell-based assays supporting LAM-resistant hepatitis B virus (HBV) replication will not only provide tools for investigating the replication property, but also screening for antiviral agents efficiently inhibiting the replication of LAM-resistant HBV variants. Accordingly, a human hepatoma (HepG2)-derived cell line was established by stable transfection of a plasmid containing a 1.2 unit length of HBV genome harboring rtL180M and rtM204V mutations that confer LAM resistance. In addition to support efficient viral genome replication, the cell line also produces high levels of HBV virions and subviral particles. As expected, HBV DNA replication in this cell line is completely resistant to lamivudine, but sensitive to adefovir (ADV), entecavir (ETV) and tenofovir (TDF). The cell line is suitable for screening for antiviral agents that inhibit LAM-resistant HBV replication and inhibitors of HBsAg biosynthesis and secretion, which may reduce HBsAg antigenemia and ultimately help to restore host antiviral immune response against HBV and cure chronic HBV infection. PMID:24583110

  18. A Novel Pyridazinone Derivative Inhibits Hepatitis B Virus Replication by Inducing Genome-Free Capsid Formation

    PubMed Central

    Wang, Ya-Juan; Lu, Dong; Xu, Yi-Bin; Xing, Wei-Qiang; Tong, Xian-Kun; Wang, Gui-Feng; Feng, Chun-Lan; He, Pei-Lan; Zuo, Jian-Ping

    2015-01-01

    Here we first identified a novel pyridazinone derivative, compound 3711, as a nonnucleosidic hepatitis B virus (HBV) inhibitor in a cell model system. 3711 decreased extracellular HBV DNA levels by 50% (50% inhibitory concentration [IC50]) at 1.5 ± 0.2 μM and intracellular DNA levels at 1.9 ± 0.1 μM, which demonstrated antiviral activity at levels far below those associated with toxicity. Both the 3TC/ETV dually resistant L180M/M204I mutant and the adefovir (ADV)-resistant A181T/N236T mutant were as susceptible to 3711 as wild-type HBV. 3711 treatment induced the formation of genome-free capsids, a portion of which migrated faster on 1.8% native agarose gel. The induced genome-free capsids sedimented more slowly in isopycnic CsCl gradient centrifugation without significant morphological changes. 3711 treatment decreased levels of HBV DNA contained in both secreted enveloped virion and naked virus particles in supernatant. 3711 could interfere with capsid formation of the core protein (Cp) assembly domain. A Cp V124W mutant, which strengthens capsid interdimer interactions, recapitulated the effect of 3711 on capsid assembly. Pyridazinone derivative 3711, a novel chemical entity and HBV inhibitor, may provide a new opportunity to combat chronic HBV infection. PMID:26349829

  19. The Use of Cytochrome C Oxidase Enzyme Activity and Immunohistochemistry in Defining Mitochondrial Injury in Kidney Disease.

    PubMed

    Zsengellér, Zsuzsanna K; Rosen, Seymour

    2016-09-01

    The renal biopsy is a dynamic way of looking at renal disease, and tubular elements are an important part of this analysis. The mitochondria in 20 renal biopsies were examined by immunohistochemical (electron transport chain enzyme: cytochrome C oxidase IV [COX IV]) and enzyme histochemical methods (COX), both by light and electron microscopy. The distal convoluted tubules and thick ascending limbs showed the greatest intensity in the COX immunostains and enzyme activity in controls. The degree of mitochondrial COX protein and enzyme activity diminished as the tubules became atrophic. With proximal hypertrophic changes, there was great variation in both COX activity and protein expression. In contrast, in three cases of systemic lupus erythematosus, biopsied for high-grade proteinuria, the activity was consistently upregulated, whereas protein expression remained normal. These unexpected findings of heterogeneous upregulation in hypertrophy and the dyssynchrony of protein expression and activity may indicate mitochondrial dysregulation. Functional electron microscopy showed COX activity delineated by the intense mitochondrial staining in normal or hypertrophic proximal tubules. With atrophic changes, residual small mitochondria with diminished activity could be seen. With mitochondrial size abnormalities (enlargement and irregularity, adefovir toxicity), activity persisted. In the renal biopsy, mitochondrial analysis is feasible utilizing immunohistochemical and enzyme histochemical techniques. PMID:27578326

  20. Oxethazaine inhibits hepatitis B virus capsid assembly by blocking the cytosolic calcium-signalling pathway.

    PubMed

    Zhang, Lin; Liu, Chunlan; Xiao, Yu; Chen, Xulin

    2016-05-01

    Chronic hepatitis B virus (HBV) infection is a serious public health problem and may progress to liver fibrosis, cirrhosis and hepatocellular carcinoma. It is currently treated with PEGylated IFN-α2a and nucleoside/nucleotide analogues (NAs). However, PEGylated IFN treatment has problems of high cost, low efficiency and side effects. Long-term administration of NAs is necessary to avoid virus relapse, which can cause drug resistance and side effects. New efforts are now being directed to develop novel anti-HBV drugs targeting either additional viral targets other than viral DNA polymerase or host targets to improve the treatment of chronic hepatitis B. In this study, we discovered that oxethazaine, approved for clinic use in a few countries such as Japan, India, South Africa and Brazil, can dose-dependently reduce the levels of HBV envelope antigen, extracellular HBV DNA in supernatants and intracellular HBV total DNA. However, the levels of HBV cccDNA and HBV RNAs were not affected by oxethazaine treatment. Further study confirmed that oxethazaine acts on the virus assembly stage of the HBV life cycle. A study of the mechanisms of oxethazaine suggested that this drug inhibits HBV replication and capsid assembly by blocking the cytosolic calcium-signalling pathway. Moreover, oxethazaine could inhibit the replication of lamivudine/entecavir-dual-resistant and adefovir-resistant HBV mutants. In conclusion, our study suggests that oxethazaine may serve as a promising drug, or could be used as a starting point for anti-HBV drug discovery. PMID:26838678

  1. Adenine: an important drug scaffold for the design of antiviral agents

    PubMed Central

    Wang, Changyuan; Song, Zhendong; Yu, Haiqing; Liu, Kexin; Ma, Xiaodong

    2015-01-01

    Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template. PMID:26579473

  2. Specific primer sets used to amplify by PCR the hepatitis B virus overlapping S/Pol region select different viral variants.

    PubMed

    Cuestas, M L; Mathet, V L; Oubiña, J R

    2012-10-01

    PCR detection of viral genomes has provided new insights into viral diagnosis. Nowadays, it is the most frequently used nucleic acid testing (qualitative and quantitative) technique. The aim of this study was to analyse the major circulating hepatitis B virus (HBV) variants PCR-amplified by three sets of primers in a patient infected with genotype E. The HBV S/Pol overlapping genomic region was amplified from the serum of an infected child using three primer sets previously described. Sequence analysis corresponding to the HBV S/Pol region revealed the presence of different viral populations depending on the set of primers used. D144A S-escape mutant was detected with two of the primer sets, while the rtL217R mutant within the Pol - conferring resistance to Adefovir - could be picked up with a different pair of primer sets. This study undoubtedly implies that the description of viral polymorphisms should be stated together with the sequence of the primers used for PCR amplification when studies of escape and/or antiviral-resistant HBV mutants are carried out. PMID:22967107

  3. Roles of hepatocyte nuclear factors in hepatitis B virus infection

    PubMed Central

    Kim, Doo Hyun; Kang, Hong Seok; Kim, Kyun-Hwan

    2016-01-01

    Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage in the HBV life cycle (the reverse transcription step in the nucleocapsid). Therefore, an understanding of the factors regulating cccDNA transcription is required to stop this process. Among numerous factors, hepatocyte nuclear factors (HNFs) play the most important roles in cccDNA transcription, especially in the generation of viral genomic RNA, a template for HBV replication. Therefore, proper control of HNF function could lead to the inhibition of HBV replication. In this review, we summarize and discuss the current understanding of the roles of HNFs in the HBV life cycle and the upstream factors that regulate HNFs. This knowledge will enable the identification of new therapeutic targets to cure CHB. PMID:27610013

  4. Pericardial effusions with tamponade and visceral constriction in patients with rheumatoid arthritis on tumour necrosis factor (TNF)-inhibitor therapy.

    PubMed

    Soh, May Ching; Hart, Hamish H; Corkill, Michael

    2009-04-01

    Tumour necrosis factor-inhibitor (TNF-inhibitor) therapy is increasingly used for the treatment of rheumatoid arthritis. While it is effective for the articular manifestations of rheumatoid arthritis we have reason to believe that it is less effective for extra-articular disease. We present two cases of life-threatening cardiac tamponade in two patients with well-controlled rheumatoid arthritis on adalimumab. An extensive literature search was carried out and three other patients were found. We believe that these cases highlight the need for rheumatologists to be vigilant for extra-articular manifestations of rheumatoid arthritis even in the presence of quiescent joint disease while on TNF-inhibitors. PMID:20374322

  5. 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

  6. Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls.

    PubMed

    Silva, Léia C R; Ortigosa, Luciena C M; Benard, Gil

    2010-11-01

    TNF-α is a potent inducer of the inflammatory response, a key regulator of innate immunity and plays an important role in the regulation of Th1 immune responses against intracellular bacteria and certain viral infections. However, dysregulated TNF can also contribute to numerous pathological situations. These include immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and severe chronic plaque psoriasis. Animal and human studies concerning the role of TNF-α in IMIDs have led to the development of a therapy based on TNF blockage. This article focuses first on the potential mechanisms by which the three currently licensed agents, adalimumab, etarnecept and infliximab, decrease the inflammatory activity of patients with different IMIDs. Second, it focuses on the risks, precautions and complications of the use of TNF-α inhibitors in these patients. PMID:21091114

  7. [Psoriatic arthritis and etanercept].

    PubMed

    Pedraz, J; Daudén, E

    2010-05-01

    Psoriatic arthritis (PA) is a chronic inflammatory condition whose symptoms generally appear after the skin symptoms. Making an early diagnosis and treatment of the disease is of vital importance because of the potential development of mutilating and deforming arthritis. Classical treatments of PA include the use of non-steroid anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARD) such as methotrexate, sulfasalazine, or gold, and finally, leflunomide. Research on the pathophysiology of psoriasis and of the PA has led to the incorporation of biological treatments, specifically anti-TNF drugs. The three treatments used most in PA are etanercept, infliximab and adalimumab. Of all these, we are going to make a systematic review of the principal studies available on etanercept for the treatment of PA. PMID:20492877

  8. Recent advances in the use of Anti-TNFα therapy for the treatment of juvenile idiopathic arthritis.

    PubMed

    Taddio, Andrea; Cattalini, Marco; Simonini, Gabriele; Cimaz, Rolando

    2016-06-01

    Juvenile Idiopathic Arthritis (JIA) encompasses a group of diseases of unknown etiology having in common arthritis in at least 1 joint that persists for 6 weeks and begins before 16 years of age, with other conditions excluded. With a prevalence of 1 per 1,000 children in the USA, JIA is the most common pediatric rheumatic illness and a major cause of acquired childhood disability. During the last 20 years, the advent of host immune response modifiers known as biologic agents, in particular the anti-TNFα agents (etanercept, infliximab, adalimumab), which directly inhibit the action of pro-inflammatory mediators, has revolutionized the treatment and the expected outcome of JIA. This article highlights treatment indications of anti-TNFα drugs and their more frequent side effects in JIA patients. PMID:26809126

  9. [Tofacitinib for the treatment of rheumatoid arthritis].

    PubMed

    Tanaka, Yoshiya

    2016-06-01

    The combined use of synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as methotrexate and biological DMARDs (bDMARDs) has revolutionized treatment of rheumatoid arthritis (RA). Remission is now realistic targets, achieved by a large proportion of RA patients. However, bDMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active RA patients with sDMARD-naïve, inadequately responsive to sDMARDs or TNF-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. The common adverse events were related to infection, hematologic and hepatic disorders and association of tofacitinib with carcinogenicity and infections remains debated. PMID:27311188

  10. Current management of scalp psoriasis.

    PubMed

    Guenther, L

    2015-01-01

    The scalp is involved in up to 80% of individuals with psoriasis. Eighty percent of those with scalp psoriasis experience a negative impact on quality of life. Topical treatment with corticosteroids with or without vitamin D3 analogues is the mainstay of treatment. Topical therapy most suitable for the scalp is formulated as a solution, lotion, gel, foam, spray, oil, or shampoo. Twice weekly maintenance in frequent relapsers may decrease the time to first relapse. Intralesional steroids, phototherapy and the excimer laser are occasionally used for resistant cases. In patients with moderate-to-severe psoriasis, apremilast, adalimumab and etanercept have been shown to significantly improve scalp psoriasis. They should be considered in patients who have failed topical therapy. PMID:26382557

  11. [Juvenile arthritides].

    PubMed

    Horneff, G

    2010-10-01

    Arthritis in children represents a diagnostic and therapeutic challenge. The diagnostic spectrum is broad and a very precise indication for diagnostic and therapeutic procedures, especially in small children, is important. In addition to acute arthritides - viral arthritis, reactive arthritis, Lyme arthritis and septic arthritis - secondary chronic arthritis related to an underlying disease as well as juvenile idiopathic arthritis (JIA), the most common chronic inflammatory systemic disease in children, need to be considered. This overview is a guide to the diagnosis of arthritis in childhood and to evidence-based therapy of JIA in particular. This consists of a combination of nonsteroidal anti-inflammatory drugs, systemic and intraarticular corticosteroids, traditional DMARDs such as sulfasalazine, methotrexate and leflunomide, the TNF inhibitors etanercept, adalimumab and, with restrictions, infliximab, other biopharmaceuticals such as anakinra, canakinumab and rilonacept, and tocilizumab and finally, abatacept. PMID:20798949

  12. Perioperative management of tumor necrosis factor-alpha blocker-treated psoriatic patients: Case reports and review.

    PubMed

    Kawakami, Hiroshi; Matsumoto, Yuka; Abe, Namiko; Katori, Youich; Takahashi, Kousuke; Tsuboi, Ryoji; Okubo, Yukari

    2016-02-01

    Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque-type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)-α blocker therapy. Three GPP cases experienced uneventful post-surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF-α blockers in all cases were determined following the Japanese guideline. PMID:26346621

  13. Methotrexate: new therapeutic approaches.

    PubMed

    Puig, L

    2014-01-01

    Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab. PMID:23434058

  14. Pharmacodynamics of TNF-α inhibitors in psoriasis.

    PubMed

    Vergou, Theognosia; Moustou, Aikaterini-Evangelia; Sfikakis, Petros P; Antoniou, Christina; Stratigos, Alexander J

    2011-07-01

    Over the last two decades, research developments have revolutionized our understanding of the pathogenesis of psoriasis and of the contribution of several cytokines in the manifestation of the disease. The key role of TNF-α in the pathogenesis of psoriasis has been extensively studied and its therapeutic action, initially observed in experimental models, has been clinically translated into therapeutic agents with remarkable efficacy in the treatment of the disease. There are currently two classes of marketed biologic drugs that reduce TNF-α bioavailability and are used clinically in psoriasis: the soluble TNF-α receptor-Fc fusion protein (etanercept) and the anti-TNF-α monoclonal antibodies (adalimumab and infliximab). The present article reviews the pharmacodynamic properties of the three TNF-α inhibitors and discusses possible differences in their mode of action, clinical efficacy and safety profile. PMID:22114860

  15. Herpes Simplex Virus Sepsis in a Young Woman with Crohn's Disease.

    PubMed

    Haag, Lea-Maxie; Hofmann, Jörg; Kredel, Lea Isabell; Holzem, Christina; Kühl, Anja A; Taube, Eliane T; Schubert, Stefan; Siegmund, Britta; Epple, Hans-Jörg

    2015-12-01

    We present the case of a herpes simplex virus-1 [HSV-1] sepsis with severe herpes hepatitis in a young female treated with triple immunosuppressive therapy [adalimumab, azathioprine, prednisolone] for refractory Crohn's disease [CD]. The patient presented with high fever, generalised abdominal tenderness, strongly elevated transaminases, coagulopathy, and pancytopenia. Comprehensive diagnostics including blood HSV-1 polymerase chain reaction [PCR], liver biopsy, and immunohistochemistry revealed the diagnosis of fulminant herpes hepatitis. HSV-1 positivity of cutaneous lesions proved the disseminated nature of the infection. Early treatment with intravenous acyclovir led to a rapid improvement of the patient's condition and resulted in a full recovery of her liver function. This is the first reported case of HSV-sepsis in a patient with CD. Physicians treating inflammatory bowel disease [IBD] patients with combined immunosuppressive therapy should be aware of the possibility of herpes hepatitis, and early empirical antiviral therapy should be considered in immunosuppressed patients presenting with fever and severe anicteric hepatitis. PMID:26351382

  16. Treatment of uveitis associated with juvenile idiopathic arthritis.

    PubMed

    Bou, Rosa; Iglesias, Estíbaliz; Antón, Jordi

    2014-08-01

    Chronic anterior uveitis affects 10-30 % of patients with juvenile idiopathic arthritis (JIA) and is still a cause of blindness in childhood. In most patients it is asymptomatic, bilateral, and recurrent, so careful screening and early diagnosis are important to obtain the best long-term prognosis. The treatment of chronic uveitis associated with JIA is challenging. Initial treatment is based on topical steroids and mydriatic drops. Methotrexate is the most common first-line immunomodulatory drug used. For refractory patients, biologicals, mainly the anti-tumor-necrosis-factor (TNF) drugs adalimumab and infliximab, have been revealed to be effective and have changed the outcome for these patients. Collaboration between pediatric rheumatologists and ophthalmologists is important for the successful diagnosis and treatment of patients with uveitis associated with JIA. PMID:24938442

  17. A 28-Year-Old Man Presenting With Intractable Dry Cough and a History of Ulcerative Colitis.

    PubMed

    Lücker, Lise M; Hachulla, Anne-Lise; Lador, Frédéric; Chizzolini, Carlo; Adler, Dan

    2016-05-01

    A 28-year-old man of Japanese descent presented to the ED with a 2-month history of dry cough, shortness of breath, and weakness. He did not complain of fever, chest pain, or abdominal symptoms, and had no history of smoking. The patient's medical history was significant for an episode of ulcerative colitis 6 years previously after presenting with bloody diarrhea, stomach pain, fever, weight loss, and bilateral episcleritis. He had been treated consecutively with mesalazine, azathioprine, infliximab, golimumab, and adalimumab. Concomitant respiratory symptoms had been present during 2 flare-ups of severe ulcerative colitis disease activity and were successfully treated with a course of oral prednisone. PMID:27157229

  18. Erythrodermic psoriasis: current and future role of biologicals.

    PubMed

    Stinco, Giuseppe; Errichetti, Enzo

    2015-04-01

    Erythrodermic psoriasis (EP) is a severe form of psoriasis that may be associated with serious and sometimes fatal complications. The treatment of EP is often a challenge, since several factors, including treatment failure or possible complications, may limit favorable outcomes with traditional drugs. Recent evidence suggests that biological drugs, including both anti-tumor necrosis factor alpha agents and ustekinumab, may be useful in improving the management of EP. Unfortunately, since subjects with EP are usually excluded from pivotal trials involving biological agents, this evidence is currently dispersed in small case series and single case reports. In this paper, we briefly analyze conventional therapies for EP, before going on to critically evaluate the existing clinical evidence for the role of current biological drugs, namely infliximab, etanercept, adalimumab, and ustekinumab. Finally, we discuss the potential benefits that newer/developmental biological agents could bring to the management of EP. PMID:25752640

  19. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-11-01

    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(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (Z)-4-Hydroxytamoxifen, [18F]-FPS; Adalimumab, alefacept, alemtuzumab, alfimeprase, aprepitant, aripiprazole, atomoxetine hydrochloride; Belatacept, bortezomib; C340, caspofungin acetate, clazosentan sodium, Cypher; Darbepoetin alfa, DB-289, decitabine, dronedarone hydrochloride, duloxetine hydrochloride; Eletriptan, entecavir, ertapenem sodium, escitalopram oxalate, eszopiclone, etoricoxib; Gaboxadol, gadofosveset sodium, galiximab, gemifloxacin mesilate, glutamine; Human insulin; I-131 ch-TNT-1/B, indiplon, inhaled insulin, isatoribine; L-Arginine hydrochloride, liposomal doxorubicin, lopinavir/ritonavir, lumiracoxib; Magnesium sulfate; Natalizumab; Olmesartan medoxomil, omapatrilat, OncoVEX (GM-CSF); rDNA insulin, rupatadine fumarate; Sorafenib; Tadalafil, teduglutide, temsirolimus, tenofovir disoproxil fumarate, tiotropium bromide; Valdecoxib, vardenafil hydrochloride hydrate. PMID:16357953

  20. Update on Hidradenitis Suppurative (Part II): Treatment.

    PubMed

    Martorell, A; García, F J; Jiménez-Gallo, D; Pascual, J C; Pereyra-Rodríguez, J; Salgado, L; Villarrasa, E

    2015-11-01

    Although hidradenitis suppurativa is a common and serious skin condition, its treatment is not well established. It is now accepted that the moderate and severe forms of the disease are associated with marked systemic inflammation. The goal of treatment in hidradenitis suppurative is therefore to achieve systemic control of inflammation. In some cases, surgery may also be necessary to reduce the severity of the manifestations of cutaneous inflammation. Recent advances in our understanding of hidradenitis suppurativa have been accompanied by the emergence of novel approaches to its treatment, including the use of certain biologic drugs. Several clinical trials have been undertaken to test the effects of biologics (mainly adalimumab) in this setting. In this review, we analyze the different treatments available for hidradenitis suppurativa. PMID:26277040

  1. Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis.

    PubMed

    Maleki, Arash; Meese, Halea; Sahawneh, Haitham; Foster, C Stephen

    2016-07-01

    Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema. PMID:26972783

  2. Clinical management of paradoxical psoriasiform reactions during TNF- α therapy.

    PubMed

    Navarro, R; Daudén, E

    2014-10-01

    There have been reports of paradoxical induction or worsening of psoriasis during treatment with tumor necrosis factor (TNF) α agents (infliximab, etanercept, adalimumab, and certolizumab). It has been hypothesized that an imbalance between TNF-α and interferon α might have a role in the etiology and pathogenesis of these reactions. Paradoxical psoriasiform reactions can be divided clinically into de novo psoriasis and exacerbation of preexisting psoriasis. The first, which is more common and more extensively described in the literature, occurs in patients without a history of psoriasis who are receiving TNF-α therapy for another inflammatory disorder. The second can occur with or without changes in the morphology of the lesions. In this article, we review the literature on the clinical and histologic features of paradoxical psoriasiform reactions, analyze their clinical course and treatment, and propose a clinical management model for use in routine practice. PMID:23938073

  3. Successful effect of tocilizumab in anti-TNF-α-induced palmoplantar pustulosis in rheumatoid arthritis.

    PubMed

    Rueda-Gotor, Javier; González-Gay, Miguel A; Blanco Alonso, Ricardo; Gonzalez-Vela, Carmen; Lopez-Obregon, Cristina; González-López, Marcos A

    2012-10-01

    Anti-tumour necrosis factor-alpha (TNF-α) agents are effective drugs used in several chronic inflammatory diseases such as rheumatoid arthritis (RA). Psoriasiform lesions, including palmoplantar pustulosis, have been described following anti-TNF-α therapy. These lesions often resolve with topical therapy with or without discontinuation of these drugs. However, in some cases, psoriasiform lesions may persist despite anti-TNF-α withdrawal. We report on two RA patients treated with adalimumab (ADA) who developed palmoplantar pustular despite dermatological treatment and ADA discontinuation. Tocilizumab (TCZ) therapy was initiated because of persistence of skin lesions and flare of the disease. Following treatment with this drug, complete resolution of the dermatological lesions and induction of remission of RA was achieved. To the best of our knowledge, management of palmoplantar pustulosis due to TNF-α agents with TCZ leading to both improvement of the disease and resolution of the cutaneous lesions has not previously been reported. PMID:22857979

  4. Recent Advances in Treatments of Primary Focal Segmental Glomerulosclerosis in Children

    PubMed Central

    2016-01-01

    Focal segmental glomerulosclerosis (FSGS) is a nephrotic syndrome. Up to around 80% of cases of primary FSGS are resistant to steroid treatment. A large proportion of patients with steroid-resistant FSGS progress to end-stage renal disease. The purpose of treatment is to obtain a complete remission of proteinuria, a necessary step that precedes improved renal survival and reduces the risk of progression to chronic kidney disease. When this is not possible, the secondary goal is a partial remission of proteinuria. Reduction or remission of proteinuria is the most important factor predictive of renal survival. We will review the current updated strategies for treatment of primary FSGS in children, including traditional therapies consisting of corticosteroids and calcineurin inhibitors and novel therapies such as rituximab, abatacept, adalimumab, and fresolimumab. PMID:27195285

  5. Biologics in the management of psoriasis

    PubMed Central

    Bahner, Jennifer D; Cao, Lauren Y; Korman, Neil J

    2009-01-01

    Psoriasis is a chronic inflammatory systemic disease for which there exist topical, ultraviolet, systemic, and biologic treatments. Biologic agents selectively interfere with the immune mechanisms responsible for psoriasis. Etanercept, infliximab, and adalimumab target tumor necrosis factor-alpha and have demonstrated efficacy in the treatment of psoriasis and psoriatic arthritis. Alefacept and efalizumab target T lymphocytes, are effective in the treatment of psoriasis, but are not approved for psoriatic arthritis. Finally, ustekinumab and ABT-874 target interleukin-12 and interleukin-23, and they have demonstrated efficacy in the treatment of psoriasis. The objective of this review is to present efficacy and safety data from randomized controlled trials of the biologic agents in the treatment of psoriasis. PMID:21436974

  6. Polyarteritis nodosa. Diagnostic challenges in a patient with cutaneous vasculitis, psoriasis, psoriatic arthritis and pancytopenia: fatal progression after treatment with G-CSF

    PubMed Central

    Jobanputra, Paresh

    2016-01-01

    A 60-year-old man presented with cutaneous vasculitis, leucopenia and psoriasis. He was treated initially with ciclosporin A. On withdrawal of ciclosporin, due to inadequate improvement of cutaneous vasculitis, he developed psoriatic arthritis. Worsening neutropenia and pancytopenia, believed to be immune mediated, developed. He was treated with prednisolone, methotrexate and adalimumab but developed pneumocystis pneumonia. Leucocyte levels improved markedly with granulocyte colony-stimulating factor (G-CSF). However, whilst being treated with G-CSF his condition deteriorated. He developed gastrointestinal and neurological symptoms and progressive weight loss. Diagnosis was delayed, but eventually polyarteritis nodosa was diagnosed and he was treated with cyclophosphamide. The patient improved initially but died from small bowel perforation due to vasculitis. Evidence showing a temporal association of his deterioration with use of G-CSF is shown. The use of G-CSF in patients with autoimmune conditions including vasculitis should be undertaken with great caution. PMID:27123310

  7. Refractory postsurgical pyoderma gangrenosum in a patient with Beckwith Wiedemann syndrome: response to multimodal therapy

    PubMed Central

    Fakhar, Faiza; Memon, Sehrish; Deitz, Diane; Abramowitz, Richard; Alpert, Deborah R

    2013-01-01

    Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that may be difficult to diagnose and treat. We presented a 41-year-old woman who required skin grafting following third-degree burns to her left breast. She suffered recurrent graft dehiscence and infections over many years, prompting elective bilateral reduction mammoplasty. She subsequently developed suture margin ulcerations unresponsive to topical therapies and antibiotics. Skin biopsies were non-specific, and a clinical diagnosis of PG was established. Although initially responsive to corticosteroids, wounds promptly recurred following steroid taper. She was treated unsuccessfully with various immunomodulatory agents and underwent elective bilateral mastectomy. Following a mastectomy, she developed progressive deep chest wall ulcerations. She failed numerous immunomodulatory treatments, surgical wound closure and negative pressure wound therapy. Ultimately, treatment with adalimumab, mycophenolate mofetil and prednisone, in addition to hyperbaric oxygen therapy facilitated progressive healing. Our case highlights the role of collaborative multimodal therapy for the treatment of refractory PG. PMID:24154999

  8. Certolizumab pegol - A new therapeutic option for refractory disseminated pyoderma gangrenosum associated with Crohn's disease.

    PubMed

    Hurabielle, Charlotte; Schneider, Pierre; Baudry, Clotilde; Bagot, Martine; Allez, Matthieu; Viguier, Manuelle

    2016-01-01

    Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn's disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn's disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti-TNF) therapies. PMID:25909366

  9. Predictors of Switching Anti-Tumor Necrosis Factor Therapy in Patients with Ankylosing Spondylitis

    PubMed Central

    Lee, Jeong-Won; Kang, Ji-Hyoun; Yim, Yi-Rang; Kim, Ji-Eun; Wen, Lihui; Lee, Kyung-Eun; Park, Dong-Jin; Kim, Tae-Jong; Park, Yong-Wook; Lee, Shin-Seok

    2015-01-01

    The aim of this study was to investigate the potential predictors of switching tumor necrosis factor (TNF)-α inhibitors in Korean patients with ankylosing spondylitis (AS). The patients who had been treated with TNF-α inhibitors were divided into two groups depending on whether they had switched TNF-α inhibitors. Demographic, clinical, laboratory, and treatment data at the time of initiation of TNF-α inhibitor treatment were compared between switchers and non-switchers, and within switchers according to the reasons for switching. Of the 269 patients, 70 (23%) had switched TNF-α inhibitors once; of these, 11 switched again. The median follow-up time was 52.7 months. Three- and five-year drug survival rates were 52%/48% for infliximab, 62%/42% for etanercept, and 71%/51% for adalimumab, respectively. Switchers were more likely to be prescribed disease-modifying anti-rheumatic drugs than non-switchers. A history of joint surgery and complete ankylosis of the sacroiliac joint was more frequent in switchers. Multivariate Cox’s proportional hazard analysis showed that the use of adalimumab as the first TNF-α inhibitor was less likely to lead to switching and complete ankylosis of the sacroiliac joints was more likely to lead to switching. The principal reasons for switching were drug inefficacy and adverse events, but the differences in the clinical data of these two groups of switchers were not significant. In AS patients who are candidates for TNF-α inhibitor therapy, switching may improve the therapeutic outcome based on clinical information. PMID:26176701

  10. Downregulation of Immunoglobulin-Like Transcript-4 (ILT4) in Patients with Psoriatic Arthritis

    PubMed Central

    Bergamini, Alberto; Chimenti, Maria Sole; Baffari, Eleonora; Guarino, Maria Domenica; Gigliucci, Gianfranco; Perricone, Carlo; Perricone, Roberto

    2014-01-01

    Objective The immunoglobulin-like transcript-4 (ILT4) is an inhibitory receptor that modulates the activity of innate immune agents. We determined the expression of ILT4 and analysed the relationship with the expression of costimulatory proteins and tumor necrosis factor-α (TNF-α) production in monocytes from patients with psoriatic arthritis (PsA) starting anti-TNF treatment. Methods Peripheral blood monocytes from 15 healthy controls and from 16 patients with PsA were activated in vitro by CD40 ligand (CD40L) and analyzed for ILT4, CD40, CD80 and CD86 expression, and spontaneous lipopolysaccharide (LPS)-induced TNF-α production by flow cytometry, before and after treatment with adalimumab. Results The percentage of ILT4-negative monocytes was greater in PsA patients compared to controls and negatively correlated with DAS44. Normal monocytes treated with sera of PsA patients showed a reduced expression of ILT4 compared with monocytes exposed to sera from controls. CD40, CD80 and CD86 expression was higher in patients compared to controls. Both spontaneous and LPS-induced TNF-α production was restricted to ILT4-negative monocytes and was greater in PsA patients compared to controls. Finally, twelve weeks-treatment with adalimumab resulted in a significant increase of ILT4 expression and a decrease of costimulatory molecules expression in PsA patients, compared to pre-therapy levels. Conclusions These data support the possibility that changes in the immunophenotype of monocytes play a role in the pathogenesis of PSA. Thus, modulation of the expression of ILT4 may represent an enticing new therapeutic target. PMID:24676037

  11. Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

    PubMed Central

    Onuoha, Shimobi C.; Ferrari, Mathieu; Sblattero, Daniele

    2015-01-01

    Objective Biologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. Methods Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. Results Intact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules. Conclusion The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of

  12. Paradoxical Autoinflammatory Skin Reaction to Tumor Necrosis Factor Alpha Blockers Manifesting as Amicrobial Pustulosis of the Folds in Patients With Inflammatory Bowel Diseases

    PubMed Central

    Marzano, Angelo V.; Tavecchio, Simona; Berti, Emilio; Gelmetti, Carlo; Cugno, Massimo

    2015-01-01

    Abstract The therapy of inflammatory bowel disease, particularly with tumor necrosis factor (TNF) blockers, may be associated with a number of cutaneous adverse effects, including psoriasis-like, eczema-like, and lichenoid eruptions. Other rare skin complications are neutrophilic dermatoses such as amicrobial pustulosis of the folds (APF), which is a chronic relapsing pustular disorder classified in this spectrum. The authors analyzed clinical, histopathologic, and cytokine expression profiles of 3 inflammatory bowel disease patients with APF triggered by adalimumab (patient 1) and infliximab (patients 2 and 3). All 3 patients presented with sterile pustules involving the cutaneous folds, genital regions, and scalp 6 months after starting adalimumab (patient 1) and 9 months after starting infliximab (patients 2 and 3). Histology was characterized by epidermal spongiform pustules with a dermal neutrophilic and lymphocytic infiltrate. Tumor necrosis factor blocker withdrawal associated with topical and systemic corticosteroids induced complete remission of APF in all 3 patients. The expressions of interleukin (IL)-1 beta and its receptors as well as TNF alpha and its receptors were significantly higher in APF than in controls. Also IL-17, leukocyte selectin, and chemokines, such as IL-8, [C-X-C motif] chemokine ligand 1/2/3 (C = cysteine, X = any amino acid), [C-X-C motif] chemokine ligand 16 (C = cysteine, X = any amino acid), and RANTES (regulated on activation, normal T cell expressed and secreted) were significantly overexpressed. Finally, the authors found significant overexpression of both metalloproteinases 2/9 and their inhibitors 1/2. The observation of 3 patients with APF following anti-TNF therapy expands not only the clinical context of APF but also the spectrum of anti-TNF side effects. Overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF is autoinflammatory in origin. PMID

  13. Serum C-reactive protein levels in Japanese patients with psoriasis and psoriatic arthritis: Long-term differential effects of biologics.

    PubMed

    Asahina, Akihiko; Umezawa, Yoshinori; Yanaba, Koichi; Nakagawa, Hidemi

    2016-07-01

    Psoriasis has been shown to accompany systemic inflammation. We aimed to examine serum C-reactive protein (CRP) levels in Japanese psoriatic patients, and to elucidate their long-term as well as short-term changes by treatment with different biologics. A retrospective study was conducted in those who initiated and successfully continued the treatment for up to 24 months with either infliximab, adalimumab or ustekinumab, at the psoriasis special clinic of Jikei University School of Medicine. A total of 212 patients were included, 171 with plaque-type psoriasis (PsV) and 41 with psoriatic arthritis (PsA). A statistically significant elevation of CRP values was found in the group with a Psoriasis Area and Severity Index (PASI) of 12 or more compared with the PASI of less than 12 for both PsV and PsA. The CRP-positive patients had a higher proportion of PsA compared with the CRP-negative patients, and they had significantly higher PASI scores. Serum CRP values declined as early as at 3 months after systemic treatment with biologics. Tumor necrosis factor (TNF)-α antagonists did lead to a notable and sustained CRP decline up to 24 months. Infliximab showed rapid decline, while CRP decline by adalimumab treatment was time-dependent. The interleukin-12/23 p40 antagonist, ustekinumab, appeared to be less potent than TNF-α antagonists in stabilizing CRP values at low levels despite good control of cutaneous lesions. In conclusion, serum CRP levels can be used to assess disease severity in Japanese psoriatic patients as a marker of systemic inflammation. TNF-α antagonists may be more beneficial than ustekinumab in this regard. PMID:26704718

  14. Clinical features of active tuberculosis that developed during anti-tumor necrosis factor therapy in patients with inflammatory bowel disease

    PubMed Central

    Lee, Jang Wook; Park, Ji Hoon; Kim, Jeong Wook; Kang, Sang Bum; Koo, Ja Seol; Kim, Young-Ho; Kim, You Sun; Joo, Young Eun; Chang, Sae Kyung

    2016-01-01

    Background/Aims Anti-tumor necrosis factor (TNF) therapy for active ulcerative colitis (UC) and Crohn's disease (CD) is associated with increased risks of tuberculosis (TB) infection. We analyzed the incidence and clinical features of Korean patients with inflammatory bowel disease (IBD) who developed active TB during anti-TNF therapy. Methods Ten cases of active TB developed in patients treated with infliximab (n=592) or adalimumab (n=229) for UC (n=160) or CD (n=661) were reviewed. We analyzed demographics, interval between start of anti-TNF therapy and active TB development, tests for latent TB infection (LTBI), concomitant medications, and the details of diagnosis and treatments for TB. Results The incidence of active TB was 1.2% (10/821): 1.5% (9/592) and 0.4% (1/229) in patients receiving infliximab and adalimumab, respectively. The median time to the development of active TB after initiation of anti-TNF therapy was three months (range: 2–36). Three patients had past histories of treatment for TB. Positive findings in a TB skin test (TST) and/or interferon gamma releasing assay (IGRA) were observed in three patients, and two of them received anti-TB prophylaxis. Two patients were negative by both TST and IGRA. The most common site of active TB was the lungs, and the active TB was cured in all patients. Conclusions Active TB can develop during anti-TNF therapy in IBD patients without LTBI, and even in those with histories of TB treatment or LTBI prophylaxis. Physicians should be aware of the potential for TB development during anti-TNF therapy, especially in countries with a high prevalence of TB. PMID:27175115

  15. Uveitis Reactivation in Children Treated with Tumor Necrosis Factor-α Inhibitors

    PubMed Central

    Lerman, Melissa A.; Lewen, Michael D.; Kempen, John H.; Mills, Monte D.

    2016-01-01

    PURPOSE To evaluate reactivation of pediatric uveitis during/following treatment with TNF-alpha inhibition (anti-TNFα). DESIGN Retrospective cohort study. METHODS We assessed the incidence of uveitis reactivation in children ≤18 years who had achieved uveitis quiescence under anti-TNFα. Survival analysis was used to calculate reactivation rates while still on (primary outcome), and following discontinuation of (secondary outcome), anti-TNFα. Potential predictive factors were assessed. RESULTS Among 50 children observed to develop quiescence of uveitis under anti-TNFα, 39 met criteria to be “at risk” of the primary (19 for the secondary) outcome. 60% were female, ~half had Juvenile Idiopathic Arthritis, and most were treated with infliximab. Overall, the estimated proportion relapsing within 12 months was 27.8% (95% confidence interval [CI]: 15.9-45.8%); the estimated probability of reactivation was higher following (63.8% [95% CI: 38.9-87.7%]), than before (21.6% [95% CI: 10.8-40.2%]), anti-TNFα discontinuation. Amongst those who discontinued anti-TNFα, the likelihood of reactivation was higher for those treated with adalimumab vs. infliximab (Hazard Ratio [HR] 13.4, p=0.01, 95% CI: 2.2-82.5) and those with older age at uveitis-onset (HR 1.3, p=0.09, 95% CI: 1.0-1.7). The duration of suppression, on medication, did not significantly affect the likelihood of reactivation when quiescence was maintained for ≥1.5 years. CONCLUSIONS Approximately 75% of children remaining on anti-TNFα following achievement of uveitis quiescence remain quiescent at one year. However, most reactivate following anti-TNFα discontinuation. These results suggest that infliximab more often is followed by remission, off medication, than adalimumab. The data do not suggest that maintenance of suppression, for more than 1.5 years decreases the reactivation risk. PMID:25892124

  16. Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis.

    PubMed

    Zhang, Xingming; Liang, Fuxiang; Yin, Xiaoxue; Xiao, Xiaojuan; Shi, Peiyu; Wei, Dang; Yao, Liang; Wang, Qi; Chen, Yaolong

    2014-02-01

    The aim of this systematic review and meta-analysis is to assess the efficacy and safety of tofacitinib for the treatment of patients with acute rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drug (DMARD). Randomized controlled trials were searched in MEDLINE (1966-2013), Embase (1947-2013), the Cochrane Central Register of Controlled Trials (1948-2013), WHO International Clinical Trial Registration Platform (2004-2013), Clinical Trial.gov (1999-2013), and China Biology Medicine disc (1978-2013). The review included 10 studies involving 4,929 patients. A pooled analysis of six studies showed that tofacitinib had a superior effect over placebo (both with background therapy) at weeks 12 and 24. Also, the pooled results of three studies showed that tofacitinib monotherapy had a significantly greater effect over placebo. Compared to adalimumab, tofacitinib was found to be more efficacious as well. For safety, tofacitinib monotherapy had less serious adverse events (sAE) than placebo but not other adverse effects (oAE). In the comparison of tofacitinib and placebo both with background therapy, no difference in sAE and oAE were found. However, the quality of the evidence was quite low when evaluated using GRADE. Tofacitinib alone, or together with non-biologic DMARDs, was associated with more favorable remission in the signs and symptoms of RA than adalimumab or placebo. Also, tofacitinib monotherapy was safer than placebo with regards to reported sAE, but not oAE. However, the quality of evidence is exceedingly low; long-term, large-scale, and high-quality post-marketing research is suggested to further verify the conclusion. PMID:24389749

  17. The influence of behavioural and psychological factors on medication adherence over time in rheumatoid arthritis patients: a study in the biologics era

    PubMed Central

    Morgan, Catharine; McBeth, John; Cordingley, Lis; Watson, Kath; Hyrich, Kimme L.; Symmons, Deborah P. M.

    2015-01-01

    Objectives. To investigate levels of self-reported adherence to biologic treatment and establish the contribution of demographic, physical and psychological factors to biologic medication adherence in an RA cohort. Methods. Adalimumab-treated patients were recruited through the British Society for Rheumatology Biologics Register for RA between May 2007 and April 2009. Demographic and baseline psychological measures including illness and medication beliefs were collected. Disease activity (28-item DAS), physical function (HAQ) and quality of life (36-item Short Form Health Survey) were also measured at baseline and at 6, 12 and 18 months. Adherence was assessed at each follow-up using the patient self-completed Compliance Questionnaire for Rheumatology (CQR). Multilevel mixed effects modelling analysis was performed to investigate predictors of adherence. Results. Of the 329 Adalimumab-treated patients included, low adherence (CQR score <65) was reported in 23%, with 41% reporting low adherence at at least one time point. After controlling for age and disease duration, factors independently predictive of increased adherence were increased belief in medication necessity, with baseline effect diminishing over time [β coefficient 1.68 (s.e. 0.19), P = 0.0001], lower medication concerns [0.50 (0.15), P = 0.001], with this effect remaining throughout follow-up, increased professional or family member support [0.81 (0.32), P = 0.01], strong views of illness being chronic [0.32 (0.14), P = 0.025] and increased treatment control [0.41 (0.19), P = 0.032]. Conclusion. Wider recognition of the importance of psychological factors, particularly medication beliefs, in driving medication adherence could have substantial clinical and health economic benefits in RA. The psychological factors we have identified are putative targets for strategies to improve adherence in RA. PMID:25972390

  18. An analysis of current pharmaceutical industry practices for making clinical trial results publicly accessible.

    PubMed

    Viereck, Christopher; Boudes, Pol

    2009-07-01

    We compared the clinical trial transparency practices of US/European pharma by analyzing the publicly-accessible clinical trial results databases of major drugs (doripenem, varenicline, lapatinib, zoledronic acid, adalimumab, insulin glargine, raltegravir, gefitinib). We evaluated their accessibility and utility from the perspective of the lay public. We included databases on company websites, http://www.clinicalstudyresults.org, http://www.clinicaltrials.gov and http://clinicaltrials.ifpma.org. Only 2 of 8 company homepages provide a direct link to the results. While the use of common terms on company search engines led to results for 5 of the 8 drugs following 2-4 clicks, no logical pathway was identified. The number of clinical trials in the databases was inconsistent: 0 for doripenem to 45 for insulin glargine. Results from all phases of clinical development were provided for 2 (insulin glargine and gefitinib) of the 8 drugs. Analyses of phase III reports revealed that most critical elements of the International Conference of Harmonization E3 Structure and Content of Synopses for Clinical Trial Reports were provided for 2 (varenicline, lapatinib) of the 8 drugs. For adalimumab and zoledronic acid, only citations were provided, which the lay public would be unable to access. None of the clinical trial reports was written in lay language. User-friendly support, when provided, was of marginal benefit. Only 1 of the databases (gefitinib) permitted the user to find the most recently updated reports. None of the glossaries included explanations for adverse events or statistical methodology. In conclusion, our study indicates that the public faces significant hurdles in finding and understanding clinical trial results databases. PMID:19348964

  19. Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence

    PubMed Central

    Fadda, Valeria; Maratea, Dario; Trippoli, Sabrina; Gatto, Roberta; De Rosa, Mauro; Marinai, Claudio

    2014-01-01

    Background: No equivalence analysis has yet been conducted on the effectiveness of biologics in rheumatoid arthritis. Equivalence testing has a specific scientific interest, but can also be useful for deciding whether acquisition tenders are feasible for the pharmacological agents being compared. Methods: Our search covered the literature up to August 2014. Our methodology was a combination of standard pairwise meta-analysis, Bayesian network meta-analysis and equivalence testing. The agents examined for their potential equivalence were etanercept, adalimumab, golimumab, certolizumab, and tocilizumab, each in combination with methotrexate (MTX). The reference treatment was MTX monotherapy. The endpoint was ACR50 achievement at 12 months. Odds ratio was the outcome measure. The equivalence margins were established by analyzing the statistical power data of the trials. Results: Our search identified seven randomized controlled trials (2846 patients). No study was retrieved for tocilizumab, and so only four biologics were evaluable. The equivalence range was set at odds ratio from 0.56 to 1.78. There were 10 head-to-head comparisons (4 direct, 6 indirect). Bayesian network meta-analysis estimated the odds ratio (with 90% credible intervals) for each of these comparisons. Between-trial heterogeneity was marked. According to our results, all credible intervals of the 10 comparisons were wide and none of them satisfied the equivalence criterion. A superiority finding was confirmed for the treatment with MTX plus adalimumab or certolizumab in comparison with MTX monotherapy, but not for the other two biologics. Conclusion: Our results indicate that these four biologics improved the rates of ACR50 achievement, but there was an evident between-study heterogeneity. The head-to-head indirect comparisons between individual biologics showed no significant difference, but failed to demonstrate the proof of no difference (i.e. equivalence). This body of evidence presently

  20. [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. PMID:17094336

  1. Biologic efficacy optimization-a step towards personalized medicine.

    PubMed

    Kiely, Patrick D W

    2016-05-01

    This following is a review of the factors that influence the outcome of biologic agents in the treatment of adult RA and, when synthesized into the clinical decision-making process, enhance optimization. Adiposity can exacerbate inflammatory diseases; patients with high BMI have worse outcomes from RA, including TNF inhibitors (TNFis), whereas the efficacy of abatacept and tocilizumab is unaffected. Smoking adversely affects TNFi outcomes but has less or no effect on the efficacy of rituximab and tocilizumab, and the effect on abatacept is unknown. Patients who are positive for ACPA and RF have better efficacy with rituximab and abatacept than those who are seronegative, whereas the influence of serotype is less significant for tocilizumab and more complex for TNFis. All biologics seem to do better when co-prescribed with MTX, whereas in monotherapy, tocilizumab is superior to adalimumab and prescription of a non-MTX DMARD has advantages over no DMARD for rituximab and adalimumab. Monitoring of TNFi drug levels is an exciting new field, correlating closely with efficacy in RA and PsA, and is influenced by BMI, adherence, co-prescribed DMARDs and anti-drug antibodies. The measurement of trough levels provides a potential tool for patients who are not doing well to determine early whether to switch within the TNFi class (if levels are low) or to a biologic with an alternative mode of action (if levels are normal or high). Conversely, the finding of supratherapeutic levels has the potential to enable individual patient selection for dose reduction without the risk of flare. PMID:26424837

  2. Psoriasis and psoriasiform lesions induced by TNFα antagonists: the experience of a tertiary care hospital from northern Spain.

    PubMed

    López-Robles, Alejandra; Queiro, Rubén; Alperi, Mercedes; Alonso, Sara; Riestra, José L; Ballina, Javier

    2012-12-01

    The aim of this study was to investigate the cumulated incidence and clinical characteristics of the psoriasiform lesions seen in a wide cohort of rheumatic patients exposed to anti-TNFα drugs in a tertiary care hospital from northern Spain. The study population included 450 patients exposed to anti-TNFα agents from 2001 to 2007 and treated in a university hospital in northern Spain. Two hundred patients were exposed to infliximab (44%), 129 (29%) to etanercept, and 121 (27%) to adalimumab. The cumulated incidence (CI) of this skin reaction was calculated for each of the three agents studied. Psoriasis and psoriasiform lesions were documented in 7 patients diagnosed with different rheumatic inflammatory conditions (1.56%). Cases of this adverse effect were identified with all three anti-TNFα agents available at that time, but less frequently with infliximab (CI: 0.5%) compared with etanercept (CI: 2.3%) or adalimumab (CI: 2.5%). The most common lesion was palmoplantar pustulosis (71.3% of the cases), and the latency period to the development of the lesions ranged from 4 to 38 months (mean 9 months). In four of the 7 patients, treatment was suspended, while in the remaining three patients treatment was continued. The CI of this skin reaction in our setting is similar to that published by others. Infliximab was found to be less frequently associated with this adverse event. In our experience, it is not always necessary to stop anti-TNFα therapy for the skin lesions to improve. PMID:22187056

  3. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).

    PubMed

    Warren, Richard B; Smith, Catherine H; Yiu, Zenas Z N; Ashcroft, Darren M; Barker, Jonathan N W N; Burden, A David; Lunt, Mark; McElhone, Kathleen; Ormerod, Anthony D; Owen, Caroline M; Reynolds, Nick J; Griffiths, Christopher E M

    2015-11-01

    Drug survival reflects a drug's effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients. PMID:26053050

  4. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol.

    PubMed

    Pasut, Gianfranco

    2014-04-01

    PEGylation of biological proteins, defined as the covalent conjugation of proteins with polyethylene glycol (PEG), leads to a number of biopharmaceutical improvements, including increased half-life, increased solubility and reduced aggregation, and reduced immunogenicity. Since their introduction in 1990, PEGylated proteins have significantly improved the management of various chronic diseases, including rheumatoid arthritis (RA) and Crohn's disease. Certolizumab pegol is the only PEGylated anti-tumour necrosis factor (TNF)-α agent. It is a PEGylated, humanised, antigen-binding fragment of an anti-TNF monoclonal antibody. Unlike other anti-TNF agents, it has no crystallisable fragment (Fc) domain. Because of its novel structure, certolizumab pegol may have a different mechanism of action to the other anti-TNF agents, and also has different pharmacodynamic properties, which could possibly translate to a different safety profile. Pharmacodynamic studies have shown that certolizumab pegol binds to TNF with a higher affinity than adalimumab and infliximab. Certolizumab pegol is also more potent at neutralising soluble TNF-mediated signalling than adalimumab and infliximab, and has similar or lesser potency to etanercept. Certolizumab pegol does not cause detrimental in vitro effects such as degranulation, loss of cell integrity, apoptosis, complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Certolizumab pegol may also penetrate more effectively into inflamed arthritic tissue than other anti-TNF agents, and is not actively transported across the placenta during pregnancy. Pharmacokinetic studies in healthy volunteers demonstrated that single intravenous and subcutaneous doses of certolizumab pegol had predictable pharmacokinetics. The pharmacokinetics of certolizumab pegol in patients with RA and Crohn's disease were consistent with pharmacokinetics in healthy volunteers. PMID:24687235

  5. TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice.

    PubMed

    Marchesoni, Antonio; Zaccara, Eleonora; Gorla, Roberto; Bazzani, Chiara; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola; Caporali, Roberto; Bobbio-Pallavicini, Francesca; Favalli, Ennio Giulio

    2009-09-01

    A cohort of rheumatoid arthritis (RA) patients in the Lombardy Rheumatology Network (LOHREN) registry and receiving anti-TNF therapy was evaluated after 6, 12, 24, and 36 months. Of the 1114 patients in the registry 1064 met the clinical criteria for inclusion with 519 receiving infliximab, 303 adalimumab, and 242 etanercept. The therapeutic survival curve of these patients showed that the likelihood of continuing anti-TNF therapy was 78.8% after 12 months, 65.2% after 24 months, and 52.9% after 36 months, with a risk of dropout similar for inefficacy and adverse events. There were 405 anti-TNF therapy discontinuations (38.1%): 180 (16.9%) due to inefficacy, 194 (18.2%) adverse events, and 31 (2.9%) other reasons. Four deaths (2 septicemia, 1 postinfective cerebritis, 1 heart failure) were considered to be related to anti-TNF therapy. Of the discontinuations, 219 (54.1%) occurred within the first 12 months: 110 due to adverse events, 89 inefficacy, and 20 due to other reasons. After 36 months, the likelihood of survival on etanercept (62.5%) was significantly greater than the likelihood of survival on infliximab (49.1%) or adalimumab (53.6%). A higher risk of therapy discontinuations due to adverse events was associated with increasing age, a corticosteroid > 5 mg/day, a high erythrocyte sedimentation rate (ESR), a higher risk of therapy discontinuations due to inefficacy was associated with the previous use of > or = 4 disease-modifying antirheumatic drugs (DMARDs) and a high ESR. Comorbidities, increasing DAS28 values and co-therapy with methotrexate were associated with a lower risk of discontinuation. PMID:19758236

  6. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry

    PubMed Central

    Mariette, Xavier; Tubach, Florence; Bagheri, Haleh; Bardet, Michel; Berthelot, Jean-Marie; Gaudin, Philippe; Heresbach, Denis; Martin, Antoine; Schaeverbeke, Thierry; Salmon, Dominique; Lemann, Marc; Hermine, Olivier; Raphael, Martine; Ravaud, Philippe

    2010-01-01

    Objective To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare risks for different anti-TNF agents. Methods We designed a national prospective registry (RATIO) from 2004 to 2006, for collecting all cases of lymphoma in French patients receiving anti-TNF therapy, whatever the indication. We conducted a case-control analysis including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population used as reference.. Results We collected 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B-cell and 5 T-cell), 5 Hodgkin’s lymphoma (HL) and 2 Hodgkin’s-like lymphoma. Epstein-Barr virus (EBV) was detected in 2 of 2 Hodgkin’s-like lymphoma, 3 of 5 HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: SIR = 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4– 1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio=4.7 (1.3– 17.7) and 4.1 (1.4–12.5), respectively. The sex and age- adjusted incidence rate of lymphoma was 42.1 per 100,000 patient-years. The standardized incidence ratio (SIR) was 2.4 (95% confidence interval [CI] 1.7–3.2). Conclusion Some lymphomas associated with immunosuppression may occur in patients receiving anti TNF therapy, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy. PMID:19828563

  7. 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. PMID:26934060

  8. In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV.

    PubMed

    Hazen, Richard; Harvey, Robert; Ferris, Robert; Craig, Charles; Yates, Phillip; Griffin, Philip; Miller, John; Kaldor, Istvan; Ray, John; Samano, Vincente; Furfine, Eric; Spaltenstein, Andrew; Hale, Michael; Tung, Roger; St Clair, Marty; Hanlon, Mary; Boone, Lawrence

    2007-09-01

    Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC(50)s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC(50)s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC(50)s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro. PMID:17620375

  9. Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance

    PubMed Central

    Kim, Beom Kyung; Park, Yong Kwang; Park, Eun-Sook; Ahn, Sang Hoon; Shin, Gu-Choul; Park, Soree; Kang, Hong Seok; Rhee, Jin-Kyu; Yang, Sung-Il; Chong, Youhoon; Kim, Kyun-Hwan

    2015-01-01

    The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV. PMID:26322642

  10. Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance.

    PubMed

    Ahn, Sung Hyun; Kim, Doo Hyun; Lee, Ah Ram; Kim, Beom Kyung; Park, Yong Kwang; Park, Eun-Sook; Ahn, Sang Hoon; Shin, Gu-Choul; Park, Soree; Kang, Hong Seok; Rhee, Jin-Kyu; Yang, Sung-Il; Chong, Youhoon; Kim, Kyun-Hwan

    2015-01-01

    The emergence of compensatory mutations in the polymerase gene of drug resistant hepatitis B virus (HBV) is associated with treatment failure. We previously identified a multi-drug resistant HBV mutant, which displayed resistance towards lamivudine (LMV), clevudine (CLV), and entecavir (ETV), along with a strong replication capacity. The aim of this study was to identify the previously unknown compensatory mutations, and to determine the clinical relevance of this mutation during antiviral therapy. In vitro mutagenesis, drug susceptibility assay, and molecular modeling studies were performed. The rtL269I substitution conferred 2- to 7-fold higher replication capacity in the wild-type (WT) or YMDD mutation backbone, regardless of drug treatment. The rtL269I substitution alone did not confer resistance to LMV, ETV, adefovir (ADV), or tenofovir (TDF). However, upon combination with YMDD mutation, the replication capacity under LMV or ETV treatment was enhanced by several folds. Molecular modeling studies suggested that the rtL269I substitution affects template binding, which may eventually lead to the enhanced activity of rtI269-HBV polymerase in both WT virus and YMDD mutant. The clinical relevance of the rtL269I substitution was validated by its emergence in association with YMDD mutation in chronic hepatitis B (CHB) patients with sub-optimal response or treatment failure to LMV or CLV. Our study suggests that substitution at rt269 in HBV polymerase is associated with multi-drug resistance, which may serve as a novel compensatory mutation for replication-defective multi-drug resistant HBV. PMID:26322642

  11. Traditional Chinese medicine and related active compounds: a review of their role on hepatitis B virus infection.

    PubMed

    Qi, F H; Wang, Z X; Cai, P P; Zhao, L; Gao, J J; Kokudo, N; Li, A Y; Han, J Q; Tang, W

    2013-12-01

    Since the significant public health hazard of Hepatitis B virus (HBV) infection and obvious drug resistance and dose-dependent side effects for common antiviral agents (e.g., interferon α, lamivudine, and adefovir), continuous development of agents to treat HBV infection is urgently needed. Traditional Chinese medicine (TCM) is an established segment of the health care system in China. Currently, it is widely used for chronic hepatitis B (CHB) in China and many parts of the world. Over a long period of time in clinical practice and in basic research progress, the effectiveness and beneficial contribution of TCM on CHB have been gradually known and confirmed. Based upon our review of related papers and because of our prior knowledge and experience, we have selected some Chinese medicines, including Chinese herbal formulas (e.g., Xiao-Chai-Hu-Tang, Xiao-Yao-San, and Long-Dan-Xie-Gan-Tang), single herbs (e.g., Phyllanthus niruri, Radix astragali, Polygonum cuspidatum, Rheum palmatum, and Salvia miltiorrhiza) and related active compounds (e.g., wogonin, artesunate, saikosaponin, astragaloside IV, and chrysophanol 8-O-beta-Dglucoside) and Chinese medicine preparations (e.g., silymarin, silibinin, kushenin, and cinobufacini), which seem effective and worthy of additional and indepth study in treating CHB, and we have given them a brief review. We conclude that these Chinese herbal medicines exhibit significant anti-HBV activities with improved liver function, and enhanced HBeAg and HBsAg sero-conversion rates as well as HBV DNA clearance rates in HepG2 2.2.15 cells, DHBV models, or patients with CHB. We hope this review will contribute to an understanding of TCM and related active compounds as an effective treatment for CHB and provide useful information for the development of more effective antiviral drugs. PMID:24423652

  12. Dynamic Changes of Treg and Th17 Cells and Related Cytokines Closely Correlate With the Virological and Biochemical Response in Chronic Hepatitis B Patients Undergoing Nucleos(t)ide Analogues Treatment

    PubMed Central

    Yu, Xue-Ping; Guo, Ru-Yi; Su, Mi-Long; Ming, De-Song; Lin, Cheng-Zu; Deng, Yong; Lin, Zhen-Zhong; Su, Zhi-Jun

    2013-01-01

    Background: The restoration of HBV-specific T-cell response during antiviral therapy is associated with CD4+T-cell activity. Treg cells and Th17 cells are subtypes of CD4+T cell. However, it has remained unknown how the Treg and Th17 cells and their associated cytokines affect nucleos(t)ide analogues (NA) antiviral efficacy. Objectives: The aim of the present study was to provide a new insight to evaluate the NA antiviral therapy for patients with chronic hepatitis B (CHB). Patients and Methods: Forty-four CHB patients hospitalized between July 2010 and August 2011 were enrolled in this study. They were received NA (entecavir, lamivudine and adefovir) treatment for 14.42 ± 13.08 weeks, and the peripheral blood was collected. The frequencies of Treg and Th17 cells were detected by flow cytometric analysis, and the levels of IL-10, TGF-β1, IL-17 and IL-23 were measured by enzyme-linked immunosorbent assay (ELISA). Results: In complete and partial-responders, Treg cells frequencies and IL-10, TGF-β1, IL-23 levels were all decreased significantly after NA therapy, while Th17 cells and the IL-17 levels were increased slightly. Treg/Th17 ratio was only dramatically declined in complete-responders. But there was no significant difference in non-responders. Either HBV DNA decreased by at least 2 log copies /mL or ALT turned to normal level, Treg cells frequencies and IL-10, TGF-β1, IL-23 levels were significantly reduced. Meanwhile, Treg cells were positively correlated with HBV DNA and ALT. Conclusions: The changes of Treg and Th17 cells and their associated cytokines were related to virological and biochemical responses. PMID:24403916

  13. Human Immunodeficiency Virus Protease Inhibitors Interact with ATP Binding Cassette Transporter 4/Multidrug Resistance Protein 4: A Basis for Unanticipated Enhanced Cytotoxicity

    PubMed Central

    Fukuda, Yu; Takenaka, Kazumasa; Sparreboom, Alex; Cheepala, Satish B.; Wu, Chung-Pu; Ekins, Sean; Ambudkar, Suresh V.

    2013-01-01

    Human immunodeficiency virus (HIV) pharmacotherapy, by combining different drug classes such as nucleoside analogs and HIV protease inhibitors (PIs), has increased HIV-patient life expectancy. Consequently, among these patients, an increase in non-HIV–associated cancers has produced a patient cohort requiring both HIV and cancer chemotherapy. We hypothesized that multidrug resistance protein 4/ATP binding cassette transporter 4 (MRP4/ABCC4), a widely expressed transporter of nucleoside-based antiviral medications as well as cancer therapeutics might interact with PIs. Among the PIs evaluated (nelfinavir, ritonavir, amprenavir, saquinavir, and indinavir), only nelfinavir both effectively stimulated MRP4 ATPase activity and inhibited substrate-stimulated ATPase activity. Saos2 and human embryonic kidney 293 cells engineered to overexpress MRP4 were then used to assess transport and cytotoxicity. MRP4 expression reduced intracellular accumulation of nelfinavir and consequently conferred survival advantage to nelfinavir cytotoxicity. Nelfinavir blocked Mrp4-mediated export, which is consistent with its ability to increase the sensitivity of MRP4-expressing cells to methotrexate. In contrast, targeted inactivation of Abcc4/Mrp4 in mouse cells specifically enhanced nelfinavir and 9-(2-phosphonylmethoxyethyl) adenine cytotoxicity. These results suggest that nelfinavir is both an inhibitor and substrate of MRP4. Because nelfinavir is a new MRP4/ABCC4 substrate, we developed a MRP4/ABCC4 pharmacophore model, which showed that the nelfinavir binding site is shared with chemotherapeutic substrates such as adefovir and methotrexate. Our studies reveal, for the first time, that nelfinavir, a potent and cytotoxic PI, is both a substrate and inhibitor of MRP4. These findings suggest that HIV-infected cancer patients receiving nelfinavir might experience both enhanced antitumor efficacy and unexpected adverse toxicity given the role of MRP4/ABCC4 in exporting nucleoside

  14. Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B.

    PubMed

    Kim, Jeong Tae; Jeong, Hye Won; Choi, Ki Hwa; Yoon, Tae Young; Sung, Nohyun; Choi, Young Ki; Kim, Eun Ha; Chae, Hee Bok

    2014-11-14

    Several clinical trials have demonstrated the potent antiviral efficacy of entecavir (ETV), and this relatively new nucleoside analogue drug has rapidly become a frequently prescribed therapy for chronic hepatitis B (CHB) worldwide. While the studies have also shown a good overall safety profile for ETV, adverse drug reactions (ADRs) in patients with advanced cirrhosis have been reported and represent a broad spectrum of drug-induced injuries, including lactic acidosis, myalgia, neuropathy, azotemia, hypophosphatemia, muscular weakness, and pancreatitis, as well as immune-mediated responses (i.e., allergic reactions). Cutaneous ADRs associated with ETV are very rare, with only two case reports in the publicly available literature; both of these cases were classified as unspecified hypersensitivity allergic (type I) ADR, but neither were reported as pathologically proven or as evaluated by cytokine release analysis. Here, we report the case of a 45-year-old woman who presented with a generalized maculopapular rash after one week of ETV treatment for lamivudine-resistant CHB. The patient reported having experienced a similar skin eruption during a previous three-month regimen of ETV, for which she had self-discontinued the medication. Histopathological analysis of a skin biopsy showed acanthotic epidermis with focal parakeratosis and a perivascular lymphocytic infiltrate admixed with interstitial eosinophils in the papillary and reticular dermis, consistent with a diagnosis of drug sensitivity. A lymphocyte stimulation test showed significantly enhanced IL-4, indicating a classification of type IVb delayed hypersensitivity. The patient was switched to an adefovir-lamivudine combination regimen and the skin eruption resolved two weeks after the ETV withdrawal. This case represents the first pathologically and immunologically evidenced ETV-induced delayed type hypersensitivity skin reaction reported to date. Physicians should be aware of the potential, although rare

  15. A five years study of antiviral effect of entecavir in Chinese chronic hepatitis B patients

    PubMed Central

    Liu, Kehui; Xiang, Xiaogang; Bao, Rebecca; Chen, Rong; Liu, Yunye; Xie, Jingdong; Guo, Qing; Bao, Shisan; Xie, Qing; Wang, Hui

    2016-01-01

    Entecavir (ETV) is a potent viral replication inhibitor for chronic hepatitis B (CHB) patients. To investigate the efficacy of ETV in Chinese nucleos(t)ide(NA)-experienced CHB patients. Among 89 CHB patients with ETV monotherapy for ≥6 months, 33/89 (37%) or 56/89 (73%) were NA-naïve or NA-experienced. During a median follow-up of 5.75 years, all NA-naïve CHB patients achieved VR without genotypic ETV-resistance. However, VR was observed in 50/56 (~90%) of NA-experienced CHB patients during a median follow-up of 4.75 years. Antiviral efficacy was not reduced in patients with previous lamivudine (LAM) with/without LAM-resistance (HR 0.465; 95% CI 0.196–1.100; p > 0.05) (HR 0.472; 95% CI 0.205–1.091; p > 0.05). Patients with a primary treatment failure to adefovir (ADV) had a reduced probability of achieving VR compared to NA-naïve (HR 0.496; 95% CI 0.287–0.857; p < 0.01). Previous ADV-experienced patients with a partial VR (HR 1.253; 95% CI 0.429–3.665; p > 0.05) did not influence antiviral response to ETV. The antiviral efficacy of ETV is not influenced by previous treatment LAM with/without LAM-resistance. ETV may still be an option in ADV-experienced patients with a partial VR, but not advised in patients with a primary treatment failure to ADV. PMID:27364728

  16. A five years study of antiviral effect of entecavir in Chinese chronic hepatitis B patients.

    PubMed

    Liu, Kehui; Xiang, Xiaogang; Bao, Rebecca; Chen, Rong; Liu, Yunye; Xie, Jingdong; Guo, Qing; Bao, Shisan; Xie, Qing; Wang, Hui

    2016-01-01

    Entecavir (ETV) is a potent viral replication inhibitor for chronic hepatitis B (CHB) patients. To investigate the efficacy of ETV in Chinese nucleos(t)ide(NA)-experienced CHB patients. Among 89 CHB patients with ETV monotherapy for ≥6 months, 33/89 (37%) or 56/89 (73%) were NA-naïve or NA-experienced. During a median follow-up of 5.75 years, all NA-naïve CHB patients achieved VR without genotypic ETV-resistance. However, VR was observed in 50/56 (~90%) of NA-experienced CHB patients during a median follow-up of 4.75 years. Antiviral efficacy was not reduced in patients with previous lamivudine (LAM) with/without LAM-resistance (HR 0.465; 95% CI 0.196-1.100; p > 0.05) (HR 0.472; 95% CI 0.205-1.091; p > 0.05). Patients with a primary treatment failure to adefovir (ADV) had a reduced probability of achieving VR compared to NA-naïve (HR 0.496; 95% CI 0.287-0.857; p < 0.01). Previous ADV-experienced patients with a partial VR (HR 1.253; 95% CI 0.429-3.665; p > 0.05) did not influence antiviral response to ETV. The antiviral efficacy of ETV is not influenced by previous treatment LAM with/without LAM-resistance. ETV may still be an option in ADV-experienced patients with a partial VR, but not advised in patients with a primary treatment failure to ADV. PMID:27364728

  17. Curious discoveries in antiviral drug development: the role of serendipity.

    PubMed

    De Clercq, Erik

    2015-07-01

    Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses. PMID:25726922

  18. Clinical Relevance of Minimal Residual Viremia during Long-Term Therapy with Nucleos(t)ide Analogues in Patients with Chronic Hepatitis B

    PubMed Central

    Maier, Melanie; Liebert, Uwe G.; Wittekind, Christian; Kaiser, Thorsten; Berg, Thomas; Wiegand, Johannes

    2013-01-01

    Background Successful therapy of chronic hepatitis B with nucleos(t)ide analogues (NUCs) has been defined by undetectable HBV-DNA determined with conventional PCR (lower limit of detection (LLD) 60–80 IU/mL) in clinical registration trials. However, current EASL guidelines recommend highly sensitive real-time PCR (LLD<10–20 IU/mL) and define treatment response by HBV-DNA<10 IU/mL. Aim We evaluated frequency and relevance of minimal residual viremia (MRV) during long-term NUC-treatment in a real-life setting. Methods Frozen serum samples (HBV-DNA negative by in-house PCR, LLD <73 IU/mL) were re-analyzed by real-time PCR (LLD<10 IU/mL, Abbott, Germany). MRV was defined by real time PCR positivity and conventional PCR negativity. Results 237 samples of six HBsAg carriers and 27 NUC-treated CHB patients were analyzed (treatment period 28 (11–111) months, different treatment regimens with mono- or combination therapy). MRV was detected in 31/33 individuals (n = 160/237 serum samples) and more frequent in HBsAg carriers (95%) and HBeAg positive (87%) compared to HBeAg negative patients (53%) (p<0.0001, respectively). Five HBsAg carriers, five HBeAg positive, and four HBeAg negative individuals were continuously HBV-DNA positive. MRV was not significantly more often observed during NUC-monotherapies compared to combination therapies. Concomitant immunosuppressive therapy was present in nine cases and did not influence the results. Viral resistance occurred in three immunocompetent patients with adefovir or lamivudine monotherapy. Conclusions MRV is frequently observed during long-term NUC-therapy. Adjustment of treatment with highly potent NUCs does not seem to be necessary in case of minimal residual viremia in a real-life setting. PMID:23826307

  19. Therapy of chronic viral hepatitis: a critical view.

    PubMed

    Rizzetto, M

    1999-11-01

    Many oral nucleoside analogues that are potent inhibitors of hepatitis B virus have recently been developed for the treatment of hepatitis B. The problems with these drugs are bioavailability, toxicity and the time-dependent emergence of resistant hepatitis B virus mutants. Lamivudine appears to be the most useful in terms of clinical benefit, safety and tolerance. It is active on wild type hepatitis B virus as well as on HBeAg-minus variants of the virus. However, although hepatitis B virus is consistently repressed while on therapy, only a minority of patients are cured or remain in remission after Lamivudine withdrawal. Maintenance therapy would appear to be in order, but the long-term use of Lamivudine is precluded by the emergence of polymerase gene-mutants which may rekindle disease. Combination with other antivirals (Adefovir?) active also against Lamivudine escape mutants opens promising new prospects. There is, as yet, no valid therapy for chronic hepatitis D virus hepatitis. Attempts to improve the results of alpha-interferon therapy in chronic hepatitis C with new interferons, or the manipulation of interferon monotherapy so as to obtain the maximum results compatible with tolerance, have not produced significantly better results than the classic protocols of alpha-interferon monotherapy. A more concrete improvement has been achieved by the combination of interferon with Ribavirin, with the overall rate of response increasing three times compared to interferon monotherapy. Anaemia, however, is a common additional side-effect induced by Ribavirin. Combination therapy has become the treatment of choice for interferon naive patients as well as for interferon relapses; it is not efficacious in patients who have not responded to interferon. PMID:10730571

  20. Progressive painless lower limbs weakness in a dialyzed patient: undiagnosed tertiary syphilis: a case report

    PubMed Central

    2010-01-01

    Introduction Syphilis is a sexually transmitted disease, remaining under-estimated, under-recognized due to the variability of clinical presentation and ageing of the population with chronic comorbidities. Hence, some manifestations of the past are nowadays superimposed on the course of chronic diseases. Clinical suspicion should be guided by past medical history of contracting any other sexual disease in a heterosexual person or man who has sex with man. Case presentation We describe a rare case of tertiary syphilis in a hemodialyzed diabetic patient whom was career of chronic liver disease due to the evolution of chronic hepatitis B virus infection complicated by a hepatocellular carcinoma. Initial orientation in diagnosing this rare presentation of progressive painless lower limbs weakness was attributed to possible side effects of ongoing anti viral therapy including lamivudine and adefovir. We continued administering both drugs while patient notified a spectacular improvement under Ceftriaxone therapy introduced empirically for a possible chest infection. Routine ophthalmologic examination realized in a teaching hospital, scheduled without knowing the course of late infection showed the presence of a syphilitic uveitis. Conclusion This case emphasizes the need for a high index of clinical suspicion for syphilis before the occurrence of symptoms related to its end organ damage dominated by neurosyphilis form. Early diagnosis is the key to preventing significant morbidity and mortality and improving prognosis. However, in the setting of chronic diseases such as chronic kidney diseases either before setting up methods of renal replacement therapy or under immune-suppressive therapy; clinical presentation might resemble any disease, delaying the certitude of the diagnosis by prescribing a rapid plasma reagin. PMID:20180955

  1. HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy.

    PubMed

    Stelma, F; Jansen, L; Sinnige, M J; van Dort, K A; Takkenberg, R B; Janssen, H L A; Reesink, H W; Kootstra, N A

    2016-08-01

    Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy. PMID:26945896

  2. A Meta-Analysis of the Efficacy of Interferon Monotherapy or Combined with Different Nucleos(t)ide Analogues for Chronic Hepatitis B

    PubMed Central

    Zhou, Jialing; Wu, Xiaoning; Wei, Wei; You, Hong; Jia, Jidong; Kong, Yuanyuan

    2016-01-01

    Background: The aim of the present study was to compare the efficacy of interferon (IFN) with or without different nucleos(t)ide analogues (NAs). Methods: The PubMed, Wan Fang and CNKI databases were searched to identify relevant trials up to May 2015. Meta-analysis was performed with Review Manager 5.0. The stability and reliability were evaluated by publication bias tests. Results: Fifty-six studies fulfilled the criteria for the meta-analysis. Compared with IFN monotherapy, combination therapy were superior in HBV DNA undetectable rate (Risk Ratio (RR) = 1.55, 95% confidence interval (CI): 1.44–1.66, p < 0.00001), HBeAg and HBsAg loss rate (RR = 1.38, 95% CI: 1.22–1.56, p < 0.00001; RR = 1.69, 95% CI: 1.03–2.78, p = 0.04, respectively) at the end of week 48 treatment. Sub-analysis showed the RRs of virological response for entecavir (ETV), adefovir (ADV), and lamivudine (LAM) were 1.64, 1.61 and 1.52, respectively; RRs of HBeAg loss rate were 1.34, 1.71 and 1.34, respectively. However, at the end of follow-up, IFN plus NAs therapy was better than IFN monotherapy only in terms of HBV DNA undetectable rate (p = 0.0007). Conclusions: Combination therapy was better than IFN monotherapy in virological and serological responses at the end of treatment. After follow-up, only HBV DNA undetectable rate was superior for combination therapy. PMID:27455288

  3. Management of chronic hepatitis B in children: an unresolved issue.

    PubMed

    Della Corte, Claudia; Nobili, Valerio; Comparcola, Donatella; Cainelli, Francesca; Vento, Sandro

    2014-05-01

    Although a rather benign course of chronic hepatitis B virus (HBV) infection during childhood has been described, 3-5% and 0.01-0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma before adulthood. Considering the whole lifetime, the risk of hepatocellular carcinoma rises to 9-24% and the incidence of cirrhosis to 2-3% per year. The aim of this article is to review the current knowledge regarding the natural history and treatment of chronic hepatitis B in children and to focus on critical aspects and unresolved questions in the management of childhood HBV infection. A literature search was carried out on MEDLINE, EMBASE, and Web of Science for articles published in English in peer-reviewed journals from January 1980 to February 2013. The search terms used included "Hepatitis B virus infection," "children," "HBV," "interferon," "lamivudine," "adefovir," "entecavir," and "tenofovir." Articles resulting from these searches and relevant references cited in the articles retrieved were reviewed. The current goals of therapy are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis. Therapeutic options for children are currently limited, and the risk for viral resistance to current and future therapies is a particular concern. Based on the data available at this time, it is the consensus of the panel that it is not appropriate to treat children in the immune-tolerant phase or in the inactive carrier state. For children in the immune-active or reactivation phases, liver histology can help guide treatment decisions. Outside of clinical trials, interferon is the agent of choice in most cases; currently, available nucleoside analogs are secondary therapies. PMID:24863185

  4. Prediction of virologic response to tenofovir mono-rescue therapy for multidrug resistant chronic hepatitis B.

    PubMed

    Lee, Sangheun; Park, Jun Yong; Kim, Do Young; Kim, Beom Kyung; Kim, Seung Up; Song, Kijun; Ku, Hye Jin; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-06-01

    Most guidelines suggest combination therapy including nucleoside and nucleotide analogues for the treatment of chronic hepatitis B (CHB) with multidrug resistance (MD-R). However, long-term combination treatment can evoke high costs and safety problems. Therefore, we investigated the efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy for viral suppression in patients with CHB exhibiting MD-R. We reviewed patients with CHB exhibiting antiviral drug resistance treated by TDF mono-rescue therapy from December 2012 to June 2014. The patients were categorized into three groups: lamivudine-resistance (LAM-R) group (n = 290), and LAM-R + adefovir-resistance (ADV-R) group (n = 43), and LAM-R + entecavir-resistance (ETV-R) group (n = 113). We compared the virologic response rate according to the multiplicity of resistance and investigated the predictive factors of a virologic response. For a median of 15 months (range, 6-24 months) of TDF mono-rescue therapy, the cumulative virologic response rates were 82.8, 81.4, and 84.1% in the LAM-R, LAM-R + ADV-R, and LAM-R + ETV-R groups, respectively (P = 0.239). Multivariate analysis revealed that multiplicity of resistance did not influence the achievement of a virologic response (P = 0.218). However, the baseline HBV DNA level significantly influenced the achievement of a virologic response for the treatment of CHB with MD-R (P < 0.001). TDF mono-rescue therapy is an appropriate treatment for CHB with MD-R, and the baseline HBV DNA level is a significant predictive factor for a virologic response. These factors should be considered before treating CHB with MD-R. J. Med. Virol. 88:1027-1034, 2016. © 2015 Wiley Periodicals, Inc. PMID:26538234

  5. Biological therapies in the spondyloarthritides--the current state.

    PubMed

    Braun, J; Sieper, J

    2004-09-01

    Therapeutic options for patients suffering from the more severe spondyloarthritides (SpA) have been rather limited in the last decades. Evidence is now accumulating that anti-tumour necrosis factor (TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published concerning more than 1000 patients with AS and PsA, this treatment seems to be even more effective than in rheumatoid arthritis (RA). The anti-TNFalpha agents currently available, infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira), are approved for the treatment of RA in the USA and Europe. The situation for SpA is different from RA because there is an unmet medical need, especially in AS, since no therapies with disease-modifying anti-rheumatic drugs (DMARDs) are available for severely affected patients, especially those with spinal disease. Thus, TNF blockers may even be considered a first-line treatment in a patient with active AS and PsA whose condition is not sufficiently controlled with non-steroidal anti-inflammatory drugs (NSAIDs) in the case of axial disease, and sulphasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg is required, and intervals of between 6 and 12 weeks are necessary to constantly suppress disease activity-also a major aim for long-term treatment. The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are almost no studies yet on adalimumab (standard dose in RA, 20-40 mg subcutaneously every 1-2 weeks) in SpA. Infliximab and etanercept are now both approved for AS in Europe. The efficacy of etanercept was first demonstrated in PsA, and it is now approved for this indication in the USA and Europe. There is preliminary evidence that both agents also work in other SpA, such as undifferentiated SpA (uSpA). Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis

  6. 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

  7. Glucocorticoid-Responsive Cold Agglutinin Disease in a Patient with Rheumatoid Arthritis.

    PubMed

    Honne, Kyoko; Nagashima, Takao; Iwamoto, Masahiro; Kamesaki, Toyomi; Minota, Seiji

    2015-01-01

    A 57-year-old man with rheumatoid arthritis developed severe anemia during treatment with adalimumab plus methotrexate. Cold agglutinin disease was diagnosed because haptoglobin was undetectable, cold agglutinin was positive (1 : 2048), and the direct Coombs test was positive (only to complement). Although the cold agglutinin titer was normalized (1 : 64) after treatment with prednisolone (0.7 mg/kg/day for two weeks), the patient's hemoglobin did not increase above 8 g/dL. When cold agglutinins were reexamined using red blood cells suspended in bovine serum albumin, the titer was still positive at 1 : 1024. Furthermore, the cold agglutinin had a wide thermal amplitude, since the titer was 1 : 16 at 30°C and 1 : 1 at 37°C. This suggested that the cold agglutinin would show pathogenicity even at body temperature. After the dose of prednisolone was increased to 1 mg/kg/day, the patient's hemoglobin rapidly returned to the normal range. The thermal amplitude test using red blood cells suspended in bovine serum albumin is more sensitive than the standard test for detecting pathogenic cold agglutinins. PMID:26346552

  8. Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

    PubMed Central

    Martin, Pauline L; Bugelski, Peter J

    2012-01-01

    Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’ and United States Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found. PMID:22168335

  9. 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). PMID:26463246

  10. Tumor necrosis factor-alpha antagonists and neuropathy.

    PubMed

    Stübgen, Joerg-Patrick

    2008-03-01

    Tumor necrosis factor (TNF)-alpha plays an important role in many aspects of immune system development, immune-response regulation, and T-cell-mediated tissue injury. The evidence that TNF-alpha, released by autoreactive T cells and macrophages, may contribute to the pathogenesis of immune-mediated demyelinating neuropathies is reviewed. TNF-alpha antagonists (infliximab, etanercept, adalimumab) are indicated for the treatment of advanced inflammatory rheumatic and bowel disease, but these drugs can induce a range of autoimmune diseases that also attack the central and peripheral nervous systems. Case histories and series report on the association between anti-TNF-alpha treatment and various disorders of peripheral nerve such as Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies. The proposed pathogeneses of TNF-alpha-associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin, vasculitis-induced nerve ischemia, and inhibition of signaling support for axons. Most neuropathies improve over a period of months by withdrawal of the TNF-alpha antagonist, with or without additional immune-modulating treatment. Preliminary observations suggest that TNF-alpha antagonists may be useful as an antigen-nonspecific treatment approach to immune-mediated neuropathies in patients with a poor response to, or intolerance of, standard therapies, but further studies are required. PMID:18041052

  11. Very low-calorie ketogenic diet may allow restoring response to systemic therapy in relapsing plaque psoriasis.

    PubMed

    Castaldo, Giuseppe; Galdo, Giovanna; Rotondi Aufiero, Felice; Cereda, Emanuele

    2016-01-01

    Psoriasis is a chronic disease associated with overweight/obesity and related cardiometabolic complications. The link between these diseases is likely the inflammatory background associated with adipose tissue, particularly the visceral one. Accordingly, previous studies have demonstrated that in the long-term weight loss may improve the response to systemic therapies. We report a case report of a woman in her 40s suffering from relapsing moderate-to-severe plaque psoriasis and obesity-related metabolic syndrome, in whom adequate response to ongoing treatment with biological therapy (adalimumab) was restored after only 4 weeks of very low-calorie, carbohydrate-free (ketogenic), protein-based diet. Accordingly, through rapid and consistent weight loss, very low calorie ketogenic diet may allow restoring a quick response to systemic therapy in a patient suffering from relapsing psoriasis. This intervention should be considered in overweight/obese patients before the rearrangement of systemic therapy. Nonetheless, studies are required to evaluate whether very low calorie ketogenic diets should be preferred to common low-calorie diets to improve the response to systemic therapy at least in patients with moderate-to-severe psoriasis. PMID:26559897

  12. Benefit–risk assessment of golimumab in the treatment of refractory ulcerative colitis

    PubMed Central

    Pugliese, Daniela; Felice, Carla; Landi, Rosario; Papa, Alfredo; Guidi, Luisa; Armuzzi, Alessandro

    2016-01-01

    Significant advances in the management of patients with ulcerative colitis (UC) have been made since the introduction of anti-tumor necrosis factor (TNF)-alpha agents, especially for those who fail or do not tolerate conventional therapies. Two drugs, infliximab first, then adalimumab afterward, showed effectiveness in inducing and maintaining long-term remission both in pivotal trials as well as in clinical practice. However, approximately 25% of patients with UC, who fail or do not tolerate all available therapies, require a colectomy for refractory disease. The therapeutic scenario of UC has been recently upgraded by the introduction of golimumab, the latest anti TNF-alpha agent to be approved. Golimumab is a totally humanized monoclonal antibody, administered by a subcutaneous injection every 4 weeks. Treatment with golimumab has shown to be effective to induce sustained clinical benefit in tough-to-treat patients with UC, including steroid and/or immunosuppressive refractory and steroid-dependent patients. In this review, we summarize all available efficacy and safety data of golimumab in UC, analyzing the potential therapeutic position for the treatment of refractory patients with UC. PMID:26893582

  13. 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

  14. Current therapies in rheumatoid arthritis: a Latin American perspective.

    PubMed

    Burgos-Vargas, Rubén; Catoggio, Luis Jose; Galarza-Maldonado, Claudio; Ostojich, Kasmir; Cardiel, Mario H

    2013-01-01

    Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting the synovium of joints, tendons, and some extra-articular sites. RA prevalence in Latin America ranges from 0.4 to 1.6%. Early treatment of RA translates into a substantial reduction in the cost to society. In light of this, early disease clinics are being established in some countries. Barriers to RA management, such as delay in referral to rheumatologists and limited access to therapy, have been identified. Evidence-based treatment guidelines have been adapted by countries according to their own situations. The need for keeping accurate records of biologics prescribed has been addressed by biologic registries, thereby contributing toward a better understanding of rheumatic diseases and their treatment. Current biologics include the tumor necrosis factor (TNF)-α inhibitors (etanercept, infliximab, and adalimumab), B-cell depletion agent (rituximab), interleukin-6 receptor blocker (tocilizumab), and T-cell co-stimulatory blocker (abatacept). Future therapies include kinase inhibitors (tofacitinib and fostamatinib), alternative TNF-α inhibitors (golimumab and certolizumab), and biosimilars. PMID:23337169

  15. Human IgG1 antibodies suppress angiogenesis in a target-independent manner

    PubMed Central

    Bogdanovich, Sasha; Kim, Younghee; Mizutani, Takeshi; Yasuma, Reo; Tudisco, Laura; Cicatiello, Valeria; Bastos-Carvalho, Ana; Kerur, Nagaraj; Hirano, Yoshio; Baffi, Judit Z; Tarallo, Valeria; Li, Shengjian; Yasuma, Tetsuhiro; Arpitha, Parthasarathy; Fowler, Benjamin J; Wright, Charles B; Apicella, Ivana; Greco, Adelaide; Brunetti, Arturo; Ruvo, Menotti; Sandomenico, Annamaria; Nozaki, Miho; Ijima, Ryo; Kaneko, Hiroki; Ogura, Yuichiro; Terasaki, Hiroko; Ambati, Balamurali K; Leusen, Jeanette HW; Langdon, Wallace Y; Clark, Michael R; Armour, Kathryn L; Bruhns, Pierre; Verbeek, J Sjef; Gelfand, Bradley D; De Falco, Sandro; Ambati, Jayakrishna

    2016-01-01

    Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies. PMID:26918197

  16. Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report

    PubMed Central

    Daferera, Niki; Kumawat, Ashok Kumar; Hultgren-Hörnquist, Elisabeth; Ignatova, Simone; Ström, Magnus; Münch, Andreas

    2015-01-01

    In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1β, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-γ, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis. PMID:26019474

  17. Is there truly a risk of lymphoma from biologic therapies?

    PubMed Central

    Dommasch, Erica; Gelfand, Joel M.

    2009-01-01

    The treatment of psoriasis has undergone a revolution with the advent of biologic therapies, including infliximab, etanercept, adalimumab, efalizumab, and alefacept. Biologics are generally safe and well tolerated. However, there has been concern over the risk of lymphoma with use of these agents due to their immunosuppressive properties. This review summarizes the current evidence in regards to lymphoma risk with biologic therapy obtained from case reports and case series, observational studies, clinical trials, and meta-analyses. The majority of data for T-cell inhibitors comes from case reports and relatively small, short term clinical trials. In addition to published case reports and case series, TNF-α inhibitors have also been studied extensively in large cohort studies and meta-analyses of clinical trials derived primarily from the rheumatoid arthritis population. Current data are not sufficient to completely rule out an increased risk of lymphoma associated with biologics, nor has a causal relationship between lymphoma and biologics been well established. Short- to intermediate-term treatment with biologics (e.g. up to 4 years) appears to be very safe with respect to lymphoma risk, especially with TNF-α inhibitors in which their potential risks appear to be well defined. Continued vigilance is warranted, however, in the appropriate patient, the risk-to-benefit profile of psoriasis treatment with respect to lymphoma risk appears highly favorable. PMID:19845719

  18. EFFECT OF THERAPY WITH ANTI-TNF α DRUGS AND DMARD ON DISEASE ACTIVITY AND HEALTH RELATED QUALITY OF LIFE AMONG WOMEN WITH RHEUMATOID ARTHRITIS.

    PubMed

    Kopciuch, Dorota; Paczkowska, Anna; Leszczynsk, Piotr; Michalak, Michal; Nowakowskai, Elzbieta

    2016-01-01

    The aim of this pilot study was to evaluate the response to 16 and 52 weeks of treatment with adalimumab and etanercept and its effect on disease activity and quality of life in patients with rheumatoid arthritis (RA). Patients were selected from 2155 medical cards of patients of Connective Tissue Health Centre (Poznań, Poland) who were refractory to conventional treatment with disease modifying anti-rheumatic drugs. To assess the disease activity, Disease Activity Score (DAS28) was used and the measurement of quality of life was evaluated with the Polish version of the WHOQoL-Bref questionnaire. To assess the disability, we have used Health Assessment Questionnaire Disability Index (HAQ-DI) and to assess the patients' pain caused by RA, Visual Analogue Scale (VAS) was used. The results of the study show a significant decrease in inflammatory activity of the disease and, consequently, an improvement in quality of life after anti-TNF α treatment. Results obtained with TNF-blockers after 52 weeks of treatment in RA objectively show the efficacy of these drugs and also the patients' perception of the effect on their quality of life. Study results also indicate changes in disability caused by RA and patients' pain due to disease between 16 and 52 weeks of treatment. PMID:27180448

  19. A generic approach to engineer antibody pH-switches using combinatorial histidine scanning libraries and yeast display

    PubMed Central

    Schröter, Christian; Günther, Ralf; Rhiel, Laura; Becker, Stefan; Toleikis, Lars; Doerner, Achim; Becker, Janine; Schönemann, Andreas; Nasu, Daichi; Neuteboom, Berend; Kolmar, Harald; Hock, Björn

    2015-01-01

    There is growing interest in the fast and robust engineering of protein pH-sensitivity that aims to reduce binding at acidic pH, compared to neutral pH. Here, we describe a novel strategy for the incorporation of pH-sensitive antigen binding functions into antibody variable domains using combinatorial histidine scanning libraries and yeast surface display. The strategy allows simultaneous screening for both, high affinity binding at pH 7.4 and pH-sensitivity, and excludes conventional negative selection steps. As proof of concept, we applied this strategy to incorporate pH-dependent antigen binding into the complementary-determining regions of adalimumab. After 3 consecutive rounds of separate heavy and light chain library screening, pH-sensitive variants could be isolated. Heavy and light chain mutations were combined, resulting in 3 full-length antibody variants that revealed sharp, reversible pH-dependent binding profiles. Dissociation rate constants at pH 6.0 increased 230- to 780-fold, while high affinity binding at pH 7.4 in the sub-nanomolar range was retained. Furthermore, binding to huFcRn and thermal stability were not affected by histidine substitutions. Overall, this study emphasizes a generalizable strategy for engineering pH-switch functions potentially applicable to a variety of antibodies and further proteins-based therapeutics. PMID:25523975

  20. Use of Biologics in Pouchitis – A Systematic Review

    PubMed Central

    Herfarth, Hans H.; Long, Millie D; Isaacs, Kim L

    2015-01-01

    Data about the effectiveness of biologics, including anti-TNF therapy and anti-integrin strategies, in antibiotic refractory pouchitis or Crohn’s disease-associated pouch complications are sparse. We performed a systematic review of the literature in Medline and Web of Science. All English language publications and meeting abstracts describing patients with pouchitis treated with anti-TNF or anti-integrin therapies were included. We identified a total of 17 papers and 2 abstracts, most of these retrospective case series, including a total of 192 patients treated either with infliximab (IFX; n=140) or adalimumab (ADA; n=52). No reports were found for anti-integrin therapies or other anti-TNF agents such as certolizumab pegol or golimumab. Due to the heterogeneity of the studies, small numbers of patients, differing co-treatments and subjective outcome definitions, the exact efficacy of these biologic therapies cannot be assessed in a combined fashion. Overall IFX appears to have good clinical effectiveness in selected patients achieving up to 80% short and around 50% long-term response, whereas the few data available for ADA are not sufficient to draw valid conclusions. Larger prospectively collected multi-center data with clearly defined inclusion criteria and outcomes are necessary to better define the clinical value of anti-TNF therapy in patients with antibiotic refractory pouchitis or Crohn’s-like complications of the pouch. PMID:26084005

  1. Noninfectious interstitial lung disease during infliximab therapy: Case report and literature review

    PubMed Central

    Caccaro, Roberta; Savarino, Edoardo; D’Incà, Renata; Sturniolo, Giacomo Carlo

    2013-01-01

    Pulmonary abnormalities are not frequently encountered in patients with inflammatory bowel diseases. However, lung toxicity can be induced by conventional medications used to maintain remission, and similar evidence is also emerging for biologics. We present the case of a young woman affected by colonic Crohn’s disease who was treated with oral mesalamine and became steroid-dependent and refractory to azathioprine and adalimumab. She was referred to our clinic with a severe relapse and was treated with infliximab, an anti-tumor necrosis factor α (TNF-α) antibody, to induce remission. After an initial benefit, with decreases in bowel movements, rectal bleeding and C-reactive protein levels, she experienced shortness of breath after the 5th infusion. Noninfectious interstitial lung disease was diagnosed. Both mesalamine and infliximab were discontinued, and steroids were introduced with slow but progressive improvement of symptoms, radiology and functional tests. This represents a rare case of interstitial lung disease associated with infliximab therapy and the effect of drug withdrawal on these lung alterations. Given the increasing use of anti-TNF-α therapies and the increasing reports of pulmonary abnormalities in patients with inflammatory bowel diseases, this case underlines the importance of a careful evaluation of respiratory symptoms in patients undergoing infliximab therapy. PMID:23983443

  2. [The future of inflammatory bowel disease from the perspective of Digestive Disease Week 2012].

    PubMed

    Gomollón, Fernando

    2012-09-01

    The new information presented in Digestive Disease Week has allowed us to speculate on the future of inflammatory bowel disease. Manipulation of diet and the microbioma will probably play an increasingly important role in the treatment of this disease and, in the long term, in its prevention. Biological agents will probably be used earlier and more widely; new information on levels of biological agents, mucosal healing and new comparative studies will also allow these agents to be used in a more precise and personalized way. In addition to infliximab, adalimumab, natalizumab and certolizumab, other biological agents will be employed; among the first of these to be used will be ustekinumab, golimumab and vedolizumab. In the near future, biological agents will be used as frequently in ulcerative colitis as in Crohn's disease. New healthcare models will be developed that will progressively include greater participation among patients and nurses. The ability to predict new diagnostic and prognostic models will allow decisions to be more individualized. PMID:23018007

  3. The Role of Biological Agents and Immunomodulators in Treatment Strategies for Thyroid Eye Disease: An Evidence-based Review.

    PubMed

    Ginter, Anna; Migliori, Michael E

    2016-01-01

    Graves' Disease is an autoimmune disease where circulating antibodies bind to the thyrotropin receptors on the thyroid gland. These bound antibodies mimic thyroid stimulating hormone without the normal feedback from the anterior pituitary, causing hyperthyroidism and thyrotoxicosis. These antibodies also interact with orbital tissues and cause the characteristic orbital findings of thyroid eye disease (TED). It is not clearly understood why anatomically and physiologically distinct tissues like the thyroid gland and orbit are affected selectively, or why the orbital disease tends to be self-limited. Identifying and understanding these processes is critical to targeting therapy. In the active phase of the disease patients may experience orbital inflammation, eyelid and conjunctiva edema (chemosis), eyelid retraction, proptosis, ocular motility restriction, and optic nerve compression. Current treatment strategies for the ocular symptoms have been predominantly directed at symptomatic relief. More recently, investigators have concentrated their efforts to better understanding the underlying pathophysiologic processes to direct therapy at these processes. This review examines the current literature exploring a variety of newer therapeutic alternatives, including immunomodulative and suppressive agents, targeted at strategic points of the active-phase TED pathophysiological pathways. Specifically, biological agents including rituximab, adalimumab, intravenous immunoglobulin and others are reviewed with considerations for pathophysiology, extent of literature support, and adverse effects. [Full article available at http://rimed.org/rimedicaljournal-2016-06.asp, free with no login]. PMID:27247969

  4. Cost-effectiveness of Crohn’s disease post-operative care

    PubMed Central

    Wright, Emily K; Kamm, Michael A; Dr Cruz, Peter; Hamilton, Amy L; Ritchie, Kathryn J; Bell, Sally J; Brown, Steven J; Connell, William R; Desmond, Paul V; Liew, Danny

    2016-01-01

    AIM: To define the cost-effectiveness of strategies, including endoscopy and immunosuppression, to prevent endoscopic recurrence of Crohn’s disease following intestinal resection. METHODS: In the “POCER” study patients undergoing intestinal resection were treated with post-operative drug therapy. Two thirds were randomized to active care (6 mo colonoscopy and drug intensification for endoscopic recurrence) and one third to drug therapy without early endoscopy. Colonoscopy at 18 mo and faecal calprotectin (FC) measurement were used to assess disease recurrence. Administrative data, chart review and patient questionnaires were collected prospectively over 18 mo. RESULTS: Sixty patients (active care n = 43, standard care n = 17) were included from one health service. Median total health care cost was $6440 per patient. Active care cost $4824 more than standard care over 18 mo. Medication accounted for 78% of total cost, of which 90% was for adalimumab. Median health care cost was higher for those with endoscopic recurrence compared to those in remission [$26347 (IQR 25045-27485) vs $2729 (IQR 1182-5215), P < 0.001]. FC to select patients for colonoscopy could reduce cost by $1010 per patient over 18 mo. Active care was associated with 18% decreased endoscopic recurrence, costing $861 for each recurrence prevented. CONCLUSION: Post-operative management strategies are associated with high cost, primarily medication related. Calprotectin use reduces costs. The long term cost-benefit of these strategies remains to be evaluated. PMID:27076772

  5. Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases

    PubMed Central

    Silacci, Michela; Lembke, Wibke; Woods, Richard; Attinger-Toller, Isabella; Baenziger-Tobler, Nadja; Batey, Sarah; Santimaria, Roger; von der Bey, Ulrike; Koenig-Friedrich, Susann; Zha, Wenjuan; Schlereth, Bernd; Locher, Mathias; Bertschinger, Julian; Grabulovski, Dragan

    2016-01-01

    Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis (ClinicalTrials.gov Identifier: NCT02243787). PMID:26390837

  6. Emerging Treatment Options in Mild to Moderate Ulcerative Colitis

    PubMed Central

    Lichtenstein, Gary R.; Hanauer, Stephen B.; Sandborn, William J.

    2015-01-01

    Ulcerative colitis (UC) is a chronic inflammatory condition associated with rectal bleeding and urgency, tenesmus, and diarrhea. Several medical therapies can be used in the treatment of UC. Aminosalicylates are widely used based on their efficacy in the induction and maintenance of remission. Although corticosteroids are effective in patients with more severe disease, systemic use is associated with significant safety concerns. The newer corticosteroid budesonide has lower systemic bioavailability and, consequently, a more favorable safety profile. A budesonide extended-release formulation allows once-daily dosing and delivers the agent locally throughout the colon. Biologic agents used for the treatment of moderate to severe UC include the tumor necrosis factor inhibitors infliximab, adalimumab, and golimumab, and the integrin inhibitor vedolizumab. Rectally administered therapy can also be useful in the treatment of UC. In October 2014, the US Food and Drug Administration approved a budesonide foam formulation for inducing remission in patients with active mild to moderate distal UC extending up to 40 cm from the anal verge. Budesonide foam rapidly distributes to the sigmoid colon and the rectum and avoids some of the drawbacks of suppositories and enemas. PMID:26491415

  7. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa

    PubMed Central

    Savva, Athina; Kersten, Brigit; Pistiki, Aikaterini; van de Veerdonk, Frank L.; Netea, Mihai G.; van der Meer, Jos W.; Giamarellos-Bourboulis, Evangelos J.

    2015-01-01

    Background Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). Methods Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured. Results CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8. Conclusions Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF. PMID:26091259

  8. An Update on Medical Treatment Options for Hidradenitis Suppurativa.

    PubMed

    Deckers, I E; Prens, E P

    2016-02-01

    Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory nodules mostly located in the armpits and groin. Over the years multiple treatments for HS have been proposed; however, to date a cure is still lacking. In this update we provide an overview of most drug treatments reported on for HS, where possible with their mode of action and side effects. In mild cases, clindamycin lotion or resorcinol cream have proven effective. Tetracyclines are a first-line systemic option in more widespread or severe cases, followed by the combination of clindamycin and rifampicin. However, the recurrence rate is high after discontinuation of clindamycin plus rifampicin combination therapy. Long-term treatment with retinoids, especially acitretin is feasible, although teratogenicity has to be taken into account in females of reproductive age. Multiple anti-inflammatory drugs have been suggested for HS, such as dapsone, fumarates or cyclosporine. However, their effectiveness in HS is based on small case series with varying results. If most common treatments have failed, biologics (e.g., infliximab or adalimumab) are the next step. Although not addressed in this review, surgical interventions are often needed to achieve remission. PMID:26659474

  9. Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases.

    PubMed

    Silacci, Michela; Lembke, Wibke; Woods, Richard; Attinger-Toller, Isabella; Baenziger-Tobler, Nadja; Batey, Sarah; Santimaria, Roger; von der Bey, Ulrike; Koenig-Friedrich, Susann; Zha, Wenjuan; Schlereth, Bernd; Locher, Mathias; Bertschinger, Julian; Grabulovski, Dragan

    2016-01-01

    Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( ClinicalTrials.gov Identifier: NCT02243787). PMID:26390837

  10. Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis

    PubMed Central

    Migliore, Alberto; Bizzi, Emanuele; Egan, Colin Gerard; Bernardi, Mauro; Petrella, Lea

    2015-01-01

    Background Biological agents provide an important therapeutic alternative for rheumatoid arthritis patients refractory to conventional disease-modifying antirheumatic drugs. Few head-to-head comparative trials are available. Purpose The aim of this meta-analysis was to compare the relative efficacy of different biologic agents indicated for use as monotherapy in rheumatoid arthritis. Methods A systemic literature search was performed on electronic databases to identify articles reporting double-blind randomized controlled trials investigating the efficacy of biologic agents indicated for monotherapy. Efficacy was assessed using American College of Rheumatology (ACR) 20, 50, and 70 criteria at 16–24 weeks. Relative efficacy was estimated using Bayesian mixed-treatment comparison models. Outcome measures were expressed as odds ratio and 95% credible intervals. Results Ten randomized controlled trials were selected for data extraction and analysis. Mixed-treatment comparison analysis revealed that tocilizumab offered 100% probability of being the best treatment for inducing an ACR20 response versus placebo, methotrexate, adalimumab, or etanercept. Likewise, for ACR50 and ACR70 outcome responses, tocilizumab had a 99.8% or 98.7% probability of being the best treatment, respectively, compared to other treatments or placebo. Tocilizumab increased the relative probability of being the best treatment (vs methotrexate) by 3.2-fold (odds ratio: 2.1–3.89) for all ACR outcomes. Conclusion Tocilizumab offered the greatest possibility of obtaining an ACR20, ACR50, and ACR70 outcome vs other monotherapies or placebo. PMID:26366085

  11. Inflammatory bowel disease surgery in the biologic era

    PubMed Central

    Ferrari, Linda; Krane, Mukta K; Fichera, Alessandro

    2016-01-01

    Anti-tumour necrosis factor (TNF)-α therapy has revolutionized inflammatory bowel disease (IBD) treatment. Infliximab and adalimumab either as monotherapy or in combination with an immunomodulator are able to induce clinical and biological remission in patients with moderate and severe Crohn’s disease (CD) and ulcerative colitis (UC). These new therapies have led to a shift in the goals of IBD management from just controlling clinical symptoms to preventing disease progression. However, despite these advances in medical therapy, surgery is still required in 30%-40% of patients with CD and 20%-30% of patients with UC at some point during their lifetime. While biologics certainly play a major role in the medical treatment of IBD, there is concern about the effects of these anti-TNF-α agents on postoperative complications and morbidity. The purpose of this article is to review the role of surgery in the treatment of IBD in the age of biologics and the impact of these medications on per-operative outcomes. In this manuscript we review the relationship between biologic agents and surgery in the treatment of IBD. We also discuss in detail the periopetative risks and complications. PMID:27231514

  12. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols.

    PubMed

    Gupta, Subash C; Tyagi, Amit K; Deshmukh-Taskar, Priya; Hinojosa, Myriam; Prasad, Sahdeo; Aggarwal, Bharat B

    2014-10-01

    Human tumor necrosis factor (TNF), first isolated by our group as an anticancer agent, has been now shown to be a primary mediator of inflammation. Till today 19 different members of the TNF superfamily which interact with 29 different receptors, have been identified. Most members of this family exhibit pro-inflammatory activities, in part through the activation of the transcription factor, nuclear factor-kappaB (NF-κB). Thus TNF and the related pro-inflammatory cytokines have been shown to play a key role in most chronic diseases such as cancer, rheumatoid arthritis, cardiovascular diseases, psoriasis, neurologic diseases, Crohn's disease, and metabolic diseases. Therefore, agents that can modulate the TNF-mediated inflammatory pathways may have potential against these pro-inflammatory diseases. Although blockers of TNF-α, such as infliximab (antibody against TNF-α), adalimumab (humanized antibody against TNF-α), and etanercept (soluble form of TNFR2) have been approved for human use, these blockers exhibit numerous side effects. In this review, we describe various plant-derived polyphenols that can suppress TNF-α activated inflammatory pathways both in vitro and in vivo. These polyphenols include curcumin, resveratrol, genistein, epigallocatechin gallate, flavopiridol, silymarin, emodin, morin isoliquiritigenin, naringenin, ellagic acid, apigenin, kaempferol, catechins, myricetin, xanthohumol, fisetin, vitexin, escin, mangostin and others. Thus these polyphenols are likely to have potential against various pro-inflammatory diseases. PMID:24946050

  13. Can we reduce the dosage of biologics in spondyloarthritis?

    PubMed

    Olivieri, Ignazio; D'Angelo, Salvatore; Padula, Angela; Leccese, Pietro; Nigro, Angelo; Palazzi, Carlo

    2013-05-01

    TNF blockers have revolutionized the management of spondyloarthritis (SpA). To date, four anti-TNFα agents (etanercept, infliximab, adalimumab, golimumab) have been approved for the management of ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The first objective in the management of AS and PsA with TNF inhibitors is to reduce disease activity to clinical remission or low disease activity. After remission has been achieved, this state should be maintained as long as possible. However, the financial burden associated with the cost of anti-TNF agents as well as concerns about their long-term safety suggest reducing the dosage of the drug or discontinuing the therapy in the hopes of drug-free remission. The aim of this review is to examine what has, till now, been published on this topic in axial SpA, which includes AS and non-radiographic axial SpA (nr-axSpA), peripheral SpA and PsA. Discontinuation of therapy in axial SpA is not possible in the majority of patients, while on the contrary, reducing the dosage often is. In some patients with peripheral SpA and PsA it is also possible to discontinue therapy and to achieve drug-free remission. PMID:22940233

  14. Fecal stream diversion and mucosal cytokine levels in collagenous colitis: A case report.

    PubMed

    Daferera, Niki; Kumawat, Ashok Kumar; Hultgren-Hörnquist, Elisabeth; Ignatova, Simone; Ström, Magnus; Münch, Andreas

    2015-05-21

    In this case report, we examined the levels of cytokines expressed before and during fecal stream diversion and after intestinal continuity was restored in a patient with collagenous colitis. We report the case of a 46-year-old woman with chronic, active collagenous colitis who either failed to achieve clinical remission or experienced adverse effects with the following drugs: loperamide, cholestyramine, budesonide, methotrexate and adalimumab. Due to the intractable nature of the disease and because the patient was having up to 15 watery bowel movements per day, she underwent a temporary ileostomy. Colonic biopsies were analyzed for mucosal cytokine protein levels before and during fecal stream diversion and after intestinal continuity was restored. Mucosal protein levels of interleukin (IL)-1β, IL-2, IL-6, IL-12, IL-17 A, IL-23, TNF, IFN-γ, IL-4, IL-5, IL-10 and IL-13 were all higher during active disease and decreased to non-detectable or considerably lower levels during fecal stream diversion. One month after the restoration of bowel continuity, when the patient experienced a relapse of symptoms, IL-2, IL-23 and IL-21 levels were again increased. Our results indicate that fecal stream diversion in this patient suppressed the levels of all cytokines analyzed in colonic biopsies. With the recurrence of clinical symptoms and histological changes after bowel reconstruction, the levels of primarily proinflammatory cytokines increased. Our findings support the hypothesis that a luminal factor triggers the inflammation observed in collagenous colitis. PMID:26019474

  15. Whole cell-based surface plasmon resonance measurement to assess binding of anti-TNF agents to transmembrane target.

    PubMed

    Ogura, Takeharu; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2016-09-01

    We developed a technique for the measurement of surface plasmon resonance (SPR) to detect interactions of anti-tumor necrosis factor (TNF) agents with transmembrane TNF-α (mTNF-α) on living whole cells. The injection of a suspension of mTNF-α expressing Jurkat cells, used as an analyte, gave a clear binding response to anti-TNF agents, such as etanercept, infliximab and adalimumab, immobilized on sensorchip. The binding response of the analyte cells increased in a concentration-dependent manner and was competitively reduced by adding soluble TNF receptors to the analyte cell suspension. Treatment of analyte cells with free anti-TNF agent before injection reduced the binding response between the analyte cells and immobilized-etanercept on sensorchip, and the inhibitory effect of free anti-TNF agent was concordant with the affinity of anti-TNF agent for soluble TNF-α. These findings indicate that the SPR response arises from specific binding between anti-TNF agent and its target on cell membrane. PMID:27349512

  16. 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. PMID:24594669

  17. Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease.

    PubMed

    Dhaneshwar, Suneela S

    2014-04-01

    Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD. PMID:24707139

  18. Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease.

    PubMed

    Androulakis, Ioannis; Zavos, Christos; Christopoulos, Panagiotis; Mastorakos, George; Gazouli, Maria

    2015-12-21

    Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor (TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that anti-TNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of anti-TNF therapeutic agents on pregnancy outcomes. PMID:26715803

  19. 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. PMID:25819232

  20. Advances in rheumatology: new targeted therapeutics.

    PubMed

    Tak, Paul P; Kalden, Joachim R

    2011-01-01

    Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice. PMID:21624184

  1. Abatacept: a review of its use in the management of rheumatoid arthritis.

    PubMed

    Keating, Gillian M

    2013-07-01

    The biological disease-modifying antirheumatic drug abatacept (Orencia) has a novel mechanism of action; its activity is mediated via the selective modulation of T cell co-stimulation. This article reviews the clinical efficacy and tolerability of intravenous and subcutaneous abatacept in patients with rheumatoid arthritis (RA) and intravenous abatacept in patients with juvenile idiopathic arthritis (JIA), as well as summarizing its pharmacological properties. In patients with RA, the beneficial effects of intravenous or subcutaneous abatacept on signs and symptoms, disease activity, the progression of structural damage, physical function and/or health-related quality of life were seen in a number of well-designed trials, including in methotrexate-naive patients with early RA and poor prognostic factors and in patients with established RA and an inadequate response to either methotrexate or anti-tumour necrosis factor therapy. Subcutaneous abatacept plus methotrexate was also noninferior to subcutaneous adalimumab plus methotrexate in patients with active RA who were naive to biological therapy and had an inadequate response to methotrexate. In paediatric patients with JIA, intravenous abatacept improved signs and symptoms and delayed the time to flare. Abatacept was generally well tolerated in RA and JIA and was associated with low rates of immunogenicity. In conclusion, abatacept is an important option for use in the treatment of RA and JIA. PMID:23794171

  2. Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan

    PubMed Central

    Komoto, Shunsuke; Motoya, Satoshi; Nishiwaki, Yuji; Matsui, Toshiyuki; Kunisaki, Reiko; Matsuoka, Katsuyoshi; Yoshimura, Naoki; Kagaya, Takashi; Naganuma, Makoto; Hida, Nobuyuki; Watanabe, Mamoru; Hibi, Toshifumi; Suzuki, Yasuo; Miura, Soichiro

    2016-01-01

    Background/Aims Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. Methods This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. Results Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). Conclusions Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion. PMID:27175114

  3. Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease

    PubMed Central

    Dhaneshwar, Suneela S

    2014-01-01

    Despite the advent of biological products, such as anti-tumor necrosis factor-α monoclonal antibodies (infliximab and adalimumab), for treatment of moderate to severe cases of inflammatory bowel disease (IBD), most patients depend upon aminosalicylates as the conventional treatment option. In recent years, the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin, omega-3 fatty acids, probiotics and innovative formulations such as high-dose, once-daily multi-matrix mesalamine, which are designed to minimize the inflammatory process through inhibition of different targets. Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid (ASA) in the form of sulfasalazine, balsalazide, olsalazine and ipsalazine, but rarely for its positional isomer 4-ASA - a well-established antitubercular drug that is twice as potent as 5-ASA against IBD, and more specifically, ulcerative colitis. The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD. The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD. PMID:24707139

  4. Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs.

    PubMed

    Jinesh, Sandhya

    2015-06-01

    Tumor necrosis factor (TNF) is a key regulator of inflammatory processes in several immune-mediated inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. Inactivating TNF has been found to be a plausible approach in treating these conditions. Two major strategies have been adopted by scientists to inactivate TNF: one is to use monoclonal antibodies (mAbs) that bind to TNF, and the other is to use fusion proteins that bind to TNF, both inactivate TNF and help to prevent TNF-mediated inflammatory processes. Monoclonal antibodies (mAbs) are biological products that selectively bind to specific antigen molecules, and fusion proteins are soluble receptors that bind to TNF. These types of drugs are generally known as biologics and there has been an explosion in the development and testing of biologics since the 1994 US approval and launch of abciximab, a mAb that binds to GPIIb/IIIa on platelets. Anti-TNF drugs that are currently approved by FDA for treating inflammatory conditions include adalimumab, certolizumab pegol, golimumab, infliximab and etanercept. Since these agents are complex protein molecules, the pharmacodynamics and pharmacokinetics of these drugs are different from small-molecule anti-inflammatory agents. This review focuses on the pharmaceutical aspects of these drugs such as mechanism of action, adverse effects, pharmacokinetics and drug interactions. An effort was also taken to compare the pharmacodynamics and pharmacokinetic properties of these drugs, with the available data at this time. PMID:25687751

  5. Factors associated with the prescription of "traditional" or "biological" systemic treatment in psoriasis.

    PubMed

    Tabolli, Stefano; Paradisi, Andrea; Giannantoni, Patrizia; Gubinelli, Emanuela; Abeni, Damiano

    2015-02-01

    Abstract The choice of an adequate psoriasis treatment is critical to good disease management and to overall patient health. It is estimated that about 20-30% of patients requires systemic treatment: "traditional" (methotrexate, acitretina and cyclosporin) or "biological" (etanercept, adalimumab and infliximab). Clinical records of 784 outpatients with psoriasis were analyzed. 51.5% received traditional treatments and 48.5% a biological treatment. Males were 67.8% of patients. Psoriatic arthritis was observed in 37.3%. Females and younger patients were more likely to receive biological treatments. No differences were observed for Body Mass Index or for presence of comorbidities. Patients with psoriatic arthritis were also more frequently prescribed biological drug treatment. In a multivariate logistic regression model, only the older age-group (≥60 years) had a statistically significant OR (p=0.001) with a reduction of about 80% the likelihood of receiving biological treatment compared to the younger age-group (<40 years). Patients with a PASI score ≥20 and patients with arthritis have a probability to be prescribed biologics about five times higher than the other patients. In conclusion, younger age, psoriatic arthritis and the previous use of systemic drugs are factors associated with the use of biological treatment rather than the traditional systemic drugs. PMID:24559128

  6. Gateways to clinical trials. December 2008.

    PubMed

    Tomillero, A; Moral, M A

    2008-12-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables 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: AAV1/SERCA2a; Abatacept, ABT-263, Adalimumab, Aflibercept, Afobazole, Aliskiren fumarate, Anakinra, Atazanavir/ritonavir, Aviscumine, Axitinib, Azacitidine; Bevacizumab, Biphasic insulin aspart, Bortezomib, Briobacept; Carmoterol hydrochloride, CCX-282, Ceftobiprole medocaril, Certolizumab pegol, Cetuximab; Darifenacin hydrobromide, Dasatinib, Denosumab, Doripenem, Duloxetine hydrochloride; E-7080, Epratuzumab, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe/simvastatin; Gefitinib, Golimumab; gamma-Hydroxybutyrate sodium; Imatinib mesylate, Insulin detemir, Insulin glulisine, IVX-0142; Laquinimod sodium, Linezolid, Lopinavir/ritonavir; Ocrelizumab, Omalizumab; Parecoxib sodium, Pemetrexed disodium, Pregabalin; Rosuvastatin calcium, Rotigotine; Sorafenib, Sugammadex sodium; Tapentadol hydrochloride, Tenofovir disoproxil fumarate/emtricitabine, Tocilizumab; Ularitide, Ustekinumab; Valsartan/amlodipine besylate, Varenicline tartrate, Vatalanib succinate, Vildagliptin, Vorinostat. PMID:19271026

  7. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease.

    PubMed

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-06-01

    Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy. PMID:23745038

  8. Femtomolar Fab binding affinities to a protein target by alternative CDR residue co-optimization strategies without phage or cell surface display

    PubMed Central

    Plittersdorf, Hanna; Hesse, Oliver; Scheidig, Andreas; Strerath, Michael; Gritzan, Uwe; Pellengahr, Klaus; Scholz, Peter; Eicker, Andrea; Myszka, David; Haupts, Ulrich

    2012-01-01

    In therapeutic or diagnostic antibody discovery, affinity maturation is frequently required to optimize binding properties. In some cases, achieving very high affinity is challenging using the display-based optimization technologies. Here we present an approach that begins with the creation and clonal, quantitative analysis of soluble Fab libraries with complete diversification in adjacent residue pairs encompassing every complementarity-determining region position. This was followed by alternative recombination approaches and high throughput screening to co-optimize large sets of the found improving mutations. We applied this approach to the affinity maturation of the anti-tumor necrosis factor antibody adalimumab and achieved ~500-fold affinity improvement, resulting in femtomolar binding. To our knowledge, this is the first report of the in vitro engineering of a femtomolar affinity antibody against a protein target without display screening. We compare our findings to a previous report that employed extensive mutagenesis and recombination libraries with yeast display screening. The present approach is widely applicable to the most challenging of affinity maturation efforts. PMID:22531438

  9. 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

  10. Efficacy of Anti-TNFα in Severe and Refractory Neuro-Behcet Disease: An Observational Study.

    PubMed

    Desbois, Anne Claire; Addimanda, Olga; Bertrand, Anne; Deroux, Alban; Pérard, Laurent; Depaz, Raphael; Hachulla, Eric; Lambert, Marc; Launay, David; Subran, Benjamin; Ackerman, Felix; Mariette, Xavier; Cohen, Fleur; Marie, Isabelle; Salvarini, Carlo; Cacoub, Patrice; Saadoun, David

    2016-06-01

    To report the safety and efficacy of anti-tumor necrosis factor α (TNFα) therapy in severe and refractory neuro-Behçet disease (NBD) patients.Observational, multicenter study including 17 BD patients (70.6% of male, with a median age of 39.3 [24-60] years), with symptomatic parenchymal NBD, refractory to previous immunosuppressant and treated with anti-TNFα (infliximab 5 mg/kg [n = 13] or adalimumab [n = 4]). Complete remission was defined by the disappearance of all neurological symptoms and by the improvement of radiological abnormalities at 12 months.Overall improvement following anti-TNF was evidenced in 16/17 (94.1%) patients including 6 (35.3%) complete response and 10 (58.8%) partial response. The median time to achieve remission was 3 months (1-6). The median Rankin score was 2 (1-4) at the initiation of anti-TNFα versus 1 (0-4) at the time of remission (P = 0.01). Corticosteroids have been stopped in 4 (23.5%) patients, and reduced by more than 50% as compared with the dosage at baseline in 10 (58.8%) patients. Side effects occurred in 23.5% of patients and required treatment discontinuation in 17% of cases.TNF blockade represents an effective therapeutic approach for patients with severe and refractory NBD, a difficult to treat population. PMID:27281066

  11. Psoriatic arthritis treatment: biological response modifiers.

    PubMed

    Mease, P J; Antoni, C E

    2005-03-01

    In recent years there has been a surge of interest in the treatment of chronic inflammatory disorders as a result of the development and application of targeted biological therapies. The elucidation of the overlapping cellular and cytokine immunopathology of such diverse conditions as rheumatoid arthritis (RA), Crohn's disease, and psoriasis points to specific targets for bioengineered proteins or small molecules. Similar to clinical trials in RA, trials in psoriatic arthritis (PsA) have shown excellent clinical results with the tumour necrosis factor (TNF) blockers, etanercept, infliximab, and adalimumab in a variety of domains including the joints, quality of life, function, and slowing of disease progress as evidenced radiologically. In addition, these agents have shown benefit in domains more unique to PsA, such as the skin lesions of psoriasis, enthesitis, and dactylitis, pointing out the similar pathogenesis of the disease in the skin, the tendons, and the synovial membrane. This therapy has been generally safe and well tolerated in clinical trials of PsA. Other logical candidates for targeted therapy in development include other anti-TNF agents, costimulatory blockade agents that affect T cell function, blockers of other cytokines such as interleukin (IL)-1, 6, 12, 15, or 18, and B cell modulatory medicines. Also, it will be useful to learn more about the effects of combining traditional disease modifying drugs and the newer biologicals. PMID:15708944

  12. Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis

    PubMed Central

    Kivelevitch, Dario; Mansouri, Bobbak; Menter, Alan

    2014-01-01

    Psoriasis is a chronic, immune-mediated inflammatory disease affecting both the skin and joints. Approximately 20% of patients suffer a moderate to severe form of skin disease and up to 30% have joint involvement. Standard therapies for psoriasis include topical medications, phototherapy, and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti-inflammatory drugs followed by disease modifying antirheumatic drugs and/or tumor necrosis factor (TNF)-α inhibitors and interleukin-12/23p40 inhibitors. Treatment of both diseases is typically driven by disease severity. In the past decade, major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies, which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis. Anti-TNF-α agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis. Currently approved anti-TNF-α agents include etanercept, adalimumab, and infliximab for psoriasis and psoriatic arthritis as well as golimumab and certolizumab for psoriatic arthritis. In this article, we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis. PMID:24790410

  13. FDAAA legislation is working, but methodological flaws undermine the reliability of clinical trials: a cross-sectional study

    PubMed Central

    Atallah, Álvaro N.

    2015-01-01

    The relationship between clinical research and the pharmaceutical industry has placed clinical trials in jeopardy. According to the medical literature, more than 70% of clinical trials are industry-funded. Many of these trials remain unpublished or have methodological flaws that distort their results. In 2007, it was signed into law the Food and Drug Administration Amendments Act (FDAAA), aiming to provide publicly access to a broad range of biomedical information to be made available on the platform ClinicalTrials (available at https://www.clinicaltrials.gov). We accessed ClinicalTrials.gov and evaluated the compliance of researchers and sponsors with the FDAAA. Our sample comprised 243 protocols of clinical trials of biological monoclonal antibodies (mAb) adalimumab, bevacizumab, infliximab, rituximab, and trastuzumab. We demonstrate that the new legislation has positively affected transparency patterns in clinical research, through a significant increase in publication and online reporting rates after the enactment of the law. Poorly designed trials, however, remain a challenge to be overcome, due to a high prevalence of methodological flaws. These flaws affect the quality of clinical information available, breaching ethical duties of sponsors and researchers, as well as the human right to health. PMID:26131374

  14. Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease.

    PubMed

    Levin, Alon D; Wildenberg, Manon E; van den Brink, Gijs R

    2016-08-01

    Several anti-tumour necrosis factor [TNF] blocking strategies have been evaluated in patients with Crohn's disease. Compounds that have been tested included the full monoclonal IgG1 antibodies infliximab and adalimumab, the pegylated anti-TNF F[ab']2 fragment certolizumab, an IgG4 anti-TNF CDP571 with reduced affinity for the Fc receptor, the soluble TNF receptor I onercept, and the TNF receptor II-Fc fusion protein etanercept. The endpoints of these studies suggest that not all methods of blocking TNF are equal. Here we will review the differences in the clinical, biochemical, and endoscopic endpoints of the major clinical studies. Collectively the data suggest that only IgG1 monoclonal antibodies have the ability to induce complete clinical, biochemical, and endoscopic remission. We discuss the potential multiple modes of action that may contribute to the response to full IgG1 anti-TNFs, focusing on the rapid induction of lamina propria T cell apoptosis and Fc receptor-dependent induction of M2-type wound-healing macrophages. We discuss how novel insights into the mechanism of action of anti-TNFs in Crohn's disease may contribute to the development of novel anti-TNFs with improved efficacy. PMID:26896086

  15. Mucosal healing in inflammatory bowel diseases: a systematic review.

    PubMed

    Neurath, Markus F; Travis, Simon P L

    2012-11-01

    Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted. PMID:22842618

  16. 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

  17. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-06-01

    (+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan. PMID:19649342

  18. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2008-06-01

    (+)-Dapoxetine hydrochloride, (R)-Etodolac; Abatacept, ABT-510, Adalimumab, Agatolimod sodium, Alemtuzumab, Alvocidib hydrochloride, Aminolevulinic acid methyl ester, Aripiprazole, AS01B, AS02B, AS02V, Azacitidine; Becatecarin, Bevacizumab, Bevirimat, Bortezomib, Bremelanotide; CAIV-T, Canfosfamide hydrochloride, CHR-2797, Ciclesonide, Clevidipine; Darbepoetin alfa, Decitabine, Degarelix acetate, Dendritic cell-based vaccine, Denosumab, Desloratadine, DMXB-Anabaseine, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Eicosapentaenoic acid/docosahexaenoic acid, Eletriptan, Enzastaurin hydrochloride, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumarate, Fulvestrant; Gefitinib, GM-CSF DNA, GSK-690693; H5N1 avian flu vaccine, Hepatitis B hyperimmunoglobulin, Human Fibroblast Growth Factor 1, Hypericin-PVP; Icatibant acetate, Iclaprim, Immunoglobulin intravenous (human), Ipilimumab, ISS-1018; L19-IL-2, Lapuleucel-T, Laropiprant, Liposomal doxorubicin, LP-261, Lumiracoxib, LY-518674; MDV-3100, MGCD-0103, Mirabegron, MyoCell; NASHA/Dx, Niacin/laropiprant; O6-Benzylguanine, Ocrelizumab, Olmesartan medoxomil, Omalizumab; P-276-00, Paclitaxel nanoparticles, Paclitaxel nanoparticles, Padoporfin, Paliperidone, PAN-811, Pegaptanib octasodium, Pegfilgrastim, Pemetrexed disodium, PF-00299804, Pimecrolimus, Prasugrel, Pregabalin; Reolysin, Rimonabant, Rivaroxaban, Rosuvastatin calcium; Satraplatin, SCH-697243,Selenite sodium, Silodosin, Sorafenib, Sunitinib malate; Talarozole, Taxus, Temsirolimus, Tocilizumab, Tolevamer potassium sodium, Tremelimumab, TTP-889; Uracil; V-260, Valsartan/amlodipine besylate, Vardenafil hydrochloride hydrate, Varenicline tartrate, Varespladib, Vitespen, Voclosporin, VX-001; Xience V; Zotarolimus-eluting stent. PMID:18806898

  19. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-06-01

    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: 131-I-chlorotoxin; Ad5CMV-p53, adalimumab, albumin interferon alfa, alemtuzumab, aliskiren fumarate, aminolevulinic acid methyl ester, anakinra, AR-C126532, atomoxetine hydrochloride; Bevacizumab, bosentan, botulinum toxin type B, brimonidine tartrate/timolol maleate; Calcipotriol/betamethasone dipropionate, cangrelor tetrasodium, cetuximab, ciclesonide, cinacalcet hydrochloride, collagen-PVP, Cypher; Darbepoetin alfa, darusentan, dasatinib, denosumab, desloratadine, dexosome vaccine (lung cancer), dexrazoxane, dextromethorphan/quinidine sulfate, duloxetine hydrochloride; ED-71, eel calcitonin, efalizumab, entecavir, etoricoxib; Falciparum merozoite protein-1/AS02A, fenretinide, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gefitinib, ghrelin (human); hLM609; Icatibant acetate, imatinib mesylate, ipsapirone, irofulven; LBH-589, LE-AON, levocetirizine, LY-450139; Malaria vaccine, mapatumumab, motexafin gadolinium, muraglitazar, mycophenolic acid sodium salt; nab-paclitaxel, nelarabine; O6-Benzylguanine, olmesartan medoxomil, orbofiban acetate; Panitumumab, peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, peptide YY3-36, pleconaril, prasterone, pregabalin; Ranolazine, rebimastat, recombinant malaria vaccine, rosuvastatin calcium; SQN-400; Taxus, tegaserod maleate, tenofovir disoproxil fumarate, teriparatide, troxacitabine; Valganciclovir hydrochloride, Val-Tyr sardine peptidase, VNP-40101M, vorinostat. PMID:16845450

  20. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2010-05-01

    O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent. PMID:20508873

  1. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses, which has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, providing information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abacavir sulfate; abciximab; abetimus sodium; adalimumab; aldesleukin; almotriptan; alteplase; amisulpride; amitriptyline hydrochloride; amoxicillin trihydrate; atenolol; atorvastatin calcium; atrasentan; Beclometasone dipropionate; bosentan; Captopril; ceftriaxone sodium; cerivastatin sodium; cetirizine hydrochloride; cisplatin; citalopram hydrobromide; Dalteparin sodium; darusentan; desirudin; digoxin; Efalizumab; enoxaparin sodium; ertapenem sodium; esomeprazole magnesium; estradiol; ezetimibe; Famotidine; farglitazar; fluorouracil; fluticasone propionate; fosamprenavir sodium; Glibenclamide; glucosamine sulfate; Heparin sodium; HSPPC-96; hydrochlorothiazide; Imatinib mesilate; implitapide; Lamivudine; lansoprazole; lisinopril; losartan potassium; l-Propionylcarnitine; Melagatran; metformin hydrochloride; methotrexate; methylsulfinylwarfarin; Nateglinide; norethisterone; Olmesartan medoxomil; omalizumab; omapatrilat; omeprazole; oseltamivir phosphate; oxatomide; Pantoprazole; piperacillin sodium; pravastatin sodium; Quetiapine hydrochloride; Rabeprazole sodium; raloxifene hydrochloride; ramosetron hydrochloride; ranolazine; rasburicase; reboxetine mesilate; recombinant somatropin; repaglinide; reteplase; rosiglitazone; rosiglitazone maleate; rosuvastatin calcium; Sertraline; simvastatin; sumatriptan succinate; Tazobactam sodium; tenecteplase; tibolone; tinidazole; tolterodine tartrate; troglitazone; Uniprost; Warfarin sodium; Ximelagatran. PMID:11980386

  2. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2005-12-01

    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-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib

  3. 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. PMID:24698590

  4. Redo Ileal pouch-anal anastomosis combined with anti-TNF-α maintenance therapy for Crohn's disease with pelvic fistula: report of two cases.

    PubMed

    Araki, Toshimitsu; Okita, Yoshiki; Fujikawa, Hiroyuki; Ohi, Masaki; Tanaka, Koji; Inoue, Yasuhiro; Uchida, Keiichi; Mohri, Yasuhiko; Kusunoki, Masato

    2014-10-01

    Pouch failure has been reported to occur after ileal pouch-anal anastomosis for Crohn's disease. We report two cases of patients with Crohn's disease, who underwent redo ileal pouch-anal anastomosis (redo-IPAA) combined with anti-TNF-α maintenance therapy, with good functional results. The first patient, a man with presumed ulcerative colitis, suffered pelvic fistula recurrence and anastomotic dehiscence. He underwent redo-IPAA, at which time longitudinal ulcers were found. Infliximab was started 4 days postoperatively and continued. The second patient, a woman treated for ulcerative colitis, underwent laparoscopic IPAA 8 years later. After the development of a pelvic fistula, twisted mesentery of the ileal pouch was found intraoperatively and Crohn's disease was diagnosed. Adalimumab therapy resulted in fistula closure. Redo-IPAA was performed to normalize the twisted mesentery of the ileal pouch. No complications have been observed in either patient, both of whom have experienced good functional results after closure of the covering stomas. PMID:24442570

  5. Ureaplasma septic arthritis in an immunosuppressed patient with juvenile idiopathic arthritis.

    PubMed

    George, Michael David; Cardenas, Ana Maria; Birnbaum, Belinda K; Gluckman, Stephen J

    2015-06-01

    Mycoplasmas, including Ureaplasma and Mycoplasma species, are uncommon but important causes of septic arthritis, especially affecting immunosuppressed patients. Many of the reported cases have been associated with congenital immunodeficiency disorders, especially hypogammaglobulinemia. Mycoplasmas are difficult to grow in the laboratory, and these infections may be underdiagnosed using culture techniques. We report a case of a 21-year-old woman with juvenile idiopathic arthritis and hip arthroplasties treated with rituximab and adalimumab who developed urogenital infections and soft tissue abscesses followed by knee arthritis with negative routine cultures. Ureaplasma species was identified from synovial fluid on 2 separate occasions using a broad-range 16S ribosomal RNA gene polymerase chain reaction. Azithromycin led to rapid improvement in symptoms, but after completion of therapy, involvement of the hip prosthesis became apparent, and again, 16S rRNA gene polymerase chain reaction was positive for Ureaplasma species. The literature is reviewed with a discussion of risk factors for Mycoplasma septic arthritis, clinical presentation, methods of diagnosis, and treatment. PMID:26010188

  6. Sex Differences in the Treatment of Psoriatic Arthritis: A Systematic Literature Review.

    PubMed

    Generali, Elena; Sciré, Carlo A; Cantarini, Luca; Selmi, Carlo

    2016-01-01

    Psoriatic arthritis (PsA) is a chronic inflammatory condition associated with skin psoriasis and manifests a wide clinical phenotype, with proposed differences between sexes. Current treatments are based on traditional disease-modifying anti-rheumatic drugs (DMARD), and biologic agents and studies have reported different clinical response patterns depending on sex factors. We aimed to identify sex differences in drug retention rate in patients with PsA and performed a systematic research on MEDLINE, EMBASE and Cochrane databases (1979 to June 2015) for studies regarding effectiveness (measured as drug retention rate) in PsA in both traditional DMARDs and biologics. Demographic data as well as retention rates between sexes were extracted. From a total 709 retrieved references, we included 9 articles for the final analysis. Only one study reported data regarding DMARDs, while eight studies reported retention rate for anti-tumor necrosis factor (TNF) biologics, mainly infliximab, adalimumab and etanercept. No differences were reported in retention rates between sexes for methotrexate, while women manifested lower retention rates compared to men with regard to anti-TNF. We highlight the need to include sex differences in the management flow chart of patients with PsA. PMID:27228644

  7. Treatment of generalized granuloma annulare - a systematic review.

    PubMed

    Lukács, J; Schliemann, S; Elsner, P

    2015-08-01

    Granuloma annulare (GA) is a benign inflammatory skin disease. Localized GA is likely to resolve spontaneously, while generalized GA (GGA) is rare and may persist for decades. GGA usually is resistant to a variety of therapeutic modalities and takes a chronic course. The objective of this study was to summarize all reported treatments of generalized granuloma annulare. This is a systematic review based on MEDLINE, Embase and Cochrane Central Register search of articles in English and German and a manual search, between 1980 and 2013, to summarize the treatment of generalized granuloma annulare. Most medical literature on treatment of GGA is limited to individual case reports and small series of patients treated without a control group. Randomized controlled clinical studies are missing. Multiple treatment modalities for GGA were reported including topical and systemic steroids, PUVA, isotretinoin, dapsone, pentoxifylline, hydroxychloroquine, cyclosporine, IFN-γ, potassium iodide, nicotinamide, niacinamide, salicylic acid, dipyridamole, PDT, fumaric acid ester, etanercept, infliximab, adalimumab. While there are numerous case reports of successful treatments in the literature including surgical, medical and phototherapy options, well-designed, randomized, controlled clinical trials are required for an evidence-based treatment of GGA. PMID:25651003

  8. ASAS classification criteria for axial spondyloarthritis: time to modify.

    PubMed

    Akkoc, Nurullah; Khan, Muhammad A

    2016-06-01

    The relationship between ankylosing spondylitis and the recently proposed entity called axial spondyloarthritis with its radiographic and non-radiographic forms that have been defined by the Assessment of Spondyloarthritis International Society (ASAS) criteria for axial spondyloarthritis (axSpA), is currently being debated. The Food and Drug Agency (FDA) had criticized the ASAS criteria and the studies which used these criteria to enroll patients in a clinical trial of certolizumab and adalimumab for the treatment of non-radiographic axial spondyloarthritis. The primary aim of classification criteria is to create homogenous patient populations for basic and clinical research. But the multi-arm construct of the ASAS criteria is a potential source of heterogeneity reducing their utility. Criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances. We provide evidence to conclude that it is time to modify the ASAS Criteria for axSpA, and we propose some of the steps that can be taken to start moving forward in improving the validity of these criteria. PMID:27094940

  9. Tumor necrosis factor-α inhibitor therapy and fetal risk: A systematic literature review

    PubMed Central

    Marchioni, Renée M; Lichtenstein, Gary R

    2013-01-01

    Tumor necrosis factor-α inhibitors (anti-TNFs) are effective in the treatment of inflammatory bowel disease (IBD) recalcitrant to conventional medical therapy. As the peak incidence of IBD overlaps with the prime reproductive years, it is crucial to establish pharmacologic regimens for women of childbearing age that achieve effective disease control without posing significant fetal harm. A systematic literature review was performed to identify all human studies with birth outcomes data after maternal exposure to infliximab, adalimumab, or certolizumab pegol within 3 mo of conception or during any trimester of pregnancy. Live births, spontaneous abortions or stillbirths, preterm or premature births, low birth weight or small for gestational age infants, and congenital abnormalities were recorded. Fifty selected references identified 472 pregnancy exposures. The subsequent review includes general information regarding anti-TNF therapy in pregnancy followed by a summary of our findings. The benefits of biologic modalities in optimizing disease control during pregnancy must be weighed against the potential toxicity of drug exposure on the developing fetus. Although promising overall, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the limitations of available data and lack of controlled trials. PMID:23674866

  10. Optimal management of steroid-dependent ulcerative colitis

    PubMed Central

    Khan, Hafiz M Waqas; Mehmood, Faisal; Khan, Nabeel

    2015-01-01

    Ulcerative colitis (UC) is a chronic inflammatory condition that is variable in both extent and severity of disease as well as response to therapy. Corticosteroids (CSs) were the first drugs used in the management of UC and are still used for induction of remission. However, because of their extensive side-effect profile, they are not utilized for maintenance of remission. In view of this, CS-free remission has become an important end point while evaluating therapeutic agents used in the management of UC. This review highlights the results of various studies conducted to evaluate the efficacy of different medications to attain CS-free remission in the setting of active UC. The drugs reviewed include established agents such as thiopurines, methotrexate, infliximab, adalimumab, vedolizumab, golimumab, and newer experimental agents, and if all else fails, colectomy will be performed. The efficacy of these drugs is evaluated individually. Our aim is to provide a synopsis of the work done in this field to date. PMID:26648749

  11. Safety and efficacy of calcium folinate in psoriasis: an observational study.

    PubMed

    Carlesimo, M; Mari, E; Arcese, A; De Angelis, F; Palese, E; Abruzzese, C; De Marco, G; Cattaruzza, M S; Camplone, G

    2010-01-01

    An association between psoriasis and cardiovascular diseases has been reported, and treatment of this condition is often considered difficult because the conventional systemic therapies often show several side effects. To assess the efficacy and tolerability of a new drug, folinate calcium, to treat psoriasis, a total of 58 patients affected by active psoriasis were enrolled in a variable period study. These patients had clinically stable, plaque psoriasis involving greater than or equal 6% body surface area. Thirty of these patients were treated with folinate calcium therapy, 15 mg orally once daily, for a variable period based on each patients clinical response. The comparison was made with 28 psoriatic patients treated with conventional systemic therapies (cyclosporine, acitretin, etanercept, efalizumab, infliximab, adalimumab). A clinical improvement was observed in both group, but in the first one we did not observe any side effects, whereas some important side effects were observed in the second. These preliminary results support the effectiveness and tolerability of folinate calcium treatment in psoriasis. PMID:20646362

  12. Promising biological therapies for ulcerative colitis: A review of the literature

    PubMed Central

    Akiho, Hirotada; Yokoyama, Azusa; Abe, Shuichi; Nakazono, Yuichi; Murakami, Masatoshi; Otsuka, Yoshihiro; Fukawa, Kyoko; Esaki, Mitsuru; Niina, Yusuke; Ogino, Haruei

    2015-01-01

    Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC. PMID:26600980

  13. A stonemason with accelerated silicosis in the setting of tumour necrosis factor alpha inhibitor therapy.

    PubMed

    Baird, Timothy; Putt, Michael; Dettrick, Andrew

    2016-09-01

    We present the case of a 26-year-old stonemason with accelerated silicosis in the setting of treatment for psoriasis with the tumour necrosis factor alpha (TNF-alpha) inhibitor adalimumab. Accelerated silicosis is an important occupational lung disease with a poor prognosis and limited treatment options [1]. Although the exact pathogenesis remains unknown, it is suggested that secretion of cytokines, including TNF-alpha, plays a central role in disease progression [1,2]. Importantly, however, TNF-alpha inhibitors, in addition to resulting in an increased risk of infection, are also now being seen to cause interstitial lung disease [3,4]. To our knowledge, this is the first documented patient to develop silicosis whilst on TNF-alpha inhibitor therapy. This case challenges the theory behind TNF-alpha's exact role in the pathogenesis of silicosis and lung fibrosis, highlights the importance of monitoring individuals with both occupational and drug exposures, and illustrates the increasing difficulties physicians face in investigating patients with pulmonary infiltrates and multiple possible aetiologies. PMID:27516887

  14. Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model.

    PubMed

    Li, Linzhong; Gardner, Iain; Dostalek, Miroslav; Jamei, Masoud

    2014-09-01

    Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data. PMID:25004823

  15. Efficacy of Anti-TNFα in Severe and Refractory Neuro-Behcet Disease

    PubMed Central

    Desbois, Anne Claire; Addimanda, Olga; Bertrand, Anne; Deroux, Alban; Pérard, Laurent; Depaz, Raphael; Hachulla, Eric; Lambert, Marc; Launay, David; Subran, Benjamin; Ackerman, Felix; Mariette, Xavier; Cohen, Fleur; Marie, Isabelle; Salvarini, Carlo; Cacoub, Patrice; Saadoun, David

    2016-01-01

    Abstract To report the safety and efficacy of anti-tumor necrosis factor α (TNFα) therapy in severe and refractory neuro-Behçet disease (NBD) patients. Observational, multicenter study including 17 BD patients (70.6% of male, with a median age of 39.3 [24–60] years), with symptomatic parenchymal NBD, refractory to previous immunosuppressant and treated with anti-TNFα (infliximab 5 mg/kg [n = 13] or adalimumab [n = 4]). Complete remission was defined by the disappearance of all neurological symptoms and by the improvement of radiological abnormalities at 12 months. Overall improvement following anti-TNF was evidenced in 16/17 (94.1%) patients including 6 (35.3%) complete response and 10 (58.8%) partial response. The median time to achieve remission was 3 months (1–6). The median Rankin score was 2 (1–4) at the initiation of anti-TNFα versus 1 (0–4) at the time of remission (P = 0.01). Corticosteroids have been stopped in 4 (23.5%) patients, and reduced by more than 50% as compared with the dosage at baseline in 10 (58.8%) patients. Side effects occurred in 23.5% of patients and required treatment discontinuation in 17% of cases. TNF blockade represents an effective therapeutic approach for patients with severe and refractory NBD, a difficult to treat population. PMID:27281066

  16. TNF inhibitor therapy for rheumatoid arthritis

    PubMed Central

    MA, XIXI; XU, SHENGQIAN

    2013-01-01

    Immunotherapy has markedly improved treatment outcomes in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-α antagonists, such as infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOLI) and certolizumab pegol (CZP) have been widely used for the treatment of RA. IFX provides significant, clinically relevant improvement in physical function and the quality of life, inhibits progressive joint damage and sustains improvement in the signs and symptoms of patients with RA. ETN is effective and safe for patients with RA. Combination therapy with ETN plus methotrexate (MTX) reduces disease activity, decreases total joint score progression, slows the pace of joint destruction and improves function more effectively compared to any of the monotherapies. ADA with or without MTX also relieves the signs and symptoms of RA. CZP and GOLI expand the therapeutic schedule for patients with RA. The TNF-α inhibitors have similar efficacy, but distinct clinical pharmacokinetic and -dynamic properties. The common adverse events of these TNF-α antagonists include adverse reactions, infections and injection-site reaction. Additionally, these adverse events are mostly mild or moderate and their incidence is low. Certain patients exhibit a lack of response to anti-TNF-α therapies. Some patients may discontinue the initial drug and switch to a second anti-TNF-α agent. The shortage of clinical response to one agent may not predict deficiency of response to another. This review mainly addresses the latest developments of these biological agents in the treatment of RA. PMID:24648915

  17. Biological therapy for dermatological manifestations of inflammatory bowel disease

    PubMed Central

    Zippi, Maddalena; Pica, Roberta; De Nitto, Daniela; Paoluzi, Paolo

    2013-01-01

    Ulcerative colitis and Crohn’s disease are the two forms of inflammatory bowel disease (IBD). The advent of biological drugs has significantly changed the management of these conditions. Skin manifestations are not uncommon in IBD. Among the reactive lesions (immune-mediated extraintestinal manifestations), erythema nodosum (EN) and pyoderma gangrenosum (PG) are the two major cutaneous ills associated with IBD, while psoriasis is the dermatological comorbidity disease observed more often. In particular, in the last few years, anti-tumor necrosis factor (TNF)-α agents have been successfully used to treat psoriasis, especially these kinds of lesions that may occur during the treatment with biological therapies. The entity of the paradoxical manifestations has been relatively under reported as most lesions are limited and a causal relationship with the treatment is often poorly understood. The reason for this apparent side-effect of the therapy still remains unclear. Although side effects may occur, their clinical benefits are undoubted. This article reviews the therapeutic effects of the two most widely used anti-TNF-α molecules, infliximab (a fusion protein dimer of the human TNF-α receptor) and adalimumab (a fully human monoclonal antibody to TNF-α), for the treatment of the major cutaneous manifestations associated with IBD (EN, PG and psoriasis). PMID:24303470

  18. Drug-induced lupus after treatment with infliximab in rheumatoid arthritis.

    PubMed

    Benucci, Maurizio; Li Gobbi, Francesca; Fossi, Fiammetta; Manfredi, Mariangela; Del Rosso, Angela

    2005-02-01

    We report a case of a 45-year-old man with an 8-month history of rheumatoid arthritis, who was treated with hydroxychloroquine 400 mg per day and 15 mg intramuscular methotrexate per week without reaching a good control of the disease. The patient was successfully treated with 3 mg/kg infliximab for 20 weeks. Before the last infusion, drug-induced lupus (DIL) was diagnosed based on the clinical features of fever > 37.5 degrees C, recurrence of active synovitis, myalgia, erythematosus rash, pericardial and pleural effusion, and of some laboratory findings (antinuclear antibodies 1:160 and anti double-strand DNA positive by DNA recombinant plasmid assay dsDNA). After infliximab discontinuation and the beginning of therapy with methylprednisolone, lupus symptoms resolved within 6 weeks. A new rheumatoid arthritis flare, occurring after 8 weeks, was controlled by methotrexate plus leflunomide. We also review the development of antinuclear and antidouble-strand DNA antibodies and drug-induced lupus in patients treated with anti-TNFalpha agents (infliximab, etanercept, and adalimumab). PMID:16357696

  19. Skin manifestations induced by TNF-alpha inhibitors in juvenile idiopathic arthritis.

    PubMed

    Pontikaki, Irene; Shahi, Edit; Frasin, Lucretia Adina; Gianotti, Raffaele; Gelmetti, Carlo; Gerloni, Valeria; Meroni, Pier Luigi

    2012-04-01

    The tumor necrosis factor alpha (TNFα) inhibitors have been used with good clinical results in the treatment of juvenile idiopathic arthritis (JIA). Anti TNFα therapy is generally well tolerated. Besides the site injection reactions, other various cutaneous manifestations have been encountered as adverse events. Here, we report four young patients receiving treatment with anti-TNFα (infliximab, adalimumab, and etanercept) for JIA developing different skin manifestations more than 1 year after the initiation of therapy. They underwent a dermatological exam. All four patients were ACR-Ped 30 responders to anti-TNF drugs. The first patient developed cutaneous vasculitis, the second one had lichen planus manifestations, while the third and the fourth developed psoriatic palmoplantar pustulosis accompanied by plaque-type psoriasis localized to the scalp. None of the patients had a personal or family history of dermatological diseases. In the first two patients, skin lesions healed with topical treatment after the discontinuation of anti-TNF agent, while psoriatic lesions did not resolve despite discontinuation of the drug and dermatological treatment. TNF inhibition can be both anti-inflammatory and pro-inflammatory. Cutaneous manifestations could be considered as a paradoxical adverse event of the anti-TNF-alpha treatment not only in rheumatoid arthritis but also in juvenile idiopathic arthritis. PMID:21403999

  20. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists.

    PubMed

    Hawryluk, Elena B; Linskey, Katy R; Duncan, Lyn M; Nazarian, Rosalynn M

    2012-05-01

    Biologic therapies targeting tumor necrosis factor (TNF)-alpha have become a mainstay in the management of a number of autoimmune diseases. We report a series of adverse skin eruptions in six patients (four females, two males, age: 21-58 years, mean: 39) receiving 4 months to 10 years (mean 3.1 years) of anti-TNF-alpha therapies (infliximab, n = 4; adalimumab, n = 1 or etanercept, n = 1). The following drug-associated diagnoses were made in eight skin biopsies performed at Massachusetts General Hospital between 3/2007 and 10/2010: pustular folliculitis, psoriasis, interface dermatitis, neutrophilic eccrine hidradenitis, Sweet's syndrome, lupus, vasculitis and palmoplantar pustulosis. The descriptions of neutrophilic eccrine hidradenitis-like and Sweet's-like hypersensitivity eruptions induced by anti-TNF-alpha therapies are the first such cases described in the literature. Each cutaneous eruption improved or resolved with switching to a different TNF-alpha inhibitor, discontinuation of the anti-TNF-alpha agent, and/or topical or systemic steroids. There was a clear chronologic relationship with, and clinical remission upon withdrawal or steroid suppression of the anti-TNF-alpha agents. The mechanism for such diverse cutaneous eruptions among this class of medications remains poorly understood. The cutaneous adverse reaction profile of TNF-alpha inhibitors is broad and should be considered in the histopathologic differential in this clinical setting. PMID:22515220

  1. Novel therapies for FSGS: preclinical and clinical studies.

    PubMed

    Malaga-Dieguez, Laura; Bouhassira, Diana; Gipson, Debbie; Trachtman, Howard

    2015-03-01

    Focal segmental glomerulosclerosis (FSGS) is a rare but important cause of end-stage kidney disease in children and adults. Current therapy, consisting of corticosteroids and calcineurin inhibitors, fails to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop new treatments for this glomerulopathy. Traditional approaches have focused on agents that modulate the immune system. In this review, we summarize preclinical and clinical data with newer agents that may ameliorate FSGS. We focus on drugs that inhibit immune injury or inflammation, such as abatacept, rituximab, adalimumab, and stem cells. The potential of agents that block the glomerular action of circulating permeability factors such as soluble urokinase receptor is reviewed. Finally, because fibrosis represents the final common pathway of glomerular damage in FSGS, the experience with a wide range of antifibrotic agents is presented. Despite extensive research on the podocyte dysfunction in the pathogenesis of FSGS, there are few agents that directly target podocyte structure or viability. We conclude that FSGS is a heterogeneous disorder and that intensified translational research is vital to improve our understanding of distinct subtypes that have a defined prognosis and predictable response to targeted therapeutic interventions. PMID:25704355

  2. Investigational new drugs in the treatment of inflammatory bowel disease: a review

    PubMed Central

    Williams, Imogen; Goh, Jason

    2011-01-01

    The unraveling of the immuno-pathobiology of inflammatory bowel disease (IBD) in the past three decades has ushered in a new era of translational medicine. The biotechnology revolution has resulted in a paradigm shift in how clinicians view and treat IBD. Anti-tumor necrosis factor (TNF)-α strategies using infliximab and adalimumab currently dominate the therapeutic arena. Better understanding of how these biologicals work is driving the quest for loftier therapeutic goals of achieving mucosal healing, sustaining deep remission, and even modifying the natural history of IBD. However, not all patients respond to anti-TNF drugs. Immune-mediated adverse reactions and loss of efficacy with time also limit their use. There are many investigational drugs undergoing active clinical trials. Many have not fulfilled their early promises but some are potentially making the transition from bench to trial and to the bedside in the near future. Clinicians and investigators need to underpin our excitement with caution for the unknown long-term consequences of modulating cytokines and selective adhesion molecules in human. Here we provide an overview of investigational new drugs and other therapeutic strategies currently undergoing clinical trials in IBD. PMID:27186106

  3. Janus kinase inhibitors for rheumatoid arthritis.

    PubMed

    Yamaoka, Kunihiro

    2016-06-01

    Treatment of autoimmune diseases, such as rheumatoid arthritis (RA), has advanced substantially over the past decade with the development of biologics targeting inflammatory cytokines. Recent progress in treating RA has been achieved with janus kinase (JAK) inhibitors (Jakinibs), an orally available disease-modifying anti-rheumatic drug targeting the intracellular kinase JAK and with similar efficacy to biologics. The first Jakinib approved for RA was tofacitinib, which exerted superiority to methotrexate and non-inferiority to tumor necrosis factor (TNF) inhibitors. In recent years, the Jakinib baricitinib has demonstrated superiority to both methotrexate and a TNF inhibitor, adalimumab. Given these promising findings, Jakinibs are expected to represent the next generation compounds for treating RA, and a number of Jakinibs are currently in clinical trials. Jakinibs can differ substantially in their selectivity against JAKs; tofacitinib and baricitinib target multiple JAKs, whereas the most recently developed Jakinibs target only a single JAK. The influence of Jakinib selectivity on efficacy and side effects is of great interest, requiring further careful observation. PMID:26994322

  4. Inflammatory bowel disease surgery in the biologic era.

    PubMed

    Ferrari, Linda; Krane, Mukta K; Fichera, Alessandro

    2016-05-27

    Anti-tumour necrosis factor (TNF)-α therapy has revolutionized inflammatory bowel disease (IBD) treatment. Infliximab and adalimumab either as monotherapy or in combination with an immunomodulator are able to induce clinical and biological remission in patients with moderate and severe Crohn's disease (CD) and ulcerative colitis (UC). These new therapies have led to a shift in the goals of IBD management from just controlling clinical symptoms to preventing disease progression. However, despite these advances in medical therapy, surgery is still required in 30%-40% of patients with CD and 20%-30% of patients with UC at some point during their lifetime. While biologics certainly play a major role in the medical treatment of IBD, there is concern about the effects of these anti-TNF-α agents on postoperative complications and morbidity. The purpose of this article is to review the role of surgery in the treatment of IBD in the age of biologics and the impact of these medications on per-operative outcomes. In this manuscript we review the relationship between biologic agents and surgery in the treatment of IBD. We also discuss in detail the periopetative risks and complications. PMID:27231514

  5. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2002-12-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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, adalimumab, AERx morphine sulphate, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, almotriptan, amprenavir, aripiprazole, atenolol, atorvastatin calcium; BSYX-A110; Cantuzumab mertansine, capravirine, CDP-571, CDP-870, celecoxib; Delavirdine mesilate, docetaxel, dofetilide, donepezil hydrochloride, duloxetine hydrochloride, dutasteride, dydrogesterone; Efavirenz, emtricitabine, enjuvia, enteryx, epristeride, erlotinib hydrochloride, escitalopram oxalate, etanercept, etonogestrel, etoricoxib; Fesoterodine, finasteride, flt3ligand; Galantamine hydrobromide, gemtuzumab ozogamicin, genistein, gepirone hydrochloride; Indinavir sulfate, infliximab; Lamivudine, lamivudine/zidovudine/abacavir sulfate, leteprinim potassium, levetiracetam, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, losartan potassium; MCC-465, MRA; Nebivolol, nesiritide, nevirapine; Olanzapine, OROS(R)-Methylphenidate hydrochloride; Peginterferon alfa-2a, peginterferon alfa-2b, Pimecrolimus, polyethylene glycol 3350, pramlintide acetate, pregabalin, PRO-2000; Risedronate sodium, risperidone, ritonavir, rituximab, rivastigmine tartrate, rofecoxib, rosuvastatin calcium; Saquinavir mesilate, Stavudine; Tacrolimus, tadalafil, tamsulosin hydrochloride, telmisartan, tomoxetine hydrochloride, treprostinil sodium, trimegestone, trimetrexate; Valdecoxib, venlafaxine hydrochloride; Zoledronic acid monohydrate. PMID:12616965

  6. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-12-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been 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: Abetimus sodium, adalimumab, alefacept, alemtuzumab, almotriptan, AMGN-0007, anakinra, anti-CTLA-4 Mab, L-arginine hydrochloride, arzoxifene hydrochloride, astemizole, atazanavir sulfate, atlizumab; Belimumab, BG-9928, binodenoson, bosentan, botulinum toxin type B, bovine lactoferrin, BufferGel; Caspofungin acetate, ciclesonide,cilomilast, ciluprevir, clofarabine, CVT-3146; Darbepoetin alfa, desloratadine, diflomotecan, doripenem, dronedarone hydrochloride, drotrecogin alfa (activated), DT388-GM-CSF, duloxetine hydrochloride, E-5564, efalizumab, enfuvirtide, esomeprazole magnesium, estradiol acetate, ETC-642, exenatide, exisulind, ezetimib; Febuxostat; Gallium maltolate, ganirelix acetate, garenoxacin mesilate, gefitinib; H11, HuMax; IL-15, IDD-1, IGIV-C, imatinib mesylate, ISIS-14803, ITF-1697, ivabradine hydrochloride; KRN-5500; L-365260, levetiracetam, levosimendan, licofelone, linezolid, LJP-1082, lopinavir lumiracoxib; MCC-478, melatonin, morphine hydrochloride, morphine-6-glucuronide, moxidectin; N-Acetylcarnosine, natalizumab, NM-702, NNC-05-1869, NSC-703940; Ocinaplon OM-89, omalizumab, omeprazole/ sodium bicarbonate, OPC-28326, ospemifene; PEG-filgrastim peginterferon alfa-2a, pegsunercept, pirfenidone, pralmorelin, pregabalin; Recombinant glucagon-like peptide-1 (7-36) amide, repifermin, RSD-1235; S-8184, selodenoson, sodium dichloroacetate, suberanilohydroxamic acid; TAS-102, terfenadine, teriparatide, tipranavir troxacitabine; Ximelagatran; YM-337. PMID:14735233

  7. Gateways to clinical trials. March 2003.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2003-03-01

    Gateways to clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and devlopment protal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AAV-CF, adalimumab, ademetionine, afeletecan hydrochloride, agomelatine, alemtuzumab, almotriptan, amdoxovir, aplidine, aranose, arsenic sulfide, atazanavir, atlizumab; Bimatoprost, BMS-181176, BMS-188667, bortezomib, bryostatin 1; Combretastatin A-4 phosphate; Darbepoetin alfa, darusentan, deferasirox, desloratadine, DTaP-HBV-IPV/Hib-vaccine, DTI-0009; Eculizumab, edodekin alfa, emtricitabine, enfuvirtide, epoetin, esomeprazole magnesium etoricoxib; Fampridine, fenretinide, FR-146687; Galiximab, gamma-Hydroxybutyrate sodium, ganirelix acetate, gefitinib, Gemtuzumab ozogamicin, gimatecan; HEA125xOKT3, hIL-13-PE38QQR, HSV-2 theracine, Hu14.18-IL-2, human gammaglobulin; Idraparinux sodium, imatinib mesylate, IMiD3, insulin detemir, interleukin-4, irofulven, ISAtx-247; JT-1001; Levetiracetam, levosimendan, liposomal doxorubicin, liposomal vincristine sulfate, lixivaptan, lopinavir, lumiracoxib; Maxacalcitol, melatonin, midostaurin, MLN-518; Neridronic acid, nesiritide, nitronaproxen; Oblimersen sodium, oregovomab; PEG-filgrastim polyglutamate paclitaxel, prasterone, pregabalin; Rosuvastatin calcium, rotigotine hydrochloride; SGN-30; T-1249, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipranavir, TMC-114, trabectedin, transdermal selegiline; UK-427857; Valdecoxib, valganciclovir hydrochloride, vardenafil, vatalanib succinate, vincristine sulfate TCS; Zofenopril calcium. PMID:12731460

  8. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-11-01

    5-Methyltetrahydrofolate, (R)-flurbiprofen; Ad5CMV-p53, adalimumab, alefacept, alemtuzumab, Alequel, alicaforsen sodium, almotriptan, anakinra, aprepitant, aripiprazole, armodafinil; Bevacizumab, bortezomib, bosentan; Canfosfamide hydrochloride, ciclesonide, clofarabine, Cypher; Darbepoetin alfa, diclofenac potassium, drotrecogin alfa (activated), duloxetine hydrochloride; Eel calcitonin, eletriptan, eplerenone, everolimus, ezetimibe; Frovatriptan; Gefitinib, gamma-hydroxybutyrate sodium; HKI-272, HYB-165; Ibutamoren mesylate, imatinib mesylate, interleukin-21, ixabepilone; KRN-951; L-Arginine hydrochloride, levodopa/carbidopa/entacapone; Micafungin sodium, motexafin gadolinium, mycophenolic acid sodium salt; Nesiritide; Peginterferon alfa-2a, pitavastatin calcium, pralatrexate, pregabalin, pVAX/L523S-Ad.L523S; Rasagiline mesylate, recombinant human nerve growth factor, regadenoson, rF-PSA, rimonabant, rizatriptan, rofecoxib, rosuvastatin calcium, rV-B7.1, rV-PSA; Sipuleucel-T, sirolimus-eluting stent, solifenacin succinate, sorafenib, sunitinib malate; Talactoferrin alfa, Taxus, tegaserod maleate, teriparatide, tipifarnib; Valdecoxib, vandetanib, vatalanib succinate; WT1-peptide vaccine; Xaliproden hydrochloride. (c) 2006 Prous Science. All rights reserved. PMID:17200730

  9. Osteoarthritis year in review 2015: clinical.

    PubMed

    Sharma, L

    2016-01-01

    The purpose of this review is to highlight clinical research in osteoarthritis (OA). A literature search was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) with the search terms "osteoarthritis [All Fields] AND treatment [All Fields]" and the following limits activated: humans, English language, all adult 19+ years, published between April 1, 2014 and April 1, 2015. A second literature search was then conducted with the search terms "osteoarthritis [All Fields] AND epidemiology [All Fields]", with the same limits. Reports of surgical outcome, case series, surgical technique, tissue sample or culture studies, trial protocols, and pilot studies were excluded. Of 1523, 150 were considered relevant. Among epidemiologic and observational clinical studies, themes included physical activity, early knee OA, and confidence/instability/falls. Symptom outcomes of pharmacologic treatments were reported for methotrexate, adalimumab, anti-nerve growth factor monoclonal antibodies, strontium ranelate, bisphosphonates, glucosamine, and chondroitin sulfate, and structural outcomes of pharmacologic treatments for strontium ranelate, recombinant human fibroblast growth factor 18, and glucosamine and chondroitin sulfate. Symptom outcomes of non-pharmacologic interventions were reported for: neuromuscular exercise, quadriceps strengthening, weight reduction and maintenance, TENS, therapeutic ultrasound, stepped care strategies, cognitive behavior therapy for sleep disturbance, acupuncture, gait modification, booster physical therapy, a web-based therapeutic exercise resource center for knee OA; hip physical therapy for hip OA; and joint protection and hand exercises for hand OA. Structure outcomes of non-pharmacologic interventions were reported for patellofemoral bracing. PMID:26707991

  10. When Good Intentions Go Awry: Modification of a Recombinant Monoclonal Antibody in Chemically Defined Cell Culture by Xylosone, an Oxidative Product of Ascorbic Acid.

    PubMed

    Chumsae, Chris; Hossler, Patrick; Raharimampionona, Haly; Zhou, Yu; McDermott, Sean; Racicot, Chris; Radziejewski, Czeslaw; Zhou, Zhaohui Sunny

    2015-08-01

    With the advent of new initiatives to develop chemically defined media, cell culture scientists screen many additives to improve cell growth and productivity. However, the introduction or increase of supplements, typically considered beneficial or protective on their own, to the basal media or feed stream may cause unexpected detrimental consequences to product quality. For instance, because cultured cells are constantly under oxidative stress, ascorbic acid (vitamin C, a potent natural reducing agent) is a common additive to cell culture media. However, as reported herein, a recombinant monoclonal antibody (adalimumab) in cell culture was covalently modified by xylosone (molecular weight 148), an oxidative product of ascorbate. Containing reactive carbonyl groups, xylosone modifies various amines (e.g., the N-termini of the heavy and light chains and susceptible lysines), forming either hemiaminal (+148 Da) or Schiff base (imine, +130 Da) products. Our findings show, for the first time, that ascorbate-derived xylosone can contribute to an increase in molecular heterogeneity, such as acidic species. Our work serves as a reminder that additives to cell culture and their metabolites may become reactive and negatively impact the overall product quality and should be carefully monitored with any changes in cell culture conditions. PMID:26151084

  11. Update on the management of chronic eczema: new approaches and emerging treatment options

    PubMed Central

    Walling, Hobart W; Swick, Brian L

    2010-01-01

    Atopic dermatitis (AD) is a common disease with worldwide prevalence, affecting up to 20% of children and 3% of adults. Recent evidence regarding pathogenesis has implicated epidermal barrier defects deriving from filagrin mutations with resulting secondary inflammation. In this report, the authors comprehensively review the literature on atopic dermatitis therapy, including topical and systemic options. Most cases of AD will benefit from emollients to enhance the barrier function of skin. Topical corticosteroids are first-line therapy for most cases of AD. Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) are considered second line therapy. Several novel barrier-enhancing prescription creams are also available. Moderate to severe cases inadequately controlled with topical therapy may require phototherapy or systemic therapy. The most commonly employed phototherapy modalites are narrow-band UVB, broadband UVB, and UVA1. Traditional systemic therapies include short-term corticosteroids, cyclosporine (considered to be the gold standard), methotrexate, azathioprine, mycophenolate mofetil, and most recently leflunamide. Biologic therapies include recombinant monoclonal antibodies acting on the immunoglobulin E / interleukin-5 pathway (omalizumab, mepolizumab), acting as tumor necrosis factor-α inhibitors (infliximab, etanercept, adalimumab), and acting as T-cell (alefacept) and B-cell (rituxumab) inhibitors, as well as interferon γ and intravenous immunoglobulin. Efficacy, safety, and tolerability are reviewed for each medication. PMID:21437065

  12. Hepatitis B in HIV patients: what is the current treatment and what are the challenges?

    PubMed

    Soriano, Vincent; Tuma, Paula; Vispo, Eugenia; Labarga, Pablo; Fernández, José Vicente; Medrano, José; Barreiro, Pablo

    2009-03-01

    Chronic hepatitis B affects 5-10% of HIV patients in Western countries. Lamivudine should no longer be used as a single anti-HBV agent in HIV-HBV co-infected patients, given its limited antiviral potency and high risk of selection of resistance, which further results in wide cross-resistance to all other nucleoside analogues. Recent reports of transmission of lamivudine-resistant HBV in HIV patients are of especial concern, and large surveillance studies suggest that it may occur in up to 10% of new HBV infections in Western countries. Another worrisome aspect of the selection of lamivudine-resistant HBV is the potential for selection of vaccine escape mutants. Currently, tenofovir must be viewed as the drug of choice in HIV-HBV co-infected patients in whom antiretroviral therapy is advised. Its co-formulation with emtricitabine (Truvada) is particularly convenient for treating both HIV and HBV in co-infected individuals. While pegIFN-alpha monotherapy for 1 year may be considered for HIV-HBV coinfected individuals with good spontaneous HIV control (elevated CD4 cell count, low plasma HIV-RNA), and certain HBV features (genotype A, HBeAg+, low serum HBV-DNA and elevated ALT), it is clear that very few coinfected patients fulfill these criteria. In HBeAg-negative HIV patients, adefovir may be an option but the relatively low antiviral potency of this drug discourages its wide use. Given its potential anti-HIV activity, both entecavir and telbivudine must only be prescribed with antiretroviral agents. Lack of information about potential pharmacodynamic interactions between entecavir and abacavir (both are guanosine analogues) or between telbivudine and zidovudine or stavudine (all are thymidine analogues) further discourages their concomitant use. At this time, most experts agree that early introduction of anti-HBV active HAART is the best strategy for the treatment of chronic hepatitis B in HIV patients, and Truvada must be part of the triple regimen. PMID:19731560

  13. In search of a selective antiviral chemotherapy.

    PubMed Central

    De Clercq, E

    1997-01-01

    This article describes several approaches to a selective therapy of virus infections: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU [brivudin]) for the therapy of herpes simplex virus type 1 and varicella-zoster virus infections: (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC [cidofovir]) for the therapy of various DNA virus (i.e., herpesvirus, adenovirus, papillomavirus, polyomavirus, and poxvirus) infections; 9-(2-phosphonylmethoxyethyl)adenine (PMEA [adefovir]) for the therapy of retrovirus, hepadnavirus, and herpesvirus infections; (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for the therapy and prophylaxis of retrovirus and hepadnavirus infections; and nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(IH)-one and -thione (TIBO), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), alpha-anilinophenylacetamide (alpha-APA), and 2',5'bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxat hiole- 2",2"-dioxide)pyrimidine (TSAO) derivatives, and thiocarboxanilides for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. For the clinical use of NNRTIs, some guidelines have been elaborated, such as starting treatment with combinations of different compounds at sufficiently high concentrations to effect a pronounced and sustained suppression of the virus. Despite the diversity of the compounds described here and the different viruses at which they are targeted, they have a number of characteristics in common. As they interact with specific viral proteins, the compounds achieve a selective inhibition of the replication of the virus, which, in turn, should be able to develop resistance to the compounds. However, as has been established for the NNRTIs, the problem of viral resistance may be overcome if the compounds are used from the start at sufficiently high doses, which could be reduced if different compounds are combined. For HIV infections, drug treatment

  14. Pretransplant Hepatitis B Viral Infection Increases Risk of Death After Kidney Transplantation

    PubMed Central

    Lee, Jeonghwan; Cho, Jang-Hee; Lee, Jong Soo; Ahn, Dong-Won; Kim, Chan-Duck; Ahn, Curie; Jung, In Mok; Han, Duck Jong; Lim, Chun Soo; Kim, Yon Su; Kim, Young Hoon; Lee, Jung Pyo

    2016-01-01

    Abstract Clinical outcomes in kidney transplant recipients (KTRs) with hepatitis B virus (HBV) have not been thoroughly evaluated. Here, we investigated recent posttransplant clinical outcomes of KTRs with HBV and compared them with KTRs with hepatitis C virus (HCV) and seronegative KTRs. Of 3855 KTRs from April 1999 to December 2011, we enrolled 3482 KTRs who had viral hepatitis serology data; the patients were followed up for 89.1 ± 54.1 months. The numbers of recipients with HBV and HCV were 160 (4.6%) and 55 (1.6%), respectively. We analyzed the clinical outcomes, including overall mortality and graft failure, among patients who had undergone kidney transplantation. Patients with HBV showed poorer survival (P = 0.019; adjusted hazard ratio [HR] = 2.370; 95% confidence interval [CI]: 1.155–4.865) than KTRs without HBV. However, the graft survival of patients with chronic hepatitis B did not differ from that of patients without HBV. Hepatic complications were the primary causes of mortality of KTRs with HBV. Mortality significantly correlated with a higher grade of inflammation (P = 0.002) and with the use of lamivudine or adefovir antiviral treatment (P = 0.016). HBV-positive KTRs treated with the new-generation antiviral agent entecavir showed improved patient survival compared with KTRs receiving lamivudine (log-rank P = 0.050). HCV did not affect patient survival; however, it increased the incidence of graft failure (P = 0.010; adjusted HR = 2.899; 95% CI: 1.289–6.519). KTRs with HCV had an increased incidence of acute rejection (log-rank P = 0.005, crude HR = 2.144; 95% CI: 1.341–3.426; P = 0.001). KTRs with chronic hepatitis B may exhibit poor survival due to post-transplantation hepatic complications. Pretransplant histological liver evaluations and adequate antiviral management with potent nucleoside/nucleotide analogues are needed to improve the survival of KTRs with chronic hepatitis B even when liver

  15. Medical management of chronic liver diseases in children (part I): focus on curable or potentially curable diseases.

    PubMed

    El-Shabrawi, Mortada H F; Kamal, Naglaa M

    2011-12-01

    The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic

  16. Thiopurines related malignancies in inflammatory bowel disease: Local experience in Granada, Spain

    PubMed Central

    Gómez-García, María; Cabello-Tapia, Maria José; Sánchez-Capilla, Antonio Damián; De Teresa-Galván, Javier; Redondo-Cerezo, Eduardo

    2013-01-01

    AIM: To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines. METHODS: We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, χ2 test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios. RESULTS: Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 ± 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 ± 55.7 mo (range: 1-300 mo) and the accumulated dose along this time was 274.32 ± 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 ± 23.9 mg/d (range: 25-150 mg/d), mean usage time of 23.37 ± 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 ± 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines

  17. Current concepts in the management of rheumatoid arthritis

    PubMed Central

    Tanaka, Yoshiya

    2016-01-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and “deep remission” at the discontinuation was a key factor to keep the treatment holiday of biological DMARD. PMID:26932398

  18. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

    PubMed Central

    Pasadhika, Sirichai; Rosenbaum, James T

    2014-01-01

    Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. PMID:24600203

  19. Predictive factors of radiological progression after 2 years of remission-steered treatment in early arthritis patients: a post hoc analysis of the IMPROVED study

    PubMed Central

    Akdemir, Gülşah; Verheul, Marije K; Heimans, Lotte; Wevers-de Boer, Kirsten V C; Goekoop-Ruiterman, Yvonne P M; van Oosterhout, Maikel; Harbers, Joop B; Bijkerk, Casper; Steup-Beekman, Gerda M; Lard, Leroy R; Huizinga, Tom W J; Trouw, Leendert A; Allaart, Cornelia F

    2016-01-01

    Objectives To identify predictive factors of radiological progression in early arthritis patients treated by remission-steered treatment. Methods In the IMPROVED study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (disease activity score (DAS) <1.6 after 4 months) tapered prednisone to zero. Patients not in early remission were randomised to arm 1: MTX plus hydroxychloroquine, sulfasalazine and prednisone, or to arm 2: MTX plus adalimumab. Predictors of radiological progression (≥0.5 Sharp/van der Heijde score; SHS) after 2 years were assessed using logistic regression analysis. Results Median (IQR) SHS progression in 488 patients was 0 (0–0) point, without differences between RA or UA patients or between treatment arms. In only 50/488 patients, the SHS progression was ≥0.5: 33 (66%) were in the early DAS remission group, 9 (18%) in arm 1, 5 (10%) in arm 2, 3 (6%) in the outside of protocol group. Age (OR (95% CI): 1.03 (1.00 to 1.06)) and the combined presence of anticarbamylated protein antibodies (anti-CarP) and anticitrullinated protein antibodies (ACPA) (2.54 (1.16 to 5.58)) were independent predictors for SHS progression. Symptom duration <12 weeks showed a trend. Conclusions After 2 years of remission steered treatment in early arthritis patients, there was limited SHS progression in only a small group of patients. Numerically, patients who had achieved early DAS remission had more SHS progression than other patients. Positivity for both anti-CarP and ACPA and age were independently associated with SHS progression. Trial registration numbers ISRCTN Register number 11916566 and EudraCT number 2006 06186-16. PMID:26925251

  20. Biologic agents in juvenile spondyloarthropathies.

    PubMed

    Katsicas, María Martha; Russo, Ricardo

    2016-01-01

    The juvenile spondyloarthropathies (JSpA) are a group of related rheumatic diseases characterized by involvement of peripheral large joints, axial joints, and entheses (enthesitis) that begin in the early years of life (prior to 16(th) birthday).The nomenclature and concept of spondyloarthropathies has changed during the last few decades. Although there is not any specific classification of JSpA, diseases under the spondyloarthropathy nomenclature umbrella in the younger patients include: the seronegative enthesitis and arthropathy (SEA) syndrome, juvenile ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease-associated arthritis. Moreover, the ILAR criteria for Juvenile Idiopathic Arthritis includes two categories closely related to spondyloarthritis: Enthesitis-related arthritis and psoriatic arthritis.We review the pathophysiology and the use of biological agents in JSpA. JSpA are idiopathic inflammatory diseases driven by an altered balance in the proinflammatory cytokines. There is ample evidence on the role of tumor necrosis factor (TNF) and interleukin-17 in the physiopathology of these entities. Several non-biologic and biologic agents have been used with conflicting results in the treatment of these complex diseases. The efficacy and safety of anti-TNF agents, such as etanercept, infliximab and adalimumab, have been analysed in controlled and uncontrolled trials, usually showing satisfactory outcomes. Other biologic agents, such as abatacept, tocilizumab and rituximab, have been insufficiently studied and their role in the therapy of SpA is uncertain. Interleukin-17-blocking agents are promising alternatives for the treatment of JSpA patients in the near future. Recommendations for the treatment of patients with JSpA have recently been proposed and are discussed in the present review. PMID:26968522

  1. Survival of disease-modifying antirheumatic drugs used as the first antirheumatic medication in the treatment of ankylosing spondylitis in Finland. A nationwide population-based register study.

    PubMed

    Relas, Heikki; Kautiainen, Hannu; Puolakka, Kari; Virta, Lauri J; Leirisalo-Repo, Marjatta

    2014-08-01

    The tight national drug reimbursement regulations in the treatment of ankylosing spondylitis (AS) in Finland lead to the practice that at least one traditional disease-modifying antirheumatic drug (DMARD), if not contraindicated, has been tried and has failed before a patient can be eligible for reimbursement of anti-tumour necrosis factor (TNF) treatment. The aim of the present study is to evaluate drug survival of the firstly prescribed DMARDs in patients with AS. All AS patients from January 1, 2000 to December 31, 2007 were collected from the nationwide drug reimbursement registry maintained by the Social Insurance Institution (SII). Data on antirheumatic medication came from the prescription registry of SII. A total of 2,890 AS patients (60 % males) were identified. Sulfasalazine (SSA) monotherapy was the most common first antirheumatic treatment (2,319 patients, 87 %), followed by methotrexate (MTX) monotherapy (230 patients, 9 %) and by hydroxychloroquine monotherapy (77 patients, 3 %). A combination of two or more DMARDs was used by 44 patients (2 %). Only seven patients (0.3 %) had biological (etanercept or adalimumab) started as the first antirheumatic drug. Median survival time of SSA monotherapy was 4.5 years (95 % CI 4.2 to 4.8) and that of MTX was 1.9 years (95 % CI 1.5 to 2.1). SSA is almost the standard as the first antirheumatic treatment of AS in Finland. Although the clinical efficiency of SSA was not evaluable in the present study, these data suggest that the use of SSA can at least postpone the need and start of TNF inhibitors with marked economic consequences. PMID:24907035

  2. Fecal transplantation - the new, inexpensive, safe, and rapidly effective approach in the treatment of gastrointestinal tract diseases.

    PubMed

    Oprita, R; Bratu, M; Oprita, B; Diaconescu, B

    2016-01-01

    Introduction. Fecal transplantation was shown to effectively reduce the reoccurrence in patients with refractory Clostridium difficile infection. New data suggest that fecal transplantation could also be efficient in other gastrointestinal diseases, for instance in inflammatory bowel disease, irritable bowel syndrome, but, there are also some data that could imply the efficacy outside the gastrointestinal tract. Fecal transplantation should be considered a unique agent, capable of treating severe diseases, with essentially no adverse reactions, presenting a cure rate of over 90%. Materials and methods. This prospective study included 33 patients, of whom 28 patients with recurrent or resistant Clostridium difficile infection, who failed to be treated with conventional therapy, which presupposed vancomycin administration and 5 patients with inflammatory bowel disease, more precisely with ulcerative colitis, refractory on biologic agents (infliximab and adalimumab). In most of the cases, fecal transplant was realized with the infusion of stool through colonoscopy. Results. Most of the patients from both groups (Clostridium difficile infection and Ulcerative Colitis) responded (31 patients) with a total relief of the symptoms, after 1 FMT for Clostridium difficile group and after more than one for the ulcerative colitis group. The so-called primary cure rate was 96.42% for Clostridium group. For ulcerative colitis, group 3 of the patients needed 3 or 4 infusions for symptom relief. One patient was categorized as non-responsive (patient with UC) and needed surgery. Due to non-fecal transplant related causes, one death was reported. Conclusions. Fecal transplant is highly effective, safe, with practically no adverse effects, inexpensive, a procedure easy to be done that could be introduced in Clostridium difficile treatment protocols. As for ulcerative colitis treatment with FMT, future randomized controlled trials are needed to prove its efficiency. PMID:27453747

  3. The Impact of Preoperative Serum anti-TNFα Therapy Levels on Early Postoperative Outcomes in Inflammatory Bowel Disease Surgery

    PubMed Central

    Lau, Cheryl; Dubinsky, Marla; Melmed, Gil; Vasiliauskas, Eric; Berel, Dror; McGovern, Dermot; Ippoliti, Andrew; Shih, David; Targan, Stephan; Fleshner, Phillip

    2016-01-01

    Objective Assess the impact of preoperative serum anti-TNFα drug levels on 30-day postoperative morbidity in inflammatory bowel disease patients. Summary Background Data Studies on the association of anti-TNFα drugs and postoperative outcomes in IBD are conflicting due to variable pharmacokinetics of anti-TNFα drugs.. It remains to be seen whether preoperative serum anti-TNFα drug levels correlate with postoperative morbidity. Methods 30 days postoperative outcomes of consecutive IBD surgical patients with serum drawn within 7 days pre-operatively, were studied. The total serum level of 3 anti-TNF-α drugs (infliximab, adalimumab, certolizumab) was measured, with ≥0.98 µg/ml considered as detected. Data was also reviewed according to a clinical cut off value of 3 µg/ml. Results 217 patients (123 Crohn’s disease (CD) and 94 ulcerative colitis (UC)) were analyzed. 75 of 150 (50%) treated with anti-TNFα therapy did not have detected levels at the time of surgery. In the UC cohort, adverse postoperative outcomes rates between the undetectable and detectable groups were similar when stratified according to type of UC surgery. In the CD cohort, there was a higher but statistically insignificant rate of adverse outcomes in the detectable vs undetectable groups. Using acut-off level of 3 µg/ml, postoperative morbidity (OR=2.5, p=0.03) and infectious complications (OR=3.0, p=0.03) were significantly higher in the ≥ 3 µg/ml group. There were higher rates of postoperative morbidity (p=0.047) and hospital readmissions (p=0.04) in the ≥ 8 µg/ml compared to < 3 µg/ml group. Conclusion Increasing preoperative serum anti-TNFα drug levels are associated with adverse postoperative outcomes in CD but not UC patients. PMID:24950263

  4. IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans[S

    PubMed Central

    Müller, Nike; Schulte, Dominik M.; Türk, Kathrin; Freitag-Wolf, Sandra; Hampe, Jochen; Zeuner, Rainald; Schröder, Johann O.; Gouni-Berthold, Ioanna; Berthold, Heiner K.; Krone, Wilhelm; Rose-John, Stefan; Schreiber, Stefan; Laudes, Matthias

    2015-01-01

    Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans had no effect. The specificity of IL-6 in regulating Lp(a) was further demonstrated by serological measurements of human subjects (n = 1,153) revealing that Lp(a) levels are increased in individuals with elevated serum IL-6. Transcriptomic analysis of human liver biopsies (n = 57) revealed typical IL-6 response genes being correlated with the LPA gene expression in vivo. On a molecular level, we found that TCZ inhibited IL-6-induced LPA mRNA and protein expression in human hepatocytes. Furthermore, examination of IL-6-responsive signal transducer and activator of transcription 3 binding sites within the LPA promoter by reporter gene assays, promoter deletion experiments, and electrophoretic mobility shift assay analysis showed that the Lp(a)-lowering effect of TCZ is specifically mediated via a responsive element at −46 to −40. Therefore, IL-6 blockade might be a potential therapeutic option to treat elevated Lp(a) serum concentrations in humans and might be a noninvasive alternative to lipid apheresis in the future. PMID:25713100

  5. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn’s disease treated with anti-tumor necrosis factor antibodies

    PubMed Central

    Eder, Piotr; Michalak, Michal; Katulska, Katarzyna; Lykowska-Szuber, Liliana; Krela-Kazmierczak, Iwona; Stawczyk-Eder, Kamila; Klimczak, Katarzyna; Szymczak, Aleksandra; Linke, Krzysztof

    2015-01-01

    The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies - infliximab (IFX), adalimumab (ADA) in Crohn’s disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17 - were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4 – 25) and 2.4 (95% CI 1.2 – 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1 – 2); p = 0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered. PMID:25993615

  6. Cost-effectiveness of systemic treatments for moderate-to-severe psoriasis in the German health care setting.

    PubMed

    Küster, Denise; Nast, Alexander; Gerdes, Sascha; Weberschock, Tobias; Wozel, Gottfried; Gutknecht, Mandy; Schmitt, Jochen

    2016-05-01

    Systemic treatments of moderate-to-severe psoriasis differ substantially in terms of effectiveness and costs. Comprehensive economic-evaluations of all systemic treatments for psoriasis from a societal perspective are missing. The objective of our study was to compare the cost-effectiveness all systemic treatments approved for moderate-to-severe psoriasis from a societal perspective, by including all cost categories. An incremental cost-effectiveness-analysis was performed for all systemic treatments for psoriasis, currently recommended by the German S3-Guideline i.e. methotrexate, cyclosporine, fumaric acid esters, and retinoids, adalimumab, etanercept, infliximab and ustekinumab. We used a Markov model with time-dependent transition probabilities and a time horizon of 2 years to investigate incremental cost-effectiveness ratios. Both direct and indirect costs were considered to reflect the societal perspective. Effectiveness outcome was PASI-75 response. One-way and probabilistic sensitivity analyses explored the effect of treatment duration, discount rate, effectiveness, and the perspective (societal vs. healthcare system) on the findings. According to the base-case analysis a cost-effective treatment pathway for moderate-to-severe psoriasis starts with methotrexate, followed by ustekinumab 90 mg and infliximab, if methotrexate does not achieve or maintain PASI-75 response. Sensitivity analyses confirmed the general robustness of these findings with methotrexate being most cost-effective. However, from a third-party-payer perspective (without indirect cost) conventional therapies were generally more cost-effective than biologics. From a value-based healthcare perspective, methotrexate should be the systemic treatment of first choice, ustekinumab 90 mg second choice and infliximab third choice for patients with moderate-to-severe psoriasis. From a societal perspective, the other treatments are less efficient according to our model. From a third

  7. Current concepts in the management of rheumatoid arthritis.

    PubMed

    Tanaka, Yoshiya

    2016-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD. PMID:26932398

  8. Onset of lupus like syndrome in patients with spondyloarthritis treated with anti-TNF-α

    PubMed Central

    2012-01-01

    Background The anti-TNFα therapy has been since its approval by the FDA, along with nonsteroidal antiinflammatory drugs (NSAIDs), one of the most important therapies for control of spondyloarthritis (SpA). The onset of Lupus Like Syndrome (LLS) has been described in patients with rheumatoid arthritis (RA) treated with anti-TNFα therapy but there is little literature on the occurrence of this entity in patients with SpA. Methods We studied 57 patients with SpA who received more than 1 year of anti-TNFα therapy (infliximab, adalimumab or etanercept). Patients were analyzed for the development of LLS, in addition to measuring ANA levels ≥ 1:160 and Anti-dsDNA (measured by IIF). Results In total, 7.01% of patients treated with anti-TNFα had titers of ANA ≥ 1:160, whereas 3.5% of patients had serum levels of dsDNA. However, only one patient (1.75%; n = 1) experienced clinical symptoms of LLS; this was a female patient with a history of psoriatic arthritis. Conclusions The presence of LLS secondary to anti-TNFα therapy in patients with SpA is observed less frequently compared with patients with RA. LLS was only detected in a patient with a history of psoriasis since youth, who developed psoriatic arthritis after 27 years of age and had received anti-TNFα therapy for > 2 years. This may be because LLS is an entity clearly associated with innate immunity, with little central role of B and T cells. PMID:22336076

  9. Drug Retention Rates and Treatment Discontinuation among Anti-TNF-α Agents in Psoriatic Arthritis and Ankylosing Spondylitis in Clinical Practice

    PubMed Central

    Fabbroni, Marta; Costa, Luisa; Pagano, Veronica Anna; Frediani, Bruno; Manganelli, Stefania; Galeazzi, Mauro

    2014-01-01

    Objective. The study aim was to determine treatment persistence rates and to identify causes of discontinuation in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients in clinical practice. Methods. Patients treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) were retrospectively included. Treatment persistence rates were analyzed by means of a stepwise logistic regression. Differences between therapy duration were assessed by means of an analysis of variance model (ANOVA), while a chi-square test was used to evaluate relationships between therapies and causes of treatment discontinuation and the administration of concomitant disease-modifying antirheumatic drugs (DMARDs) among therapies and types of disease considering completed courses of therapy versus courses that were discontinued. Results. 268 patients received a total of 353 anti-TNF treatment courses (97 ADA, 180 ETA, and 76 INF). Comparison among therapies showed significant difference regarding the treatment persistence rates due to the contrast between ETA and INF (P = 0.0062). We observed that 84.7% of patients were still responding after 6 months of follow-up. Comparison among diseases showed that there were significant differences between PsA and AS (P = 0.0073) and PsA and PsA with predominant axial involvement (P = 0.0467) in terms of duration of the therapy, while there were no significant differences with regard to the persistence rate. Conclusions. In this cohort, anti-TNF-α therapy was associated with high drug persistence rates. As in rheumatoid arthritis, switching to another anti-TNF-α agent can be an effective option when, during the treatment of AS or PsA, therapy is suspended because of inefficacy or an adverse event. Combination therapy with DMARDs was associated with a better persistence rate. PMID:25110401

  10. Prediction of clinical and endoscopic responses to anti-tumor necrosis factor-α antibodies in ulcerative colitis.

    PubMed

    Morita, Yukihiro; Bamba, Shigeki; Takahashi, Kenichiro; Imaeda, Hirotsugu; Nishida, Atsushi; Inatomi, Osamu; Sasaki, Masaya; Tsujikawa, Tomoyuki; Sugimoto, Mitsushige; Andoh, Akira

    2016-08-01

    Objective In patients with ulcerative colitis (UC), the relationship between the initial endoscopic findings and the response to anti-tumor necrosis factor (TNF)-α antibodies remains unclear. We herein evaluated the potential of endoscopic assessment using the ulcerative colitis endoscopic index of severity (UCEIS) to predict the response to anti-TNF-α antibodies. Methods We enrolled 64 patients with UC undergoing anti-TNF-α maintenance therapy with infliximab (IFX) or adalimumab (ADA) between April 2010 and March 2015. Anti-TNF-α trough levels were determined by ELISA. Endoscopic disease activity was assessed using the UCEIS. Results The clinical response rate at 8 weeks was 77.4% for IFX and 66.7% for ADA. Serum albumin levels were significantly higher and the UCEIS bleeding descriptor before treatment was significantly lower in the responders than in the non-responders (p < 0.05 each). The CRP levels at 2 weeks were significantly lower in the responders (p < 0.001). The serum albumin levels before treatment were significantly higher and the UCEIS erosions and ulcers descriptor was significantly lower in the mucosal healing group than in the non-mucosal healing group (p < 0.05 each). A significant and negative correlation between the trough levels of anti-TNF-α antibodies and the UCEIS descriptors was observed. The trough levels of anti-TNF-α antibodies to achieve mucosal healing were 2.7 μg/mL for IFX and 10.3 μg/mL for ADA. Conclusions The UCEIS score, as well as some clinical markers (serum albumin and CRP levels), is useful for the prediction of the treatment outcome of UC patients in response to anti-TNF-α antibodies. PMID:26888161

  11. Approaches to the treatment of early rheumatoid arthritis with disease-modifying antirheumatic drugs.

    PubMed

    Sizova, Lyudmila

    2008-08-01

    This paper reviews recent approaches to treatment of early rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs (DMARDs). The literature on treatment the early RA published between 1995 and 2007 was accessed through the PubMed database from the National Library of Medicine. Keywords were 'early rheumatoid arthritis', 'disease-modifying antirheumatic drugs', 'biologic agents' and 'combination therapy'. Only results of trials on human subjects that directly measured the effects of DMARDs or biological agents on clinical, laboratory parameters and radiological progression of early RA were selected. Combination therapy suppresses RA activity and radiological progression more effectively than monotherapy. If better control of RA is evident after 3-6 months of treatment with the combination of DMARDs, one must still decide whether to stop the first DMARD, stop the second, or continue with the combination. Combination therapy biological agents (infliximab, adalimumab) with methotrexate and etanercept therapy alone may induce remission in many patients with early RA. It is a method of choice in patients with an adverse prognosis. The main indications for combination therapy 'standard' DMARDs or combination 1 DMARDs with a biological agent are such variables as detection of a shared epitope, increase of concentration of anticyclic citrullinated peptide antibodies, rheumatoid factor, C-reactive protein, 28-joint disease activity score, Sharp score and presence of erosion in joints. The majority of rheumatologists believe that patients with RA should be treated with DMARDs earlier rather than later in the disease process. Further trials should establish the optimal approaches to early RA therapy. PMID:18537958

  12. Cost-Effectiveness Modelling of Sequential Biologic Strategies for the Treatment of Moderate to Severe Rheumatoid Arthritis in Finland

    PubMed Central

    Puolakka, K; Blåfield, H; Kauppi, M; Luosujärvi, R; Peltomaa, R; Leikola-Pelho, T; Sennfalt, K; Beresniak, A

    2012-01-01

    Objective: The main objective was to compare the cost-effectiveness of therapeutic options in moderate or severe rheumatoid arthritis (RA) when a clinical response to a first TNF-blocker, either etanercept (ETA), adalimumab (ADA), or infliximab (INF), is insufficient. Methods: Effectiveness criteria were defined as remission (RS), low disease activity (LDAS), and moderate to high disease activity (MHDAS). Cost-effectiveness was derived as cost per day in RS and in LDAS using simulation modelling to assess six sequential biologic strategies over 2 years. Each sequential treatment strategy was composed of three biologic agents and included a first anti-TNF agent, ETA, ADA or INF, followed by either abatacept (ABA) or rituximab (RTX) as a second therapeutic option in case of an insufficient response, followed by another anti-TNF agent in case of further insufficient response. Results: Over two years and taking into account biologic costs, the following estimated mean costs per day in RS and LDAS were respectively of €829 and €428 for the biologic sequence composed of ADA-ABA-ETA, €1292 and €516 for the sequence ADA-RTX-ETA, €829 and €429 for the sequence ETA-ABA-ADA, €1292 and €517 for the sequence ETARTX- ADA, €840 and €434 for the sequence INF-ABA-ETA, and €1309 and €523 for the sequence INF-RTX-ETA. Conclusion: The treatment sequences including ABA as the second biologic option appear more cost-effective than those including RTX in a patients with moderate to severe RA and an insufficient response to a first anti-TNF agent. PMID:22582103

  13. Detection of Legionella pneumophila serogroup 1 in blood cultures from a patient treated with tumor necrosis factor-alpha inhibitor.

    PubMed

    Kaku, Norihito; Yanagihara, Katsunori; Morinaga, Yoshitomo; Sato, Tsuyoshi; Nakashima, Munetoshi; Sakai, Takahiro; Tominaga, Hiroo; Wakigawa, Fumiko; Nagashima, Seiji; Fukuda, Minoru; Hashiguchi, Kohji; Kohno, Shigeru

    2013-02-01

    A 65-year-old man was admitted to our hospital with a temperature of 39.3 °C, cough, sputum, and pharyngeal discomfort that had persisted for 3 days. He had been treated with methotrexate and adalimumab (a tumor necrosis factor-alpha [TNF-α] inhibitor) for rheumatoid arthritis for 2 years, and he had also been treated with S-1 (tegafur, gimeracil, and oteracil potassium) for pancreatic metastasis of gastric cancer for 2 months. Regardless of the underlying pathologies, his general condition was good and he had worked as an electrician until 2 days before admission. However, his appetite had suddenly decreased from the day before admission, and high fever and hypoxia were also evident upon admission. A chest X-ray and computed tomography scan revealed left pleural effusion and consolidation in both lungs. The pneumonia severity index score was 165 and the risk class was V. Accordingly, we started to treat the pneumonia with a combination of levofloxacin and meropenem. Thereafter, we received positive urinary antigen test findings for Legionella pneumophila. After hospitalization, hypoxia was progressed and hypotension was emerged. Despite the application of appropriate antibiotics, vasopressors, and oxygenation, the patient died 8 h after admission. Even after his death, blood cultures were continued to consider the possibility of bacterial co-infection. Although no bacteria were detected from blood cultures, Gimenez staining revealed pink bacteria in blood culture fluids. Subsequent blood fluid culture in selective medium revealed L. pneumophila serogroup 1. Recently, TNF-α inhibitors have been described as a risk factor for Legionnaires' disease. In consideration of the increased frequency of TNF-α inhibitors, we may need to recognize anew that L. pneumophila might be a pathogen of severe community-acquired pneumonia. PMID:22911089

  14. TNF-α antagonists beyond approved indications: stories of success and prospects for the future.

    PubMed

    Karampetsou, M P; Liossis, S-N C; Sfikakis, P P

    2010-12-01

    Tumour necrosis factor alpha (TNF-α) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-α may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Over the past decade pharmaceutical agents directed against TNF-α (infliximab, adalimumab and etanercept) have been widely and successfully employed for the management of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and inflammatory bowel disease, whereas two novel anti-TNF-α agents, golimumab and certolimumab pegol, recently entered the market for the treatment of RA, AS, Crohn's disease and psoriasis. Encouraged by the positive results obtained from the use of TNF-α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-α in the pathogenesis of numerous disorders, anti-TNF-α agents have been considered for the management of diseases other than the ones they were initially approved for. Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of TNF-α blockers had been less than favourable, in other cases of non-infectious inflammatory conditions the response to TNF-α inhibition had been fairly beneficial. More specifically, according to well-documented clinical trials, anti-TNF-α agents exhibited favourable results in Behçet's disease, non-infectious ocular inflammation, pyoderma gangrenosum and hidradenitis suppurativa. In this review we discuss the successful outcomes as well as the prospects for the future from the off-label use of TNF-α antagonists. PMID:20802008

  15. Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

    PubMed Central

    Cao, Yuan; Zhao, Di; Xu, An-Tao; Shen, Jun; Ran, Zhi-Hua

    2015-01-01

    Objective: To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants). Data Sources: We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators). The following terms were used: “inflammatory bowel disease (IBD)” OR “Crohn's disease” OR “ulcerative colitis” AND (“vaccination” OR “vaccine”) AND (“corticosteroids” OR “mercaptopurine” OR “azathioprine” OR “methotrexate [MTX]”) AND “immunomodulators.” Study Selection: The inclusion criteria of articles were that the studies: (1) Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria); (2) exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3) exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents). The exclusion criteria of articles were that the studies: (1) History of hepatitis B virus (HBV), influenza or streptococcus pneumoniae infection; (2) patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3) any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection); (4) individuals with positive hepatitis markers or liver cirrhosis; (5) patients with a known allergy to eggs or other components of the vaccines and (6) pregnancy. Results: Patients treated with immunomodulators were

  16. From Synovial Tissue to Peripheral Blood: Myeloid Related Protein 8/14 Is a Sensitive Biomarker for Effective Treatment in Early Drug Development in Patients with Rheumatoid Arthritis

    PubMed Central

    Choi, Ivy Y.; Gerlag, Danielle M.; Holzinger, Dirk; Roth, Johannes; Tak, Paul P.

    2014-01-01

    Objective The change in number of CD68-positive sublining macrophages in serial synovial biopsies has been successfully used to discriminate on the group level between effective and ineffective treatment during early drug development in rheumatoid arthritis (RA) patients. Measurement of a soluble biomarker would clearly have practical advantages. Therefore, we investigated the sensitivity to change of myeloid related protein (MRP)8/14 in serum. Methods 139 RA patients who received known effective biologics (infliximab, adalimumab and rituximab) and 28 RA patients who received placebo/ineffective therapies were included. MRP8/14 levels were analyzed in baseline and follow-up serum samples and the standardized response mean (SRM) was calculated to determine the sensitivity to change of MRP8/14 in comparison to C-reactive protein (CRP) levels and the disease activity score evaluated in 28 joints (DAS28). Results In patients treated with effective treatment, the SRM for MRP8/14 was moderate (0.56), but in patients treated with placebo/ineffective treatment the SRM was 0.06, suggesting that this biomarker is perhaps not susceptible to placebo effects in proof-of-concept studies of relatively short duration. In contrast, the SRM for DAS28 was high for effective treatment (1.07), but also moderate for ineffective treatment (0.58), representing the placebo effect. The SRM for CRP was low in the effective (0.33) and ineffective (0.23) treatment groups. Conclusion These data support the notion that quantification of changes in MRP8/14 serum levels could be used to predict potential efficacy of novel antirheumatic drugs in an early stage of drug development. A positive result would support the rationale for larger, conventional clinical trials to determine whether the effects are clinically relevant. PMID:25166859

  17. The Future Is Now: Biologics for Non-Infectious Pediatric Anterior Uveitis.

    PubMed

    Lerman, Melissa A; Rabinovich, C Egla

    2015-08-01

    Anterior uveitis (AU), inflammation of the iris, choroid or ciliary body, can cause significant eye morbidity, including visual loss. In the pediatric age group, the most common underlying diagnosis for AU is juvenile idiopathic associated uveitis and idiopathic AU, which are the focus of this paper. AU is often resistant to medications such as topical corticosteroids and methotrexate. In the past 15 years, biologic agents (biologics) have transformed treatment. In this review, we discuss those in widespread use and those with more theoretical applications for anterior uveitis. Tumor necrosis factor alpha inhibitors (anti-TNFα) have been available the longest and are used widely to treat pediatric uveitis. The effects of anti-TNFα in children are described mostly in small retrospective case series. Together, the literature suggests that the majority of children treated with anti-TNFα achieve decreased uveitis activity and reduced corticosteroid burden. However, many will have disease flares even on treatment. Only a few small studies directly compare outcomes between alternate anti-TNFα (infliximab and adalimumab). The use of different uveitis grading systems, inclusion criteria, and outcome measures makes cross-study comparisons difficult. Whether the achievement and maintenance of inactive disease occurs more frequently with certain anti-TNFα remains controversial. Newer biologics that modulate the immune system differently (e.g., interfere with Th17 activation through IL-17a and IL-6 blockade, limit T lymphocyte costimulation, and deplete B lymphocytes), have shown promise for uveitis. Studies of these agents are small and include mostly adults. Additional biologics are also being explored to treat uveitis. With their advent, we are hopeful that outcomes will ultimately be improved for children with AU. With many biologics available, much work remains to identify the optimal inflammatory pathway to target in AU. PMID:25893479

  18. Characterizing unmet medical need and the potential role of new biologic treatment options in patients with ulcerative colitis and Crohn’s disease: a systematic review and clinician surveys

    PubMed Central

    McEwan, Phil C.; Maguire, Andy; Sugrue, Daniel M.; Puelles, Jorge

    2015-01-01

    Objectives Comparative outcomes of patients with ulcerative colitis (UC) and Crohn’s disease (CD) prescribed a biologic therapy are inconclusive. The aim of this research was to characterize the degree of unmet medical need in patients with UC or CD and to identify the potential role for new therapies. Methods A systematic literature review was undertaken of studies reporting outcomes associated with the use of existing biologic therapies in patients with UC or CD, focusing on the nature and rate of treatment failure. To complement the systematic review, contemporaneous data were obtained from a survey of practising gastroenterologists in the UK and France. Data were qualitatively combined in a narrative framework to evaluate the degree of unmet medical need among patients with UC or CD. Results Studies identified in the systematic review (n=120) were heterogeneous, particularly with respect to the definitions of treatment failure; estimates of treatment failure were high but uncertain. On the basis of standardized definitions, estimates of treatment failure provided by clinicians (n=102) were high, and they were higher for second-line treatment failure (primary: ≤37%; secondary: ≤41%) compared with first-line treatment failure (primary: ≤26%; secondary: ≤28%). The majority of the systematic review and survey data were reflective of outcomes with infliximab and adalimumab. Conclusion High treatment failure rates associated with existing biologics, identified by the review and clinician surveys, indicate a need for other biologic treatment options to improve the management and outcomes for people with UC and CD. Outcomes associated with existing and new biologic treatments should be investigated in head-to-head randomized trials in the context of their likely uses in clinical practice. PMID:25933126

  19. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2006-05-01

    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: Adalimumab, adenosine triphosphate, alemtuzumab, alendronate sodium/cholecalciferol, aliskiren fumarate, AMGN-0007, aminolevulinic acid methyl ester, anakinra, anidulafungin, aripiprazole, atomoxetine hydrochloride; Bevacizumab, bosentan; Calcipotriol/beta methasone dipropionate, caldaret hydrate, caspofungin acetate, cetuximab, cinacalcet hydrochloride, clopidogrel, cocaine-BSA conjugate, conivaptan hydrochloride, Cypher; Darbepoetin alfa, delmitide, desloratadine, desmoteplase, desoxyepothilone B, disufenton sodium, DU-176b, duloxetine hydrochloride, dutasteride; EBV-specific CTLs, ecogramostim, edodekin alfa, efalizumab, eletriptan, emtricitabine, entecavir, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, etoricoxib, everolimus, ezetimibe; Fanapanel, fondaparinux sodium; Gefitinib, GTI-2040, GW-501516; Her2 E75-peptide vaccine, human insulin; Ibogaine, icatibant acetate, Id-KLH vaccine, imatinib mesylate, immune globulin subcutaneous [human], indacaterol, inolimomab, ipilimumab, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, lanthanum carbonate, lenalidomide, levocetirizine, levodopa methyl ester hydrochloride/carbidopa, levodopa/carbidopa/entacapone, lidocaine/prilocaine; Maraviroc, mecasermin, melevodopa hydrochloride, mepolizumab, mitumomab; Nesiritide; Omalizumab, oral insulin; Parathyroid hormone (human recombinant), patupilone, pegaptanib sodium, PEG-filgrastim, pemetrexed disodium, photochlor, pimecrolimus, posaconazole, prasterone, prasugrel, pregabalin, prilocaine, PRX-00023; QS-21; Ranibizumab, ranirestat, rhodamine 123, rotigaptide; Sarcosine, sirolimus

  20. Differential effects of anti-TNF-α and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions.

    PubMed

    Ríos-Navarro, Cesar; de Pablo, Carmen; Collado-Diaz, Víctor; Orden, Samuel; Blas-Garcia, Ana; Martínez-Cuesta, María Ángeles; Esplugues, Juan V; Alvarez, Angeles

    2015-10-15

    Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-α (adalimumab, infliximab and etanercept) and anti-IL-12/23 (ustekinumab) on interactions between human leukocytes and endothelial cells in a flow chamber that reproduced in vivo conditions. Clinical concentrations of anti-TNF-α were evaluated on the leukocyte recruitment induced by a variety of endothelial (TNF-α, interleukin-1β, lymphotoxin-α and angiotensin-II) and leukocyte (PAF, IL-12 and IL-23) stimuli related to inflammation and atherosclerosis. Treatment with anti-TNF-α, even before or after establishing the inflammatory situation induced by TNF-α, diminished leukocyte-endothelial cell interactions induced by this stimuli. Our results also implicated adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the actions of anti-TNF-α in terms of leukocyte adhesion to endothelium. However, anti-TNF-α drugs did not influence the actions of interleukin-1β, but prevented those of lymphotoxin-α and angiotensin-II. However, once established, inflammatory response elicited by the latter three stimuli could not be reversed. Pre-treatment with anti-TNF-α, also prevented leukocyte actions induced by IL-23 on PBMC rolling flux and rolling velocity and by IL-12 on PMN adhesion. Ustekinumab exhibited a more discreet profile, having no effect on leukocyte recruitment induced by any of the endothelial stimuli, while blocking the effects of IL-23 on leukocyte activation and those of IL-12 on PMN adhesion and PAF on PBMC rolling velocity. These findings endorse the idea that biological anti-inflammatory drugs, in particular anti-TNF-α, have the capacity to influence cardiovascular risk accompanying psoriasis and rheumatoid arthritis by ameliorating vascular inflammation. PMID:26344475

  1. New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease.

    PubMed

    Slevin, Stephanie M; Egan, Laurence J

    2015-12-01

    Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance. PMID:26348448

  2. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2006-01-01

    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: ABT-510, adalimumab, alefacept, ambrisentan, aminolevulinic acid methyl ester, armodafinil, aselizumab, asenapine maleate, azelnidipine; Bevacizumab, bexarotene, bimosiamose, biphasic insulin aspart, bortezomib, bosentan, BQ-123; C340, cannabidiol, caspofungin acetate, CC-4047, certolizumab pegol, cetuximab, ciclesonide, cilansetron, Cypher; Dabigatran etexilate, darbepoetin alfa, darifenacin hydrobromide, desloratadine, dexosome vaccine (melanoma), dimethyl fumarate, dronabinol/cannabidiol, drospirenone, drospirenone/estradiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Efalizumab, eglumetad hydrate, emoxipin hydrochloride, eplerenone, erlotinib hydrochloride, escitalopram oxalate, etonogestrel/ethinylestradiol; Garenoxacin mesilate, gamma-hydroxybutyrate sodium, gefitinib; H5N1 pandemic influenza vaccine, human growth hormone-(177-191), human insulin; Indacaterol, INKP-100, INKP-102, insulin glargine, i.v. gamma-globulin; KLH; Lapatinib, L-arginine hydrochloride, lasofoxifene tartrate, levocetirizine, licochalcone A, LMI vaccine, lomefloxacin, lubiprostone, lumiracoxib; Miglustat, mycograb; Natalizumab, NCX-4016, nortopixantrone hydrochloride; Olmesartan medoxomil, omalizumab, oral insulin, OrM3; Parathyroid hormone (human recombinant), parecoxib sodium, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, pemetrexed disodium, pexelizumab, photochlor, pimecrolimus, pneumococcal 7-valent conjugate vaccine, polyphenon E; R-126638, R-411, resveratrol, roflumilast, RS-86, ruboxistaurin mesilate hydrate, rupatadine fumarate; Sipuleucel-T, somatropin, St. John's Wort extract; Tadalafil, Taxus

  3. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-01-01

    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:(R)-Flurbiprofen, 90Yttrium-DOTA-huJ591; ABT-510, ACP-103, Ad5-FGF4, adalimumab, ademetionine, AG-7352, alemtuzumab, Amb a 1 ISS-DNA, anakinra, apaziquone, aprepitant, aripiprazole, atazanavir sulfate; BAL-8557, bevacizumab, BMS-188797, bortezomib, bosentan, brivudine; Calcipotriol/betamethasone dipropionate, cannabidiol, caspofungin acetate, catumaxomab, CERE-120, cetuximab, ciclesonide, cilomilast, cizolirtine citrate, Cypher, cystemustine; Dalbavancin, darifenacin hydrobromide, dasatinib, deferasirox, denosumab, desmoteplase, dihydrexidine, dimethyl fumarate, dutasteride, DW-166HC; Eculizumab, enfuvirtide, entecavir, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, eszopiclone, etoricoxib, everolimus; Fallypride, febuxostat, fenretinide, fesoterodine, fingolimod hydrochloride; Gabapentin enacarbil, gefitinib; hMaxi-K, human papillomavirus vaccine, HYAL-CT1101; Imatinib mesylate, indiplon, inolimomab, ISAtx-247; J591; Lacosamide, landiolol, lasofoxifene tartrate, lestaurtinib, lidocaine/prilocaine, linezolid, lixivaptan, lonafarnib, lopinavir, lopinavir/ritonavir, lumiracoxib; Natalizumab, nesiritide; OC-108, omalizumab, onercept, OSC; Palifermin, palonosetron hydrochloride, parathyroid hormone (human recombinant), parecoxib sodium, PD-MAGE-3 vaccine, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, pegsunercept, pelitinib, pitavastatin calcium, plerixafor hydrochloride, posaconazole, prasterone sulfate, pregabalin; Ramelteon, ranelic acid distrontium salt, rasburicase, rosuvastatin calcium, rotigotine, RSD-1235, rufinamide, rupatadine fumarate; Sarizotan hydrochloride, SHL-749

  4. Biosimilars in dermatology

    PubMed Central

    Olek-Hrab, Karolina; Karczewski, Jacek; Teresiak-Mikołajczak, Ewa; Adamski, Zygmunt

    2015-01-01

    Over the last decade the availability of biological drugs for the treatment of psoriasis vulgaris, psoriatic arthritis and many other inflammatory diseases has revolutionized the treatment of these diseases around the world. Due to the high cost of therapy, the search has started for biosimilars. In dermatology the greatest interest in biosimilar medicines concerns inhibitors of tumor necrosis factor a (TNF-α), for use in the treatment of psoriasis vulgaris and psoriatic arthritis (infliximab, etanercept, adalimumab). The most important element of the safety of biologicals is their immunogenicity. Therefore, when discussing biosimilars, attention needs to be paid to the dangers of their immune activity. In view of the fact that the drugs contain and aggregates, produced by living organisms or cultures of living cells, they cannot be compared in any way to low molecular weight synthetic generics (called generics). Biosimilars are authorized for use in patients and treated as equivalent to the reference medicine only after passing a number of studies and assessments. As it is well known, the development of medicine and pharmacology is extremely intense, and the market in biological medicine is developing much faster than that of all other drugs, which underlines their important role in modern medicine. Currently, the subject of biosimilars is one of the most important challenges and topics of discussion around the world, including pharmacovigilance and legal and economic regulatory standards. It seems inevitable that biosimilar products will be introduced for the treatment of diseases with indications corresponding to the original product on which they are based. PMID:26759547

  5. Improved safety of biologic therapy for rheumatoid arthritis over the 8-year period since implementation in Japan: long-term results from a multicenter observational cohort study.

    PubMed

    Kojima, Toshihisa; Takahashi, Nobunori; Funahashi, Koji; Asai, Shuji; Terabe, Kenya; Kaneko, Atsushi; Hirano, Yuji; Hayashi, Masatoshi; Miyake, Hiroyuki; Oguchi, Takeshi; Takagi, Hideki; Kanayama, Yasuhide; Yabe, Yuichiro; Watanabe, Tsuyoshi; Fujibayashi, Takayoshi; Shioura, Tomone; Ito, Takayasu; Yoshioka, Yutaka; Ishikawa, Hisato; Asai, Nobuyuki; Takemoto, Toki; Kojima, Masayo; Ishiguro, Naoki

    2016-04-01

    This study aimed to compare the long-term safety of biologics by initiation year of treatment in patients with rheumatoid arthritis (RA) in Japan. RA patients who started their first biologics including infliximab, etanercept, adalimumab, and tocilizumab between 2003 and 2008 were identified in the Tsurumai Biologics Communication Registry (TBCR), multicenter observational cohort, and followed for 2 years or until discontinuation of the drugs. We identified baseline predictors for adverse events (AEs) resulting in discontinuation of the first TNFI using Cox proportional hazards regression analysis. A total of 874 cases (1,340 person-years) were observed. During the observation period, 96 AEs (4.7 events/100 person-years) occurred. From 2003 to 2008, there were significant changes in disease duration, Steinbrocker stage, and disease activity in those aged ≤64 years with no increase of incidence of AEs, whereas those aged >64 years had no significant changes in these variables. In the later initiation year of treatment with biologics, the fewer AEs were observed (log-rank, p = 0.017, 2008 vs. 2003-2005). Multivariate analysis showed that the initiation year significantly impacted the incidence of AEs 6 months into the observation period [initiation at 2008 (vs. 2003-2005): OR: 0.30, 95 % CI: (0.14-0.68)] after adjusting for variables at baseline. The decrease of AEs in the later initiation year was evident in those aged >64 years. The safety of biologic therapy improved over the course of the 8 years from its implementation in Japan. PMID:26846135

  6. Joint position statement by “Sociedad Española de Patología Digestiva” (Spanish Society of Gastroenterology) and “Sociedad Española de Farmacología” (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease.

    PubMed

    Argüelles-Arias, Federico; Barreiro-de-Acosta, Manuel; Carballo, Fernando; Hinojosa, Joaquín; Tejerina, Teresa

    2013-01-01

    Biological drugs or biopharmaceutical products, manufactured with or from living organisms using biotechnology, have represented a therapeutic revolution for the control of inflammatory bowel disease (IBD). At present, in this indication and in our country, only two biological are approved, infliximab (IFX) and adalimumab (ADA), both of them monoclonal antibodies against tumor necrosis factor alpha. Effectiveness data are strong for both therapies, with maximum levels of scientific evidence.The upcoming expiry date for these biologicals´ patents has allowed the potential marketing of so-called biosimilar agents for the IBD indication. While biosimilars are conceptually for biological what generics are for chemical drugs, the structural complexity of biosimilars and their biological and manufacturing variability lead to consider validation processes for these two types in humans as highly differential. Thus, in our setting, under the coverage of "Agencia Española del Medicamento y Productos Sanitarios (AEMPS)" (Spanish Agency of Medicines and Medical Devices), guidelines issued by the European Medicines Agency (EMA) are to be applied, which states that a number of stages or steps must be overcome in order to obtain approval for a biosimilar agent.However, despite the presence of these recommendations by EMA, which must be met by a biosimilar in order to be licensed in our marketplace, relevant uncertainties persist that only future decisions by EMA and AEMPS may clarify. The present stance by our task force is that biosimilar development should be undertaken according to established regulations, thus certifying their efficacy and safety. Similarly, this task force considers that results obtained from studies in rheumatoid arthritis (RA) should not be extrapolated to IBD since the biological variability of these complex structures will not ensure a lack of noticeable changes in efficacy and safety. PMID:23548008

  7. Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis.

    PubMed

    Yiu, Zenas Z N; Exton, Lesley S; Jabbar-Lopez, Zarif; Mohd Mustapa, M Firouz; Samarasekera, Eleanor J; Burden, A David; Murphy, Ruth; Owen, Caroline M; Parslew, Richard; Venning, Vanessa; Ashcroft, Darren M; Griffiths, Christopher E M; Smith, Catherine H; Warren, Richard B

    2016-08-01

    A comprehensive evaluation of the risk of serious infections in biologic therapies for psoriasis is lacking. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) and prospective cohort studies reporting serious infections in people taking any licensed biologic therapy for psoriasis compared with those taking placebo, nonbiologic therapy, or other biologic therapies. The quality of the studies was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. No significant heterogeneity was detected in data from 32 RCTs (n = 13,359 participants) and one cohort study (n = 4,993 participants). In adults, low- to very-low-quality RCT data showed no significant difference between any biologic therapy and placebo at weeks 12-16 (overall pooled Peto odds ratio = 0.71, 95% confidence interval = 0.36-1.41) and weeks 20-30 (odds ratio = 2.27, 95% confidence interval = 0.45-11.49). No significant differences were found in any of the other comparisons in underpowered RCT data. Prospective cohort study data of low quality suggests that only adalimumab (adjusted hazard ratio [adjHR] = 2.52, 95% confidence interval = 1.47-4.32) was associated with a significantly higher risk of serious infection compared with retinoid and/or phototherapy in adults. No association between biologic therapies and serious infections in patients with psoriasis who were eligible for RCTs was detected. Further observational studies are needed to inform the uncertainty around this risk in the real world. PMID:27085754

  8. Gateways to clinical trials.

    PubMed

    Moral, M A; Tomillero, A

    2008-03-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has 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: 131-I-Chlorotoxin, 423557; Abatacept, Ad.Egr.TNF.11D, Adalimumab, AE-941, Ambrisentan, AMR-001, Anacetrapib, Anakinra, Aripiprazole, Atazanavir sulfate; BAY-639044, Bazedoxifene acetate, Belimumab, Bevacizumab, Bortezomib, Botulinum toxin type B, Brivaracetam, Bucindolol hydrochloride; Carfilzomib, Carisbamate, CCX-282, CD20Bi, Ceftobiprole, Certolizumab pegol, CF-101, Cinacalcet hydrochloride, Cypher; Darifenacin hydrobromide, Degarelix acetate, Denosumab, Desvenlafaxine succinate, Dexlansoprazole, Dexverapamil, Drotrecogin alfa (activated), Duloxetine hydrochloride, Dutasteride; Efalizumab, EPs-7630, Escitalopram oxalate, Etoricoxib; Fluticasone furoate, Fondaparinux sodium, Fospropofol disodium; Hexadecyloxypropyl-cidofovir, HIV gp120/NefTat/AS02A, HPV-6/11/16/18; INCB-18424, Incyclinide, Inhalable human insulin, Insulin detemir; KNS-760704, KW-0761; Lacosamide, Lenalidomide, Levetiracetam, Licofelone, Lidocaine/prilocaine; mAb 216, MEDI-528, Men ACWY, Meningococcal C-CRM197 vaccine, Methylnaltrexone bromide; Nemifitide ditriflutate, Nicotine conjugate vaccine, Nilotinib hydrochloride monohydrate; Octaparin; Parathyroid hormone (human recombinant), Pegaptanib octasodium, Pitrakinra, Prasterone, Pregabalin; Ranelic acid distrontium salt, Rasagiline mesilate, Retigabine, Rimonabant, RTS,S/AS02D; Sarcosine, Sitaxentan sodium, Solifenacin succinate, Sunitinib malate; Taranabant, Taxus, Teduglutide, Teriparatide, Ticagrelor, Travoprost, TRU-015; USlipristal acetate, Urocortin 2; Vardenafil hydrochloride hydrate; YM-155, Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, Zoledronic acid monohydrate, Zotarolimus

  9. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-09-01

    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: A-007, A6, adalimumab, adenosine triphosphate, alefacept, alemtuzumab, AllerVax Ragweed, amphora, anakinra, angiotensin-(1-7), anidulafungin, apomine, aripiprazole, atomoxetine hydrochloride, avanafil; BAL-8557, becatecarin, bevacizumab, biphasic insulin aspart, BMS-188797, bortezomib, bosentan, botulinum toxin type B, brivudine; Calcipotriol/betamethasone dipropionate, caspofungin acetate, catumaxomab, certolizumab pegol, cetuximab, CG-0070, ciclesonide, cinacalcet hydrochloride, clindamycin phosphate/benzoyl peroxide, cryptophycin 52, Cypher; Dabigatran etexilate, darapladib, darbepoetin alfa, decitabine, deferasirox, desloratadine, dexanabinol, dextromethorphan/quinidine sulfate, DMF, drotrecogin alfa (activated), duloxetine hydrochloride; E-7010, edaravone, efalizumab, emtricitabine, entecavir, eplerenone, erlotinib hydrochloride, escitalopram oxalate, estradiol valerate/dienogest, eszopiclone, exenatide, ezetimibe; Fondaparinux sodium, fulvestrant; Gefitinib, gestodene, GYKI-16084; Hyaluronic acid, hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, indiplon, insulin glargine; Juzen-taiho-to; Lamivudine/zidovudine/abacavir sulfate, L-arginine hydrochloride, lasofoxifene tartrate, L-BLP-25, lenalidomide, levocetirizine, levodopa/carbidopa/entacapone, lexatumumab, lidocaine/prilocaine, lubiprostone, lumiracoxib; MAb-14.18, mitoquidone; Natalizumab, neridronic acid, neuradiab; Olpadronic acid sodium salt, omalizumab; p53-DC vaccine, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, perifosine, pimecrolimus, prasterone, prasugrel, PRO-2000

  10. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-09-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has 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: AAV1/SERCA2a, Abacavir sulfate/lamivudine, Adalimumab, Aliskiren fumarate, Ambrisentan, Aripiprazole, AT-7519, Atazanavir sulfate, Atomoxetine hydrochloride, Azacitidine, Azelnidipine; Besifloxacin hydrochloride, Bevacizumab, Bioabsorbable everolimus-eluting coronary stent, Bortezomib, Bosentan, Budesonide/formoterol fumarate; CAIV-T, Carisbamate, Casopitant mesylate, Certolizumab pegol, Cetuximab, Ciclesonide, Ciprofloxacin/dexamethasone, CTCE-9908; Dalcetrapib, Darunavir, Deferasirox, Desloratadine, Disitertide, Drotrecogin alfa (activated), DTA-H19, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Efalizumab, Emtricitabine, Eribulin mesilate, Escitalopram oxalate, Eszopiclone, EUR-1008, Everolimus-eluting coronary stent, Exenatide; Fampridine, Fluticasone furoate, Formoterol fumarate/fluticasone propionate, Fosamprenavir calcium, Fulvestrant; Gabapentin enacarbil, GS-7904L; HPV-6/11/16/18, Human Secretin, Hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, Imexon, Inalimarev/Falimarev, Indacaterol, Indacaterol maleate, Inhalable human insulin, Insulin detemir, Insulin glargine, Ixabepilone; L-Alanosine, Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Loratadine/montelukast sodium, Lutropin alfa; MeNZB, Mepolizumab, Micafungin sodium, Morphine hydrochloride; Nabiximols, Nikkomycin Z; Olmesartan medoxomil, Omalizumab; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Perifosine, PF-489791, Plitidepsin, Posaconazole, Pregabalin; QAX-576; Raltegravir potassium, Ramelteon, Rasagiline

  11. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X

    2008-01-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prouse Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 101M, 3F8; Abatacept, ABT-263, Adalimumab, AG-7352, Agatolimod sodium, Alfimeprase, Aliskiren fumarate, Alvimopan hydrate, Aminolevulinic acid hexyl ester, Ammonium tetrathiomolybdate, Anakinra, Aripiprazole, AS-1404, AT-9283, Atomoxetine hydrochloride, AVE-1642, AVE-9633, Axitinib, AZD-0530; Becocalcidiol, Belotecan hydrochloride, Bevacizumab, BG-9928, BIBF-1120, BMS-275183, Bortezomib, Bosentan; Catumaxomab, Cetuximab, CHR-2797, Ciclesonide, Clevidipine, Cypher, Cytarabine/daunorubicin; Darifenacin hydrobromide, Darunavir, Denosumab, Desvenlafaxine succinate, Disufenton sodium, Duloxetine hydrochloride, Dutasteride; Eculizumab, Efalizumab, Eicosapentaenoic acid/docosahexaenoic acid, Eplerenone, Epratuzumab, Erlotinib hydrochloride, Escitalopram oxalate, Ethynylcytidine, Etravirine, Everolimus, Ezetimibe; Fulvestrant; Garenoxacin mesilate, Gefitinib, Gestodene; HI-164, Hydralazine hydrochloride/isosorbide dinitrate; Icatibant acetate, ICX-RHY, Idraparinux sodium, Indacaterol, Ispronicline, Ivabradine hydrochloride, Ixabepilone; KB-2115, KW-2449; L-791515, Lapatinib ditosylate, LGD-4665, Licofelone, Liposomal doxorubicin, Lisdexamfetamine mesilate, Lumiracoxib; Methoxy polyethylene glycol-epoetin-beta, Miglustat, Mipomersen sodium, Mitumprotimut-T, MK-0822A, MK-0974; Nelarabine; Obatoclax mesylate, Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide; Paliperidone, Palonosetron hydrochloride, Panitumumab, Pegfilgrastim, Peginterferon alfa-2a, Pemetrexed disodium, Perospirone hydrochloride, Pertuzumab, Pimecrolimus, Pitrakinra, Pixantrone maleate, Posaconazole, Pregabalin; Quercetin; RALGA, Raltegravir

  12. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2007-10-01

    (-)-Epigallocatechin gallate, [188Re]-P2045, 12B75, 89-12; Abacavir sulfate/lamivudine, Abatacept, Abiraterone acetate, ABT-869, Adalimumab, Ad-rh Endostatin, AI-700, Alemtuzumab, Alvimopan hydrate, Amrubicin hydrochloride, AP-12009, Apomab 7.3, Arformoterol tartrate, Aripiprazole, AS-1404, Azacitidine, AZD-0530; Bevacizumab, BHT-3009, Biapenem, Bortezomib, Bosentan, Bremelanotide; CA9-SCAN, Calcitonin gene-related peptide, Canertinib dihydrochloride, Cannabidiol, Carboxyamidotriazole, Caspofungin acetate, Celgosivir, Certolizumab pegol, Cinacalcet hydrochloride, Clevudine, CP-751871, Curcumin, Cx-401, Cypher; Darunavir, Decitabine, Deforolimus, Dexamet, Dipyridamole/prednisolone, Drospirenone, Drospirenone/estradiol, DTPw-HepB-Hib, Duloxetine hydrochloride; Efalizumab, Emtricitabine, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone; Ferumoxtran-10, Ferumoxytol, Fondaparinux sodium, Fosaprepitant dimeglumine; gamma-Hydroxybutyrate sodium, Gefitinib, Genistein, Ghrelin (human), Gimatecan, GM-CSF PMED, Golimumab, gp100 PMED; Imatinib mesylate, Immunoglobulin intravenous (human), IV Gamma-globulin; LA-419, Laropiprant, L-BLP-25, Levodopa/carbidopa/entacapone, Lidocaine/prilocaine, Lopinavir/ritonavir, Lumiracoxib, LY-2076962; Mepolizumab, Methylnaltrexone bromide, Mitiglinide calcium hydrate, Mycophenolic acid sodium salt, Myristyl nicotinate; Natalizumab, Nesiritide, Niacin/lovastatin; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide, Ozarelix; Palonosetron hydrochloride, Parathyroid hormone (human recombinant), Pazopanib hydrochloride, Pegaptanib octasodium, Pegfilgrastim, Peginterferon alfa- 2a, Peginterferon alfa-2b, Pegvisomant, Pemetrexed disodium, Pexelizumab, Picoplatin, Pimecrolimus, Posaconazole, Pregabalin, PRO-1762, Progesterone caproate, Prulifloxacin; Ramelteon, Ranelic acid distrontium salt, Reparixin, Rosuvastatin calcium; Rotigotine; Satraplatin, Sertraline, Sipuleucel-T, SLIT-cisplatin, SNDX-275

  13. Novel strategies for the treatment of inflammatory bowel disease: Selective inhibition of cytokines and adhesion molecules

    PubMed Central

    Nakamura, Kazuhiko; Honda, Kuniomi; Mizutani, Takahiro; Akiho, Hirotada; Harada, Naohiko

    2006-01-01

    The etiology of inflammatory bowel disease (IBD) has not yet been clarified and immunosuppressive agents which non-specifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Such recent advances in the understanding of the pathogenesis of IBD created a recent trend of novel biological therapies which specifically inhibit the molecules involved in the inflammatory cascade. Major targets for such treatment are inflammatory cytokines and their receptors, and adhesion molecules. A chimeric anti-TNF-α monoclonal antibody, infliximab, has become a standard therapy for CD and it is also likely to be beneficial for UC. Several anti-TNF reagents have been developed but most of them seem to not be as efficacious as infliximab. A humanized anti-TNF monoclonal antibody, adalimumab may be useful for the treatment of patients who lost responsiveness or developed intolerance to infliximab. Antibodies against IL-12 p40 and IL-6 receptor could be alternative new anti-cytokine therapies for IBD. Anti-interferon-γ and anti-CD25 therapies were developed, but the benefit of these agents has not yet been established. The selective blocking of migration of leukocytes into intestine seems to be a nice approach. Antibodies against α4 integrin and α4β7 integrin showed benefit for IBD. Antisense oligonucleotide of intercellular adhesion molecule 1 (ICAM-1) may be efficacious for IBD. Clinical trials of such compounds have been either recently reported or are currently underway. In this article, we review the efficacy and safety of such novel biological therapies for IBD. PMID:16937430

  14. Translation and validation of non-English versions of the Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire

    PubMed Central

    Doward, Lynda C; McKenna, Stephen P; Meads, David M; Twiss, James; Revicki, Dennis; Wong, Robert L; Luo, Michelle P

    2007-01-01

    Background The Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire is a unidimensional, disease-specific measure developed in the UK and the Netherlands. This study describes its adaptation into other languages. Methods The UK English ASQOL was translated into US English; Canadian French and English; French; German; Italian; Spanish; and Swedish (dual-panel methods). Cognitive debriefing interviews were conducted with AS patients. Psychometric/scaling properties were assessed using data from two Phase III studies of adalimumab. Baseline and Week-2 data were used to assess test-retest reliability. Validity was determined by correlation of ASQOL with SF-36 and BASFI and by discriminative ability of ASQOL based on disease severity. Item response theory (Rasch model) was used to test ASQOL's scaling properties. Results Cognitive debriefing showed the new ASQOL versions to be clear, relevant and comprehensive. Sample sizes varied, but were sufficient for: psychometric/scaling assessment for US English and Canadian English; psychometric but not scaling analyses for German; and preliminary evidence of these properties for the remaining languages. Test-retest reliability and Cronbach's alpha coefficients were high: US English (0.85, 0.85), Canadian English (0.87, 0.86), and German (0.77, 0.79). Correlations of ASQOL with SF-36 and BASFI for US English, Canadian English, and German measures were moderate, but ASQOL discriminated between patients based on perceived disease severities (p < 0.01). Results were comparable for the other languages. US English and Canadian English exhibited fit to the Rasch model (non-significant p-values: 0.54, 0.68), confirming unidimensionality. Conclusion The ASQOL was successfully translated into all eight languages. Psychometric properties were excellent for US English, Canadian English, and German, and extremely promising for the other languages. PMID:17274818

  15. Biosimilars in dermatology.

    PubMed

    Mazur, Małgorzata; Olek-Hrab, Karolina; Karczewski, Jacek; Teresiak-Mikołajczak, Ewa; Adamski, Zygmunt

    2015-10-01

    Over the last decade the availability of biological drugs for the treatment of psoriasis vulgaris, psoriatic arthritis and many other inflammatory diseases has revolutionized the treatment of these diseases around the world. Due to the high cost of therapy, the search has started for biosimilars. In dermatology the greatest interest in biosimilar medicines concerns inhibitors of tumor necrosis factor a (TNF-α), for use in the treatment of psoriasis vulgaris and psoriatic arthritis (infliximab, etanercept, adalimumab). The most important element of the safety of biologicals is their immunogenicity. Therefore, when discussing biosimilars, attention needs to be paid to the dangers of their immune activity. In view of the fact that the drugs contain and aggregates, produced by living organisms or cultures of living cells, they cannot be compared in any way to low molecular weight synthetic generics (called generics). Biosimilars are authorized for use in patients and treated as equivalent to the reference medicine only after passing a number of studies and assessments. As it is well known, the development of medicine and pharmacology is extremely intense, and the market in biological medicine is developing much faster than that of all other drugs, which underlines their important role in modern medicine. Currently, the subject of biosimilars is one of the most important challenges and topics of discussion around the world, including pharmacovigilance and legal and economic regulatory standards. It seems inevitable that biosimilar products will be introduced for the treatment of diseases with indications corresponding to the original product on which they are based. PMID:26759547

  16. Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis.

    PubMed

    Ternant, David; Bejan-Angoulvant, Theodora; Passot, Christophe; Mulleman, Denis; Paintaud, Gilles

    2015-11-01

    Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity. PMID:26123705

  17. Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-α therapy.

    PubMed

    McGeough, Cathy M; Berrar, Daniel; Wright, Gary; Mathews, Clare; Gilmore, Paula; Cunningham, Rodat T; Bjourson, Anthony J

    2012-06-01

    The identification of patients who will respond to anti-tumor necrosis factor alpha (anti-TNF-α) therapy will improve the efficacy, safety, and economic impact of these agents. We investigated whether killer cell immunoglobulin-like receptor (KIR) genes are related to response to anti-TNF-α therapy in patients with rheumatoid arthritis (RA). Sixty-four RA patients and 100 healthy controls were genotyped for 16 KIR genes and human leukocyte antigen-C (HLA-C) group 1/2 using polymerase chain reaction sequence-specific oligonucleotide probes (PCR-SSOP). Each patient received anti-TNF-α therapy (adalimumab, etanercept, or infliximab), and clinical responses were evaluated after 3 months using the disease activity score in 28 joints (DAS28). We investigated the correlations between the carriership of KIR genes, HLA-C group 1/2 genes, and clinical data with response to therapy. Patients responding to therapy showed a significantly higher frequency of KIR2DS2/KIR2DL2 (67.7% R vs. 33.3% NR; P = 0.012). A positive clinical outcome was associated with an activating KIR-HLA genotype; KIR2DS2 (+) HLA-C group 1/2 homozygous. Inversely, non-response was associated with the relatively inhibitory KIR2DS2 (-) HLA-C group 1/2 heterozygous genotype. The KIR and HLA-C genotype of an RA patient may provide predictive information for response to anti-TNF-α therapy. PMID:21373785

  18. An appraisal of golimumab in the treatment of severe, active nonradiographic axial spondyloarthritis

    PubMed Central

    Paccou, Julien; Flipo, René-Marc

    2016-01-01

    Golimumab (Simponi®) is a fully human tumor necrosis factor α inhibitor (TNFi) antibody administered subcutaneously. In the European Union, golimumab is indicated for the treatment of adults with severe, active axial spondyloarthritis (axSpA), which includes both ankylosing spondylitis (AS) and nonradiographic axSpA (nr-axSpA). In the US, it is indicated for the treatment of adults with active AS only. This article reviews the efficacy and tolerability of golimumab in nr-axSpA patients compared to other TNFi agents (adalimumab, infliximab, etanercept, and certolizumab pegol). In one ongoing, well-designed controlled study (GO-AHEAD), data at 16 weeks showed that treatment with golimumab (50 mg every 4 weeks) was effective in improving the clinical signs and symptoms of disease in nr-axSpA patients. In addition, 16 weeks of treatment with golimumab reduced inflammation in the sacroiliac joints and spine in patients with nr-axSpA. Moreover, objective evidence of active inflammation at baseline, such as a positive magnetic resonance imaging scan and/or an elevated CRP level, was a good predictor of treatment response to golimumab. Golimumab was generally well tolerated in this study, with a tolerability profile consistent with that seen in previous clinical trials for other indications. Although additional long-term data are needed, current evidence indicates that golimumab is an effective option for the treatment of nr-axSpA. However, in the absence of comparative head-to-head trials, there is no recommended hierarchy for the first prescription of a TNFi agent for the treatment of either nr-axSpA or AS. PMID:27468228

  19. Nocardia infections among immunomodulated inflammatory bowel disease patients: A review.

    PubMed

    Abreu, Cândida; Rocha-Pereira, Nuno; Sarmento, António; Magro, Fernando

    2015-06-01

    Human nocardiosis, caused by Nocardia spp., an ubiquitous soil-borne bacteria, is a rare granulomatous disease close related to immune dysfunctions. Clinically can occur as an acute life-threatening disease, with lung, brain and skin being commonly affected. The infection was classically diagnosed in HIV infected persons, organ transplanted recipients and long term corticosteroid treated patients. Currently the widespread use of immunomodulators and immunossupressors in the treatment of inflammatory diseases changed this scenario. Our purpose is to review all published cases of nocardiosis in immunomodulated patients due to inflammatory diseases and describe clinical and laboratory findings. We reviewed the literature concerning human cases of nocardiosis published between 1980 and 2014 in peer reviewed journals. Eleven cases of nocardiosis associated with anti-tumor necrosis factor (TNF) prescription (9 related with infliximab and 2 with adalimumab) were identified; 7 patients had inflammatory bowel disease (IBD), 4 had rheumatological conditions; nocardia infection presented as cutaneous involvement in 3 patients, lung disease in 4 patients, hepatic in one and disseminated disease in 3 patients. From the 10 cases described in IBD patients 7 were associated with anti-TNF and 3 with steroids and azathioprine. In conclusion, nocardiosis requires high levels of clinical suspicion and experience of laboratory staff, in order to establish a timely diagnosis and by doing so avoid worst outcomes. Treatment for long periods tailored by the susceptibility of the isolated species whenever possible is essential. The safety of restarting immunomodulators or anti-TNF after the disease or the value of prophylaxis with cotrimoxazole is still debated. PMID:26074688

  20. The use of upconverting phosphors in point-of-care (POC) testing

    NASA Astrophysics Data System (ADS)

    Tanke, Hans J.; Zuiderwijk, Michel; Wiesmeijer, Karien C.; Breedveld, Robert N.; Abrams, William R.; de Dood, Claudia J.; Tjon Kon Fat, Elisa M.; Corstjens, Paul L. A. M.

    2014-03-01

    Point-of-care (POC) testing is increasingly applied as a cost effective alternative to many diagnostic tests. Key in POC testing is to create sufficient assay sensitivity with relatively low cost reagents and equipment. For this purpose we have employed a unique reporter, upconverting phosphor (UCP) particles, in combination with lateral flow (LF) assays. UCPs, submicron ceramic particles doped with rare earth ions (lanthanides), convert infrared to visible light and do not suffer from autofluorescence which limits conventional fluorescence based assays. Low cost handheld readers and microfluidics were evaluated in various applications. Designed assays are well suited for applications outside diagnostic laboratories, in resource poor settings, and can even be used by patients at home. Using two distinctly different UCP-LF assay formats, we focussed on assays for infectious diseases based on the detection of pathogen-specific antibodies and/or antigens including nucleic acids to demonstrate active infection with HIV. Only minor adaptation of the standard UCP-LF assay format is needed to render the format suitable for applications involving low affinity capture antibodies (e.g. in the detection of neurotoxin, botulism), capture of small molecules (e.g. detection of melatonin, a key hormone in chronopharmacology) or the use of dry UCP reagents (e.g. detection of protein based fruit-ripening markers, of economic interest in agriculture). Finally, we anticipate on developments in healthcare (personalized medicine) by discussing the potential of one of the UCP-LF assay formats to measure serum trough levels of immunodrugs (e.g. infliximab or adalimumab) in patients treated for inflammatory bowel disease and rheumatoid arthritis.

  1. Spinal Inflammation in the Absence of Sacroiliac Joint Inflammation on Magnetic Resonance Imaging in Patients With Active Nonradiographic Axial Spondyloarthritis

    PubMed Central

    van der Heijde, Désirée; Sieper, Joachim; Maksymowych, Walter P; Brown, Matthew A; Lambert, Robert G W; Rathmann, Suchitrita S; Pangan, Aileen L

    2014-01-01

    Objective To evaluate the presence of spinal inflammation with and without sacroiliac (SI) joint inflammation on magnetic resonance imaging (MRI) in patients with active nonradiographic axial spondyloarthritis (SpA), and to compare the disease characteristics of these subgroups. Methods ABILITY-1 is a multicenter, randomized, controlled trial of adalimumab versus placebo in patients with nonradiographic axial SpA classified using the Assessment of SpondyloArthritis international Society axial SpA criteria. Baseline MRIs were centrally scored independently by 2 readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) method for the SI joints and the SPARCC 6–discovertebral unit method for the spine. Positive evidence of inflammation on MRI was defined as a SPARCC score of ≥2 for either the SI joints or the spine. Results Among patients with baseline SPARCC scores, 40% had an SI joint score of ≥2 and 52% had a spine score of ≥2. Forty-nine percent of patients with baseline SI joint scores of <2, and 58% of those with baseline SI joint scores of ≥2, had a spine score of ≥2. Comparison of baseline disease characteristics by baseline SI joint and spine scores showed that a greater proportion of patients in the subgroup with a baseline SPARCC score of ≥2 for both SI joints and spine were male, and patients with spine and SI joint scores of <2 were younger and had shorter symptom duration. SPARCC spine scores correlated with baseline symptom duration, and SI joint scores correlated negatively with the baseline Bath Ankylosing Spondylitis Disease Activity Index, but neither correlated with the baseline Ankylosing Spondylitis Disease Activity Score, total back pain, the patient's global assessment of disease activity, the Bath Ankylosing Spondylitis Functional Index, morning stiffness, nocturnal pain, or C-reactive protein level. Conclusion Assessment by experienced readers showed that spinal inflammation on MRI might be observed in half of

  2. Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation?

    PubMed

    Mekinian, Arsène; Cohen, Jonathan; Alijotas-Reig, Jaume; Carbillon, Lionel; Nicaise-Roland, Pascale; Kayem, Gilles; Daraï, Emile; Fain, Olivier; Bornes, Marie

    2016-07-01

    To describe and analyze the benefit of immunomodulatory drugs for recurrent miscarriages and implantation failures. The literature research was conducted in Medline, Embase and Cochrane Library concerning recurrent miscarriages and implantation failures and steroids, progesterone, intralipids, TNF-α antagonists, G-CSF, hydroxychloroquine, intravenous immunoglobulins, endometrial scratching. Using meta-analysis, modest benefit was found for progesterone to obtain a live birth, with odds ratio at 1.38 (95% CI: 1.07-1.77) and significant heterogeneity (P = 0.01, I(2) = 78%). In early ≥3 miscarriages, patients treated by TNF-α antagonists (adalimumab or etanercept; n = 17) combined with low-dose aspirin, heparin and intravenous immunoglobulins have a live births of 71% (12/17), vs 19% with aspirin+heparin (4/21) (P = 0.0026). Sixty-eight patients with unexplained recurrent miscarriage were randomized to receive either G-CSF (filgastrim, Neupogen, 1 μ/kg/day SC, n = 35) after the ovulation until the 9th weeks of gestation or placebo (n = 33). Among patients treated with G-CSF, 29/35 (82.8%) have live birth and 16/33 (48.5%) of controls (P = 0.006). Among 200 women with recurrent miscarriages and implantation failure treated with intralipids, the pregnancy rate was 52%, with pregnancy ongoing/live birth rate at 91%. The physiopathological rational for immunotolerance failure in this topic raise the need to demonstrate the efficacy of immunomodulatory drugs, define the patients subsets and develop treatment strategies. PMID:26847715

  3. Latent tuberculosis screening tests and active tuberculosis infection rates in Turkish inflammatory bowel disease patients under anti-tumor necrosis factor therapy

    PubMed Central

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