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Sample records for adalimumab adefovir dipivoxil

  1. [Adefovir dipivoxil-induced Fanconi syndrome and hypophosphatemic osteomalacia associated with muscular weakness in a patient with chronic hepatitis B].

    PubMed

    Li, Ling; Dong, Guang-fu; Zhang, Xiao; Xie, Yue-sheng

    2011-11-01

    Adefovir dipivoxil is commonly used for treatment of chronic hepatitis B. The renal toxicity of adefovir dipivoxil is dose- and time-related, occurring often in patients with a daily dose over 30 mg and those with impaired renal function. We report a case of chronic hepatitis B with a history of taking adefovir dipivoxil at 10 mg/day for 4 years. The patient complained of lumbosacral and joint pain and had the diagnosis of ankylosing spondylitis (AS) or spondyloarthropathy in several hospitals before admission in our hospital. A diagnosis of acquired Fanconi syndrome and hypophosphatemia osteomalacia associated with progressive muscular weakness was made eventually. We reviewed the literature and found reports of only fewer than 10 similar cases. Clinical attention should be given to kidney damage induced by adefovir dipivoxil.

  2. Coformer selection based on degradation pathway of drugs: a case study of adefovir dipivoxil-saccharin and adefovir dipivoxil-nicotinamide cocrystals.

    PubMed

    Gao, Yuan; Gao, Jing; Liu, Ziling; Kan, Hongliang; Zu, Hui; Sun, Wanjin; Zhang, Jianjun; Qian, Shuai

    2012-11-15

    Adefovir dipivoxil (AD) is a bis(pivaloyloxymethyl) prodrug of adefovir with chemical stability problem. It undergoes two degradation pathways including hydrolysis and dimerization during storage. Pharmaceutical cocrystallization exhibits a promising approach to enhance aqueous solubility as well as physicochemical stability. In this study we attempted to prepare and investigate the physiochemical properties of AD cocrystals, which were formed with two coformers having different acidity and alkalinity (weakly acidic saccharin (SAC) and weakly basic nicotinamide (NCT)). The presence of different coformer molecules along with AD resulted in altered physicochemical properties. AD-SAC cocrystal showed great improvement in solubility and chemical stability, while AD-NCT did not. Several potential factors giving rise to different solid-state properties were summarized. Different coformers resulted in different cocrystal formation, packing style and hydrogen bond formation. This study could provide the coformer selection strategy based on degradation pathways for some unstable drugs in pharmaceutical cocrystal design.

  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. Pathological femoral fractures due to osteomalacia associated with adefovir dipivoxil treatment for hepatitis B: a case report

    PubMed Central

    2012-01-01

    We present a case of a 62-year-old man who underwent total hip arthroplasty for treatment of pathologic femoral neck fracture associated with adefovir dipivoxil-induced osteomalacia. He had a 13-month history of bone pain involving his shoulders, hips, and knee. He received adefovir dipivoxil for treatment of lamivudine-resistant hepatitis B virus infection for 5 years before the occurrence of femoral neck fracture. Orthopedic surgeons should be aware of osteomalacia and pathological hip fracture caused by drug-induced renal dysfunction, which results in Fanconi’s syndrome. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1600344696739249 PMID:22906214

  6. Th1 and Th2 immune response in chronic hepatitis B patients during a long-term treatment with adefovir dipivoxil.

    PubMed

    Jiang, Yanfang; Ma, Zhenhua; Xin, Guijie; Yan, Hongqing; Li, Wanyu; Xu, Huining; Hao, Chunhai; Niu, Junqi; Zhao, Pingwei

    2010-01-01

    Adefovir dipivoxil treatment has significantly improved the outcome of chronic hepatitis B virus (HBV) infection. However, it remains largely unknown how immune system responds to the treatment. Chronic HBV patients were treated with adefovir dipivoxil and examined for serum HBV DNA loads, cytokines, and T helper (Th1) and 2 (Th2) cytokine producing T cells during 104 weeks of the treatment. Th1/Th2 cytokines producing T cells were significantly lower in chronic HBV patients as compared to normal individuals. Adefovir dipivoxil treatment led to the increase of Th1/Th2 cytokines producing T cells and serum cytokine levels in association with the decline of HVB DNA load. In contrast, Th1/Th2 cytokines producing T cells remained lower in one patient detected with adefovir dipivoxil resistant HBV A181T/V mutation. This study has established inverse correlation of the increase of Th1/Th2 immunity and the decline of HBV DNA load in chronic HBV patients during adefovir dipivoxil treatment. PMID:21127728

  7. 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.

  8. 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.

  9. Effect of adefovir dipivoxil on T cell immune function in the treatment of chronic hepatitis B and hepatocirrhosis

    PubMed Central

    Tian, Liting; Fu, Qilin; Huang, Fu

    2016-01-01

    The aim of the present study was to investigate the T cell immune function in chronic hepatitis B hepatocirrhosis patients at the compensated and decompensated stage following treatment with adefovir dipivoxil. A total of 104 patients diagnosed with hepatitis B hepatocirrhosis during the period from October 2013 to October 2014 were enrolled in the study. Among the cases, there were 56 cases at compensated stage, and another 48 at decompensated stage. Adefovir dipivoxil was administered for antiviral therapy (10 mg/time, 1 time/day, for a total of 24 weeks), and we compared the virus disappearance rate, liver function improvement and T cell immune function between the two groups before and after treatment. The difference between the virus disappearance rate in the two groups was not statistically significant (P>0.05). The decreased level of ALT decrease in the compensated group was significantly higher than that in the decompensated group, while the increased level of albumin in the compensated group was significantly higher as well. The differences showed statistical significance (P<0.05). After treatment, the level of CD4+ and CD4+/CD8+ ratio were higher than before treatment, while the level of CD8+ was lower after treatment than before treatment in the two groups. The differences all showed statistical significance (P<0.05). The CD4+CXCR5+ T follicular helper (TFH) cell level in the two groups was higher after treatment, as was interleukin-2 and interferon-γ. The differences all showed statistical significance (P<0.05). As for comparison between groups, the difference had no statistical significance (P>0.05). Adefovir dipivoxil treatment can improve T cell immune function at the compensated and decompensated stages in chronic hepatitis B hepatocirrhosis patients. This may be associated with virus disappearance and liver function improvement.

  10. Effect of adefovir dipivoxil on T cell immune function in the treatment of chronic hepatitis B and hepatocirrhosis

    PubMed Central

    Tian, Liting; Fu, Qilin; Huang, Fu

    2016-01-01

    The aim of the present study was to investigate the T cell immune function in chronic hepatitis B hepatocirrhosis patients at the compensated and decompensated stage following treatment with adefovir dipivoxil. A total of 104 patients diagnosed with hepatitis B hepatocirrhosis during the period from October 2013 to October 2014 were enrolled in the study. Among the cases, there were 56 cases at compensated stage, and another 48 at decompensated stage. Adefovir dipivoxil was administered for antiviral therapy (10 mg/time, 1 time/day, for a total of 24 weeks), and we compared the virus disappearance rate, liver function improvement and T cell immune function between the two groups before and after treatment. The difference between the virus disappearance rate in the two groups was not statistically significant (P>0.05). The decreased level of ALT decrease in the compensated group was significantly higher than that in the decompensated group, while the increased level of albumin in the compensated group was significantly higher as well. The differences showed statistical significance (P<0.05). After treatment, the level of CD4+ and CD4+/CD8+ ratio were higher than before treatment, while the level of CD8+ was lower after treatment than before treatment in the two groups. The differences all showed statistical significance (P<0.05). The CD4+CXCR5+ T follicular helper (TFH) cell level in the two groups was higher after treatment, as was interleukin-2 and interferon-γ. The differences all showed statistical significance (P<0.05). As for comparison between groups, the difference had no statistical significance (P>0.05). Adefovir dipivoxil treatment can improve T cell immune function at the compensated and decompensated stages in chronic hepatitis B hepatocirrhosis patients. This may be associated with virus disappearance and liver function improvement. PMID:27698751

  11. 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

  12. Adefovir

    MedlinePlus

    Adefovir is used to treat chronic (long-term) hepatitis B infection (swelling of the liver caused by a ... analogs. It works by decreasing the amount of hepatitis B virus (HBV) in the body. Adefovir will not ...

  13. Cost-effectiveness analysis of lamivudine, telbivudine, and entecavir in treatment of chronic hepatitis B with adefovir dipivoxil resistance

    PubMed Central

    Wang, Guiliang; Liu, Yan; Qiu, Ping; Zhou, Shu-Feng; Xu, Linfang; Wen, Ping; Wen, Jianbo; Xiao, Xianzhong

    2015-01-01

    The purpose of this study was to analyze the cost-effectiveness of lamivudine (LMV), telbivudine (LdT), and entecavir (ETV) in treatment of chronic hepatitis B with adefovir dipivoxil (ADV) resistance. Two hundred and fifty-two patients were recruited and screened for resistance to ADV and randomly assigned into three groups: LMV + ADV, LdT + ADV, and ETV + ADV. The ratio of biochemical response, virological response, seroconversion of hepatitis Be antigen (HBeAg)/hepatitis Be antibody (HBeAb), viral breakthrough, and the cost and effectiveness of treatments were analyzed. A comparison of the results of the ratio of biochemical response, virological response and seroconversion of HBeAg/HBeAb, showed no statistical difference between the three groups, with the economic cost of LMV + ADV the lowest, LdT + ADV the middle, and ETV + ADV the highest. The side effects of the three plans are all rare and tolerable. LMV + ADV is the optimal rescue strategy, and LdT + ADV the alternative selection in the economically less developed regions, while ETV + ADV was used in the economically developed regions. PMID:26082614

  14. 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

  15. 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

  16. Adalimumab Injection

    MedlinePlus

    ... not improved when treated with other medications, ulcerative colitis (a condition which causes swelling and sores in ... adalimumab injection to treat Crohn's disease or ulcerative colitis, your doctor may tell you to inject the ...

  17. Adefovir added to lamivudine for hepatitis B recurrent infection in refractory B-cell chronic lymphocytic leukemia on prolonged therapy with Campath-1H.

    PubMed

    Cortelezzi, Agostino; Viganò, Mauro; Zilioli, Vittorio R; Fantini, Norma N; Pasquini, Maria C; Deliliers, Giorgio Lambertenghi; Colombo, Massimo; Lampertico, Pietro

    2006-04-01

    We describe a case of severe reactivation of occult hepatitis B virus infection in a 49-year-old man, who was treated with high doses of chlorambucil for a Binet stage A B-cell chronic lymphocytic leukemia (B-CLL). The patient was initially treated with lamivudine and subsequently with lamivudine and adefovir dipivoxil combination therapy to control viral replication and allow for long-term anti-cancer chemotherapy with alemtuzumab (Campath-1H), which was introduced to rescue for a B-CLL relapse. During 20 months of anti-HBV therapy, ALT and HBV-DNA levels progressively declined and B-CLL was successfully kept under control by long-term alemtuzumab administration.

  18. Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis.

    PubMed

    Česnek, Michal; Jansa, Petr; Šmídková, Markéta; Mertlíková-Kaiserová, Helena; Dračínský, Martin; Brust, Tarsis F; Pávek, Petr; Trejtnar, František; Watts, Val J; Janeba, Zlatko

    2015-08-01

    Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50 =0.145 μM). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough.

  19. A novel baseline hepatitis B virus sequencing-based strategy for predicting adefovir antiviral response.

    PubMed

    Wang, Yu-Wei; Shan, Xuefeng; Huang, Yao; Deng, Haijun; Huang, Wen-Xiang; Zhang, Da-Zhi; Chen, Juan; Tang, Ni; Shan, You-Lan; Guo, Jin-Jun; Huang, Ailong

    2015-07-01

    Adefovir dipivoxil (ADV) is used as first-line monotherapy or rescue therapy in chronic hepatitis B (CHB) patients. In this study, we sought to identify nucleotide changes in the reverse transcriptase (RT) of hepatitis B virus (HBV) at baseline and explore their predictive value for ADV antiviral response. Ultra-deep pyrosequencing (UDPS) was utilized to determine HBV genetic variability within the RT region at baseline and during a 48-week ADV therapy. According to the viral load at the end of ADV treatment, all patients were classified into responders (HBV DNA level reduction of ⩾ 3 log 10 IU/mL) and suboptimal responders (HBV DNA level reduction of <3 log 10 IU/mL). Based on UDPS data at baseline, we identified 11 nucleotide substitutions whose combination frequency was significantly associated with the antiviral response among 36 CHB patients in the study group. However, the baseline distribution and frequency of rt181 and rt236 substitutions known to confer ADV resistance was a poor predictor for the antiviral response. Compared with baseline serum HBeAg, HBV-DNA and ALT levels, the baseline HBV sequence-based model showed higher predictive accuracy for ADV response. In an independent cohort of 31 validation patients with CHB, the sequence-based model provided greater predictive potency than the HBeAg/HBV-DNA/ALT and the HBeAg/HBV-DNA/ALT/sequence combinations. Taken together, we confirm the presence of ADV resistance variants in treatment-naïve patients and firstly unravel the predictive value of the baseline mutations in the HBV RT region for ADV antiviral response.

  20. Adefovir is effective to promote development of immunity to donor origin hepatitis B virus in an allogeneic transplant recipient: a case report.

    PubMed

    Yaşar, D G; Suyanı, E; Özenirler, S; Sucak, G T

    2013-03-01

    Hepatitis B infection is a serious health problem in endemic areas particularly among immunocompromised patients. The more profound immunosuppression in recipients of hematopoietic stem cell transplantations (HCT) can lead to more complicated hepatitis B virus (HBV)-related events. Despite the high risk of recipient infection allogeneic HCT donors with HBV infection are not excluded in the absence of an alternative donor. A 25 year-old man with severe aplastic anemia underwent allogeneic HCT from his HLA-identical sibling. The patient was hepatitis B naive and had normal liver function tests. However the donor had hepatitis B surface antigen (HbsAg) positivity, and collected stem cells were positive for HBV DNA (1 × 10(4) copies/mL). Lamivudine was initiated to treat the patient prior to transplantation. Forty days after the HCT, the patient displayed hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis B e antibody (HBeAb), with HBV-DNA negativity. Cyclosporine was tapered and finally stopped at day + 256. On day +368, 112 days after the cessation of cyclosporine HBV reactivation was detected with an HBV-DNA level of 10 × 10(4) copies/mL despite lamivudine. After demonstration of the YMDD mutation, adefovir dipivoxil was combined with lamivudine. The HBV-DNA became negative; AST ALT levels decreased to normal levels after a month of combination therapy. In conclusion adefovir was effective to treat lamivudine-resistant HBV infection in an allogeneic HCT recipient. PMID:23498831

  1. Adalimumab: A Review in Chronic Plaque Psoriasis.

    PubMed

    Burness, Celeste B; McKeage, Kate

    2015-12-01

    Adalimumab (Humira(®)) is a fully human monoclonal antibody against tumour necrosis factor (TNF), formulated for subcutaneous administration. It is well established in the treatment of adults with moderate-to-severe chronic plaque psoriasis and has recently received approval in the EU for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age. In a phase III trial in paediatric patients, a significantly greater proportion of patients receiving adalimumab 0.8 mg/kg (to a maximum of 40 mg) every other week (eow) achieved a ≥75 % improvement from baseline in Psoriasis Area and Severity Index than those receiving methotrexate after 16 weeks of treatment. In adults, well-designed randomized clinical trials demonstrated that adalimumab 40 mg eow effectively reduced the signs and symptoms of psoriasis and improved dermatology-specific and general measures of health-related quality of life, with these benefits sustained during long-term treatment. Adalimumab was generally well tolerated, compared with placebo or methotrexate, during clinical trials in paediatric and adult patients with chronic plaque psoriasis. Thus, adalimumab remains an important treatment strategy in adults with moderate-to-severe chronic plaque psoriasis and provides a promising new systemic treatment option for children and adolescents from 4 years of age with severe psoriasis.

  2. Adalimumab in Crohn’s disease

    PubMed Central

    Van Assche, Gert; Vermeire, Séverine; Rutgeerts, Paul

    2007-01-01

    Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel diseases (IBD), it does not provide a cure for IBD and recent evidence has demonstrated that the immunogenicity of this chimeric anti-TNF antibody is associated with secondary loss of response and intolerance. In ulcerative colitis (UC) the efficacy of infliximab was demonstrated in two large clinical trials, but long-term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last two years. For Crohn’s disease (CD) two anti-TNF agents, the fully human IgG1 anti-TNF monoclonal adalimumab and the humanized pegylated Fab-fragment certolizumab-pegol and the humanized anti α4 integrin IgG4 antibody both have demonstrated efficacy as maintenance agents. Adalimumab has been approved to treat active rheumatoid arthritis, psoriatric arthritis, and ankylosing spondylitis, and recently moderate-to-severe luminal CD has been added as an indication for this agent both by the FDA and EMEA. Further evidence is needed to establish the therapeutic potential of adalimumab in fistulizing CD and in UC. The benefit to risk ratio of anti-TNF agents in refractory IBD is clearly positive and since most of the toxicity is class specific, adalimumab is expected to have a safety profile similar to that of infliximab except for adverse events related to infusions. PMID:19707306

  3. 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

  4. The economics of adalimumab for ulcerative colitis.

    PubMed

    Xie, Feng

    2015-06-01

    Ulcerative colitis is a chronic inflammatory disease, characterized by diffuse mucosal inflammation in the colon. Adalimumab, as a TNF-α blocker, offers a safe and efficacious treatment option for patients with moderate to severe ulcerative colitis and refractory or intolerant to conventional medications; however, its cost-effectiveness profile has not yet been well established. Future economic evaluations should choose appropriate comparators in the context of target-reimbursement decision making and focus on cost-effectiveness over a long time horizon.

  5. The Effect of Prophylactic Lamivudine plus Adefovir Therapy Compared with Lamivudine Alone in Preventing Hepatitis B Reactivation in Lymphoma Patients with High Baseline HBV DNA during Chemotherapy

    PubMed Central

    Wu, Shaoxu; Geng, Qirong; Huang, Huiqiang; Lin, Tongyu; Jiang, Wenqi; Xia, Zhongjun; Duan, Huaxin; Rao, Huilan; Yao, Mengfei; Hu, Liyang

    2016-01-01

    Prophylactic antiviral therapy is essential for lymphoma patients with high baseline HBV DNA who undergo cytotoxic chemotherapy. However, there are limited data on the optimal options. The present study was designed to compare the efficacy of prophylactic lamivudine (LAM) with lamivudine plus adefovir dipivoxil (LAM+ADV) in preventing hepatitis B virus (HBV) reactivation in lymphoma with, pre-chemotherapy HBV DNA load ≥2000 IU/ml. We retrospectively analyzed the medical records of 86 lymphoma patients with baseline HBV DNA load ≥2000 IU/ml during chemotherapy and received LAM or LAM+ADV as prophylaxis between January 1, 2008 and November 30, 2014 at Sun Yat-sen University Cancer Center, China. Sixty-five patients received LAM and 21 received LAM+ADV. The rate was significantly lower in the LAM+ADV group compared with the LAM group for HBV reactivation (23.8% vs 55.4%; p = 0.012), while no difference was observed between the two groups in patients for HBV-related hepatitis (21.3% vs 33.3%; p   =  0.349), and chemotherapy disruption (10.9% vs 19.0%; p = 0.337). In a multivariate analysis of factors associated with HBV reactivation in these patients, LAM+ADV treatment and HBeAg negative were the independent protective factors. Therefore, LAM+ADV should be considered for antiviral prophylaxis in lymphoma patients with pre-chemotherapy HBV DNA load ≥2000 IU/ml. Further study is warranted to confirm these findings. PMID:27711135

  6. 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.

  7. Efficacy and safety of adalimumab in ankylosing spondylitis

    PubMed Central

    Mounach, Aziza; El Maghraoui, Abdellah

    2014-01-01

    Ankylosing spondylitis (AS) is the most common and most severe subtype of spondyloarthritis. It also may be an outcome of any of the other spondyloarthritis subtypes. AS preferentially affects the sacroiliac joints and the tip of the column, with a tendency to later ankylosis. Peripheral joints, enthesis, and other extra-articular involvement may be observed. Tumor necrosis factor (TNF) inhibitors are now well-established, effective drugs in the treatment of AS symptoms. Adalimumab, which is a fully human monoclonal antibody that binds to and neutralizes TNF, has demonstrated efficacy in treating AS symptoms, including axial involvement, peripheral arthritis, enthesitis, uveitis, gut involvement, and psoriasis. Furthermore, adalimumab has showed an overall acceptable safety profile. In this paper, we review the efficacy and safety profile of adalimumab in the treatment of AS, and discuss its differences from the other anti-TNF drugs reported in the literature.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. [Peripheral corneal melting syndrome in psoriatic arthritis treated with adalimumab].

    PubMed

    Restrepo, Juan Pablo; Medina, Luis Fernando; Molina, María del Pilar

    2015-01-01

    Peripheral corneal melting syndrome is a rare immune condition characterized by marginal corneal thinning and sometimes perforation. It is associated with rheumatic and non-rheumatic diseases. Few cases of peripheral corneal melting have been reported in patients with psoriasis. The pathogenesis is not fully understood but metalloproteinases may play a pathogenic role. Anti-TNF therapy has shown to decrease skin and serum metalloproteinases levels in psoriasis. We report a 61-year-old man with peripheral corneal melting syndrome associated with psoriatic arthritis who received Adalimumab to control skin and ocular inflammation. To our knowledge, this is the first case report of peripheral corneal melting syndrome in psoriatic arthritis treated with Adalimumab showing resolution of skin lesions and complete healing of corneal perforation in three months.

  13. Yellow Fever Vaccination of a Primary Vaccinee During Adalimumab Therapy.

    PubMed

    Nash, Esther R; Brand, Myron; Chalkias, Spyridon

    2015-01-01

    In this case report, we describe a 63-year-old female with Crohn's disease since age 16 years, and on adalimumab therapy, who inadvertently received a yellow fever vaccine (YFV) 4 days before her next dose of adalimumab. She had never received YFV. Her next dose of tumor necrosis factor (TNF) antagonist was held. She did not report any adverse effects referable to the vaccine. Reverse transcriptase-polymerase chain reaction (RT-PCR) for yellow fever (YF) viral RNA on days 12 and 18 postvaccination was negative. Neutralizing antibody to YF virus vaccine was immunoprotective on day 18 following vaccination, which further increased by day 26. A neutralizing antibody obtained 2 years following vaccination also remained immunoprotective.

  14. Psoriatic arthritis and chronic lymphoedema: treatment efficacy by adalimumab.

    PubMed

    Tong, Denise; Eather, Sharron; Manolios, Nicholas

    2009-11-01

    Lymphoedema is a rare complication of psoriatic arthritis (PsA) and inflammatory joint disease, with no response noted to disease-modifying drugs. However, reports are emerging of a beneficial effect on lymphoedema in patients treated with tumor necrosis factor-alpha antagonists for PsA (Etanercept), rheumatoid arthritis (Etanercept) and ankylosing spondylitis (Infliximab). We describe a psoriatic arthritis patient whose lymphoedema greatly improved following commencement of adalimumab.

  15. 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

  16. Adalimumab-associated antiphospholipid syndrome: a case report and review of the literature.

    PubMed

    Hemmati, Iman; Kur, Jason

    2013-07-01

    This study aims for the presentation of the first reported case of adalimumab-associated antiphospholipid syndrome (APS) and review of the literature on adalimumab-induced vasculitis and APS. A case of APS associated with adalimumab use in a 67-year-old woman is reported. The English medical literature was reviewed for antitumor necrosis factor (TNF) agents and their association with APS and vasculitis. Adalimumab is a fully humanized monoclonal antibody targeted against TNF alpha that is widely used in the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and Crohn's disease. Literature review reveals several cases of anti-TNF-induced vasculitis including cases associated with adalimumab. We report the first case of adalimumab-induced APS in a 67-year-old woman who developed APS and vasculitis associated with de novo positive anti-cardiolipin (aCL) antibody following the third dose of adalimumab therapy for the treatment of spondyloarthropathy. This is the first case demonstrating that a short course of adalimumab therapy may induce immunoglobulin M aCL autoantibodies leading to APS. With the growing use of anti-TNF medications in immune-mediated and inflammatory diseases, adalimumab and other anti-TNF medications should be considered as a possible explanation for APS.

  17. Long-term treatment of rheumatoid arthritis with adalimumab

    PubMed Central

    Murdaca, Giuseppe; Spanò, Francesca; Puppo, Francesco

    2013-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint damage and progressive disability, an increased risk of morbidity related to comorbid conditions and substantial socioeconomic costs. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine known to have a central role in the initial host response to infection and in the pathogenesis of various immune-mediated diseases, such as RA, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, Crohn’s disease, and systemic lupus erythematosus. Five TNF-α inhibitors are available for the clinical use: infliximab; adalimumab; etanercept; golimumab; and certolizumab pegol. Infliximab is a chimeric human/murine IgG1 monoclonal antibody (mAb); adalimumab, and golimumab are human mAbs; certolizumab pegol is composed of the fragment antigen-binding anti-binding domain of a humanized anti-TNF-α mAb, combined with polyethylene glycol to increase its half-life in the body; etanercept is a fusion protein that acts as a “decoy receptor” for TNF-α. In this paper, we will briefly review the current data on efficacy and safety of adalimumab in patients with RA, its potential beneficial effects upon comorbid conditions, such as endothelial dysfunction and accelerated atherosclerosis in RA, and the immunogenicity.

  18. Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a phase I/II study.

    PubMed

    Kamp, W; Schokker, J; Cambridge, E; De Jong, S; Schuurman, R; De Groot, T; Boucher, C A

    1999-01-01

    The compound 9-(2-phosphonylmethoxyethyl)adenine (adefovir; PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus (HIV) type 1 and 2, herpes simplex virus (HSV) type 1 and 2, human papillomavirus virus (HBV) and Epstein-Barr virus (EBV). Adefovir also proved to be effective in vivo against feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in rhesus monkeys. In an open, non-placebo-controlled trial the antiviral activity of weekly doses of adefovir in nine patients with AIDS or AIDS-related complex was studied for a period of 11 weeks. CD4 cell counts at baseline were between 10 and 450 cells/mm3, HIV-1 RNA levels at baseline were between 24,210 copies/ml and 406,197 copies/ml. The drug was administered intravenously at a dose of 1000 mg every week and plasma viral load was assessed at multiple points during the study. Administration of adefovir was tolerated well and no severe side effects were seen. The response to adefovir treatment differed widely between patients. The increase in CD4 cell count at end point ranged from -40 to 120 cell/mm3. The lowest HIV RNA levels were measured after 3-5 days, showing an increase thereafter. The nadir in viral load was achieved after 2 weeks, with a mean viral load decline of 0.7 from baseline. The decrease of the HIV RNA level at end point ranged from -0.3 log10 to 1.8 log10 with a mean decrease of 0.4 log10. Our results indicate that adefovir given intravenously once weekly has a short-lasting initial antiviral effect. The effect of more frequent dosing requires further evaluation. If adefovir is to be useful clinically, it needs to be combined with other antiviral agents.

  19. Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients

    PubMed Central

    Pereira-Gómez, Marianoel; Bou, Juan-Vicente; Andreu, Iván; Sanjuán, Rafael

    2016-01-01

    The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10−5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses. PMID:27649318

  20. Lamivudine/Adefovir Treatment Increases the Rate of Spontaneous Mutation of Hepatitis B Virus in Patients.

    PubMed

    Pereira-Gómez, Marianoel; Bou, Juan-Vicente; Andreu, Iván; Sanjuán, Rafael

    2016-01-01

    The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10-5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses. PMID:27649318

  1. Successful use of adalimumab in patient with treatment-refractory microscopic colitis.

    PubMed

    Anderson, Rebecca Jane; Makins, Richard

    2016-01-01

    A 50-year-old woman with treatment-refractory lymphocytic colitis was diagnosed with ankylosing spondylitis. She was started on adalimumab injections which significantly improved her stool frequency and consistency and, consequently, her quality of life. PMID:27530873

  2. Long-term use of adalimumab in the treatment of rheumatic diseases

    PubMed Central

    Papagoras, Charalampos; Voulgari, Paraskevi V; Drosos, Alexandros A

    2009-01-01

    Adalimumab, a fully humanized monoclonal antibody against tumor necrosis factor-alpha (TNFα), has been evaluated in various randomized placebo-controlled trials in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis. In the short time frame of these trials adalimumab has been shown to be effective in reducing disease activity, slowing radiographic disease progression and improving patients’ quality of life, while at the same time demonstrating an acceptable safety profile. Furthermore, release of adalimumab on the market, prospective observational studies, as well as open-label extensions of the original double-blind trials have provided experience and data about the long-term efficacy and safety of the drug. Initial effectiveness, in terms of reducing disease activity, is sustained, while in most cases patients treated with adalimumab experienced a slower radiographic progression and consequently less disability and improved health-related quality-of-life outcomes. Moreover, long-standing treatment of thousands of patients with adalimumab outside the controlled context of clinical trials was not related to new safety signals, with the most common adverse events being respiratory infections. The most common serious adverse events seem to be tuberculosis reactivation, while a putative association with malignant lymphoma development is not yet proven. Besides, both of these adverse reactions pertain to the whole TNFα blocker group. In conclusion, adalimumab is a safe and effective option for the treatment of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis.

  3. 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

  4. A Randomized, Double‐Blind, Placebo‐Controlled Multicenter Study of Adalimumab in Pediatric Patients With Enthesitis‐Related Arthritis

    PubMed Central

    Tse, Shirley M. L.; Horneff, Gerd; Pangan, Aileen L.; Kalabic, Jasmina; Goss, Sandra; Unnebrink, Kristina; Anderson, Jaclyn K.

    2015-01-01

    Objective Enthesitis‐related arthritis (ERA) is a juvenile idiopathic arthritis (JIA) category, primarily affecting entheses and peripheral joints. This study evaluated efficacy, safety, and pharmacokinetics of adalimumab versus placebo in patients with ERA. Methods This is a phase III, multicenter, randomized double‐blind study in patients ages ≥6 to <18 years with ERA treated with adalimumab (24 mg/m2, maximum dose 40 mg every other week) or placebo for 12 weeks, followed by up to 192 weeks of open‐label adalimumab. The primary end point was percent change from baseline in number of active joints with arthritis (AJC) at week 12. Samples were collected to determine adalimumab serum concentrations. Adverse events (AEs) were assessed throughout the study. Results Forty‐six patients were randomized (31 adalimumab/15 placebo). At baseline, mean age was 12.9 years, mean duration of ERA symptoms was 2.6 years, mean AJC was 7.8, and mean enthesitis count was 8.1. Mean percent change from baseline in AJC at week 12 was greater in the adalimumab group versus placebo (−62.6% versus −11.6%; P = 0.039). Most secondary variables favored adalimumab versus placebo at week 12. Treatment response further increased with continued adalimumab therapy through week 52. Mean steady‐state adalimumab serum concentrations were 7.5–11.8 μg/ml, similar to patients age ≥2 years with polyarticular JIA. AE rates were similar between placebo and adalimumab: any AE (53.3% versus 67.7%), serious AEs (0% versus 3.2%), and infectious AEs (20.0% versus 29.0%). Conclusion Adalimumab reduced signs and symptoms of ERA at week 12, with improvement sustained through week 52. The safety profile was consistent with previous adalimumab studies. PMID:26223543

  5. 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

  6. Modeling and Simulating Dynamics of Complete- and Poor-Response Chronic Hepatitis B Chinese Patients for Adefovir and Traditional Chinese Medicine Plus Adefovir Therapy

    PubMed Central

    Min, Lequan; Chen, Xiao; Ye, Yongan; Zhang, Qun; Ru, Shuying; Li, Xiaoke

    2013-01-01

    ChiCTR-TRC-11001263 study was the first large-scale double-blind randomized placebo-controlled traditional Chinese medicines (TCMs) and adefovir (ADV) antihepatitis B virus (HBV) infection trial in the world. A total of 560 hepatitis B e antigen- (HBeAg-) positive Chinese patients with chronical HBV were randomly classified, in 1 : 1 ratio, into two groups: experimental group (EXG) receiving TCMs + ADV and controlled group (CTG) receiving ADV + TCM-placebo treatment for 48 weeks. This paper introduces two models to model and simulate the evolutions of dynamics for the complete-response patients and the poor-response patients in EXG and CTG, respectively. The stimulated mean HBV DNA and alanine aminotransferase (ALT) levels were close to the patients' experimental data. Analysis and simulations suggest that the activated patients' immune functions by TCMs + ADV may not only clear infected hepatocytes, but also clear HBV, which made the complete-response patients' mean serum HBV DNA levels in EXG reduce rapidly 12 weeks' earlier than the ones in CTG. One can assume that both the TCMs and ADV have the function of preventing complete-response patients' infected hepatocytes from being injured by cytotoxic T lymphocytes (CTLs); the patients' activated immune cells may also block HBV replications. PMID:24282437

  7. Spotlight on adalimumab in the treatment of active moderate-to-severe hidradenitis suppurativa

    PubMed Central

    Fotiadou, Christina; Vakirlis, Efstratios; Ioannides, Dimitrios

    2016-01-01

    Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory skin disease that affects the hair follicles of the aprocrine gland-bearing anatomical areas of the body. It is characterized by deep painful nodules and abscesses that rupture and contribute to the formation of sinus tracks and scarring. The management of HS is based on the assessment of disease severity and a combination of medical and surgical treatment according to the European Guidelines. Adalimumab, a recombinant, fully humanized, anti-tumor necrosis factor alpha (anti-TNF-α) monoclonal antibody, is the only officially approved treatment for the management of moderate-to-severe HS. Case reports, concerning 42 patients who received adalimumab for severe HS (with the standard dose regimen for psoriasis), reported a cumulative response rate of 58% (≥50% in 23 patients) with a relapse rate of 71% (10 out of 14 patients). The most recent and most well-powered phase III, randomized placebo-controlled trials for the evaluation of the efficacy and safety of adalimumab in treatment of moderate-to-severe HS (PIONEER studies I and II) showed that the Hidradenitis Suppurativa Clinical Response (HiSCR) rate at week 12 was significantly higher for patients randomized to adalimumab compared to placebo. Adverse events were comparable to placebo. In conclusion, adalimumab, to date, holds the most robust data regarding treatment efficacy in HS. Larger, registry-based studies are needed to further establish the efficacy and safety profile of this anti-TNF-α agent in HS. PMID:27799806

  8. 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

  9. Profile of adalimumab and its potential in the treatment of uveitis

    PubMed Central

    Balevic, Stephen J; Rabinovich, C Egla

    2016-01-01

    Uveitis refers to the presence of intraocular inflammation, and as a strict definition compromises the iris and ciliary body anteriorly and the choroid posteriorly (the uvea). Untreated, uveitis can lead to visual loss or blindness. The etiology of uveitis can include both infectious and noninfectious (usually immune-mediated) causes, the latter of which are often mediated predominantly by Th1 CD4+ T-cells that secrete proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of uveitis, which at high concentrations can cause excess inflammation and tissue damage. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. Historically, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have revolutionized therapy for noninfectious uveitis. Adalimumab has shown efficacy in treating refractory uveitis in multiple settings, including idiopathic disease, juvenile idiopathic arthritis, sarcoidosis, Behçets disease, and uveitis secondary to spondyloarthropathies, among several other noninfectious uveitis conditions. In this paper, we will review the profile of adalimumab, the role of TNF-α in uveitis, discuss safety data, and summarize key articles evaluating the efficacy of adalimumab in treating uveitis secondary to the most commonly associated autoimmune diseases. PMID:27698552

  10. Profile of adalimumab and its potential in the treatment of uveitis

    PubMed Central

    Balevic, Stephen J; Rabinovich, C Egla

    2016-01-01

    Uveitis refers to the presence of intraocular inflammation, and as a strict definition compromises the iris and ciliary body anteriorly and the choroid posteriorly (the uvea). Untreated, uveitis can lead to visual loss or blindness. The etiology of uveitis can include both infectious and noninfectious (usually immune-mediated) causes, the latter of which are often mediated predominantly by Th1 CD4+ T-cells that secrete proinflammatory cytokines. Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine involved in the pathogenesis of uveitis, which at high concentrations can cause excess inflammation and tissue damage. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF-α. Historically, corticosteroids and methotrexate were used to treat uveitis; however, newer biologic agents such as adalimumab have revolutionized therapy for noninfectious uveitis. Adalimumab has shown efficacy in treating refractory uveitis in multiple settings, including idiopathic disease, juvenile idiopathic arthritis, sarcoidosis, Behçets disease, and uveitis secondary to spondyloarthropathies, among several other noninfectious uveitis conditions. In this paper, we will review the profile of adalimumab, the role of TNF-α in uveitis, discuss safety data, and summarize key articles evaluating the efficacy of adalimumab in treating uveitis secondary to the most commonly associated autoimmune diseases.

  11. 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

  12. 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

  13. 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

  14. Is adalimumab protective in ischemia-reperfusion injury in lung?

    PubMed Central

    Kurt, Aysel; Tumkaya, Levent; Kalkan, Yildiray; Turut, Hasan; Cure, Medine Cumhur; Cure, Erkan; Sehitoglu, Ibrahim; Bilgin, Hacer; Usta, Mustafa

    2015-01-01

    Objective(s): Increasing cytokines and reactive oxygen species (ROS) during ischemia reperfusion (I-R) leads to the lung damage. Adalimumab (Ada) is a potent tumor necrosis factor-alpha (TNF-α) inhibitor agent. We aimed to evaluate whether Ada would prevent the lung tissue from damage development over the I-R process. Materials and Methods: Twenty seven Wistar albino male rats were divided into three groups (each group had 9 rats). To the control group, only laparotomy procedure was carried out. For I-R group, first infrarenal abdominal aorta was cross-clamped during 2 hr, and then reperfusion was performed for 2 hr. To I-R+Ada group, first a single dose of 50 mg/kg Ada was given intraperitoneally and 5 days later, same I-R procedure was carried out. Results: Levels of TNF-α, malondialdehyde (MDA), myeloperoxidase (MPO), endothelin-1 (ET-1) and caspase-3 enzyme activity of I-R group were higher than that of both I-R+ Ada [TNF-α (P=0.021), MDA (P=0.029), MPO (P=0.012), ET-1 (P=0.036, caspase-3 (P=0.007), respectively] and control group [TNF-α (P=0.008), MDA (P<0.001), MPO (P=0.001), ET-1 (P<0.001), caspase-3 (P<0.001), respectively]. In I-R group, severe damage was detected by hematoxylin-eosin staining. This damage was found less severe in Ada treatment group. Conclusion: The release of cytokines and ET-1 in a large proportion after I-R injury, and generating of ROS in excessive quantity could cause severe damage in the lung tissue. Ada could be considered as a protective agent for lung tissue during I-R process. PMID:26949496

  15. Multiple sclerosis during adalimumab treatment in a case with ankylosing spondylitis.

    PubMed

    Uygunoğlu, Uğur; Uluduz, Derya; Taşçılar, Koray; Saip, Sabahattin

    2014-01-01

    Ankylosing spondylitis is a chronic and progressive inflammatory disease involving the sacroiliac joints with HLA-B27 positivity in 85% of the patients and radiologically evidence of sacroiliitis. It is associated with several extraarticular manifestations, but neurological complications are rare. Occurrence of multiple sclerosis in patients with ankylosing spondylitis has been reported in limited cases. Adalimumab, a TNF-α antagonist, offers a significant improvement in ankylosing spondylitis and is considered to be less immunogenic and more tolerable than other TNF-α blockers. A case of multiple sclerosis coexisted with HLA-B27 positive ankylosing spondylitis after treated with adalimumab was reported.

  16. Successful treatment of Acrodermatitis continua of Hallopeau associated with psoriatic arthritis with adalimumab

    PubMed Central

    Lefkir, Salima; Slimani, Samy; Brahimi, Nadjia; Ladjouze-Rezig, Aicha

    2015-01-01

    Acrodermatitis continua of Hallopeau (ACH) is a rare form of pustular psoriasis, mainly affecting distal phalanges of hands and feet. Many therapeutic options exist; however, it tends to be resistant to treatment. We report a 26-year-old man presented with a very severe psoriatic arthritis associated with ACH. Although this patient was resistant to a first line treatment (glucocorticoids and methotrexate), a rapid and dramatic improvement was observed after adalimumab was introduced. The effectiveness and tolerance of the treatment were maintained during the 12-month period of follow-up. This is the first report of the efficacy of adalimumab on ACH in a patient presented with psoriatic arthropathy.

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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

  2. Severe candida laryngitis in a patient with rheumatoid arthritis treated with adalimumab

    PubMed Central

    Kobak, Şenol; Yılmaz, Hatice; Güçlü, Oğuz; Öğretmen, Zerrin

    2014-01-01

    Rheumatoid arthritis is a chronic erosive rheumatic disease that can present with polyarticular involvement. Anti-TNF-alpha drugs are used in cases that are resistant to traditional disease-modifying antirheumatic drugs (DMARDs). Anti-TNF-alpha drugs are groundbreaking drugs, the efficacy of which has been proven in the treatment of rheumatoid arthritis. However, the data concerning safety remain limited and contradictory. The risk of tuberculosis reactivation, various infections, as well as lymphoproliferative disease and/or secondary malignancy is a matter of discussion. In this report, we report a 52-year-old male patient using adalimumab for active rheumatoid arthritis who presented to our polyclinic with generalized mouth and throat sores, hoarseness, and swallowing difficulty. Candida laryngitis was detected in the laryngoscopy and culture samples. Adalimumab was discontinued, and the infection was controlled with anti-fungal treatment. PMID:27708907

  3. 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

  4. 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.

  5. 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

  6. A Case Report of Acute Cellular Rejection Following Intestinal Transplantation Managed With Adalimumab.

    PubMed

    Rao, B; Jafri, S-M; Kazimi, M; Mullins, K; Raoufi, M; Segovia, M C

    2016-03-01

    There is a higher incidence of acute cellular rejection (ACR) in small bowel transplantation (SBT) compared with transplantation of other solid organs. Although there are reports on the use of infliximab to successfully treat ACR refractory to other treatments, there are no reports, to our knowledge, regarding the use of adalimumab. We present a case of a female patient with a history of Crohn's disease who underwent an isolated SBT and developed an episode of severe ACR. She was initially treated with methylprednisolone, thymoglobulin, basiliximab, and a dosage adjustment of tacrolimus. Results of repeat endoscopies and biopsies revealed no significant improvement. The patient initiated treatment with adalimumab every 2 weeks for a total of 6 months, in addition to maintenance treatment with prednisone and tacrolimus. Subsequent evaluations showed gradual improvement to normal mucosa and villi without ulceration. A regimen that incorporates adalimumab can thus be used to treat ACR after intestinal transplantation. Larger multicenter studies are needed to show the full efficacy of this therapeutic regimen.

  7. 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

  8. Real-Life Treatment Paradigms Show Adalimumab Is Cost-Effective for the Management of Ulcerative Colitis

    PubMed Central

    Ung, Victoria; Kroeker, Karen I.; Lee, Thomas; Wang, Haili; Jacobs, Phil; Halloran, Brendan P.

    2016-01-01

    Background. Adalimumab is effective for the maintenance of remission in patients with moderate-to-severe ulcerative colitis (UC). Currently, biologic therapies are used in cases where patients fail conventional medical therapies. If biologic therapies are not available, patients often choose to remain in an unwell state rather than undergo colectomy. Objective. The aim of the study was to evaluate the cost-effectiveness of adalimumab in patients with UC where adalimumab was readily available compared to not available. Methods. A previously validated Markov model was used to simulate disease progression of patients with UC who are corticosteroid-dependent and/or did not respond to thiopurine therapy. Utility scores and transition probabilities between health states were determined by using data from randomized controlled trials and real-life observational studies. Costs were obtained from the Ontario Case Costing Initiative and the Alberta Health Schedule of Medical Benefits. Results. The incremental cost-effectiveness ratios for readily available adalimumab treatment of UC were $40,000 and $59,000 per quality-adjusted life year, compared with ongoing medical therapy in an unwell state, at 5-year and 10-year treatment time horizons, respectively. Conclusion. Considering real-life patient preferences to avoid colectomy, adalimumab is cost-effective according to a willingness-to-pay threshold of $80,000 for treatment of UC. PMID:27781203

  9. 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

  10. Pneumocystosis in a patient with Crohn's disease treated with combination therapy with adalimumab.

    PubMed

    Desales, Ana L; Mendez-Navarro, Jorge; Méndez-Tovar, Luis J; Ortiz-Olvera, Nayeli X; Cullen, Garret; Ocampo, Joaquín; Lemus, Willian; Tun, Amina E; Mayoral-Zavala, Arturo; Dehesa-Violante, Margarita

    2012-05-01

    Pneumocystis jirovecii pneumonia (PCP) is a potential complication of immunosuppression. Crohn's disease (CD) is an immune granulomatous disorder characterized by transmural inflammation that can affect any part of the gastrointestinal tract. Its treatment is based on steroids and immunosuppressants but in non-responders, biologic compounds such as anti-tumor necrosis factor alpha (TNF) antibodies have been used. Neutralization of TNF causes a decrease in the inflammatory response but increases susceptibility to opportunistic infections such as fungal infections. We report a young male with chronic diarrhea, fever and weight loss who was diagnosed with CD and began conventional treatment with immunosuppressants, but due to lack of response after several weeks, biologic therapy with adalimumab was initiated. Seven weeks later he developed persistent fever and upper respiratory symptoms. After chest CT, bronchoscopy and bronchial lavage, P. jirovecii was identified by silver staining and confirmed by immunofluorescence. To our knowledge this is the second case of pneumocystosis associated with the use of adalimumab in CD and the first reported Mexican case confirmed by microbiological and immunological studies in this setting. PMID:22398055

  11. Effects of biological drug adalimumab on tumour necrosis factor-alpha-converting enzyme activation.

    PubMed

    Lisi, Sabrina; Sisto, Margherita

    2010-01-01

    Tumour necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) is a membrane-bound metalloprotease and disintegrin. It is produced by a number of host cells and is known to shed and release cell-bound cytokines, particularly members of the TNF family. No investigations into the regulation of this enzyme by autoantibodies have been reported. In this study, we tested the hypothesis that anti-Ro/SSA autoantibodies, purified from IgG fractions of patients with primary Sjögren's syndrome, are capable to regulate TACE expression and activation in human salivary gland epithelial cells (SGEC). We also evaluated the potential physiological and therapeutic consequences of TNF-alpha blocking by the biological agent adalimumab, the first fully human (100% human peptide sequences) therapeutic anti-TNF-alpha antibody, on post-translational regulation of TACE. Taken together, our results show a dose-dependent increase in TACE expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein. Adalimumab treatment brought TACE expression to levels than those observed in untreated SGEC. These findings, showing the presence of autoantibodies-dependent mechanisms by which TACE levels are regulated in human SGECs, may have implications in the context of current investigations on the pathological role of autoantibodies.

  12. Dose Escalation and Healthcare Resource Use among Ulcerative Colitis Patients Treated with Adalimumab in English Hospitals: An Analysis of Real-World Data

    PubMed Central

    Black, Christopher M.; Yu, Eric; McCann, Eilish; Kachroo, Sumesh

    2016-01-01

    Objective To describe the real-world use of adalimumab for maintenance treatment of ulcerative colitis (UC) and associated healthcare costs in English hospitals. Design Retrospective cohort study. Setting Analysis of NHS Hospital Episode Statistics linked with pharmacy dispensing data in English hospitals. Patients Adult UC patients receiving ≥240mg during adalimumab treatment induction, subsequently maintained on adalimumab. Outcomes Frequency and pattern of adalimumab use and dose escalation during maintenance treatment and associated healthcare costs (prescriptions and hospital visits). Results 191 UC patients completed adalimumab treatment induction. 83 (43.46%) dose escalated during maintenance treatment by ≥100% (equivalent to weekly dosing) (median time to dose escalation: 139 days). 56 patients (67.47%) subsequently de-escalated by ≥50% (median time to dose de-escalation: 21 days). Mean all-cause healthcare costs for all patients ≤12 months of index were £13,892. Dose escalators incurred greater mean healthcare costs than non-escalators ≤12 months of index (£14,596 vs. £13,351). Prescriptions accounted for 96.49% of UC-related healthcare costs (£11,090 of £11,494 in all patients). Conclusions Within the cohort, 43.46% of UC patients escalated their adalimumab dose by ≥100% and incurred greater costs than non-escalators. The apparent underestimation of adalimumab dose escalation in previous studies may have resulted in underestimated costs in healthcare systems. PMID:26919745

  13. 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.

  14. 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

  15. 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

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

    PubMed

    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. PMID:27462198

  17. Successful treatment of psoriatic onycho-pachydermo periostitis (POPP) with adalimumab.

    PubMed

    Bongartz, T; Härle, P; Friedrich, S; Karrer, S; Vogt, T; Seitz, A; Müller-Ladner, U

    2005-01-01

    Psoriatic onycho-pachydermo periostitis (POPP) is recognized as a rare subset of psoriatic arthritis, characterized by psoriatic onychodystrophy, connective tissue thickening above the distal phalanx, and a periosteal reaction. Therapy for this rare disease is based on treatments used for psoriatic arthritis, but traditional disease-modifying antirheumatic drugs, such as sulfasalazine and methotrexate, have shown inconsistent and unsatisfactory results. We report herein a successful therapeutic approach for POPP using the fully human anti-tumor necrosis factor (TNF) antibody adalimumab in a 42-year-old male patient. After 4 months of anti-TNF treatment, a remarkable normalization of the clinical appearance was achieved and magnetic resonance imaging showed complete resolution of the initial inflammatory lesions. Therefore, we consider a TNF-blocking strategy as promising for treatment of POPP.

  18. Surface plasmon resonance-based methodology for anti-adalimumab antibody identification and kinetic characterization.

    PubMed

    Real-Fernández, Feliciana; Cimaz, Rolando; Rossi, Giada; Simonini, Gabriele; Giani, Teresa; Pagnini, Ilaria; Papini, Anna Maria; Rovero, Paolo

    2015-09-01

    Adalimumab (ADA) is a TNF-α blocker drug antibody fully humanized and thus indistinguishable in structure and function from natural human IgG1, used in the juvenile idiopathic arthritis (JIA) treatment. Immunogenicity against the drug has been frequently detected in treated patients, and the presence of anti-ADA antibodies is correlated to treatment failure or lower clinical remission. Herein, we measured by surface plasmon resonance (SPR) both the binding and the affinity of anti-ADA antibodies to the ADA-immobilized biosensor. The binding of anti-ADA antibodies was evaluated by testing sera from ADA-treated patients (n = 30), untreated patients (n = 9), and healthy donors (n = 20) in the SPR biosensor. The optimal cut-off point was defined using the receiver operating characteristic curve (ROC-curve) analysis with 79 % (60.28 to 92.01 %, 95 % CI) sensitivity, 99 % (88.06 to 100.0 %, 95 % CI) specificity, and a positive likelihood ratio of 23. The area under the curve was 0.9298 (p < 0.0001). The apparent affinity of anti-ADA antibodies from pediatric patients' sera was measured, analyzing the interaction of anti-drug antibodies using whole sera, enriched IgG fractions, and isolated anti-ADA antibodies. The immobilized drug ADA interacted with purified antibodies at low affinities (10(-6) M > K D > 10(-9) M). Graphical Abstract Adalimumab immobilized on the biosensor chip surface detects specific anti-drug antibodies in treated patients' sera. PMID:26210546

  19. 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

  20. Short-term effect and adverse events of adalimumab versus placebo in inducing remission for moderate-to-severe ulcerative colitis: a meta-analysis

    PubMed Central

    Yang, Zheng; Ye, Xiao-Qing; Zhu, Yu-Zhen; Liu, Zhou; Zou, Ying; Deng, Ying; Guo, Can-Can; Garg, Sushil Kumar; Feng, Jin-Shan

    2015-01-01

    Background: Adalimumab is used in an attempt to maintain remission for Ulcerative colitis. This study was to evaluate the efficacy and adverse events of adalimumab compared with placebo in inducing remission of Ulcerative colitis. Methods: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, OVID, BIOSIS, CNKI, and Google were searched. All randomized trials comparing adalimumab with placebo in inducing remission of moderate-to-severe ulcerative colitis were included. Results: Two randomized controlled trials with a total of 754 participants met the inclusion criteria. The pooled risk ratio (RR) of clinical remission was 1.85 (95% confidence interval (CI) 1.26 to 2.72) following adalimumab treatment. RR of clinical response was 1.40 (95% CI 1.19 to 1.65) while that of mucosal healing was 1.23 (95% CI 1.03 to 1.47). RR of any adverse events was 1.00 (95% CI 0.93 to 1.09). Conclusion: Compared with placebo, administration of adalimumab may increase the proportion of patients with moderate-to-severe ulcerative colitis attaining clinical remission, clinical response and mucosal healing. Adalimumab is also tolerated well in these patients. PMID:25784977

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Four-Year Maintenance Treatment With Adalimumab in Patients with Moderately to Severely Active Ulcerative Colitis: Data from ULTRA 1, 2, and 3

    PubMed Central

    Colombel, Jean-Frederic; Sandborn, William J; Ghosh, Subrata; Wolf, Douglas C; Panaccione, Remo; Feagan, Brian; Reinisch, Walter; Robinson, Anne M; Lazar, Andreas; Kron, Martina; Huang, Bidan; Skup, Martha; Thakkar, Roopal B

    2014-01-01

    OBJECTIVES: The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented. METHODS: Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208. Corticosteroid-free remission was assessed in adalimumab-randomized patients who used corticosteroids at lead-in study baseline. Maintenance of remission per partial Mayo score and mucosal healing was assessed in patients who entered ULTRA 3 in remission per full Mayo score and with mucosal healing, respectively. As observed, last observation carried forward (LOCF) and nonresponder imputation (NRI) were used to report efficacy. Adverse events were reported for any adalimumab-treated patient. RESULTS: A total of 600/1,094 patients enrolled in ULTRA 1 or 2 were randomized to receive adalimumab and included in the intent-to-treat analyses of the studies. Of these, 199 patients remained on adalimumab after 4 years of follow-up. Rates of remission per partial Mayo score, remission per IBDQ score, mucosal healing, and corticosteroid discontinuation at week 208 were 24.7%, 26.3%, 27.7% (NRI), and 59.2% (observed), respectively. Of the patients who were followed up in ULTRA 3 (588/1,094), a total of 360 patients remained on adalimumab 3 years later. Remission per partial Mayo score and mucosal healing after ULTRA 1 or 2 to year 3 of ULTRA 3 were maintained by 63.6% and 59.9% of patients, respectively (NRI). Adverse event rates were stable over time. CONCLUSIONS: Remission, mucosal healing, and improved quality of life were maintained in patients with moderately to

  7. 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

  8. 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

  9. 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

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

    PubMed

    Wei, S S; Sinniah, R

    2013-01-01

    Adalimumab (Humira) is a tumour necrosis factor α (TNF α ) 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 TNF α 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.

  11. 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

  12. 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

  13. [Pneumocystis pneumonia developed in two patients with rheumatoid arthritis during treatment of adalimumab].

    PubMed

    Ikeuchi, Hidekazu; Umemoto, Azusa; Tsukida, Mayuko; Sakurai, Noriyuki; Maeshima, Akito; Kuroiwa, Takashi; Hiromura, Keiju; Nojima, Yoshihisa

    2011-01-01

    While tumor necrosis factor (TNF) inhibitors have dramatically improved the clinical outcomes of rheumatoid arthritis (RA) in recent years, infectious complications are a serious concern. Adalimumab (ADA) is a newly-developed human monoclonal antibody against TNF-alpha. Here we report 2 cases of pneumocystis pneumonia (PCP) which developed in RA patients during ADA therapy. One patient is a 66-year-old woman who had a history of RA for 6 months. The patient was given ADA at 40 mg biweekly for her active arthritis which had been refractory to 6 mg/week of methotrexate (MTX), and 5 mg/day of prednisolone (PSL). One hundred and six days later, she was admitted to our hospital because of fever, cough, and dyspnea. Another patient is a 62-year-old man who had a history of RA for 3 years. Since his arthritis was so active even under the treatment with MTX (8 mg/week) and PSL (15 mg/day), the patient started to be given ADA at 40 mg biweekly. After 28 days, the patient was admitted to the hospital because of dyspnea. Chest roentgenogram and computed tomography revealed interstitial pneumonia in both patients. Beta-D-glucan levels were so high in their serum suggesting the diagnosis of PCP, which was confirmed by the detection of Pneumocystis jirovecii DNA in the sputa by polymerase chain reaction. The patients were immediately treated with sulfamethoxazole/trimethoprim and high-dose prednisolone, which successfully improved pneumonia, and they were discharged from the hospital on the 8(th) and 16(th) day, respectively. PCR and β-D-glucan were useful for the early diagnosis of PCP and lead to the timely induction of adequate treatment and the rescue of these patients. PMID:22041430

  14. Practical application of acid dissociation in monitoring patients treated with adalimumab.

    PubMed

    Llinares-Tello, Francisca; Rosas-Gómez de Salazar, José; Senabre-Gallego, José Miguel; Santos-Soler, Gregorio; Santos-Ramírez, Carlos; Salas-Heredia, Esteban; Barber-Vallés, Xavier; Molina-García, Juan

    2014-12-01

    Patients treated with adalimumab (ADL) can induce anti-ADL antibodies (AAA) formation that is associated with low drug levels and clinical non-response. But, in the majority of the assays, the measurement of AAA is hampered by the presence of the drug itself. In support of immunogenicity assessment in clinical samples with subtherapeutic ADL levels, we proved acid pre-treatment for AAA detection with the Promonitor-enzyme-linked immunosorbent assay (ELISA). Were measured AAA after acidification in 32 serum samples with a subtherapeutic ADL trough level. ADL and AAA concentrations were measured by ELISA (Promonitor). The impact of drug concentration on AAA recovery (with or without acidification) was also evaluated by mixing known amounts of ADL (0.25, 0.5 and 1 mg/L) and AAA (100, 200, 300 and 400 AU/mL) from clinical samples in pooled serum. The drug significantly inhibited the detection of AAA in untreated samples. And progressively higher levels of ADL cause increasing inhibition of signal. Acid pre-treatment carried a significant increase in assay response, particularly at lower free ADL concentrations. AAA were detected in the 53 % of the samples after acid dissociation. In seven patients, the positive AAA after dissociation was detected in the first monitoring of ADL and five patients were positive 3 months later for AAA with the standard assay. Monitoring AAA using acid dissociation in patients with subtherapeutic circulating level of ADL could detect precocious problems of bioavailability, assess the immunogenicity of ADL and may be used to optimise dose regimens, thereby preventing prolonged use of inadequate therapy and guide change of treatment.

  15. The role of adalimumab in rheumatic and autoimmune disorders: comparison with other biologic agents

    PubMed Central

    Reimold, Andreas M

    2012-01-01

    Adalimumab (ADA) is a biologic medication that dampens inflammatory pathways by binding to the cytokine tumor necrosis factor alpha. The US Food and Drug Administration has approved ADA as a medication for use in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis, and juvenile idiopathic arthritis. This year marks 10 years of clinical experience with ADA. Long-term extension studies of some of the initial clinical trials, as well as data from large patient registries, are demonstrating ongoing benefit for responders. Potential side effects such as increased risk of infection, lymphoma, congestive heart failure, and demyelination continue to be examined, as the available data are not unanimous in showing an increase in incidence. In balancing both the advantages and the disadvantages of using ADA, the drug’s overall effectiveness and its availability for use in patients with hepatic or renal comorbidities are weighed against the high cost. ADA is expected to have a leading role in the treatment of rheumatoid arthritis and other inflammatory conditions for years to come. Future studies will need to address the optimal sequence of disease-modifying antirheumatic drugs and biologics to use, combinations of disease-modifying antirheumatic drugs and biologics, and head-to-head comparisons of biologics in clinical trials. For those who go into clinical remission on an anti-tumor necrosis factor medication, unanswered questions remain about identifying the patients who can maintain the remission off all drugs, or at least off injected medication. Given the cost of biologic drugs, even studies that increase the interval between drug doses in well-controlled patients could provide financial benefits.

  16. [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

  17. [Adalimumab versus etanercept in the treatment of active rheumatoid arthritis: cost-effectiveness analysis].

    PubMed

    González Álvarez, A; Gómez Barrera, M; Borrás Blasco, J; Giner Serrer, E J

    2013-01-01

    Objetivo: Valorar el grado de efectividad y eficiencia de las dos alternativas principalmente utilizadas en nuestro ámbito, etanercept (ETN) y adalimumab (ADA), para el tratamiento de pacientes diagnosticados de artritis reumatoide (AR) en condiciones reales de la práctica clínica diaria. Material y método: Se realizó un estudio observacional retrospectivo, cuyo horizonte temporal fue de 12 meses referidos al año 2012, en el que se analizaron las características de los pacientes, así como la efectividad y eficiencia de ETN y ADA en la población de estudio. Se estudiaron todos los pacientes de ambos sexos mayores de 18 años, diagnosticados de AR, atendidos en las consultas externas del Servicio de Reumatología del Sector Sanitario de Teruel. Se determinó el descenso medio del valor de DAS28 (DAS28r) de cada fármaco y se definió como unidad de efectividad en el estudio farmacoeconómico un valor DAS28 al inicio (DAS28a) inferior a 3,2 puntos y DAS28r mayor a 1,2 puntos. Como parámetro del estudio para determinar el coste-efectividad de ambas alternativas se utilizó el beneficio neto sanitario (BNS). Resultados: El valor medio de DAS28a fue 2,25 y 2,72 puntos para ETN y ADA respectivamente, con un valor DAS28r de 1,01 puntos superior para ETN, aunque sin ser estadísticamente significativo (p > 0,05). El cálculo del parámetro BNS obtuvo un valor igual a -0,121; IC95% (-0,951 a 0,709), sin embargo la inclusión del valor 0 en el intervalo de confianza hizo que no se observaran diferencias de coste-efectividad. Conclusiones: Ambas alternativas son efectivas en el tratamiento de la AR, aunque parece existir una tendencia a favor de ETN en el grado coste-efectividad sin ser significativa.

  18. [Analisis of the budget impact of adalimumab and etanercept in rheumatoid arthritis and spondyloarthropathies].

    PubMed

    González Álvarez, A; Gómez Barrera, M; Borrás Blasco, J; Giner Serret, E J

    2013-01-01

    Objetivo: Evaluar el impacto económico derivado de la ampliación de los intervalos de administración de adalimumab (ADA) y etanercept (ETN), en el tratamiento de la artritis reumatoide (AR) y espondiloartropatias (EAP) en nuestro ámbito de trabajo. Material y método: Se desarrolló un modelo de impacto presupuestario (MIP) para estimar la repercusión económica que tendría la ampliación en los intervalos habituales de administración de ADA 40 mg cada dos semanas y ETN 50 mg semanal (escenario A), por ADA 40 mg cada tres semanas y ETN 50 mg cada dos semanas (escenario B) de acuerdo a las guías y recomendaciones que se aplican a estos estudios, especificando la población diana, la perspectiva del estudio, el horizonte temporal y analizando la robustez del estudio a través de un análisis de sensibilidad univariante de tipo umbral. Resultados: Se incluyeron un total de 71 pacientes en el estudio. La aplicación del MIP mostró unos ahorros anuales para ADA y ETN de 19.784??y 38.271 ??respectivamente. El coste neto, es decir, el ahorro que esto supuso en el horizonte temporal considerado (dos años) ascendió a 116.110 ?. El análisis de sensibilidad realizado mostró que el MIP estimado para el periodo de estudio fue muy robusto ya que el resultado neto en diferentes escenarios apenas variaba, manteniéndose negativo en los nuevos escenarios. Conclusiones: La ampliación de los intervalos de administración de ADA y ETN cada tres semanas y dos semanas respectivamente, sería una estrategia que permitiría generar ahorros en el presupuesto hospitalario cercanos a los 116.110 ??en el horizonte temporal considerado, consiguiendo así una optimización del tratamiento con estos fármacos.

  19. 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

  20. Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study

    PubMed Central

    Atzeni, Fabiola; Sarzi-Puttini, Piercarlo; Dell' Acqua, Donata; de Portu, Simona; Cecchini, Germana; Cruini, Carola; Carrabba, Mario; Meroni, Pier Luigi

    2006-01-01

    Studies on autoantibody production in patients treated with tumor necrosis factor-α (TNF-α) inhibitors reported contradictory results. We investigated in a prospective study the efficacy of a treatment with human monoclonal anti-TNF-α antibody (adalimumab) in patients with rheumatoid arthritis (RA) and we evaluated the relationship between treatment efficacy and the incidence and titers of disease-associated and non-organ-specific autoantibodies. Fifty-seven patients with RA not responsive to methotrexate and treated with adalimumab were enrolled. Antinuclear, anti-double-stranded(ds)DNA, anti-extractable nuclear antigens, anti-cardiolipin (aCL), anti-β2 glycoprotein I (anti-β2GPI) autoantibodies, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies were investigated at baseline and after 6 and 12 months of follow-up. Comparable parameters were evaluated in a further 55 patients treated with methotrexate only. Treatment with adalimumab induced a significant decrease in RF and anti-CCP serum levels, and the decrease in antibody titers correlated with the clinical response to the therapy. A significant induction of antinuclear autoantibodies (ANA) and IgG/IgM anti-dsDNA autoantibodies were also found in 28% and 14.6% patients, respectively, whereas aCL and anti-β2GPI autoantibodies were not detected in significant quantities. No association between ANA, anti-dsDNA, aCL and anti-β2GPI autoantibodies and clinical manifestations was found. Clinical efficacy of adalimumab is associated with the decrease in RF and anti-CCP serum levels that was detected after 24 weeks and remained stable until the 48th week of treatment. Antinuclear and anti-dsDNA autoantibodies, but not anti-phospholipid autoantibodies, can be induced by adalimumab but to a lower extent than in studies with other anti-TNF blocking agents. PMID:16356192

  1. 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

  2. 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

  3. 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

  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. Naturally occurring hepatitis B virus (HBV) variants with primary resistance to antiviral therapy and S-mutants with potential primary resistance to adefovir in Argentina.

    PubMed

    Cuestas, María L; Rivero, Cintia W; Minassian, María L; Castillo, Amalia I; Gentile, Emiliano A; Trinks, Julieta; León, Liliana; Daleoso, Graciela; Frider, Bernardo; Lezama, Carol; Galoppo, Marcela; Giacove, Gisela; Mathet, Verónica L; Oubiña, José R

    2010-07-01

    Hepatitis B virus (HBV) variants may either emerge in patients with chronic hepatitis B (CHB) as a result of positive selection pressure exerted by their own immune response, or during therapy with nucleos(t)ide analogues (NAs). Naturally occurring HBV variants with primary antiviral resistance are rarely observed. The aim of this study was to retrospectively analyze the (eventual) circulation of HBV variants with natural resistance to NAs currently used as therapy for CHB in Argentina. This study reports 13 cases of CHB-infected patients with natural antiviral resistance to at least one NA. Five of them were also carriers of S-variants that might escape the humoral immune system recognition with potential resistance to adefovir. In addition to the already reported A2 HBV subgenotype association to NAs natural resistance, E and F genotypes association to such resistance is described for the first time. These findings suggest that sequence analysis of the HBV reverse transcriptase might be an essential tool before starting antiviral therapy, in order to choose the proper NAs for optimizing the therapeutic management of chronically infected patients. Moreover, the circulation and transmission of S-mutants with resistance to such antiviral drugs should be of public health concern as they may represent an additional risk for the community.

  6. Naturally occurring hepatitis B virus (HBV) variants with primary resistance to antiviral therapy and S-mutants with potential primary resistance to adefovir in Argentina.

    PubMed

    Cuestas, María L; Rivero, Cintia W; Minassian, María L; Castillo, Amalia I; Gentile, Emiliano A; Trinks, Julieta; León, Liliana; Daleoso, Graciela; Frider, Bernardo; Lezama, Carol; Galoppo, Marcela; Giacove, Gisela; Mathet, Verónica L; Oubiña, José R

    2010-07-01

    Hepatitis B virus (HBV) variants may either emerge in patients with chronic hepatitis B (CHB) as a result of positive selection pressure exerted by their own immune response, or during therapy with nucleos(t)ide analogues (NAs). Naturally occurring HBV variants with primary antiviral resistance are rarely observed. The aim of this study was to retrospectively analyze the (eventual) circulation of HBV variants with natural resistance to NAs currently used as therapy for CHB in Argentina. This study reports 13 cases of CHB-infected patients with natural antiviral resistance to at least one NA. Five of them were also carriers of S-variants that might escape the humoral immune system recognition with potential resistance to adefovir. In addition to the already reported A2 HBV subgenotype association to NAs natural resistance, E and F genotypes association to such resistance is described for the first time. These findings suggest that sequence analysis of the HBV reverse transcriptase might be an essential tool before starting antiviral therapy, in order to choose the proper NAs for optimizing the therapeutic management of chronically infected patients. Moreover, the circulation and transmission of S-mutants with resistance to such antiviral drugs should be of public health concern as they may represent an additional risk for the community. PMID:20403388

  7. Detection of anti-drug antibodies using a bridging ELISA compared with radioimmunoassay in adalimumab-treated rheumatoid arthritis patients with random drug levels

    PubMed Central

    Jani, Meghna; Isaacs, John D.; Morgan, Ann W.; Wilson, Anthony G.; Plant, Darren; Hyrich, Kimme L.; Chinoy, Hector

    2016-01-01

    Objective. To determine the concordance between RIA and bridging ELISA at detecting anti-drug antibodies (ADAbs) in the context of random adalimumab levels and investigate the additional clinical utility of detecting ADAbs in RA patients who test ADAb positive by RIA and negative by ELISA. Methods. ADAb levels were determined using RIA and bridging ELISA in 63 adalimumab-treated RA patients (159 samples). Immunogenicity concordance was determined using receiver operating characteristic curves. To determine the additional clinical value provided by a positive RIA in the presence of negative ELISA, association between treatment response (ΔDAS28), adalimumab drug levels and ADAbs was evaluated longitudinally using generalized estimating equation. Results. Of the 60 RIA+ samples (n = 31 patients), 19 (n = 10 patients) were also ELISA+, corresponding to 31.7% of samples. Area under the curve for detecting ADAbs using ELISA (compared with RIA) using receiver operating characteristic curves was 0.65 (95% CI: 0.59, 0.71); this increased to 0.91 (95% CI: 0.81, 0.99) if ADAbs were ⩾100 AU/ml using RIA. In RIA+/ELISA− patients, adalimumab levels were associated with ΔDAS28 over 12 months [regression coefficient: 0.098 (95% CI: 0.043, 0.15), P < 0.0001] and while ADAbs were significantly associated with drug level, they were not directly associated with ΔDAS28 over 12 months [β coefficient: 0.00083 (95% CI: −0.0038 to 0.0054), P = 0.72]. Conclusion. ADAbs were detected using ELISA more frequently when present in high titres as measured by RIA. In RIA+/ELISA− patients, only drug levels were significantly associated with treatment response. Although ADAbs were not independently associated with treatment response, they may be helpful in determining the aetiology of low drug levels. PMID:27565176

  8. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis

    PubMed Central

    Gabay, Cem; McInnes, Iain B; Kavanaugh, Arthur; Tuckwell, Katie; Klearman, Micki; Pulley, Jennifer; Sattar, Naveed

    2016-01-01

    Objective Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab. Methods Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8. Results The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46 mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07 mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67 mmol/L (0.47 to 0.86)), triglycerides (0.24 mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8 weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were –3.2 and –1.1 mg/L (p=0.0077) for HDL-SAA and –4.1 and –1.3 ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was –7.12 mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria. Conclusion LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study

  9. Gateways to clinical trials.

    PubMed

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

    2005-05-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables 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: 3-AP, Adalimumab, adefovir dipivoxil, AeroDose albuterol inhaler, agalsidase alfa, alemtuzumab, aminolevulinic acid methyl ester, anidulafungin, anthrax vaccine, anti-CTLA-4 MAb, azimilide hydrochloride; Bevacizumab, BG-12, bimatoprost, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, ceftobiprole, certolizumab pegol, CG-53135, cilansetron; Darbepoetin alfa, degarelix acetate, dimethylfumarate, duloxetine hydrochloride, dutasteride; Eicosapentaenoic acid/docosahexaenoic acid, eletriptan, entecavir, esomeprazole magnesium, exatecan mesilate, exenatide, ezetimibe; Falecalcitriol, fampridine, fondaparinux sodium, fontolizumab; Gefitinib, gepirone hydrochloride; Human insulin; IDEA-070, imatinib mesylate, iodine (I131) tositumomab; Lanthanum carbonate, lubiprostone; Mafosfamide cyclohexylamine salt, melatonin; NC-531, nemifitide ditriflutate, neridronic acid, nolatrexed dihydrochloride; Oral insulin; Palifermin, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, plerixafor hydrochloride, posaconazole, pramlintide acetate, pregabalin, PT-141; Quercetin; Ranibizumab, renzapride hydrochloride, RSD-1235; Sabarubicin hydrochloride, semapimod hydrochloride, Semax, SHL-749; Tegaserod maleate, tenatoprazole, tetrodotoxin, tolevamer sodium, trabectedin, travoprost, travoprost/timolol; Valdecoxib, visilizumab, Xcellerated T cells, XP-828L; Zoledronic acid monohydrate.

  10. 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

  11. 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

  12. Gateways to clinical trials.

    PubMed

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

    2005-05-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables 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: 3-AP, Adalimumab, adefovir dipivoxil, AeroDose albuterol inhaler, agalsidase alfa, alemtuzumab, aminolevulinic acid methyl ester, anidulafungin, anthrax vaccine, anti-CTLA-4 MAb, azimilide hydrochloride; Bevacizumab, BG-12, bimatoprost, bortezomib, bosentan, botulinum toxin type B; Caspofungin acetate, ceftobiprole, certolizumab pegol, CG-53135, cilansetron; Darbepoetin alfa, degarelix acetate, dimethylfumarate, duloxetine hydrochloride, dutasteride; Eicosapentaenoic acid/docosahexaenoic acid, eletriptan, entecavir, esomeprazole magnesium, exatecan mesilate, exenatide, ezetimibe; Falecalcitriol, fampridine, fondaparinux sodium, fontolizumab; Gefitinib, gepirone hydrochloride; Human insulin; IDEA-070, imatinib mesylate, iodine (I131) tositumomab; Lanthanum carbonate, lubiprostone; Mafosfamide cyclohexylamine salt, melatonin; NC-531, nemifitide ditriflutate, neridronic acid, nolatrexed dihydrochloride; Oral insulin; Palifermin, parecoxib sodium, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, plerixafor hydrochloride, posaconazole, pramlintide acetate, pregabalin, PT-141; Quercetin; Ranibizumab, renzapride hydrochloride, RSD-1235; Sabarubicin hydrochloride, semapimod hydrochloride, Semax, SHL-749; Tegaserod maleate, tenatoprazole, tetrodotoxin, tolevamer sodium, trabectedin, travoprost, travoprost/timolol; Valdecoxib, visilizumab, Xcellerated T cells, XP-828L; Zoledronic acid monohydrate. PMID:16082427

  13. Comparison of the clinical outcomes between antiviral-naïve patients treated with entecavir and lamivudine-resistant patients receiving adefovir add-on lamivudine combination treatment

    PubMed Central

    Kim, Hong Joo; Park, Soo Kyung; Yang, Hyo Joon; Jung, Yoon Suk; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik; Choi, Kyu Yong

    2016-01-01

    Background/Aims To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. Methods This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. Results During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). Conclusion The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression. PMID:27729626

  14. Mechanism of Adefovir, Tenofovir and Entecavir Resistance: Molecular Modeling Studies of How A Novel Anti-HBV Agent (FMCA) Can Overcome the Drug Resistance.

    PubMed

    Rawal, R K; Konreddy, A K; Chu, C K

    2015-01-01

    Regardless of significant improvement in the area of anti-HBV therapy, resistance and cross-resistance against available therapeutic agents are the major consideration in drug discovery of new agents. The present study is to obtain the insight of the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of four anti-HBV agents [Adefovir (ADV), Tenofovir (TNF), Entecavir (ETV) & 2'-Fluoro-6'-methylene-carbocyclic adenosine (FMCA)]. In this regard, homology modeled structure of HBV polymerase was used for minimization, conformational search and Glide XP docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (N236T, L180M+M204V+S202G & A194T). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The domain B residue, L180 is indirectly associated with other active-site hydrophobic residues such as A87, F88 and M204, whereas the domain C residue, M204 is closely associated with sugar/pseudosugar ring positioning in the active site. These hydrophobic residues can directly influence the interaction of the incoming nucleoside triphosphates and change the binding efficacy. The carbohydrate ring part of natural substrate dATP, dGTP, FMCA and ETV, are occupied in similar passion in the grooves of HBV polymerase active site. The exocyclic double bond of Entecavir and FMCA occupies in the backside hydrophobic pocket (made by residues A87, F88, L180and M204), which enhances the overall binding affinity. Additional hydrogen bonding interaction of 2'-fluorine of FMCA with R41 residue of polymerase promotes a positive binding in wild-type as well as in ADVr, ETVr and TNFr with respect to that of entecavir. PMID:26336997

  15. 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

  16. Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients.

    PubMed

    Koike, Takao; Harigai, Masayoshi; Ishiguro, Naoki; Inokuma, Shigeko; Takei, Shuji; Takeuchi, Tsutomu; Yamanaka, Hisashi; Tanaka, Yoshiya

    2012-08-01

    This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic naïve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA.

  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. 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

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

    2014-02-01

    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.

  2. 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

  3. 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

  4. Crohn's disease of the small bowel, complicated by primary biliary cirrhosis, Hashimoto thyroiditis, and Raynaud's phenomenon: favorable response of all disorders to adalimumab treatment.

    PubMed

    Triantafillidis, John K; Durakis, Spyros; Merikas, Emmanuel

    2013-01-01

    We describe the case of a male patient suffering from long-lasting Crohn's disease of the small bowel who developed thyroiditis Hassimoto, Raynaud's phenomenon, and primary biliary cirrhosis, during the course of the underlying bowel disease. It is not clear whether these co-morbidities appeared coincidentally, or because they share some common immunopathogenetic mechanisms. In this patient, Crohn's disease favorably responded to the treatment with an anti-TNF-α agent (adalimumab). The serum titers of antimitochondrial antibodyies and cholestatic enzymes considerably reduced during the 3-year treatment with the biologic agent. Raynaud's phenomenon, also, completely disappeared. Bearing in mind the possible involvement of TNF-α in the pathogenesis of primary biliary cirrhosis, it could be argued that the clinical and laboratory improvement of liver disease, as well as the reduction in serum titers of antimitochondrial antibodies, might be due to the anti-TNF-α action of adalimumab. We suggest that it would be worth further investigating the role of biologic agents in the treatment of patients with primary biliary cirrhosis.

  5. Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: a pilot study.

    PubMed

    Fox, Joshua D; Baquerizo-Nole, Katherine L; Keegan, Brian R; Macquhae, Flor; Escandon, Julia; Espinosa, Aliette; Perez, Carmen; Romanelli, Paolo; Kirsner, Robert S

    2016-10-01

    Venous leg ulcers (VLUs) have higher tumor necrosis factor-α (TNF-α) levels compared with normal skin. Refractory VLUs of long duration have higher TNF-α levels compared with VLUs of shorter duration. As up to 75% of VLUs fail to heal with standard care, we sought to evaluate the role of anti-TNF-α therapy for patients with refractory VLUs. Evaluable data were obtained in four of five subjects with recalcitrant VLUs treated with 80 mg of subcutaneous adalimumab at week 0 and with 40 mg at week 2 along with compression therapy and were followed-up for 6 weeks. Wound biopsies taken at weeks 0 and 4 were stained with anti-TNF-α antibodies. Average 4-week percent wound size reduction was 20.5% ± 6.4%. Two patients had wound size reduction more than 25%, and their percent wound size reduction correlated to percent TNF-α staining score reductions (P = 0.02, R(2) = 0.999). VLU TNF-α level decrease 4 weeks post-adalimumab treatment correlated with wound healing.

  6. 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

  7. Anti-TNF-Alpha-Adalimumab Therapy Is Associated with Persistent Improvement of Endothelial Function without Progression of Carotid Intima-Media Wall Thickness in Patients with Rheumatoid Arthritis Refractory to Conventional Therapy

    PubMed Central

    Gonzalez-Juanatey, Carlos; Vazquez-Rodriguez, Tomas R.; Miranda-Filloy, Jose A.; Gomez-Acebo, Ines; Testa, Ana; Garcia-Porrua, Carlos; Sanchez-Andrade, Amalia; Llorca, Javier; González-Gay, Miguel A.

    2012-01-01

    To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21 mm) were compared with those found at day 0 (0.65 ± 0.16 mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA. PMID:22899879

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Successful adalimumab treatment of a psoriasis vulgaris patient with hemodialysis for renal failure: A case report and a review of the previous reports on biologic treatments for psoriasis patients with hemodialysis for renal failure.

    PubMed

    Kusakari, Yoshiyuki; Yamasaki, Kenshi; Takahashi, Toshiya; Tsuchiyama, Kenichiro; Shimada-Omori, Ryoko; Nasu-Tamabuchi, Mei; Aiba, Setsuya

    2015-07-01

    The efficacy and safety of biologic treatments have been established in patients with moderate to severe psoriasis, but there are few reports on biologic therapy for patients with psoriasis complicated by end-stage renal failure on hemodialysis (HD). In this report, we demonstrated the efficacy and safety of adalimumab for patients with severe psoriasis on HD. A 46-year-old Japanese man with a 14-year history of psoriasis was referred to our clinic in September 2009. He had developed hypertension and renal failure during a 7-year history of cyclosporin treatment. With the infliximab treatment, he achieved 75% improvement of the Psoriasis Area and Severity Index (PASI) score within 3 months from the PASI of 42.3 before the treatment. However, his renal failure gradually deteriorated, and HD was initiated at 1 year after the introduction of infliximab. Because of hydration during the i.v. injection of infliximab, he developed pulmonary edema with every infliximab treatment after starting HD. We switched to ustekinumab treatment, but his psoriasis was not improved. Then, we switched to adalimumab and achieved a PASI-100 response within 2 months. The patient received adalimumab treatment for more than a year without any adverse effects. In addition to our case, five articles reported cases of psoriasis patients with renal failure on HD who were treated with biologics. The psoriatic lesions were improved by biologics in these cases, and no severe adverse effects on the renal function were reported. Thus, biologics are a reasonable treatment option for patients with severe psoriasis with renal failure on HD.

  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.

  15. 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

  16. 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

  17. 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

  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. Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab: A Descriptive Cohort Study

    PubMed Central

    Bouchelouche, Pierre; Bartels, Else Marie; Bliddal, Henning; Bendtzen, Klaus; Stoltenberg, Michael

    2016-01-01

    Objectives With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs). Methods Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well. Results During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found. Conclusion The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure. PMID:27606615

  20. 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.

  1. 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

  2. [Treatment of hepatitis B virus infection: present and future].

    PubMed

    Planas, Ramón; Morillas, Rosa M

    2008-01-01

    The treatment of chronic hepatitis B virus (HVB) infection constitutes a challenge in spite of the advances in the therapeutic arsenal available. At the moment there are 4 approved antiviral drug groups: interferons, nucleoside analogues (lamivudine, telbivudine), nucleotide analogues (adefovir- dipivoxil) and cyclopents (entecavir), with different antiviral efficacy among them. The primary target of the treatment is a prolonged suppression of viral replication in order to avoid long term complications (cirrhosis, hepatocellular carcinoma) and increase survival. In first place we must decide when to initiate the treatment. Secondly, which is the best therapeutic option based on the demonstrated antiviral effectiveness, profile of security and appearance of resistances. And finally, the duration and modification of the treatment based on the answer to itself. The objective of this article is a practical revision of the present management of the infection by the HVB. PMID:18570812

  3. 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

  4. 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

  5. Entecavir: a review of its use in the treatment of chronic hepatitis B in patients with decompensated liver disease.

    PubMed

    Keating, Gillian M

    2011-12-24

    The oral deoxyguanosine nucleoside analogue entecavir (Baraclude®) has potent activity against hepatitis B virus (HBV) and a high genetic barrier to resistance. This article reviews the clinical efficacy and tolerability of entecavir in the treatment of chronic hepatitis B in patients with decompensated liver disease, as well as summarizing its pharmacological properties. Entecavir 1 mg/day was more effective than adefovir dipivoxil 10 mg/day in the treatment of patients with chronic hepatitis B and decompensated liver disease, according to the results of a randomized, open-label, multicentre trial. Patients were either nucleos(t)ide naive or lamivudine experienced. The reduction from baseline in HBV DNA levels at week 24 (primary endpoint) was significantly greater with entecavir than with adefovir dipivoxil. The proportion of patients with HBV DNA levels of <300 copies/mL was also significantly greater with entecavir than with adefovir dipivoxil at weeks 24, 48 and 96, as was the proportion of patients with ALT normalization. Entecavir 0.5 or 1 mg/day, tenofovir disoproxil fumarate 300 mg/day and a fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate 200 mg/300 mg per day were effective in the treatment of chronic hepatitis B in patients with decompensated liver disease, according to the 48-week analysis of a randomized, double-blind, multicentre trial, primarily designed to examine tolerability endpoints. In this trial, over one-third of patients had received previous therapy with lamivudine for ≥6 months. The efficacy of entecavir in treatment-naive patients with HBV-related decompensated cirrhosis did not significantly differ from that seen in patients with chronic hepatitis B or compensated cirrhosis (compensated group), according to the results of a prospective, nonrandomized study. After 6 or 12 months of entecavir treatment, there were no significant differences between the decompensated and compensated groups in virological

  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. 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

  8. 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

  9. 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.

  10. Natural products as promising drug candidates for the treatment of hepatitis B and C.

    PubMed

    Wohlfarth, Carolin; Efferth, Thomas

    2009-01-01

    Hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are a major threat worldwide. Combination therapy of interferon-alpha and ribavirin is currently the treatment of choice for HCV-infected patients. However, this regimen is only effective in approximately 50% of patients and provokes severe side-effects. Numerous natural alternatives for treating HCV have been suggested. Deoxynojirimycin and its derivatives are iminosugars which exert anti-HCV activity by inhibiting alpha-glucosidases. A non-immunosuppressive derivate of cyclosporine A, NIM811, exerts anti-HCV activity by binding to cyclophilin. Other natural products with promising anti-HCV activity are 2-arylbenzofuran derivatives, Mellein, and pseudoguaianolides. For HBV treatment, several drugs are available, specifically targeting the virus polymerase (lamivudine, entecavir, telbivudine, and adefovir dipivoxil). The efficacy of these drugs is hampered by the development of resistance due to point mutations in the HBV polymerase. Due to drug resistance and adverse side-effects, the search for novel drugs is mandatory. Wogonin, ellagic acid, artemisinin and artesunate, chrysophanol 8-O-beta-D-glucoside, saikosaponin C, and protostane triterpenes are active against HBV. Natural products need to be investigated in more detail to explore their potential as novel adjuncts to established HBV or HCV therapy.

  11. Natural products as promising drug candidates for the treatment of hepatitis B and C

    PubMed Central

    Wohlfarth, Carolin; Efferth, Thomas

    2009-01-01

    Hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are a major threat worldwide. Combination therapy of interferon-α and ribavirin is currently the treatment of choice for HCV-infected patients. However, this regimen is only effective in approximately 50% of patients and provokes severe side-effects. Numerous natural alternatives for treating HCV have been suggested. Deoxynojirimycin and its derivatives are iminosugars which exert anti-HCV activity by inhibiting α-glucosidases. A non-immunosuppressive derivate of cyclosporine A, NIM811, exerts anti-HCV activity by binding to cyclophilin. Other natural products with promising anti-HCV activity are 2-arylbenzofuran derivatives, Mellein, and pseudoguaianolides. For HBV treatment, several drugs are available, specifically targeting the virus polymerase (lamivudine, entecavir, telbivudine, and adefovir dipivoxil). The efficacy of these drugs is hampered by the development of resistance due to point mutations in the HBV polymerase. Due to drug resistance and adverse side-effects, the search for novel drugs is mandatory. Wogonin, ellagic acid, artemisinin and artesunate, chrysophanol 8-O-β-D-glucoside, saikosaponin C, and protostane triterpenes are active against HBV. Natural products need to be investigated in more detail to explore their potential as novel adjuncts to established HBV or HCV therapy. PMID:19060918

  12. Amidate prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine as inhibitors of adenylate cyclase toxin from Bordetella pertussis.

    PubMed

    Šmídková, Markéta; Dvoráková, Alexandra; Tloust'ová, Eva; Česnek, Michal; Janeba, Zlatko; Mertlíková-Kaiserová, Helena

    2014-01-01

    Adenylate cyclase toxin (ACT) is the key virulence factor of Bordetella pertussis that facilitates its invasion into the mammalian body. 9-[2-(Phosphonomethoxy)ethyl]adenine diphosphate (PMEApp), the active metabolite of the antiviral drug bis(POM)PMEA (adefovir dipivoxil), has been shown to inhibit ACT. The objective of this study was to evaluate six novel amidate prodrugs of PMEA, both phenyloxy phosphonamidates and phosphonodiamidates, for their ability to inhibit ACT activity in the J774A.1 macrophage cell line. The two phenyloxy phosphonamidate prodrugs exhibited greater inhibitory activity (50% inhibitory concentration [IC50] = 22 and 46 nM) than the phosphonodiamidates (IC50 = 84 to 3,960 nM). The inhibitory activity of the prodrugs correlated with their lipophilicity and the degree of their hydrolysis into free PMEA in J774A.1 cells. Although the prodrugs did not inhibit ACT as effectively as bis(POM)PMEA (IC50 = 6 nM), they were significantly less cytotoxic. Moreover, they all reduced apoptotic effects of ACT and prevented an ACT-induced elevation of intracellular [Ca(2+)]i. The amidate prodrugs were less susceptible to degradation in Caco-2 cells compared to bis(POM)PMEA, while they exerted good transepithelial permeability in this assay. As a consequence, a large amount of intact amidate prodrug is expected to be available to target macrophages in vivo. This feature makes nontoxic amidate prodrugs attractive candidates for further investigation as novel antimicrobial agents.

  13. Efficacy of cationic lipid-DNA complexes (CLDC) on hepatitis B virus in transgenic mice.

    PubMed

    Morrey, John D; Motter, Neil E; Taro, Brandon; Lay, Marla; Fairman, Jeffery

    2008-07-01

    Cationic lipid-DNA (non-coding) complexes (CLDC) are activators of the innate immune response that increase survival of rodents with some acute viral infections and cancers. CLDC were evaluated for their ability to impact viral DNA levels in transgenic mice carrying an infectious clone of hepatitis B virus (HBV). Mice used in the studies were diet-restricted as nursing pups from solid food, because the expression of HBV DNA in the liver was increased above background levels in some mice with this restriction. Survival surgery was performed on these mice to obtain liver biopsies from which to select animals with suitable levels of liver HBV DNA for entry into the experimental protocols. Intravenous administration of 5 microg/mouse of CLDC on days 1, 7 and 13 reduced liver HBV DNA to similar low levels achieved with the positive control, adefovir dipivoxil. In a subsequent experiment, the same treatment schedule was used to determine that the minimal effective CLDC dose was between 0.5 and 0.05 microg/mouse. Selective cytokines were increased in the livers of CLDC-treated compared to placebo-treated mice in a dose-responsive manner. CLDC were effective in reducing liver HBV DNA and could be considered for further evaluation in other hepatitis models. PMID:18358544

  14. A cutting-edge view on the current state of antiviral drug development.

    PubMed

    De Clercq, Erik

    2013-11-01

    Prominent in the current stage of antiviral drug development are: (i) for human immunodeficiency virus (HIV), the use of fixed-dose combinations (FDCs), the most recent example being Stribild(TM); (ii) for hepatitis C virus (HCV), the pleiade of direct-acting antivirals (DAAs) that should be formulated in the most appropriate combinations so as to obtain a cure of the infection; (iii)-(v) new strategies (i.e., AIC316, AIC246, and FV-100) for the treatment of herpesvirus infections: herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), respectively; (vi) the role of a new tenofovir prodrug, tenofovir alafenamide (TAF) (GS-7340) for the treatment of HIV infections; (vii) the potential use of poxvirus inhibitors (CMX001 and ST-246); (viii) the usefulness of new influenza virus inhibitors (peramivir and laninamivir octanoate); (ix) the position of the hepatitis B virus (HBV) inhibitors [lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF)]; and (x) the potential of new compounds such as FGI-103, FGI-104, FGI-106, dUY11, and LJ-001 for the treatment of filoviruses (i.e., Ebola). Whereas for HIV and HCV therapy is aimed at multiple-drug combinations, for all other viruses, HSV, CMV, VZV, pox, influenza, HBV, and filoviruses, current strategies are based on the use of single compounds.

  15. [Antiviral therapy for patients with chronic hepatitis B with multi-drug resistance to nucleoside analogues].

    PubMed

    Ozeki, Itaru; Hige, Shuhei; Karino, Yoshiyasu; Kimura, Mutsuumi; Arakawa, Tomohiro; Nakajima, Tomoaki; Kuwata, Yasuaki; Ohmura, Takumi; Sato, Takahiro; Toyota, Joji

    2013-01-01

    In 18 of 547 patients who had received nucleoside analogue preparations for 1 year or more, multi-drug resistance was detected, after a median follow-up of 53 months. No patient showed liver failure related to multi-drug resistance acquisition. Multi-drug resistance was associated with entecavir (ETV) therapy in 7 lamivudine (LAM) -resistant patients, combination therapy with adefovir dipivoxil (ADV) in 8 LAM-resistant patients, LAM switching to ETV in 2 patients, and initial ETV administration in 1. For treatment, combination therapy with LAM and ADV was performed. In non-responders, combination therapy with ADV and ETV was employed. In all LAM- and ADV-resistant patients, and the HBV DNA level decreased to 3.0LC/ml or less. However, a similar decrease was noted in 7 (58.3%) of 12 LAM- and ETV-resistant patients. Of the 18 patients, 1 did not respond to combination therapy with ADV and ETV. Therapy with tenofovir disoproxil fumarate (TDF) was required.

  16. 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

  17. Synthesis, characterization and biological activity of a niobium-substituted-heteropolytungstate on hepatitis B virus.

    PubMed

    Zhang, Hong; Qi, Yanfei; Ding, Yanhua; Wang, Juan; Li, Qingmei; Zhang, Jingzhou; Jiang, Yanfang; Chi, Xiumei; Li, Juan; Niu, Junqi

    2012-02-15

    To synthesise and characterize the polyoxometalate Cs(2)K(4)Na[SiW(9)Nb(3)O(40)]·H(2)O 1 for its anti-hepatitis B virus (HBV) properties by using the HepG2.2.15 cell. The methylthiazol tetrazolium assay was used to evaluate the growth inhibitory effect of Compound 1 on HepG2.2.15 cell. By using ELISA and real-time PCR, respectively, the presence of extracellular hepatitis B surface antigen (HBsAg), e antigen (HBeAg), and HBV DNA were measured. The levels of intracellular HBV DNA and mRNA were determined by using Southern blot or reverse-transcription-PCR, respectively. Intracellular distribution of antigen were measured by Western blot. A 1995 μmol/L concentration of the commercially-available hepatitis B drug, adefovir dipivoxil (ADV), was required to achieve 50% cytotoxicity against cultured cells (CC(50)) by day nine; in contrast, only 1747 μmol/L of Compound 1 was required for the same result. Treatment of HepG2.2.15 cells with Compound 1 effectively suppress the secretion of HBV antigens and HBV DNA in a dose-dependent and time-dependent manner. IC(50) values were determined to be 80 μmol/L for HBsAg, 75 μmol/L for HBeAg and 3.72 μmol/L for supernatant HBV DNA at day nine post-exposure, as opposed to 266, 296, 30.09 μmol/L, respectively, for ADV. Intracellular HBV DNA, mRNA and antigen were also found to be decreased by Compound 1. The same dose of ADV yielded a significantly less robust inhibitory effect. Compound 1 can clear HBV from hepatic cells and may represent a therapeutic agent to treat HBV infection.

  18. Treatment for hepatitis B in patients with drug resistance

    PubMed Central

    Kroy, Daniela C.

    2016-01-01

    Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication. Importantly, these drugs have different barriers to resistance, explaining the higher incidence of treatment failure in the past due to drug resistant viral strains for the older compounds LMV, LdT and ADV. On a molecular level, drug resistant mutations usually affect the reverse transcriptase domain of the HBV polymerase protein. Secondary compensatory mutations restore the replication fitness of the mutant virus. From a clinical point of view, patients undergoing antiviral therapy require regular testing for HBV DNA (every 3–6 months). In case of insufficient viral suppression or viral breakthrough (>1 log increase in HBV DNA above nadir), strict adherence to therapy needs to be ensured. If drug resistance is suspected or even molecularly confirmed, rescue therapy strategies exist, usually switching to a noncross-resistant antiviral drug. LMV, LdT and ETV resistant HBV can be treated with TDF monotherapy, ADV resistance with ETV or TDF, and insufficient responses to TDF may require ETV either as mono- or combination therapy. Complex treatment histories with many antivirals may sometimes necessitate the combination of highly effective antivirals like ETV and TDF. Novel treatment targets such as core (capsid) inhibitors, siRNA targeting protein translation, entry inhibitors or immune modulators

  19. 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

  20. Clinical characteristics and current management of hepatitis B and C in China

    PubMed Central

    Sun, Yong-Tao; Zhang, Yue-Xin; Tang, Hong; Mao, Qing; Wang, Xiao-Zhong; Zhang, Ling-Yi; Chen, Hong; Zhong, Ying-Na; Lin, Shu-Mei; Zhang, Da-Zhi

    2014-01-01

    AIM: To describe a population of outpatients in China infected by hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and assess their current management status. METHODS: A multicenter, cross-sectional study of HBV- and/or HCV-infected patients was conducted from August to November, 2011 in western China. Patients ≥ 18 years of age with HBV and/or HCV infections who visited outpatient departments at 10 hospitals were evaluated, whether treated or not. Data were collected on the day of visit from medical records and patient interviews. RESULTS: A total 4010 outpatients were analyzed, including 2562 HBV-infected and 1406 HCV-infected and 42 HBV/HCV co-infected patients. The median duration of documented infection was 7.5 years in HBV-infected and 1.8 years in HCV-infected patients. Cirrhosis was the most frequent hepatic complication (12.2%), appearing in one-third of patients within 3 years prior to or at diagnosis. The HCV genotype was determined in only 10% of HCV-infected patients. Biopsy data were only available for 54 patients (1.3%). Antiviral medications had been received by 58.2% of patients with HBV infection and 66.6% with HCV infection. Nucleos(t)ide analogs were the major antiviral medications prescribed for HBV-infected patients (most commonly adefovir dipivoxil and lamivudine). Ribavirin + pegylated interferon was prescribed for two-thirds of HCV-infected patients. In the previous 12 mo, around one-fifth patients had been hospitalized due to HBV or HCV infection. CONCLUSION: This observational, real-life study has identified some gaps between clinical practice and guideline recommendations in China. To achieve better health outcomes, several improvements, such as disease monitoring and optimizing antiviral regimens, should be made to improve disease management. PMID:25309089

  1. 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

  2. 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

  3. 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

  4. Prophylaxis against hepatitis B virus recurrence after liver transplantation: A registry study

    PubMed Central

    Shen, Shu; Jiang, Li; Xiao, Guang-Qin; Yan, Lu-Nan; Yang, Jia-Yin; Wen, Tian-Fu; Li, Bo; Wang, Wen-Tao; Xu, Ming-Qing; Wei, Yong-Gang

    2015-01-01

    AIM: To evaluate the prophylactic efficacy of hepatitis B immunoglobulin (HBIG) in combination with different nucleos(t)ide analogues. METHODS: A total of 5333 hepatitis B surface antigen-positive patients from the China Liver Transplant Registry database were enrolled between January 2000 and December 2009. Low-dose intramuscular (im) HBIG combined with one nucleos(t)ide analogue has been shown to be very cost-effective in recent reports. Hepatitis B virus (HBV) prophylactic outcomes were compared based on their posttransplant prophylactic protocols [group A (n = 4684): im HBIG plus lamivudine; group B (n = 491): im HBIG plus entecavir; group C (n = 158): im HBIG plus adefovir dipivoxil]. We compared the related baseline characteristics among the three groups, including the age, male sex, Meld score at the time of transplantation, Child-Pugh score at the time of transplantation, HCC, pre-transplantation hepatitis B e antigen positivity, pre-transplantation HBV deoxyribonucleic acid (HBV DNA) positivity, HBV DNA at the time of transplantation, pre-transplantation antiviral therapy, and the duration of antiviral therapy before transplantation of the patients. We also calculated the 1-, 3- and 5-year survival rates and HBV recurrence rates according to the different groups. All potential risk factors were analyzed using univariate and multivariate analyses. RESULTS: The mean follow-up duration was 42.1 ± 30.3 mo. The 1-, 3- and 5-year survival rates were lower in group A than in groups B (86.2% vs 94.4%, 76.9% vs 86.6%, 73.7% vs 82.4%, respectively, P < 0.001) and C (86.2% vs 92.5%, 76.9% vs 73.7%, 87.0% vs 81.6%, respectively, P < 0.001). The 1-, 3- and 5-year posttransplant HBV recurrence rates were significantly higher in group A than in group B (1.7% vs 0.5%, 3.5% vs 1.5%, 4.7% vs 1.5%, respectively, P = 0.023). No significant difference existed between groups A and C and between groups B and C with respect to the 1-, 3- and 5-year HBV recurrence rates

  5. 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

  6. 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

  7. 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

  8. 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

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

    PubMed

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

    2015-10-01

    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.

  10. 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 ...

  11. Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor.

    PubMed

    Merkac, Maja Ivartnik; Tomazic, Janez; Strle, Franc

    2015-12-01

    A 57-year-old woman, receiving TNF-alpha inhibitor adalimumab for psoriasis, presented with early Lyme neuroborreliosis (Bannwarth's syndrome). Discontinuation of adalimumab and 14-day therapy with ceftriaxone resulted in a smooth course and favorable outcome of Lyme borreliosis. This is the first report on Lyme neuroborreliosis in a patient treated with TNF-alpha inhibitor.

  12. 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 ...

  13. 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)).

  14. Impact of nucleos(t)ide analogues on the estimated glomerular filtration rate in patients with chronic hepatitis B: a prospective cohort study in China.

    PubMed

    Qi, X; Wang, J-Y; Mao, R-C; Zhang, J-M

    2015-01-01

    Chronic hepatitis B therapy with nucleos(t)ide analogues, particularly tenofovir or adefovir, may affect renal function. To date, there has not been a head-to-head controlled study to assess estimated glomerular filtration rate (eGFR) fluctuations in nucleos(t)ide-treated CHB patients. We aimed to evaluate the long-term effects of nucleos(t)ide on eGFR in Chinese patients with chronic hepatitis B. This prospective cohort study included 275 patients. Patient subgroups included those treated with lamivudine (n = 50), adefovir (n = 60), telbivudine (n = 68) and entecavir (n = 61); untreated patients (n = 36) served as control. After an average follow-up duration of 23 months, eGFR calculated by Cockcroft-Gault and Modification of Diet in Renal Disease formulas increased by 18.35 mL/min and 19.34 mL/min (P < 0.0001) in the telbivudine group, respectively, and decreased by 10.95 mL/min and 12.17 mL/min (P = 0.0001) in the adefovir group, respectively. Even if renal function was normal or mildly impaired at baseline, eGFR increased significantly more in the telbivudine group than in the other groups (P < 0.001). More patients in the adefovir group (23%) had a ≥20% decrease in eGFR than the other groups (P < 0.0001). More patients in the telbivudine group (31%) had a ≥20% increase in eGFR than the other groups (P < 0.0001). In conclusion, prolonged telbivudine therapy resulted in improved eGFR, while adefovir therapy was associated with decreased eGFR. Lamivudine and entecavir therapy did not significantly influence eGFR.

  15. Differential effects of anti-cancer and anti-hepatitis drugs on liver cystatin

    PubMed Central

    Shah, Aaliya; Priyadarshini, Medha; Khan, Mohd Shahnawaz; Aatif, Mohammad; Amin, Fakhra; Tabrez, Shams; Zaher, Galila F.; Bano, Bilqees

    2014-01-01

    The drug–protein interaction has been the subject of increasing interest over the decades. In the present communication, the interaction of liver cystatin with anti-cancer (adriamycin) and anti-hepatitis (adevofir dipivoxil) drugs was studied by thiol-protease inhibitory assay, UV absorption, fluorescence spectroscopy and circular dichroism (CD). A static type of quenching was observed between the protein and the drug molecules. Binding constant (Ka) of adriamycin to liver cystatin (LC) was found to be 1.08 × 106 M−1. Moreover, binding site number was found to be 2. Importantly, cystatin loses its activity in the presence of adriamycin. However, intrinsic fluorescence studies in the presence of adevofir dipivoxil showed enhancement in the fluorescence intensity suggesting that binding of adevofir to LC caused unfolding of the protein. The unfolding of the test protein was also accompanied by significant loss of inhibitory activity. CD spectroscopy result showed, both adriamycin and adevofir dipivoxil caused perturbation in the secondary structure of liver cystatin. The possible implications of these results will help in combating drug induced off target effects. PMID:25561887

  16. Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders

    PubMed Central

    2014-01-01

    Tumor necrosis factor alpha (TNF-?) is an important pro-inflammatory cytokine associated with a variety of ocular diseases. The currently available TNF-? inhibitors are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Experimental and clinical studies on the intravitreal use of these agents have been reported with etanercept, infliximab, and adalimumab: etanercept has shown limited efficacy in scarce reports; infliximab has been associated with local safety concerns but appears to benefit certain cases; adalimumab has shown no efficacy in cases of age-related macular degeneration (AMD) or diabetic macular edema (DME), but the combination with bevacizumab may be effective in refractory cases of macular diseases. Further preclinical and clinical studies are warranted in order to be able to obtain a more robust conclusion on the use of intravitreal TNF-? inhibitors. PMID:25825604

  17. Paradoxical Induction of Psoriasis and Lichen Planus by Tumor Necrosis Factor-α Inhibitors.

    PubMed

    Au, Sonoa; Hernandez, Claudia

    2015-01-01

    Case 1. A 33-year-old white woman presented to our clinic with a new-onset psoriasiform pustular eruption involving her palms and soles 4 months after the initiation of adalimumab for Crohn's disease. Her medical history was significant for childhood atopic dermatitis and hidradenitis suppurativa, but she had no personal or family history of psoriasis. Topical corticosteroids including hydrocortisone 2.5%, triamcinolone 0.1%, fluocinonide 0.05%, and clobetasol 0.05% were used without improvement. The pustular eruption spread to her scalp, trunk, and proximal extremities, and her toenails developed onycholysis and dystrophy. Her adalimumab was withdrawn for 1 month due to suspicion of a paradoxical pustular psoriasis reaction. After 2 weeks off adalimumab, the pustular dermatosis had significantly diminished and her gastroenterologist changed her medication to methotrexate. Her eruption continued to clear over the course of the next 6 months. PMID:26790515

  18. 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

  19. 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

  20. 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

  1. [Golimumab Therapy in Ulcerative Colitis].

    PubMed

    Moon, Won

    2016-02-01

    Ulcerative colitis is a chronic inflammatory condition of the colon, characterized by diffuse mucosal inflammation and blood-mixed diarrhea. The main treatment has been 5-aminosalicylic acid, steroid, thiopurine, and anti-tumor necrosis factor alpha (TNF-α) antibodies including infliximab, adalimumab, and golimumab. Golimumab, a new anti-TNF-α agent has been recently approved for patients with moderate to severe ulcerative colitis. Its efficacy and safety has been demonstrated in line with infliximab and adalimumab in preclinical and clinical studies. This review will focus on golimumab therapy in ulcerative colitis.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Treatment of hidradenitis suppurativa with biologic medications.

    PubMed

    Lee, Robert A; Eisen, Daniel B

    2015-11-01

    Given the absence of significant improvement in the treatment of hidradenitis suppurativa (HS) with traditional medical and surgical therapies, biologics have piqued the interest of research investigators. The efficacy of biologics in the treatment of inflammatory conditions like psoriasis and rheumatoid arthritis is well-documented. More recently, success with biologics has been demonstrated in atopic dermatitis, another dermatological condition associated with inflammatory states. Researchers have begun to probe the utility of biologic agents in less prevalent conditions that feature inflammation as a key characteristic, namely, hidradenitis suppurativa. Five agents in particular adalimumab, anakinra, etanercept, infliximab, and ustekinumab, have been explored in the setting of HS. Results to date put forward adalimumab and infliximab as biologic treatments that can safely be initiated with some expectant efficacy. Other biologic agents require more rigorous examination before they are worthy of addition to the treatment armamentarium.

  12. 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

  13. 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.

  14. [Copernican revolution in the therapy of rheumatoid arthritis: the contribution of anti-TNFalpha drugs].

    PubMed

    Bombardieri, S; Ferraccioli, G; Ferri, C; Galeazzi, M; Lapadula, G; Cerinic, M Matucci; Montecucco, C; Triolo, G; Trotta, F; Valentini, G

    2009-01-01

    TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management. PMID:19999184

  15. Prevalence and types of drug-resistant variants in Chinese patients with acute hepatitis B.

    PubMed

    Su, Feifei; Dai, Jianyi; Yang, Shoufeng; Jiang, Xiangao; Cui, Xiaoya; Ning, Hongye; Li, Junhua; Huang, Mohe

    2015-09-01

    The presence of therapy-associated hepatitis B virus (HBV) variants is the main drawback of antiviral therapy for HBV infection. Moreover, drug-resistant variants are more insensitive to a second agent and more therapy-associated mutations will be present. To apply better nucleos(t)ide analogues (NA) and reduce the occurrence of resistance, the prevalence and types of drug-resistant mutations in acute hepatitis B patients were investigated in this study. One hundred three HBV DNA-positive patients with symptomatic acute hepatitis B that were observed from 2011 to 2013 were enrolled. Direct polymerase chain reaction sequencing was used firstly to screen HBV reverse-transcriptase domain to detect HBV mutants. Five lamivudine-resistant variants were identified. Clonal sequencing was performed for 5 resistance-positive samples and 10 other random samples. Interestingly, all detected samples harbored drug-resistant mutations, although with different percentage. Thirteen harbored lamivudine-related alone (five) or together with other NA related mutations (five with adefovir, one with entecavir, and one with telbivudine), and two of them harbored adefovir-related mutations. Also, mutations associated with four currently used NA were all detected, and the frequency is in accordance with the popularity of NA used in clinical practice. These data suggest that drug-resistant variants are present in patients with acute hepatitis B and NA should be applied more carefully for chronic hepatitis B patients developed from acute hepatitis B.

  16. 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

  17. [New immunological weapons for medicine in the 21st Century: biological therapy based on the use of the latest generation monoclonal antibodies].

    PubMed

    Aguillón, Juan C; Contreras, Juan; Dotte, Andrés; Cruzat, Andrea; Catalán, Diego; Salazar, Lorena; Molina, María Carmen; Guerrero, Julia; López, Mercedes; Soto, Lilian; Salazar-Onfray, Flavio; Cuchacovich, Miguel

    2003-12-01

    The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function.

  18. 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.

  19. Indirect comparison for Anti-TNF drugs in moderate to severe ulcerative colitis.

    PubMed

    Galván-Banqueri, M; Vega-Coca, M D; Castillo-Muñoz, M A; Beltrán Calvo, C; Molina López, T

    2015-03-01

    Objetivo: Comparar la eficacia relativa de infliximab, adalimumab y golimumab mediante comparaciones indirectas (CI) ajustadas. Métodos: Se realizó una búsqueda bibliográfica que abarcó hasta Octubre 2013. Las bases de datos consultadas fueron: MEDLINE, EMBASE, the Cochrane Library, the Centre for Reviews and Dissemination y the Web of Science. Se incluyeron ensayos clínicos aleatorizados (ECA) que compararan la eficacia de infliximab, adalimumab o golimumab frente a placebo en términos de remisión clínica, respuesta clínica y curación de la mucosa. En el caso de que se incluyera más de un ECA para un mismo fármaco se llevó a cabo un metanálisis utilizado el modelo de efectos fijos. Las CI se realizaron utilizando el método de Butcher et al. Resultados: Se incluyeron 6 ECA publicados en 5 artículos: 2 para infliximab (ACT 1 y ACT 2), 2 para adalimumab (ULTRA 1 y ULTRA 2) y 2 para golimumab (PURSUIT-SC y PURSUIT-M). Los tres agentes biológicos presentaron mayor eficacia que placebo. Los resultados de las CI fueron los siguientes: en relación a la remisión clínica, en el período de inducción y en el período de mantenimiento, no hubo diferencias estadísticamente significativas entre los tres fármacos anti-TNF. En relación a la respuesta clínica y a la curación de la mucosa, en el período de inducción hay diferencias estadísticamente significativas entre infliximab y adalimumab. Conclusiones: En base a los resultados obtenidos (eficacia similar), infliximab, adalimumab y golimumab parecen ser alternativas terapéuticas. Así, otras consideraciones como la seguridad, la tolerancia y el coste-efectividad deben considerarse a la hora de seleccionar el tratamiento más adecuado.

  20. Analysis of HBV genotype, drug resistant mutations, and pre-core/basal core promoter mutations in Korean patients with acute hepatitis B.

    PubMed

    Lee, Jong Ho; Hong, Sun Pyo; Jang, Eun Sun; Park, Sang Jong; Hwang, Seong Gyu; Kang, Sook-Kyoung; Jeong, Sook-Hyang

    2015-06-01

    Acute hepatitis B, caused by hepatitis B virus (HBV) strains with drug resistant mutations or pre-core/basal core promoter (PC/BCP) mutations, is a public health concern, because this infection is often associated with poor disease outcome or difficulty in therapeutic choice. The HBV genotype, the prevalence of drug resistant mutations, and PC/BCP mutations in Korean patients with acute hepatitis B were studied. From 2006 to 2008, 36 patients with acute hepatitis B were enrolled prospectively in four general hospitals. Among them, 20 showed detectable HBV DNA (median value was 4.8 log copies/mL). HBV genotyping and analysis of HBV mutations that conferred resistance against lamivudine, adefovir, or entecavir and of PC/BCP mutations were performed using highly sensitive restriction fragment mass polymorphism (RFMP) analysis. All 20 patients were infected with HBV genotype C, which causes almost all cases of chronic hepatitis B in Korea. No patient showed mutations that conferred resistance against lamivudine (L180M, M204V/I), adefovir (A181T, N236S), or entecavir (I169M, A184T/V, S202I/G, M250V/I/L). However, four patients had BCP mutations, and two had PC mutations. Platelet counts were significantly lower in the four patients with PC/BCP mutations compared to those with wild type. In this study, all acute hepatitis B patients had genotype C HBV strains with no drug resistant mutations. However, 20% showed PC/BCP mutations. This highlights the need for further study on the significance of PC/BCP mutations.

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

    PubMed Central

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

    2014-01-01

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

  2. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

    PubMed

    Shealy, David J; Cai, Ann; Staquet, Kim; Baker, Audrey; Lacy, Eilyn R; Johns, Laura; Vafa, Omid; Gunn, George; Tam, Susan; Sague, Sarah; Wang, Dana; Brigham-Burke, Mike; Dalmonte, Paul; Emmell, Eva; Pikounis, Bill; Bugelski, Peter J; Zhou, Honghui; Scallon, Bernard J; Giles-Komar, Jill

    2010-01-01

    We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.

  3. Treatment of ankylosing spondylitis and extra-articular manifestations in everyday rheumatology practice.

    PubMed

    Elewaut, Dirk; Matucci-Cerinic, Marco

    2009-09-01

    The SpAs are a group of overlapping, chronic, inflammatory rheumatic diseases including AS, a chronic inflammatory disease primarily affecting the SI joints. In addition to inflammatory back pain, AS patients are also more likely to experience extra-articular manifestations belonging to the SpA concept which can affect the eyes, the gastrointestinal tract and the skin and other related inflammatory conditions. This review focuses on current progress in treatment options in SpA with special emphasis on extra-articular features. TNF inhibition has demonstrated effectiveness in the treatment of AS symptoms and all currently available anti-TNF agents appear to have similar efficacy. However, the efficacy of anti-TNF agents varies in the treatment of extra-articular manifestations and comorbidities. Analyses of trials of anti-TNF agents in patients with AS have revealed significant reductions in the incidence of flares of uveitis and IBD with infliximab and adalimumab (uveitis only) treatment but not with etanercept. All three anti-TNF agents (infliximab, adalimumab, etanercept) have demonstrated efficacy in psoriasis (not associated with AS). When evaluating as to which agent to use in the treatment of AS, an important consideration is the overall well-being of the patient. This should include any additional inflammatory burden that manifests in other parts of the body, which may currently be subclinical. Based on current evidence, among TNF inhibitors, the monoclonal antibodies (infliximab and adalimumab) are more appropriate than etanercept if extra-articular manifestations or comorbid conditions are present or suspected. To date, infliximab appears to be the best studied agent with a wide spectrum of proven efficacy.

  4. TNF blocker drugs modulate human TNF-α-converting enzyme pro-domain shedding induced by autoantibodies.

    PubMed

    Sisto, Margherita; Lisi, Sabrina; Lofrumento, Dario D; Caprio, Simone; Mitolo, Vincenzo; D'Amore, Massimo

    2010-11-01

    Novel biologic therapies targeted against specific components of the immune system, including blockade of TNF-α have revolutionized therapeutic approaches to inflammatory conditions and systemic inhibitors of TNF-α have been approved for the treatment of a wide variety of autoimmune diseases. No studies aimed to elucidate the effects of anti-TNF-α blockers on tumour necrosis factor-α convertase (TACE) expression and activation have yet been published. TACE is the principal protease involved in the activation of pro-TNF-α and is a target for anti-TNF-α therapy. Here we focused on regulation of TACE expression in human salivary gland epithelial cells (SGEC) treated by anti-Ro/SSA autoantibodies (autoAbs), characterizing primary Sjögren's syndrome and on the effect of anti-Ro/SSA autoAbs on TACE pro-domain shedding and activation. To test the hypothesis that anti-TNF-α blocker drugs affect TACE expression, we used Adalimumab and Etanercept to block TNF-α and evaluate the effects of these biological agents on post-translational regulation of TACE. Anti-Ro/SSA autoAbs determines TACE pro-domain shedding suggesting that TACE activity is necessary for the release of TNF-α observed in anti-Ro/SSA autoAbs-stimulated cells. The comparative efficacy analysis of the regulation of TACE activity by Adalimumab and Etanercept revealed that Adalimumab appear to be significantly more efficacious than Etanercept in preventing TACE activation caused by anti-Ro/SSA autoAbs. It is intriguing to consider that regulation of TACE may participate in the pathogenic role of autoantibodies and the modulation of TACE expression by TNF-α antagonists might contribute to the beneficial effect of these drugs in inflammatory and autoimmune diseases.

  5. 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

  6. 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

  7. 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.

  8. Application of a validated algorithm to estimate the effectiveness and cost of biologics for rheumatoid arthritis in the US pharmacy benefit manager context

    PubMed Central

    Wu, Ning; Bhurke, Sharvari; Shah, Neel; Harrison, David J

    2015-01-01

    Background Several biologic medicines are available to treat rheumatoid arthritis (RA), and they differ in administration method (subcutaneous or intravenous [IV]). We analyzed a pharmacy benefit manager database to estimate claims-based, algorithm-determined effectiveness and cost per effectively treated patient for biologics used to treat RA. Methods We analyzed the Medco Health Solutions pharmacy benefit manager database to identify patients with one or more claims for a biologic used to treat RA from 2007 to 2012. The first observed claim defined the index date, the previous 180 days were the pre-index period, and follow-up was 365 days after the index date. Effectiveness of a biologic was determined by a validated, published algorithm designed for use in claims database analyses. Cost per effectively treated patient as determined by the algorithm was calculated as the total annual cost of the biologic therapy divided by the number of effectively treated patients. Analyses were conducted for subcutaneous, IV, and individual biologics. Results The analysis population was 1,090 patients (subcutaneous: 785, IV: 305; etanercept: 440, adalimumab: 345, infliximab: 201, abatacept: 104). The mean age was 49.7±9.4 years, and 78% of the patients were female. Effectiveness according to the algorithm was higher in subcutaneous (36%) versus IV biologics (23%; P<0.001), and in etanercept (36%) versus infliximab (22%; P<0.001) and versus abatacept (24%; P=0.02). Etanercept and adalimumab were similar (35%; P=0.77). The cost per effectively treated patient according to the algorithm was $64,738 for subcutaneous biologics, $80,408 for IV biologics, $62,841 for etanercept, $67,226 for adalimumab, $90,696 for infliximab, and $62,303 for abatacept. Conclusion Effectiveness according to a validated, claims-based algorithm was higher in subcutaneous versus IV biologics. Cost per effectively treated patient according to the algorithm was approximately $16,000 less in subcutaneous

  9. Lichenoid Reactions in Association with Tumor Necrosis Factor Alpha Inhibitors: A Review of the Literature and Addition of a Fourth Lichenoid Reaction.

    PubMed

    McCarty, Morgan; Basile, Amy; Bair, Brooke; Fivenson, David

    2015-06-01

    In this manuscript, a clinical case of a patient treated with adalimumab for Behcet's disease develops lichen planopilaris. A variety of mucocutaneous lichenoid eruptions have recently been described in association with tumor necrosis factor alpha inhibitors. The authors briefly discuss the clinical and pathological presentation of lichen planopilaris as well as a potential pathogenesis of cutaneous adverse effects seen as the result of tumor necrosis factor alpha inhibitor therapy. They review all case reports of lichen planopilaris occurring on tumor necrosis factor alpha inhibitors and suggest its classification as a fourth recognized pattern on this therapy.

  10. Chronic inflammatory demyelinating polyradiculoneuropathy complicating anti TNF α therapy for chronic plaque psoriasis.

    PubMed

    Ahmed, Zahra; Powell, Robert; Llewelyn, Gareth; Anstey, Alex

    2011-12-01

    A 53-year-old woman with chronic plaque psoriasis treated with adalimumab (antitumour necrosis factor (anti TNF) α therapy) for 10 months presented with an 8 week history of hyperesthesia in a 'glove and stocking' distribution and clumsiness on walking. Nerve conduction studies confirmed the clinical diagnosis of a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). She was admitted and treated with intravenous immunoglobulin and oral steroids and made an excellent recovery. To our knowledge, this is the first published report of CIDP associated with anti TNF α therapy given to treat psoriasis.

  11. [A short history of anti-rheumatic therapy--VII. Biological agents].

    PubMed

    Pasero, G; Marson, P; Gatto, B

    2011-11-09

    The introduction of biological agents has been a major turning-point in the treatment of rheumatic diseases, particularly in rheumatoid arthritis. This review describes the principle milestones that have led, through the knowledge of the structure and functions of nucleic acids, to the development of production techniques of the three major families of biological agents: proteins, monoclonal antibodies and fusion proteins. A brief history has also been traced of the cytokines most involved in the pathogenesis of inflammatory rheumatic diseases (IL-1 and TNF) and the steps which have led to the use of the main biological drugs in rheumatology: anakinra, infliximab, adalimumab, etanercept and rituximab.

  12. 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.

  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.

  14. 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

  15. Pulmonary tuberculosis and tuberculous arthritis of knee joint associated with rheumatoid arthritis treated with anti-tumor necrosis factor (TNF)-alpha medication: a case report.

    PubMed

    Nalbant, Selim; Özyurt, Mustafa; Yıldırım, Murat; Kuskucu, Mesih

    2012-09-01

    Tuberculosis infection (TB) is one of the most important problems for the rheumatoid arthritis (RA) patients treated with anti-TNF agents. Pulmonary tuberculosis is the most common clinic form of the TB in these patients. However, tuberculosis arthritis is very rare. We present here a 72-year-old Caucasian woman with seropositive RA, treated with etanercept/adalimumab for the last 2 years, who presented with resistant knee pain and joint effusion. We believe that this treatment caused the tuberculosis in this patient, which is the most worried complication. Interestingly, tuberculosis was in the knee joint at this time.

  16. Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis

    PubMed Central

    Vickers, Adrian D.; Ainsworth, Claire; Mody, Reema; Bergman, Annika; Ling, Caroline S.; Medjedovic, Jasmina; Smyth, Michael

    2016-01-01

    Background Biological therapies are increasingly used to treat ulcerative colitis (UC). Aim To compare the efficacy of biologics in adults with moderately-to-severely active UC, stratified by prior exposure to anti-tumour necrosis factor (anti-TNF) therapy. Methods A systematic literature review was undertaken to identify studies of biologics approved for UC. Network meta-analysis was conducted for endpoints at induction and maintenance. Results Seven studies were included in the meta-analysis of induction treatment for anti-TNF therapy-naïve patients. All biologics were more effective than placebo in inducing clinical response, clinical remission, and mucosal healing. Infliximab demonstrated a statistically significant improvement over adalimumab in clinical response (odds ratio [OR] [95% credible interval (CrI)]: 2.19 [1.35–3.55]), clinical remission (OR [95% CrI]: 2.81 [1.49–5.49]), and mucosal healing (OR [95% CrI]: 2.23 [1.21–4.14]); there were no other significant differences between biologics for induction efficacy. Five studies were included in the meta-analysis of maintenance treatment, two studies rerandomised responder patients at end of induction, and three followed the same patients ‘straight through’. To account for design differences, the number of responders at end of induction was assumed to be equivalent to the number rerandomised. Vedolizumab showed significantly different durable clinical response from comparators (OR [95% CrI] infliximab 3.18 [1.14–9.20], golimumab 2.33 [1.04–5.41], and adalimumab 3.96 [1.67–9.84]). In anti-TNF therapy-experienced patients, only vedolizumab and adalimumab could be compared. At induction, no significant differences in efficacy were seen. During maintenance, vedolizumab showed significantly improved rates of mucosal healing versus adalimumab (OR [95% CrI]: 6.72 [1.36–41.0]). Conclusions This study expands the understanding of comparative efficacies of biologic treatments for UC, encompassing

  17. 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

  18. 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

  19. Biologic Therapy for Psoriatic Arthritis.

    PubMed

    Mease, Philip J

    2015-11-01

    Biologic medications, therapeutic proteins that inhibit or modulate proinflammatory immune cells and cytokines, have significantly altered clinicians' ability to effectively treat psoriatic arthritis (PsA). The first widely used biologics have been those targeting tumor necrosis factor alpha. Five agents (etanercept, infliximab, adalimumab, golimumab, and certolizumab) have shown significant benefit in all clinical domains of PsA as well as inhibiting progressive joint destruction. Treatment strategies such as treating PsA early in the disease course, treating to target and tight control, use of background methotrexate to reduce immunogenicity, and various cost-saving strategies are all being tested with biologic medicines for PsA.

  20. Economic evaluation of anti-TNF agents for patients with rheumatoid arthritis in Greece

    PubMed Central

    Fragoulakis, Vasilis; Vitsou, Elli; Hernandez, Ana Cristina; Maniadakis, Nikolaos

    2015-01-01

    Objectives We aimed to estimate the total mean annual treatment cost of different therapy options for patients with moderate-to-severe rheumatoid arthritis (RA) in Greece. Methods A cost-minimization approach was adopted. An economic model was developed to estimate the direct costs of the three widely used treatments within a 1-year time horizon, from a health care payer perspective, either for new or for existing patients. Data on resource use, dose escalation, and frequency of therapy were based on a nationwide field survey of rheumatologists. Other analyses were also undertaken based on evidence from the literature. Total cost comprised the cost of drugs, administration, and hospital day care visits. Unit cost data were obtained from the price bulletin and the government gazettes issued by the Ministry of Health. Due to the short time horizon of the study, the cost was not discounted. Results The mean annual total cost per new (or per existing) responder patient on etanercept was estimated at €9,845 (€9,840), and the total cost on etanercept/methotrexate (MTX) was estimated at €9,857 (€9,852). Therapy with etanercept had lower annual cost relative to adalimumab and infliximab. On an annual basis, it was estimated that the difference between etanercept monotherapy and adalimumab monotherapy was €544 (€1,323). Similarly, the difference between etanercept/MTX and infliximab/MTX was €1,871 (€1,490) and €543 (€1,323), respectively, relative to adalimumab/MTX. Results remained constant under other scenario analyses undertaken. Conclusion In the real-life practice setting in Greece, where dose intensity and frequency differences occur, etanercept alone or in combination with MTX, if prescribed as per label, represents the option with lower annual cost per patient when compared with adalimumab or infliximab in patients with RA. These results hold true as long as the assumptions and data used in the analysis remain stable and may alter if any of the

  1. Certolizumab pegol: new drug. As a last resort in Crohn's disease: continue to use other TNF alpha inhibitors.

    PubMed

    2009-06-01

    (1) Infliximab and adalimumab, two TNF alpha-inhibitor immunosuppressants, are both available for use as a last resort in Crohn's disease. They are effective in about one in two patients but they carry a risk of serious infections, lymphoma and aggravation of heart failure; (2) Certolizumab is a new TNF alpha-inhibitor monoclonal antibody. It is pegylated to prolong its action, hence the name certolizumab pegol; (3) Certolizumab is sold in the United States for the treatment of Crohn's disease, after failure of conventional treatments. However, the European authorities issued a negative opinion on this drug, and the European Commission refused to grant marketing authorization on 21 May 2008. It is nonetheless available for named-patient compassionate use in France; (4) Certolizumab pegol has not been compared directly with infliximab or adalimumab; (5) In a double-blind placebo-controlled trial including 662 adults with an exacerbation of Crohn's disease, a 6-month course of certolizumab pegol reduced symptom intensity in slightly more patients than placebo (23% versus 16%). However, the rate of clinical remissions was similar (about 12% of patients overall); (6) In a placebo-controlled trial in 428 patients with an initial critical response to certolizumab pegol, maintaining this treatment for 6 months was more effective than switching to placebo. Clinical remissions were obtained at the end of treatment in respectively 48% and 29% of patients; (7) These short-term trials showed a higher frequency of infections with certolizumab pegol than with placebo; these infections ranged from mild respiratory tract infections to fatal tuberculosis. Some patients also developed autoantibodies and anti-certolizumab pegol antibodies, but the clinical implications are unclear. There is also evidence of an excess risk of haemorrhage. The risk of long-term adverse effects remains to be determined; (8) Certolizumab pegol is injected subcutaneously, once a month, on an outpatient

  2. 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

  3. Interleukin 17 inhibits progenitor cells in rheumatoid arthritis cartilage

    PubMed Central

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

    2015-01-01

    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

  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.

  5. 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

  6. Managing juvenile idiopathic arthritis-associated uveitis.

    PubMed

    Hawkins, Madeleine J; Dick, Andrew D; Lee, Richard J W; Ramanan, Athimalaipet V; Carreño, Ester; Guly, Catherine M; Ross, Adam H

    2016-01-01

    Bilateral chronic anterior uveitis is an extra-articular feature of juvenile idiopathic arthritis. Although figures vary, uveitis occurs in approximately 11%-13% of patients with this disease and is most commonly associated with the female gender, oligoarthritis, and presence of antinuclear antibodies. The disease has an insidious onset and is often asymptomatic. Managing patients with juvenile idiopathic arthritis-associated uveitis remains challenging as the disease may prove to be refractory to traditional treatment regimens. Stepwise immunomodulatory therapy is indicated, with new biologic drugs being used last in cases of refractory uveitis. Small scale studies and practice have provided the evidence to undertake randomized control trials to evaluate the efficacy, safety, and cost-effectiveness of anti-tumor necrosis factor-α therapies, such as infliximab and adalimumab. These have demonstrated promising results, with further data awaited from ongoing trials for adalimumab (as SYCAMORE and ADJUVITE trials). Lower grade evidence is supporting the use of newer biologics such as rituximab, daclizumab, tocilizumab, and abatacept in those cases refractory to anti-tumor necrosis factor-α therapy.

  7. 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

  8. 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

  9. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.

    PubMed

    Blok, J L; van Hattem, S; Jonkman, M F; Horváth, B

    2013-02-01

    Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.

  10. Efficacy and safety of TNF-α inhibitors for active ankylosing spondylitis patients: Multiple treatment comparisons in a network meta-analysis

    PubMed Central

    Liu, Wei; Wu, Yuan-hao; Zhang, Lei; Liu, Xiao-ya; Bin Xue, B X; Bin Liu, B L; Wang, Yi; Ji, Yang

    2016-01-01

    Ankylosing spondylitis (AS) is an inflammatory rheumatic disease with impact on axial skeleton, peripheral joints and enthuses, and it may result in severe disabilities of those parts. Tumor necrosis factor-α (TNF-α) inhibitors are considered as an effective treatment for patients with active AS. In this study, we conducted a network meta-analysis to compare the clinical outcomes of active AS patients treated with TNF-α inhibitors. Randomized controlled trials (RCTs) evaluating the efficacy and safety of TNF-α inhibitors were retrieved in literature search and selected for meta-analysis. Changes in ASAS20 response, ASAS40 response and BASDAI 50% response were regarded as efficacy outcomes; serious adverse events (SAE) and all cause withdrawals were regarded as safety outcomes. Both traditional pairwise meta-analysis and network meta-analysis were performed. The results showed that adalimumab and infliximab had better clinical outcomes. Infliximab consistently appeared to be the most effective TNF-α inhibitors with a high risk of adverse events for patients with active AS; meanwhile, adalimumab ranked highest with respect to adverse effects with efficacy secondary to infliximab. As a result, we were unable to conclude the optimal TNF-α inhibitor and this issue should be solved by future researchers. PMID:27667027

  11. The interpretation of long-term trials of biologic treatments for psoriasis: trial designs and the choices of statistical analyses affect ability to compare outcomes across trials.

    PubMed

    Langley, R G; Reich, K

    2013-12-01

    Psoriasis is a chronic disease requiring long-term therapy, which makes finding treatments with favourable long-term safety and efficacy profiles crucial. The goal of this review is to provide the background needed to evaluate properly long-term studies of biologic treatments for psoriasis. Firstly, important elements of design and analysis strategies are described. Secondly, data from published trials of biologic therapies for psoriasis are reviewed in light of the design and analysis choices implemented in the studies. Published reports of clinical trials of biologic treatments (adalimumab, alefacept, etanercept, infliximab or ustekinumab) that lasted 33 weeks or longer and included efficacy results and statistical analysis were reviewed. Study designs and statistical analyses were evaluated and summarized, emphasizing patient follow-up methods and handling of missing data. Various trial designs and data handling methods are used in long-term studies of biologic psoriasis treatments. Responder analyses in long-term trials can be conducted in responder enrichment, re-treated nonresponder or intent-to-treat trials. Missing data can be handled in four ways, including, from most to least conservative, nonresponder imputation, last-observation-carried-forward, as-observed analysis and anytime analysis. Long-term clinical trials have shown that adalimumab, alefacept, etanercept, infliximab and ustekinumab are efficacious for psoriasis treatment; however, without common standards for these trials, direct comparisons of these agents are difficult. Understanding differences in trial design and data handling is essential to make informed treatment decisions.

  12. The interpretation of long-term trials of biologic treatments for psoriasis: trial designs and the choices of statistical analyses affect ability to compare outcomes across trials.

    PubMed

    Langley, R G; Reich, K

    2013-12-01

    Psoriasis is a chronic disease requiring long-term therapy, which makes finding treatments with favourable long-term safety and efficacy profiles crucial. The goal of this review is to provide the background needed to evaluate properly long-term studies of biologic treatments for psoriasis. Firstly, important elements of design and analysis strategies are described. Secondly, data from published trials of biologic therapies for psoriasis are reviewed in light of the design and analysis choices implemented in the studies. Published reports of clinical trials of biologic treatments (adalimumab, alefacept, etanercept, infliximab or ustekinumab) that lasted 33 weeks or longer and included efficacy results and statistical analysis were reviewed. Study designs and statistical analyses were evaluated and summarized, emphasizing patient follow-up methods and handling of missing data. Various trial designs and data handling methods are used in long-term studies of biologic psoriasis treatments. Responder analyses in long-term trials can be conducted in responder enrichment, re-treated nonresponder or intent-to-treat trials. Missing data can be handled in four ways, including, from most to least conservative, nonresponder imputation, last-observation-carried-forward, as-observed analysis and anytime analysis. Long-term clinical trials have shown that adalimumab, alefacept, etanercept, infliximab and ustekinumab are efficacious for psoriasis treatment; however, without common standards for these trials, direct comparisons of these agents are difficult. Understanding differences in trial design and data handling is essential to make informed treatment decisions. PMID:23937204

  13. 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

  14. 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

  15. 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

  16. Implementing treatment goals for successful long-term management of psoriasis.

    PubMed

    Mrowietz, U

    2012-03-01

    Treatment goals are commonly used throughout medicine to ensure efficacious therapy of diseases and to prevent complications related to uncontrolled disease activity, such as the management of hypertension and diabetes. Psoriasis is a systemic immune-mediated inflammatory disease comprising characteristic skin manifestations. A range of co-morbidities has been associated with it, including diabetes and cardiovascular diseases such as myocardial infarction (MI) and stroke. There is good evidence that the severity of skin symptoms is related to mortality associated with MI. Therefore, long-term efficacious control of skin inflammation is the treatment paradigm of choice, particularly in patients with severe skin involvement. Surveys in a number of countries have revealed a substantial under-treatment of patients with moderate-to-severe psoriasis, leaving a considerable proportion without adequate disease control. In addition, a high number of patients were not satisfied with their treatment, including the time they needed to allocate for skin therapy and the number of visits to physicians. Therefore, the use of effective therapies is necessary to achieve appropriate control of inflammation and to improve patient satisfaction. The definition of treatment goals is an appropriate instrument for raising the quality of care and sets therapeutic standards in addition to evidence-based guidelines. Consensus treatment goals for moderate-to-severe psoriasis were recently defined, and a treatment goal algorithm was developed through a Delphi process by a group of experts from 19 European countries. These have since been adopted into the update of the German S3 guidelines for treatment of psoriasis. Furthermore, a novel analysis was carried out on published Phase 3 clinical trial data from three studies of adalimumab therapy in psoriasis, which used the consented definition of moderate-to-severe disease and the proposed treatment goal algorithm. The data showed that the

  17. 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

  18. Variation at FCGR2A and Functionally Related Genes Is Associated with the Response to Anti-TNF Therapy in Rheumatoid Arthritis

    PubMed Central

    Avila-Pedretti, Gabriela; Tornero, Jesús; Fernández-Nebro, Antonio; Blanco, Francisco; González-Alvaro, Isidoro; Cañete, Juan D.; Maymó, Joan; Alperiz, Mercedes; Fernández-Gutiérrez, Benjamín; Olivé, Alex; Corominas, Héctor; Erra, Alba; Aterido, Adrià; López Lasanta, María; Tortosa, Raül; Julià, Antonio; Marsal, Sara

    2015-01-01

    Objective Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25–30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. Methods A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. Results We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). Conclusions In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes

  19. 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

  20. 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

  1. 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

  2. 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

  3. Pharmacogenetics of inflammatory bowel disease.

    PubMed

    Katsanos, Konstantinos H; Papadakis, Konstantinos A

    2014-12-01

    Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data. PMID:25521361

  4. Biologics for the treatment of pyoderma gangrenosum in ulcerative colitis

    PubMed Central

    Arivarasan, K; Bhardwaj, Vaishali; Sud, Sukrit; Sachdeva, Sanjeev

    2016-01-01

    Pyoderma gangrenosum (PG) is an uncommon extra-intestinal manifestation of inflammatory bowel disease (IBD). Despite limited published literature, biologics have caused a paradigm shift in the management of this difficult-to-treat skin condition. The clinical data and outcomes of three patients with active ulcerative colitis and concurrent PG treated with biologics (infliximab two and adalimumab one) are reviewed in this report. Biologics were added because of the sub-optimal response of the colonic symptoms and skin lesions to parenteral hydrocortisone therapy. All three patients showed a dramatic response to the addition of the biologics. In view of the rapid healing of the skin lesions, superior response rate, and the additional benefit of improvement in the underlying colonic disease following treatment, anti-tumor necrosis factor blockers should be considered as a first line therapy in the management of PG with underlying IBD. PMID:27799888

  5. Lymphocutaneous Sporotrichosis during Treatment with Anti-TNF-Alpha Monotherapy

    PubMed Central

    Ursini, Francesco; Calabria, Marilena; Bruno, Caterina; Tripolino, Cesare; Naty, Saverio; Grembiale, Rosa Daniela

    2015-01-01

    Sporotrichosis is an infectious disease caused by Sporothrix schenckii, a dimorphic fungus isolated for the first time in 1896 by Benjamin Schenck from a 36-year-old male patient presenting lesions on the right hand and arm. The infection generally occurs by traumatic inoculation of soil, plants, and organic matter contaminated with the fungus. Different clinical syndromes are described as a direct consequence of S. schenckii infection, including lymphocutaneous and disseminated forms, although extracutaneous presentations are reported most frequently in AIDS patients. Here we describe the case of a 57-year-old Caucasian male diagnosed in 2004 with ankylosing spondylitis under stable treatment with adalimumab monotherapy (40 mg every other week). During a routine follow-up visit in March 2013, he presented with multiple nodular lesions arranged in a linear fashion along the left hand and forearm. After diagnostic aspiration of the lesions, lymphocutaneous sporotrichosis was diagnosed and appropriate therapy started. PMID:25755904

  6. 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.

  7. Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease

    PubMed Central

    Scott, Frank I.; Lichtenstein, Gary R.

    2014-01-01

    While anti-TNF agents have had a marked impact in the treatment of inflammatory bowel disease, a significant number of patients lose their response to these medications over time. Clinical trials have demonstrated that antibodies against anti-TNF medications may impact treatment response and increase the risk of infusion reaction. Scheduled dosing and concurrent use of immunomodulators may help to mitigate these risks via inhibiting the formation of these antibodies. The recent availability of assays to measure anti-TNF drug levels and antibodies against anti-TNFs offer the opportunity to assess patients who have lost response with infliximab and adalimumab, and potentially determine the most appropriate therapeutic strategy. There is growing evidence that such testing improves patient outcomes and is cost-effective, although heterogeneity in the assays used in clinical and observational trials has resulted in mixed results. PMID:24452768

  8. Golimumab for the treatment of ankylosing spondylitis: a NICE single technology appraisal.

    PubMed

    Armstrong, Nigel; Joore, Manuela; van Asselt, Thea; Misso, Kate; Manning, Nathan; Tomini, Florian; Kleijnen, Jos; Riemsma, Rob

    2013-05-01

    As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the Evidence Review Group (ERG) produced a report to comment on the clinical and cost effectiveness of golimumab (Simponi(®), Merck Sharp & Dohme) for the treatment of ankylosing spondylitis (AS) relative to other comparators as presented in the manufacturer's submission (MS) to NICE. The population was those with active disease who had not responded to conventional therapy. The specified comparators were conventional care and two other tumour necrosis factor alpha (TNF-α) inhibitors (adalimumab and etanercept). Outcomes to be considered were disease activity, functional capacity, disease progression, adverse effects of treatment and health-related quality of life (HR-QOL). There were no head-to-head trials comparing TNF-α inhibitors. The submission included one trial of golimumab versus placebo (the GO-RAISE trial) and additionally seven placebo-controlled randomized controlled trials (RCTs) of other TNF-α inhibitor agents (five with etanercept, and two with adalimumab). The results of these trials were generally a statistically significant improvement from each of the TNF-α inhibitors. A Bayesian mixed treatment comparison (MTC) showed there was generally overlap in the 95 % credible intervals (CrIs) between the TNF-α inhibitors. Exceptions included a greater risk of discontinuation of treatment for golimumab than for etanercept (relative risk [RR] 4.30; 95 % CrI 1.01-18.50). The cost-effectiveness analysis (CEA) compared all of these TNF-α inhibitors. Relative effectiveness was informed only by RR of response (proportion achieving at least a 50 % improvement in Bath AS Disease Activity Index [BASDAI] score; BASDAI50) from the MTC. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) of golimumab versus conventional care was £26,597 and adalimumab and etanercept were extendedly dominated by golimumab. The

  9. Biologic therapy for refractory scleritis: a new treatment perspective.

    PubMed

    de Fidelix, Tania Sales de Alencar; Vieira, Luis Antonio; de Freitas, Denise; Trevisani, Virginia Fernandes Moça

    2015-12-01

    Scleritis is an umbrella term for a heterogeneous group of ocular diseases that can be associated with autoimmune or systemic disorders. The purpose of this article was to review the literature regarding the use of biologic drugs to treat refractory scleritis. A search of the MEDLINE, Embase, and LILACS electronic databases was conducted, and the reference lists of published articles were hand-searched. No language filters were used. This search strategy yielded no randomized trials of the use of biologic therapies to treat scleritis; only case reports and retrospective studies were retrieved. These studies suggest that monoclonal antibodies (infliximab and adalimumab) are superior to the soluble TNF receptor fusion protein etanercept for the treatment of scleritis in patients that do not respond to corticosteroids and/or to immunosuppressive treatment. Rituximab seems to be the best option for scleritis associated with vasculitis. PMID:26319144

  10. 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

  11. 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

  12. Pharmacogenetics of inflammatory bowel disease.

    PubMed

    Katsanos, Konstantinos H; Papadakis, Konstantinos A

    2014-12-01

    Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data.

  13. Medical therapy for pediatric inflammatory bowel disease.

    PubMed

    Sherlock, Mary E; Griffiths, Anne M

    2012-04-01

    Pediatric inflammatory bowel disease encompasses a spectrum of disease phenotype, severity, and responsiveness to treatment. Intestinal healing rather than merely symptom control is an especially important therapeutic goal in young patients, given the potential for growth impairment as a direct effect of persistent chronic inflammation and the long life ahead, during which other disease complications may occur. Corticosteroids achieve rapid symptom control, but alternate steroid-sparing strategies with greater potential to heal the intestine must be rapidly adopted. Exclusive enteral nutrition is an alternate short-term treatment in pediatric Crohn's disease. The results of multi-center pediatric clinical trials of both infliximab and adalimumab in Crohn's disease and of infliximab in ulcerative colitis (all in children with unsatisfactory responses to other therapies) have now been reported and guide treatment regimens in clinical practice. Optimal patient selection and timing of anti-TNF therapy requires clinical judgment. Attention must be paid to sustaining responsiveness safely.

  14. Successful treatment of psoriasis with ustekinumab in patients with multiple sclerosis.

    PubMed

    Chang, Shurong; Chambers, Cindy J; Liu, Fu-Tong; Armstrong, April W

    2015-07-15

    Psoriasis is a chronic inflammatory disease, evolving from a complex interplay of genetic and environmental factors. In the recent years, we have seen much progress in understanding the immunopathogenesis of psoriasis, paving the way for new therapies with biologics. Currently, the most commonly used biologics in psoriasis are TNF inhibitors etanercept, infliximab and adalimumab, and the IL-12/23 inhibitor ustekinumab. As TNF inhibitors are contraindicated in patients with multiple sclerosis, ustekinumab remained the only biologic available for these patient before the recent approval of Secukinumab, an IL-17A inhibitor. Herein we report two patients with multiple sclerosis and comorbid psoriasis successfully treated with ustekinumab without progression of their multiple sclerosis. Our cases demonstrate that ustekinumab is a reasonably safe choice in this patient population. We also briefly reviewed new therapies currently under investigation, which will undoubtedly further expand our armamentarium for the treatment of psoriasis in patients with neuromuscular diseases.

  15. Septic knee arthritis in Crohn’s disease biological therapy-free patient. Case report

    PubMed Central

    Pop, C; Calagiu, D; Jantea, P; Nemes, R

    2015-01-01

    A 52-year-old woman with Crohn’s disease presented with septic arthrtis of the knee. This condition coincided with a symptomatic flare of her Crohn’s disease due to an ileal inflammatory stenosis, manifested as a phlegmonous mass palpable in the right lower quadrant and a small bowel obstruction. Results of synovial fluid cultures showed the presence of Gram-negative bacillus, Klebsiella pneumoniae and the CT scan images were highly suggestive of abdominal abscess within Crohn’s disease. The patient’s condition improved after following an antibiotic treatment and after the initiation of Anti-TNF-alpha agent Adalimumab, with no further exacerbation. Septic arthritis in Crohn’s disease should be considered to have a communicating source of sepsis consisting of an abdominal abscess or fistula. Abbreviations: Anti-TNF-alpha agent = anti tumor necrosis factor alpha agent, 5-ASA = 5-aminosalicylic acid PMID:26664477

  16. Off-Label Uses of Anti-TNF Therapy in Three Frequent Disorders: Behçet's Disease, Sarcoidosis, and Noninfectious Uveitis

    PubMed Central

    Sánchez-Cano, Daniel; Callejas-Rubio, José Luis; Ruiz-Villaverde, Ricardo; Ríos-Fernández, Raquel; Ortego-Centeno, Norberto

    2013-01-01

    Tumoral necrosis factor α plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behçet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID:23983404

  17. Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis.

    PubMed

    Atzeni, Fabiola; Costa, Luisa; Caso, Francesco; Scarpa, Raffaele; Sarzi-Puttini, Piercarlo

    2015-11-01

    Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents.

  18. 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.

  19. 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

  20. [Cutaneous adverse effects of TNFalpha antagonists].

    PubMed

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  1. 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.

  2. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding.

    PubMed

    Gisbert, Javier P

    2010-05-01

    The aim of this article is to critically review available data regarding the safety of immunomodulators and biological therapies during pregnancy and breast-feeding in women with inflammatory bowel disease. Methotrexate and thalidomide can cause congenital anomalies and are contraindicated during pregnancy (and breast-feeding). Although thiopurines have a Food and Drug Administration (FDA) rating D, available data suggest that these drugs are safe and well tolerated during pregnancy. Although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe in this scenario. Treatment with cyclosporine for steroid-refractory ulcerative colitis (UC) during pregnancy can be considered safe and effective, and the use of this drug should be considered in cases of severe UC as a means of avoiding urgent surgery. Breast-feeding is contraindicated for patients receiving cyclosporine. Biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Therefore, the limited clinical results available suggest that the benefits of infliximab and adalimumab in attaining response and maintaining remission in pregnant patients might outweigh the theoretical risks of drug exposure to the fetus. Stopping therapy in the third trimester may be considered, as it seems that transplacental transfer of infliximab is low prior to this. Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an antitumor necrosis factor alpha monoclonal antibody, and therefore it may not be necessary to stop certolizumab in the third trimester. The use of infliximab is probably compatible with breast-feeding.

  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.

  4. [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.

  5. 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

  6. Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

    PubMed Central

    Emamikia, Sharzad; Arkema, Elizabeth V; Györi, Noémi; Detert, Jacqueline; Chatzidionysiou, Katerina; Dougados, Maxime; Burmester, Gerd Rüdiger; van Vollenhoven, Ronald

    2016-01-01

    Objective To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. Methods We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12–76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. Results We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Conclusions Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi. PMID:27651929

  7. RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies.

    PubMed

    Sisto, Margherita; Lisi, Sabrina; Lofrumento, Dario Domenico; Cucci, Liana; Mitolo, Vincenzo; D'Amore, Massimo

    2010-09-20

    The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-α blockade on AREG expression and TNF-α-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-α produced after anti-Ro/SSA Abs uptake via Fcγ receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-α blocking and TNF-α gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-α-induced IL-6 and IL-8 secretion in SGEC treated with anti-Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-α and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-α as stimulant, clarified that TNF-α induces IL-6 and IL-8 secretion through AREG.Laboratory Investigation advance online publication, 20 September 2010; doi:10.1038/labinvest.2010.168.

  8. 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

  9. Induction maintenance with tumour necrosis factor-inhibitor combination therapy with discontinuation versus methotrexate monotherapy in early rheumatoid arthritis: a systematic review and meta-analysis of efficacy in randomised controlled trials

    PubMed Central

    Emamikia, Sharzad; Arkema, Elizabeth V; Györi, Noémi; Detert, Jacqueline; Chatzidionysiou, Katerina; Dougados, Maxime; Burmester, Gerd Rüdiger; van Vollenhoven, Ronald

    2016-01-01

    Objective To determine whether an induction-maintenance strategy of combined therapy (methotrexate (MTX)+tumour necrosis factor (TNF) inhibitor (TNFi)) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy, since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn. Methods We performed a meta-analysis of trials using the initial combination of MTX+TNFi in conventional synthetic disease-modifying antirheumatic drug-naïve patients with early rheumatoid arthritis (RA). A systematic literature search was performed for induction-maintenance randomised controlled trials (RCTs) where initial combination therapy was compared with MTX monotherapy in patients with clinically active early RA. Our primary outcome was the proportion of patients who achieved low disease activity (LDA; Disease Activity Score (DAS)28<3.2) and/or remission (DAS28<2.6) at 12–76 weeks of follow-up. A random-effects model was used to pool the risk ratio (RR) for LDA and remission and heterogeneity was explored by subgroup analyses. Results We identified 6 published RCTs, 4 of them where MTX+adalimumab was given as initial therapy and where adalimumab was withdrawn in a subset of patients after LDA/remission had been achieved. 2 additional trials used MTX+infliximab as combination therapy. The pooled RRs for achieving LDA and clinical remission at follow-up after withdrawal of TNFi were 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively. There was significant heterogeneity between trials due to different treatment strategies, which was a limitation to this study. Conclusions Initial therapy with MTX+TNFi is associated with a higher chance of retaining LDA and/or remission even after discontinuation of TNFi.

  10. Listeriosis in patients receiving biologic therapies.

    PubMed

    Bodro, M; Paterson, D L

    2013-09-01

    The evolution of inflammatory diseases has radically changed since the introduction of biologic therapies, such as tumour necrosis factor alpha inhibitors (anti-TNFα). They, therefore, represent a widely used therapeutic modality. Nevertheless, post-marketing studies reveal an increased risk of infection in patients taking these drugs, especially granulomatous infections such as listeriosis. We aimed to evaluate the reported cases of listeriosis in patients treated with biologic treatments. We used the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) from 2004 to 2011. We also perform a literature review of previously reported cases of listeriosis in patients taking biologic therapies. We identified 266 cases of Listeria monocytogenes infection associated with biologic therapies. The majority of patients were receiving infliximab (77.1 %), followed by etanercept (11.7 %), adalimumab (9.8 %), rituximab (4.1 %), abatacept (0.4 %) and golimumab (0.4 %). Indications for the use of biologics were as follows: 47.7 % for rheumatologic diseases, 38 % for inflammatory bowel diseases, 3.4 % for haematological diseases and 10.5 % for other indications. Seventy-three percent of the patients were receiving concomitant immunosuppressant drugs, especially steroids (56 %) and methotrexate (31.6 %). The median time to the onset of infection was 184 days. Mortality rates range from 11.1 % in adalimumab-treated patients to 27.3 % in rituximab-treated patients (p = 0.7). Listeriosis is common in biologics-treated patients, especially related to infliximab use given concomitantly with other immunosuppressive therapies. Infections after treatment with biologics mostly occurred in the first year after initiating treatment. PMID:23568606

  11. The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies: what's in it for African and Middle Eastern rheumatologists.

    PubMed

    Alawadhi, Adel; Alawneh, Khaldoon; Alzahrani, Zeyad Ahmed

    2012-09-01

    Over the last decade, biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis (RA). Therapeutic antibodies such as infliximab, adalimumab, rituximab, tocilizumab, golimumab, certolizumab pegol, the receptor construct etanercept, and abatacept, an anticluster of differentiation (CD)80/anti-CD86 fusion protein, are used as treatment for RA and ankylosing spondylitis (AS). Infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept are inhibitors of tumor necrosis factor (TNF), a key regulator of inflammation. Left untreated, progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability. One limitation for the use of therapeutic antibodies is immunogenicity, the induction of antibodies by the adaptive immune system in response to foreign substances. The development of antidrug antibodies (ADAs) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS, depending on whether the ADAs are neutralizing or non-neutralizing. Studies have indicated that neutralizing ADAs are associated with a reduced efficacy, decreased drug survival, increased instances of dose escalation, and adverse events. Comparison studies of anti-TNF biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity. The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti-TNF biologic therapies. This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care.

  12. Induction of TNF-alpha-converting enzyme-ectodomain shedding by pathogenic autoantibodies.

    PubMed

    Sisto, Margherita; Lisi, Sabrina; Lofrumento, Dario Domenico; Frassanito, Maria Antonia; Cucci, Liana; D'Amore, Simona; Mitolo, Vincenzo; D'Amore, Massimo

    2009-12-01

    The release of the soluble form of tumor necrosis factor (TNF)-alpha from the plasma membrane occurs through the activation of the secretase tumor necrosis factor-alpha-converting enzyme (TACE). The current study was designed to examine whether the anti-Ro/SSA autoantibodies (Abs) are capable to regulate TACE expression in non-neoplastic human salivary gland epithelial cells (SGEC) cultures. We investigated the effect of anti-Ro/SSA Abs on the localization and abundance of cell-surface TACE and on TACE pro-domain-shedding and activation. In addition, the potential physiological consequences of TNF-alpha blockage by the biological agent Adalimumab on post-translational regulation of TACE are discussed. Anti-Ro/SSA Abs were purified from IgG fractions of patients with primary Sjögren's syndrome, using Sepharose 4B-Ro/SSA affinity columns. Flow cytometry, reverse transcription-PCR, western blot and immunohistochemistry were used to study TACE expression on SGEC and TACE regulation by Abs. Our study demonstrated a dose-dependent increase of TACE messenger RNA (mRNA) expression in anti-Ro/SSA Abs-treated SGEC, followed by internalization, pro-domain shedding and activation of TACE protein, suggesting that increased TACE activity is necessary for the release of TNF-alpha observed in anti-Ro/SSA Abs-stimulated SGEC. Adalimumab treatment brought TACE mRNA and surface TACE expression to levels than those observed in untreated SGEC. These data suggest that the effect of anti-Ro/SSA Abs on TACE expression and intracellular distribution is exerted by TNF-alpha production.

  13. Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis.

    PubMed

    Machado, Marina Amaral de Ávila; Barbosa, Mariana Michel; Almeida, Alessandra Maciel; de Araújo, Vânia Eloisa; Kakehasi, Adriana Maria; Andrade, Eli Iola Gurgel; Cherchiglia, Mariangela Leal; Acurcio, Francisco de Assis

    2013-09-01

    Biological agents directed against tumor necrosis factor (TNF) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs. To evaluate the efficacy and safety of the anti-TNF agents infliximab, etanercept, adalimumab, golimumab, and certolizumab for the treatment of ankylosing spondylitis, we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE, MEDLINE, Cochrane Controlled Trials Register and LILACS databases (September/2012), manual literature search, and the gray literature. Study selections and data collection were performed by two independent reviewers, with disagreements solved by a third reviewer. The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws. The meta-analysis was performed using the Review Manager(®) 5.1 software by applying the random effects model. Eighteen studies were included in this review. No study of certolizumab was included. Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % CI 1.91; 2.56) and 24 weeks (RR 2.68; 95 % CI 2.06; 3.48) compared with controls, which was also true for several other efficacy outcomes. Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks. Adalimumab, infliximab, etanercept, and golimumab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis. Safety outcomes deserve further study, especially with respect to long-term follow-ups.

  14. Anti-TNF therapy in the management of ocular attacks in an elderly patient with long-standing Behçet’s disease

    PubMed Central

    Karube, Hisako; Kamoi, Koju; Ohno-Matsui, Kyoko

    2016-01-01

    Background Ocular symptoms in Behçet’s disease (BD) begin mostly before 30 years of age according to international surveys, and BD activity may decrease with age. Information regarding the treatment of ocular symptoms in elderly BD patients is thus scant. Anti-TNFα antibody has recently demonstrated strong effects against recurrent uveitis in BD, but the efficacy and safety of anti-TNFα therapy in elderly patients remain unclear. We report herein the case of an elderly patient with long-standing uveitis due to BD who was successfully treated with two types of anti-TNF therapy. Case An 81-year-old Japanese man presented with a 33-year history of ocular inflammation due to BD. As immunosuppressive agents, such as cyclosporine A, were difficult to use because he had undergone removal of the left kidney due to cancer, he was treated with colchicine. However, attacks of ocular inflammation persisted around nine times a year. After colchicine had been changed to infliximab, ocular inflammation was fairly well controlled, but ocular attacks still occurred once or twice a year. As soon as intestinal hemorrhage related to BD occurred, infliximab was switched to adalimumab. After this switch, ocular attacks resolved and visual acuity was maintained at 1.0. Intestinal lesions were also well controlled, and no side effects were seen. Conclusion This represents the first report of the application of two types of anti-TNFα therapy for ocular attacks in an elderly BD patient. In addition to infliximab, adalimumab appears to offer an alternative therapy for refractory, long-standing BD-related uveitis in elderly patients. PMID:27729816

  15. B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcγRIIb, which are modulated by anti-tumor necrosis factor therapy

    PubMed Central

    2010-01-01

    Introduction Several molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcγRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy. Methods Peripheral B cells from 18 RA patients and 13 healthy donors were characterized using flow cytometry. Eleven patients who underwent a six-month adalimumab therapy were further assessed for phenotypic changes on their B cells. Results RA patients exhibited a high percentage of naïve and memory B cells expressing CD86. In contrast, expression of FcγRIIb was significantly reduced on RA memory B cells and plasmablasts as compared to healthy donors, probably due to downregulation of this receptor when differentiating from naïve to memory cells. These alterations on FcγRIIb were associated with high levels of anti-citrullinated vimentin autoantibodies. In addition, treatment with adalimumab normalized the expression of CD86 on memory B cells and reduced the expression of FcγRIIb, mainly on naïve B cells. Conclusions Our findings show that peripheral B cells from RA patients have an altered expression of key molecules, such as CD86 and FcγRIIb. Because this latter receptor is required for feedback inhibition, a deficient expression might contribute to humoral autoimmune responses. Furthermore, these molecules are likely to be influenced by inflammatory factors, since they were modulated by TNF inhibition. PMID:20398308

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

    PubMed Central

    2014-01-01

    Background An updated economic evaluation was conducted to compare the cost-effectiveness of the four tumour necrosis factor (TNF)-α inhibitors adalimumab, etanercept, golimumab and infliximab in active, progressive psoriatic arthritis (PsA) where response to standard treatment has been inadequate. Methods A systematic review was conducted to identify relevant, recently published studies and the new trial data were synthesised, via a Bayesian network meta-analysis (NMA), to estimate the relative efficacy of the TNF-α inhibitors in terms of Psoriatic Arthritis Response Criteria (PsARC) response, Health Assessment Questionnaire (HAQ) scores and Psoriasis Area and Severity Index (PASI). A previously developed economic model was updated with the new meta-analysis results and current cost data. The model was adapted to delineate patients by PASI 50%, 75% and 90% response rates to differentiate between psoriasis outcomes. Results All four licensed TNF-α inhibitors were significantly more effective than placebo in achieving PsARC response in patients with active PsA. Adalimumab, etanercept and infliximab were significantly more effective than placebo in improving HAQ scores in patients who had achieved a PsARC response and in improving HAQ scores in PsARC non-responders. In an analysis using 1,000 model simulations, on average etanercept was the most cost-effective treatment and, at the National Institute for Health and Care Excellence willingness-to-pay threshold of between £20,000 to £30,000, etanercept is the preferred option. Conclusions The economic analysis agrees with the conclusions from the previous models, in that biologics are shown to be cost-effective for treating patients with active PsA compared with the conventional management strategy. In particular, etanercept is cost-effective compared with the other biologic treatments. PMID:24444034

  17. Salvage solitaire (or, HAART takes a holiday).

    PubMed

    Mascolini, M

    1999-07-01

    Attendees at the Second International Workshop on Salvage Therapy heard little to make them optimistic about the immediate future of salvage therapy. Treatment veterans with only a few virologic failures stand a slim chance of ongoing viral control. Current salvage treatment, even combination therapy, only pushes viral loads to below 500 copies in 20 to 40 percent of patients, and those patients who have had viral loads suppressed to below 20 copies/mL stand the best chance of having a sustained response to the treatment. Results of several studies are reviewed. Adefovir, which had been considered an option, has performed poorly in trials. One table shows the effects of nonnucleoside reverse transcriptase inhibitor/protease inhibitor (NNRTI/PI) salvage therapy in the NNRTI-naive patient. Another table presents figures to show that salvage success correlates significantly with lower viral loads prior to treatment. A third table shows the "megasalvage" track record, while a fourth presents a proposal for a rapid-assessment salvage study. The concept of using drug holidays as a means to force the immune system to begin fighting HIV on its own remains controversial.

  18. Persistence versus reversion of 3TC resistance in HIV-1 determine the rate of emergence of NVP resistance.

    PubMed

    Rath, Barbara A; Olshen, Richard A; Halpern, Jerry; Merigan, Thomas C

    2012-08-01

    When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of starting nevirapine (NVP) in 3TC-resistant/NNRTI-naïve clinical isolates, and the impact of maintaining versus dropping 3TC pressure in this setting. Because M184V mutant HIV-1 seems hypersusceptible to adefovir (ADV), we also tested the effect of ADV pressure on the same isolates. We draw four conclusions from our experiments simulating combination therapy in vitro. (1) The presence of low-dose (1 μM) 3TC prevented reversal to wild-type from an M184V mutant background. (2) Adding low-dose 3TC in the presence of NVP delayed the selection of NVP-associated mutations. (3) The presence of ADV, in addition to NVP, led to more rapid reversal to wild-type at position 184 than NVP alone. (4) ADV plus NVP selected for greater numbers of mutations than NVP alone. Inference about the "selection of mutation" is based on two statistical models, one at the viral level, more telling, and the other at the level of predominance of mutation within a population. Multidrug pressure experiments lend understanding to mechanisms of HIV resistance as they bear upon new treatment strategies.

  19. Inhibition of hepatitis B virus replication by quercetin in human hepatoma cell lines.

    PubMed

    Cheng, Zhikui; Sun, Ge; Guo, Wei; Huang, Yayun; Sun, Weihua; Zhao, Fei; Hu, Kanghong

    2015-08-01

    Hepatitis B virus (HBV) infection is one of the most serious and prevalent viral diseases in the world. Although several anti-HBV drugs have been used clinically, their side and adverse effects limit treatment efficacy. Therefore, it is necessary to identify novel potential anti-HBV agents. The flavonol quercetin has shown activity against some retroviruses, but its effect on HBV remains unclear. In the present study, quercetin was incubated with HepG2.2.15 cells, as well as HuH-7 cells transfected with an HBV plasmid. Quercetin was shown to significantly reduce Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg), secretion and HBV genomic DNA levels in both cell lines. In addition, co-incubation with lamivudine (3TC), entecavir (ETV), or adefovir (Ade) further enhanced the quercetin-induced inhibition of HBV replication. This inhibition was partially associated with decreased heat shock proteins and HBV transcription levels. The results indicate that quercetin inhibited HBV antigen secretion and genome replication in human hepatoma cell lines, which suggests that quercetin may be a potentially effective anti-HBV agent.

  20. Long-term monitoring drug resistance by ultra-deep pyrosequencing in a chronic hepatitis B virus (HBV)-infected patient exposed to several unsuccessful therapy schemes.

    PubMed

    Sede, M; Ojeda, D; Cassino, L; Westergaard, G; Vazquez, M; Benetti, S; Fay, F; Tanno, H; Quarleri, J

    2012-05-01

    The aim of this study was to analyze the spectrum and dynamics of low-prevalent HBV mutations in the reverse transcriptase (rt) and S antigen by ultra-deep pyrosequencing (UDPS). Samples were obtained from a chronically infected patient who was followed throughout a thirteen-year period. This technology enabled simultaneous analysis of 4084 clonally amplified fragments from the patient allowing detecting low prevalent (<1%) mutations during the follow-up. At baseline, HBV sequences were predominately wild-type. Under sequential HBV monotherapies including lamivudine, adefovir and entecavir, a high frequency of rtM204I mutation was detected initially as unique and then coexisting with rtM204V. Both mutations were statistically associated with rtA200V and rtV207I, respectively. Once the entecavir and tenofovir combined therapy was started, polymerase and consequently envelope gene mutations appeared at several positions at a higher frequency than before, including the entecavir resistance-associated mutation rtT184L.

  1. The Discovery and Development of a Potent Antiviral Drug, Entecavir, for the Treatment of Chronic Hepatitis B

    PubMed Central

    Griffin, Jamie; Innaimo, Steven; Lehman-Mckeeman, Lois; Llamoso, Cyril

    2013-01-01

    Since the first approval of interferon for the treatment of chronic hepatitis B virus (HBV) infection in 1992, six additional antivirals have been developed: pegylated interferon-alfa2a, and the oral antivirals lamivudine, adefovir, telbivudine, entecavir and tenofovir. The availability of animal models for HBV infection and hepatocyte cell culture led to the discovery and development of oral antivirals targeted at HBV polymerase and reverse transcriptase, which inhibit viral replication. The discovery and development of entecavir, the first oral anti-HBV drug with both potent antiviral activity and a high genetic barrier to resistance, took more than 10 years before it was first approved in the USA. Since then, multiple real-life studies have provided data consistent with the findings of the registration trials and the long-term rollover study in terms of efficacy, resistance, and safety. Data from the long-term follow-up of patients enrolled in the registration studies showed that treatment with entecavir can lead to significant improvements in liver histopathology, and recent cohort studies have demonstrated that treatment with entecavir may reduce disease progression and the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. In addition, real-life studies suggest that entecavir may reduce HCC recurrence and increase survival rates in patients with HBV-related HCC post-surgical resection. PMID:26357607

  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.

  3. RNAi for Treating Hepatitis B Viral Infection

    PubMed Central

    Chen, Yong; Cheng, Guofeng

    2007-01-01

    Chronic hepatitis B virus (HBV) infection is one of the leading causes of liver cirrhosis and hepatocellular carcinoma (HCC). Current treatment strategies of HBV infection including the use of interferon (IFN)-α and nucleotide analogues such as lamivudine and adefovir have met with only partial success. Therefore, it is necessary to develop more effective antiviral therapies that can clear HBV infection with fewer side effects. RNA interference (RNAi), by which a small interfering RNA (siRNA) induces the gene silence at a post-transcriptional level, has the potential of treating HBV infection. The successful use of chemically synthesized siRNA, endogenous expression of small hairpin RNA (shRNA) or microRNA (miRNA) to silence the target gene make this technology towards a potentially rational therapeutics for HBV infection. However, several challenges including poor siRNA stability, inefficient cellular uptake, widespread biodistribution and non-specific effects need to be overcome. In this review, we discuss several strategies for improving the anti-HBV therapeutic efficacy of siRNAs, while avoiding their off-target effects and immunostimulation. There is an in-depth discussion on the (1) mechanisms of RNAi, (2) methods for siRNA/shRNA production, (3) barriers to RNAi-based therapies, and (4) delivery strategies of siRNA for treating HBV infection. PMID:18074201

  4. 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

  5. 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

  6. Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia.

    PubMed

    Andrei, G; Topalis, D; De Schutter, T; Snoeck, R

    2015-02-01

    Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.

  7. Epidemiology study of HBV genotypes and antiviral drug resistance in multi-ethnic regions from Western China

    PubMed Central

    Zhang, Qi; Liao, Yun; Chen, Jie; Cai, Bei; Su, Zhenzhen; Ying, Binwu; Lu, Xiaojun; Tao, Chuanmin; Wang, Lanlan

    2015-01-01

    Hepatitis B virus (HBV) infection is a critical global health issue and moderately epidemic in Western China, but HBV molecular epidemiology characteristics are still limited. We conducted this study to investigate HBV genotypes and antiviral resistant mutations in this multi-ethnic area. A total of 1316 HBV patients were recruited from four ethnic groups from 2011 to 2013. Genotypes and resistant mutations were determined by Sanger sequencing. Four genotypes (B, C, D and C/D) were identified. Genotype B and C were common in Han population, while genotype D was predominant in Uygurs. Genotype C was the major genotype in both Tibetans and Yis, and recombinant C/D was found in Tibetans only. Lamivudine resistance was common in all populations, especially in Hans with prevalence of 42.8%. Entecavir resistance was barely observed regardless of ethnicity. Genotype C isolates had higher rates of rtA181T/V than genotype B (13.5% vs. 5.1%, P < 0.001), in accordance with higher prevalence of resistance to adefovir (20.0% vs. 9.5%, P < 0.001). While incidence of resistant mutations to other drugs and clinical factors showed no difference among different genotypes. HBV genotypes and resistance-conferring mutations had different geographic and demographic distributions in Western China, which provided molecular epidemiology data for clinical management. PMID:26612031

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.

  13. Treatment of chronic hepatitis B with nucleos(t)ide analogues.

    PubMed

    Ohishi, Waka; Chayama, Kazuaki

    2012-03-01

    Recently antiviral therapies for chronic hepatitis B using nucleos(t)ide analogues have become standard treatment modalities on the basis of several independent guidelines, starting with those of the American Association for the Study of Liver Diseases (AASLD) and other such organizations and bodies, including the European Association for the Study of the Liver (EASL), the Asian Pacific Association for the Study of the Liver (APASL), and the Japanese Ministry of Health, Labour and Welfare (MHLW)'s research team. The philosophies underlying such treatment strategies are considered basically equivalent. MHLW's guidelines define subjects for medical intervention to be cases measuring alanine aminotransferase (ALT) ≥31 IU/L, with serological hepatitis B virus (HBV) DNA level ≥5 log copies/mL for hepatitis B e antigen (HBeAg)-positive cases, and serological HBV DNA level ≥4 log copies/mL for HBeAg-negative cases. These Japanese guidelines advocate entecavir as the first-line treatment option for nucleos(t)ide-naïve patients, and combination treatment of lamivudine and adefovir as the basis of treatment for patients with lamivudine- and/or entecavir-resistant viruses. Of particular note for patients undergoing lamivudine treatment with persistent HBV DNA level < 2.1 log copies/mL is the recommendation of a switch to entecavir. Early detection of drug-resistant virus is desirable after initiation of nucleos(t)ide analogue treatment, but such a procedure is not uniformly available at all medical institutions. Nevertheless, timely estimation of potential early-stage drug-resistant virus development is crucial for getting a head start on treatment. HBV core-related antigen (HBcrAg) level or HBV DNA level are considered useful markers for the appearance of such drug-resistant viruses.

  14. Antiviral therapy improves the survival rate and decreases recurrences and fatalities in liver cancer patients following curative resection: A meta-analysis

    PubMed Central

    ZHANG, HAO; ZHOU, YUCHEN; YUAN, GUOSHENG; ZHOU, GUANGYAO; YANG, DINGHUA; ZHOU, YUANPING

    2015-01-01

    The present study aimed to investigate the impact of postoperative antiviral treatment on tumor recurrence, fatalities and survival of patients with chronic hepatitis B virus (HBV) infection-related primary hepatocellular carcinoma (HCC). A systematic meta-analysis was performed. All the studies comparing nucleos(t)ide analogues (NAs) versus placebo or no treatment were considered. The results were expressed as relative ratio (RR) for 1-, 3- and 5-year recurrence-free survival (RFS) and overall survival (OS), recurrence HCC and fatalities with 95% confidence intervals (CI) using STATA 11.0. In total, 15 trials with 7,619 patients were included. There were significant improvements for 1-, 3- and 5-year RFS (RR, 1.09; P=0.003; RR, 1.202; P<0.001; and RR, 1.219; P=0.02; respectively) and in 3- and 5-year OS (RR, 1.087, P=0.006; and RR, 1.186; P<0.001) in the NAs group compared with the control group. Sensitivity analyses confirmed the robustness of the results. In addition, the significantly high rate of recurrence HCC and fatalities existed in the control group (RR, 1.301; P=0.002; and RR, 1.816, P<0.001). One study was for an entecavir (ETV)-treated group compared with an adefovir (ADV)-treated group and lamivudine (LAM)-treated group. The 3-year disease-free survival rate for the ETV group was significantly better compared with the ADV and LAM groups [hazard ratio (HR), 0.810; P=0.049; and HR, 0.737; P=0.007]. The present study demonstrated the beneficial effects of NAs therapy following curative treatment of HBV-related HCC. ETV may be the superior choice compared to ADV or LAM for the antiviral treatment. PMID:26807227

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Murine cytomegalovirus resistant to antivirals has genetic correlates with human cytomegalovirus.

    PubMed

    Scott, G M; Ng, H-L; Morton, C J; Parker, M W; Rawlinson, W D

    2005-08-01

    Human cytomegalovirus (HCMV) resistance to antivirals is a significant clinical problem. Murine cytomegalovirus (MCMV) infection of mice is a well-described animal model for in vivo studies of CMV pathogenesis, although the mechanisms of MCMV antiviral susceptibility need elucidation. Mutants resistant to nucleoside analogues aciclovir, adefovir, cidofovir, ganciclovir, penciclovir and valaciclovir, and the pyrophosphate analogue foscarnet were generated by in vitro passage of MCMV (Smith) in increasing concentrations of antiviral. All MCMV antiviral resistant mutants contained DNA polymerase mutations identical or similar to HCMV DNA polymerase mutations known to confer antiviral resistance. Mapping of the mutations onto an MCMV DNA polymerase three-dimensional model generated using the Thermococcus gorgonarius Tgo polymerase crystal structure showed that the DNA polymerase mutations potentially confer resistance through changes in regions surrounding a catalytic aspartate triad. The ganciclovir-, penciclovir- and valaciclovir-resistant isolates also contained mutations within MCMV M97 identical or similar to recognized GCV-resistant mutations of HCMV UL97 protein kinase, and demonstrated cross-resistance to antivirals of the same class. This strongly suggests that MCMV M97 has a similar role to HCMV UL97 in the phosphorylation of nucleoside analogue antivirals. All MCMV mutants demonstrated replication-impaired phenotypes, with the lowest titre and plaque size observed for isolates containing mutations in both DNA polymerase and M97. These findings indicate DNA polymerase and protein kinase regions of potential importance for antiviral susceptibility and replication. The similarities between MCMV and HCMV mutations that arise under antiviral selective pressure increase the utility of MCMV as a model for in vivo studies of CMV antiviral resistance. PMID:16033961

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

    PubMed Central

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

    2014-01-01

    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

  2. Human immunodeficiency virus protease inhibitors interact with ATP binding cassette transporter 4/multidrug resistance protein 4: a basis for unanticipated enhanced cytotoxicity.

    PubMed

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

    2013-09-01

    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

  3. 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

  4. 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

  5. Analysis of hepatitis B virus genotyping and drug resistance gene mutations based on massively parallel sequencing.

    PubMed

    Han, Yingxin; Zhang, Yinxin; Mei, Yanhua; Wang, Yuqi; Liu, Tao; Guan, Yanfang; Tan, Deming; Liang, Yu; Yang, Ling; Yi, Xin

    2013-11-01

    Drug resistance to nucleoside analogs is a serious problem worldwide. Both drug resistance gene mutation detection and HBV genotyping are helpful for guiding clinical treatment. Total HBV DNA from 395 patients who were treated with single or multiple drugs including Lamivudine, Adefovir, Entecavir, Telbivudine, Tenofovir and Emtricitabine were sequenced using the HiSeq 2000 sequencing system and validated using the 3730 sequencing system. In addition, a mixed sample of HBV plasmid DNA was used to determine the cutoff value for HiSeq-sequencing, and 52 of the 395 samples were sequenced three times to evaluate the repeatability and stability of this technology. Of the 395 samples sequenced using both HiSeq and 3730 sequencing, the results from 346 were consistent, and the results from 49 were inconsistent. Among the 49 inconsistent results, 13 samples were detected as drug-resistance-positive using HiSeq but negative using 3730, and the other 36 samples showed a higher number of drug-resistance-positive gene mutations using HiSeq 2000 than using 3730. Gene mutations had an apparent frequency of 1% as assessed by the plasmid testing. Therefore, a 1% cutoff value was adopted. Furthermore, the experiment was repeated three times, and the same results were obtained in 49/52 samples using the HiSeq sequencing system. HiSeq sequencing can be used to analyze HBV gene mutations with high sensitivity, high fidelity, high throughput and automation and is a potential method for hepatitis B virus gene mutation detection and genotyping.

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

    PubMed Central

    2011-01-01

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

  7. [Infectious events during the first year of treatment with an antagonist of the tumor necrosis factor].

    PubMed

    Gulín Dávila, J; González-Gay, M A

    2013-01-01

    Objetivo: Evaluar la incidencia de infecciones graves en pacientes tratados con fármacos antiTNF?, durante el primer año de tratamiento con dichos fármacos. Material y método: Estudio observacional restrospectivo, realizado en un hospital general, de una muestra de pacientes que recibieron su primer anti- TNF?, dentro de las indicaciones autorizadas, para tratar una enfermedad reumática. El seguimiento de cada paciente se realizó durante 2 años: el año previo a recibir el fármaco y el primer año tras iniciar la terapia con el mismo. Se consideraron los procesos infecciosos graves que ocasionaron hospitalización. Se realizó un estudio de cohortes antesdespués. Se calculó la tasa de incidencia como el número de eventos (infecciones) por cada 100 habitantes/ año en el primer año de tratamiento y en el año previo (período control). Se calculó el riesgo relativo. Resultados: Fueron incluidos 196 pacientes. Se documentaron 12 procesos infecciosos graves durante el primer año de tratamiento, con un riesgo relativo de 2,4. El agente biológico más relacionado con la infección fue adalimumab. Todos los pacientes que sufrieron infección habían sido tratados de forma previa o concomitante con metotrexato y el 90,6% con glucocorticoides. La principal localización de la infección fue el aparato respiratorio (58,3%), y los gérmenes, los gram positivos (58,3%). Conclusiones: El uso de anti-TNF?, principalmente adalimumab, lleva asociado un riesgo de sufrir procesos infecciosos graves, principalmente a nivel de tracto respiratorio, producidos por gérmenes gram (+). El uso de otros tratamientos inmunosupresores tales como metotrexato y glucocorticoides parece incrementar la predisposición a sufrir procesos infecciosos.

  8. 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

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

    PubMed Central

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

    2012-01-01

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

  10. Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice▿

    PubMed Central

    Yuen, Man-Fung; Lee, Sung-Hack; Kang, Hyang-Mi; Kim, Chung Ryeol; Kim, John; Ngai, Vincent; Lai, Ching-Lung

    2009-01-01

    LB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean Tmax of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption. PMID:19223649

  11. A genome-wide association study identifies a new locus associated with the response to anti-TNF therapy in rheumatoid arthritis.

    PubMed

    Julià, A; Fernandez-Nebro, A; Blanco, F; Ortiz, A; Cañete, J D; Maymó, J; Alperi-López, M; Fernández-Gutierrez, B; Olivè, A; Corominas, H; Erra, A; Acosta-Colman, I; Alonso, A; López-Lasanta, M; Tortosa, R; Tornero, J; Marsal, S

    2016-04-01

    Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept (P<1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.

  12. 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

  13. Monitoring drug and antidrug levels: a rational approach in rheumatoid arthritis patients treated with biologic agents who experience inadequate response while being on a stable biologic treatment.

    PubMed

    Mazilu, Diana; Opriş, Daniela; Gainaru, Cecilia; Iliuta, Mihaela; Apetrei, Natalia; Luca, Giorgiana; Borangiu, Andreea; Gudu, Tania; Peltea, Alexandra; Groseanu, Laura; Constantinescu, Cosmin; Saulescu, Ioana; Bojinca, Violeta; Balanescu, Andra; Predeteanu, Denisa; Ionescu, Ruxandra

    2014-01-01

    Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.

  14. 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

  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. 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.

  17. 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

  18. 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

  19. 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

  20. Advances in the management of psoriatic arthritis.

    PubMed

    Olivieri, Ignazio; D'Angelo, Salvatore; Palazzi, Carlo; Padula, Angela

    2014-09-01

    Psoriatic arthritis (PsA), which affects musculoskeletal structures, skin and nails, is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course. Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease. To include these comorbidities, 'psoriatic disease' has been suggested as an umbrella term. The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies, including, early referral from dermatologists and primary-care physicians to rheumatologists, early initiation of therapy, treating to the target of remission or low disease activity, and advances in pharmacological therapy. Outcome assessment is also improving, because of validated instruments for clinical disease manifestations. The commercialization of TNF blockers, including adalimumab, etanercept, golimumab and infliximab, is representative of a revolution in the treatment of PsA. A new anti-TNF agent, certolizumab pegol, and a fully human monoclonal antibody against IL-12 and IL-23, ustekinumab, are approved for the treatment of active PsA. The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking TNF. PsA management must now use improved measures to predict patient outcomes and define remission, and develop better-targeted therapies.

  1. 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

  2. Treatment challenges in the management of moderate-to-severe plaque psoriasis – role of secukinumab

    PubMed Central

    Malakouti, Mona; Jacob, Sharon E; Anderson, Nancy J

    2016-01-01

    Psoriasis is a chronic inflammatory skin disease that has a negative impact on psychosocial well-being and cardiometabolic health. Treatment options for moderate-to-severe psoriasis have expanded with the development of interleukin-17 (IL-17) inhibitors, the first of which is now available – secukinumab. Secukinumab is a fully human monoclonal immunoglobulin G1 κ antibody that selectively inhibits the ligand IL-17A. In head-to-head studies, it is more effective than etanercept and ustekinumab, particularly in achieving Psoriasis Area and Severity Index (PASI) 90/100 and achieving PASI 50/75 as early as week 4. No head-to-head trials are available for comparison of adalimumab to secukinumab. Significant improvement in health care-related quality of life was also observed using the dermatology quality index in clinical studies. Safety data for secukinumab is comparable to available biologics. Specific safety concerns for the use of secukinumab include its use in patients with inflammatory bowel disease, reversible transient neutropenia, in those with a latex allergy, and the occurrence of mild to moderate oral or genital candidiasis. Secukinumab is an effective and safe treatment option that achieves high clearance rates up to PASI 90 and 100 as monotherapy in cases of moderate-to-severe psoriasis. It may be particularly helpful in patients with psoriasis who have formed antidrug antibodies or failed other biologic agents and in patients with psoriatic arthritis or ankylosing spondylitis. PMID:27785085

  3. Anti-citrullinated protein antibodies are linked to erosive disease in an observational study of patients with psoriatic arthritis

    PubMed Central

    Behrens, Frank; Koehm, Michaela; Thaçi, Diamant; Gnann, Holger; Greger, Gerd; Maria Wittig, Bianca

    2016-01-01

    Objective. ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. Methods. We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. Results. Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease. Conclusion. As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity. Trial registration: ClinicalTrials.gov, NCT01111240 PMID:27330166

  4. Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies.

    PubMed

    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.

  5. Pharmacokinetics interactions of monoclonal antibodies.

    PubMed

    Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, Giorgi; Corsini, Alberto

    2016-09-01

    The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction. PMID:27438459

  6. 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

  7. 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

  8. Noninfectious interstitial lung disease during infliximab therapy: case report and literature review.

    PubMed

    Caccaro, Roberta; Savarino, Edoardo; D'Incà, Renata; Sturniolo, Giacomo Carlo

    2013-08-28

    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 5(th) 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.

  9. 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

  10. Evidence-based guidelines of the spanish psoriasis group on the use of biologic therapy in patients with psoriasis in difficult-to-treat sites (nails, scalp, palms, and soles).

    PubMed

    Sánchez-Regaña, M; Aldunce Soto, M J; Belinchón Romero, I; Ribera Pibernat, M; Lafuente-Urrez, R F; Carrascosa Carrillo, J M; Ferrándiz Foraster, C; Puig Sanz, L; Daudén Tello, E; Vidal Sarró, D; Ruiz-Villaverde, R; Fonseca Capdevila, E; Rodríguez Cerdeira, M C; Alsina Gibert, M M; Herrera Acosta, E; Marrón Moya, S E

    2014-12-01

    Psoriatic lesions affecting the scalp, nails, palms, and the soles of the feet are described as difficult-to-treat psoriasis and require specific management. Involvement of these sites often has a significant physical and emotional impact on the patient and the lesions are difficult to control with topical treatments owing to inadequate penetration of active ingredients and the poor cosmetic characteristics of the vehicles used. Consequently, when difficult-to-treat sites are involved, psoriasis can be considered severe even though the lesions are not extensive. Scant information is available about the use of biologic therapy in this setting, and published data generally comes from clinical trials of patients who also had moderate to severe extensive lesions or from small case series and isolated case reports. In this article we review the quality of the scientific evidence for the 4 biologic agents currently available in Spain (infliximab, etanercept, adalimumab, and ustekinumab) and report level i evidence for the use of biologics to treat nail psoriasis (level of recommendation A) and a somewhat lower level of evidence in the case of scalp involvement and palmoplantar psoriasis.

  11. The Role of Biological Agents and Immunomodulators in Treatment Strategies for Thyroid Eye Disease: An Evidence-based Review.

    PubMed

    Ginter, Anna; Migliori, Michael E

    2016-06-01

    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].

  12. Pharmacokinetics interactions of monoclonal antibodies.

    PubMed

    Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, Giorgi; Corsini, Alberto

    2016-09-01

    The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction.

  13. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents

    PubMed Central

    Weger, Wolfgang

    2010-01-01

    Psoriasis is a chronic inflammatory disease affecting 1–3% of the general population. Among psoriatic patients, 5–40% are affected by psoriatic arthritis. Due to the chronic nature of the disease, patients suffer from substantial psychological and financial burdens, thus adding to a significantly impaired quality of life. Traditional systemic therapies for psoriasis, such as methotrexate, cyclosporin A, retinoids or PUVA therapy, have a potential for long-term toxicity and may not always provide sufficient improvement of the disease. The development of novel therapies targeting key steps in the pathogenesis of psoriasis and psoriatic arthritis now provide new and efficient treatment options. Biological therapies for the treatment of psoriasis and/or psoriatic arthritis are defined by their mode of action and can be classified into three categories: the T-cell modulating agents (alefacept and efalizumab), the inhibitors of tumour necrosis factor-α (TNFα blockers, e.g. adalimumab, certolizumab, etanercept, golimumab and infliximab) and the inhibitors of interleukin (IL) 12 and IL-23 (e.g. ustekinumab and briakinumab). This article provides a brief overview of the currently approved biological agents in the European Union and of some newer agents, such as briakinumab, certolizumab and golimumab. PMID:20590580

  14. 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.

  15. Therapeutic strategies in psoriasis patients with psoriatic arthritis: focus on new agents.

    PubMed

    Gan, Emily Yiping; Chong, Wei-Sheng; Tey, Hong Liang

    2013-08-01

    Psoriatic arthritis affects approximately 6-42 % of patients with psoriasis. It is useful for physicians or dermatologists managing psoriasis patients to be aware of how to concurrently manage the joint manifestations, as it is preferable and convenient to use a single agent in such patients. However, only certain therapies are effective for both. Systemic agents, which can be used for both skin and joint manifestations, include methotrexate and ciclosporin. For the group of biologic agents, the tumor necrosis factor inhibitors such as adalimumab, etanercept, infliximab, golimumab and certolizumab are effective. Ustekinumab is a more recently developed agent belonging to the group of anti-IL-12p40 antibodies and has been shown to be efficacious. Newer drugs in the treatment armamentarium that have shown efficacy for both psoriasis and psoriatic arthritis consist of the anti-IL-17 agent, secukinumab, and a phosphodiesterase-4 inhibitor, apremilast. The other anti-IL-17 agents, ixekizumab and brodalumab, as well as the oral Jak inhibitor, tofacitinib, have very limited but promising data. This review paper provides a good overview of the agents that can be used for the concurrent management of skin and joint psoriasis.

  16. Landscape of Long Noncoding RNAs in Psoriatic and Healthy Skin.

    PubMed

    Gupta, Rashmi; Ahn, Richard; Lai, Kevin; Mullins, Elizabeth; Debbaneh, Maya; Dimon, Michelle; Arron, Sarah; Liao, Wilson

    2016-03-01

    We used RNA sequencing to study and characterize the long noncoding RNA (lncRNA) transcriptome in lesional skin from psoriasis patients before (PP) and after treatment (PT) with adalimumab and in normal skin from healthy individuals (NN). To this end, we sequenced total RNA from 18 psoriasis patients and 16 healthy controls. We merged three lncRNA reference datasets to create a single combined reference of 67,157 lncRNA transcripts with no overlaps. We identified differential expression of 971 lncRNAs between PP and NN, 157 between PP and PT, and 377 between PT and NN. Using differentially expressed lncRNAs between PP and NN, we identified a molecular lncRNA signature that distinguishes psoriatic skin from healthy skin. Furthermore, we performed an unsupervised hierarchical analysis that revealed distinct clustering of PP samples from NN. A coding noncoding network analysis revealed a large network of highly correlated lncRNA and protein coding transcripts that provided insight into the potential functions of unannotated lncRNAs. To the best of our knowledge, this description of both polyadenylated as well as nonpolyadenylated lncRNA transcripts in psoriasis has not been previously reported. Our findings highlight the potential importance of lncRNAs in the biology of psoriasis and response to treatment.

  17. Psoriasis Induced by Anti-Tumor Necrosis Factor Alpha Agents: A Comprehensive Review of the Literature.

    PubMed

    Ciccarelli, Fedra; De Martinis, Massimo; Sirufo, Maria Maddalena; Ginaldi, Lia

    2016-08-01

    Tumor necrosis factor alpha (TNF-α) inhibitors revolutionized the management of patients affected by autoimmune diseases such as inflammatory bowel diseases, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. The biologic agents targeted to block TNF-α such as infliximab, adalimumab, certulizumab pegol, etanercept, and golimumab, have a good safety profile; however, with increasing, broader, and prolonged use, patients could be exposed to an increased risk of adverse reactions including a wide spectrum of dermatological conditions of different etiology and morphology. Among these, of particular interest is the development of skin immune-mediated diseases that seem to be the consequence of the paradoxical inflammation induced by anti-TNF-α therapy. The majority of these lesions are identified as psoriasiform with three main morphologies and different frequency: pustular psoriasis, signs of psoriasis, and guttate; although erythrodermic or inverted psoriasis, among others, may be observed with less frequency. The increased incidence of these dermatological immune-mediated lesions highlight the importance of the skin as a main target of the side effect of anti-TNF-α agents, while the immunopathogenetic hypothesis of these paradoxical effects are quite intriguing. The aim of this review is to collect and to analyze existing knowledge to better understand the pathogenetic mechanism of these complications and suggest new fields of investigation, improve therapeutic strategies of autoimmune diseases, and prevent and/or better address such complications. PMID:27663916

  18. Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.

    PubMed

    Webb, K C; Tung, R; Winterfield, L S; Gottlieb, A B; Eby, J M; Henning, S W; Le Poole, I C

    2015-09-01

    Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

  19. 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

  20. Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn’s disease

    PubMed Central

    Ma, Christopher; Walters, Brennan; Fedorak, Richard N

    2013-01-01

    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

  1. Glucocorticoid-Responsive Cold Agglutinin Disease in a Patient with Rheumatoid Arthritis

    PubMed Central

    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

  2. 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

  3. 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

  4. Golimumab Therapy in Six Patients With Severe Pediatric Onset Crohn Disease.

    PubMed

    Merras-Salmio, Laura; Kolho, Kaija-Leena

    2016-09-01

    Anti-tumor necrosis factor-alpha (TNF-α) blockade is so far the most effective therapy for extensive pediatric Crohn disease (CD), but loss of response is frequently encountered. We describe here the use of golimumab (Simponi) in 6 pediatric CD patients with antibody formation/loss of response to infliximab and adalimumab. Most patients had undergone surgery but had poor disease control. After introduction of golimumab, the levels of inflammatory markers and fecal calprotectin declined at first, but the response was not sustained. Each patient needed dose escalation of golimumab from 4 to 2 week intervals, to maintain response and to increase trough levels. Importantly, most patients were able to attend school when undergoing golimumab therapy. As with other anti-TNFα drugs, follow-up of drug levels is advisable. Although golimumab therapy failed in most patients, it is an alternate treatment option in pediatric patients with severe CD. The therapeutic response, however, is suboptimal in anti-TNFα exposed patients.

  5. Benefit-risk assessment of golimumab in the treatment of refractory ulcerative colitis.

    PubMed

    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.

  6. Mucosal healing with thalidomide in refractory Crohn's disease patients intolerant of anti-TNF-α drugs: report of 3 cases and literature review.

    PubMed

    Scribano, Maria Lia; Cantoro, Laura; Marrollo, Marzia; Cosintino, Rocco; Kohn, Anna

    2014-07-01

    Thalidomide is an oral immunomodulatory and anti-inflammatory drug with antitumor necrosis factor-α (TNF-α) activity. Several case reports and some clinical trials have demonstrated its efficacy in the treatment of refractory Crohn's disease (CD). We report the effect and tolerability of thalidomide in 3 patients with moderate-to-severe CD who were not responsive to anti-TNF-α therapies, and review the relevant literature. The first case is of a 28-year-old female affected by Crohn's colitis complicated by a severe fistulizing perianal disease; she was treated with infliximab, adalimumab, and certolizumab pegol, which were stopped because of intolerance. The second case is of a 39-year-old female with fistulizing ileocolitis complicated by severe arthralgias and perianal disease with loss of response to infliximab and intolerance of certolizumab pegol. The third case is of a 39-year-old male with gastric and ileocolonic CD refractory to immunosuppressors and intolerant of infliximab. All the 3 cases achieved complete clinical remission and endoscopic healing of mucosal lesions at a low dose of thalidomide (50 to 150 mg/d). In our CD patients who experienced loss of response or were unable to tolerate anti-TNF-α drugs, thalidomide was an effective and well-tolerated therapy for inducing and maintaining long-term remission.

  7. Use of multiple immunosuppressive agents in recalcitrant ACANTHAMOEBA scleritis.

    PubMed

    Igras, Estera; Murphy, Conor

    2015-01-01

    A 48-year-old woman who is a contact lens wearer presented with unilateral ACANTHAMOEBA keratitis, confirmed by PCR, which responded initially to topical polyhexamethylene biguanide (PHMB) and brolene. Three months later, despite continued treatment, she developed diffuse anterior scleritis with severe pain and marked scleral injection but without evidence of recurrence keratitis. Oral non-steroidal anti-inflammatories and oral high-dose corticosteroids were added without success. Subsequent treatment with intravenous methylprednisolone and high-dose cyclosporine led to a temporary improvement. Re-presenting with signs of recurrent scleritis and severe pain, the antitumor necrosis factor monoclonal antibody adalimumab, and later oral cyclophosphamide, were added. This led to complete quiescence of the scleritis. Unfortunately, frequent recurrences of ACANTHAMOEBA keratitis and anterior uveitis occurred on immunosuppression requiring continued treatment with PHMB, brolene and topical corticosteroids. This is the first case of severe refractory ACANTHAMOEBA scleritis requiring the concomitant use of four immunosuppressive agents to achieve continued disease control. The challenges in managing this case are discussed.

  8. 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

  9. 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

  10. 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

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

    PubMed

    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.

  12. Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis

    PubMed Central

    Oray, Merih; Tuğal-Tutkun, İlknur

    2016-01-01

    Pediatric uveitis may be a serious health problem because of the lifetime burden of vision loss due to severe complications if the problem is not adequately treated. Juvenile idiopathic arthritis (JIA)-associated uveitis is characterized by insidious onset and potentially blinding chronic anterior uveitis. Periodic ophthalmologic screening is of utmost importance for early diagnosis of uveitis. Early diagnosis and proper immunomodulatory treatment are essential for good visual prognosis. The goal of treatment is to achieve enduring drug-free remission. The choice of therapeutic regimen needs to be tailored to each individual case. One must keep in mind that patients under immunomodulatory treatment should be monitored closely due to possible side effects. Local and systemic corticosteroids have long been the mainstay of therapy; however, long-term corticosteroid therapy should be avoided due to serious side effects. Steroid-sparing agents in the treatment of JIA-associated uveitis include antimetabolites and biologic agents in refractory cases. Among the various immunomodulatory agents, methotrexate is generally the first choice, as it has a well-established safety and efficacy profile in pediatric cases and does not appear to increase the risk of cancer. Other classic immunomodulators that may also be used in combination with methotrexate include azathioprine, mycophenolate mofetil, and cyclosporin A. Biologic agents, primarily tumor necrosis factor alpha inhibitors including infliximab or adalimumab, should be considered in cases of treatment failure with classic immunomodulatory agents. PMID:27800265

  13. 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.

  14. 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

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

    PubMed

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

    2016-10-01

    Treatment with systemic immunomodulatory agents is indicated for patients with moderate to severe plaque psoriasis and psoriatic arthritis. In these patients, surgery may confer an increased risk of infectious or surgical complications. We conducted a literature review to examine studies addressing the use of methotrexate, cyclosporine, and targeted immunomodulatory agents (tumor necrosis factor-alfa inhibitors, interleukin [IL]-12/23 inhibitors, IL-17 inhibitors) in patients undergoing surgery. We examined 46 total studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. One study in patients with psoriasis and psoriatic arthritis reviewed 77 procedures and did not find an elevated risk of postoperative complications with tumor necrosis factor-alfa and IL-12/23 inhibitors even with major surgeries. Based on level III evidence, infliximab, adalimumab, etanercept, methotrexate, and cyclosporine can be safely continued through low-risk operations in patients with psoriasis and psoriatic arthritis. For moderate- and high-risk surgeries, a case-by-case approach should be taken based on the patient's individual risk factors and comorbidities. PMID:27461230

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

    PubMed

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

    2016-10-01

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

  17. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles

    NASA Astrophysics Data System (ADS)

    Kishimoto, Takashi K.; Ferrari, Joseph D.; Lamothe, Robert A.; Kolte, Pallavi N.; Griset, Aaron P.; O'Neil, Conlin; Chan, Victor; Browning, Erica; Chalishazar, Aditi; Kuhlman, William; Fu, Fen-Ni; Viseux, Nelly; Altreuter, David H.; Johnston, Lloyd; Maldonado, Roberto

    2016-10-01

    The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies.

  18. Landscape of Long Noncoding RNAs in Psoriatic and Healthy Skin.

    PubMed

    Gupta, Rashmi; Ahn, Richard; Lai, Kevin; Mullins, Elizabeth; Debbaneh, Maya; Dimon, Michelle; Arron, Sarah; Liao, Wilson

    2016-03-01

    We used RNA sequencing to study and characterize the long noncoding RNA (lncRNA) transcriptome in lesional skin from psoriasis patients before (PP) and after treatment (PT) with adalimumab and in normal skin from healthy individuals (NN). To this end, we sequenced total RNA from 18 psoriasis patients and 16 healthy controls. We merged three lncRNA reference datasets to create a single combined reference of 67,157 lncRNA transcripts with no overlaps. We identified differential expression of 971 lncRNAs between PP and NN, 157 between PP and PT, and 377 between PT and NN. Using differentially expressed lncRNAs between PP and NN, we identified a molecular lncRNA signature that distinguishes psoriatic skin from healthy skin. Furthermore, we performed an unsupervised hierarchical analysis that revealed distinct clustering of PP samples from NN. A coding noncoding network analysis revealed a large network of highly correlated lncRNA and protein coding transcripts that provided insight into the potential functions of unannotated lncRNAs. To the best of our knowledge, this description of both polyadenylated as well as nonpolyadenylated lncRNA transcripts in psoriasis has not been previously reported. Our findings highlight the potential importance of lncRNAs in the biology of psoriasis and response to treatment. PMID:27015450

  19. Inhibitors of phosphodiesterase 4 (PDE 4): A new therapeutic option in the treatment of psoriasis vulgaris and psoriatic arthritis.

    PubMed

    Mazur, Małgorzata; Karczewski, Jacek; Lodyga, Martha; Żaba, Ryszard; Adamski, Zygmunt

    2015-01-01

    Psoriasis vulgaris and psoriatic arthritis are inflammatory diseases in which inflammation and sustained inducing lesions result from immune disorders associated with overactivity of T cells that produce multiple proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin (IL): IL-2, IL-12, IL-17, IL-22 or IL-23. Modern treatment of these diseases is focused on reducing the inflammatory process responsible for the development of the disease. In recent years, the treatment of psoriasis is developing at a dynamic rate. Such therapeutic advances are contributed to the possibility of patient therapy through the use of some registered biologic agents, such as TNF-α inhibitors (infliximab, etanercept and adalimumab), and an inhibitor of the p40 subunit common to IL-12 and IL-23 (ustekinumab). In addition to the already registered medications for the indications mentioned above, there is a large group of preparations that are currently undergoing clinical trials in Europe, Canada and the United States, which provides hopes of therapy efficacy and safety.

  20. AA amyloidosis in the renal allograft: a report of two cases and review of the literature.

    PubMed

    Rojas, Rebecca; Josephson, Michelle A; Chang, Anthony; Meehan, Shane M

    2012-04-01

    AA amyloidosis is a disorder characterized by the abnormal formation, accumulation and systemic deposition of fibrillary material that frequently involves the kidney. Recurrent AA amyloidosis in the renal allograft has been documented in patients with tuberculosis, familial Mediterranean fever, ankylosing spondylitis, chronic pyelonephritis and rheumatoid arthritis. De novo AA amyloidosis is rarely described. We report two cases of AA amyloidosis in the renal allograft. Our first case is a 47-year-old male with a history of ankylosing spondylitis who developed end-stage renal disease reportedly from tubulointerstitial nephritis from non-steroidal anti-inflammatory agent use. A biopsy was never performed. One year after transplantation, AA amyloidosis was identified in the femoral head and 8 years post-transplantation, AA amyloidosis was identified in the renal allograft. He was treated with colchicine and adalimumab and has stable renal function at 1 year-follow-up. Our second case is a 57-year-old male with a long history of intravenous drug use and hepatitis C infection who developed end-stage kidney disease due to AA amyloidosis. Our second patient's course was complicated by renal adenovirus, pulmonary aspergillosis and hepatitis C with AA amyloidosis subsequently being identified in the allograft 2.5 years post-transplantation. Renal allograft function remains stable 4-years post-transplantation. These reports describe clinical and pathologic features of two cases of AA amyloidosis presenting with proteinuria and focal involvement of the renal allograft.

  1. Genetics of Psoriasis and Pharmacogenetics of Biological Drugs

    PubMed Central

    Prieto-Pérez, Rocío; Cabaleiro, Teresa; Daudén, Esteban; Ochoa, Dolores; Roman, Manuel; Abad-Santos, Francisco

    2013-01-01

    Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis are unknown, although family and twin studies have shown genetic factors to play a key role in its development. The many genes associated with psoriasis and the immune response include TNFα, IL23, and IL12. Advances in knowledge of the pathogenesis of psoriasis have enabled the development of new drugs that target cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNFα, and ustekinumab, which targets the p40 subunit of IL23 and IL12). These drugs have improved the safety and efficacy of treatment in comparison with previous therapies. However, not all patients respond equally to treatment, possibly owing to interindividual genetic variability. In this review, we describe the genes associated with psoriasis and the immune response, the biological drugs used to treat chronic severe plaque psoriasis, new drugs in phase II and III trials, and current knowledge on the implications of pharmacogenomics in predicting response to these treatments. PMID:24069534

  2. Disease-modifying antirheumatic drugs and bone mass in rheumatoid arthritis.

    PubMed

    Di Munno, O; Delle Sedie, A; Rossini, M; Adami, S

    2005-01-01

    This article reviews the effects of DMARDs (including biologic agents) on bone metabolism in rheumatoid arthritis (RA). At present there is no evidence that methotrexate, at least at dosages ranging from 5 to 20 mg/week, negatively affects bone mass as measured by DXA (BMD) as documented in both cross-sectional and longitudinal studies. Most studies of cyclosporine (CyA) use reporting a reduction in erosions and joint damage with no adverse effects on bone, did not measure BMD; CyA treatment is associated with a dose-dependent increase of bone turnover as well as a decrease in both animal and human studies; however, its use in RA setting at a dose < or =5 mg/Kg/ day has so far not been associated with clinical relevant adverse effects on bone metabolism. Anti-TNF-alpha agents, infliximab reduced markers of bone turnover in two longitudinal studies. Data on BMD are not available in RA; nevertheless, an increase in BMD has been documented in spondyloarthropathies with infliximab and etanercept. No clinical data concerning BMD are available on leflunomide as well as on the newer biologic agents (adalimumab, rituximab, anakinra).

  3. Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles.

    PubMed

    Kishimoto, Takashi K; Ferrari, Joseph D; LaMothe, Robert A; Kolte, Pallavi N; Griset, Aaron P; O'Neil, Conlin; Chan, Victor; Browning, Erica; Chalishazar, Aditi; Kuhlman, William; Fu, Fen-Ni; Viseux, Nelly; Altreuter, David H; Johnston, Lloyd; Maldonado, Roberto A

    2016-10-01

    The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies.

  4. Treatment satisfaction of patients with psoriasis.

    PubMed

    Schaarschmidt, Marthe-Lisa; Kromer, Christian; Herr, Raphael; Schmieder, Astrid; Goerdt, Sergij; Peitsch, Wiebke K

    2015-05-01

    Treatment satisfaction of patients with psoriasis largely depends on the treatment modality, but evidence on preferences for specific medications is scarce. Here we assessed treatment satisfaction of 200 participants with moderate-to-severe psoriasis from a German University hospital with a 5-point scale and the Treatment Satisfaction Questionnaire for Medication (TSQM) and determined sociodemographic and disease-related influence factors. Participants obtaining biologicals and traditional systemic medications were significantly more satisfied than those receiving phototherapy or topical agents (TSQM = 323.3, 288.0, 260.6 or 266.8; p < 0.001). The highest TSQM score was calculated for ustekinumab (350.1), followed by acitretin (338.1), adalimumab (323.0), fumaric acid esters (304.7), infliximab (300.2), etanercept (298.8), and methotrexate (272.3; p < 0.001). High disease-related quality of life impairment (β = -0.437, p < 0.001) and psoriatic arthritis (β = -0.185, p = 0.005) were associated with decreased satisfaction. Optimising satisfaction is essential to improve adherence and outcome. We show high preferences for biologicals, particularly ustekinumab, but also good satisfaction with certain traditional medications.

  5. Hepatitis B virus reactivation associated with antirheumatic therapy: Risk and prophylaxis recommendations.

    PubMed

    Mori, Shunsuke; Fujiyama, Shigetoshi

    2015-09-28

    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.

  6. 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

  7. 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.

  8. 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

  9. Rheumatic manifestations in inflammatory bowel disease.

    PubMed

    Atzeni, Fabiola; Defendenti, Caterina; Ditto, Maria Chiara; Batticciotto, Alberto; Ventura, Donatella; Antivalle, Marco; Ardizzone, Sandro; Sarzi-Puttini, Piercarlo

    2014-01-01

    Musculoskeletal symptoms (articular, periarticular and muscular involvement, osteoporosis and related fractures, and fibromyalgia) are the most common frequent extra-intestinal manifestations of inflammatory bowel disease (IBD) and affect 6-46% of patients. IBD-related arthropathy is one of a group of inflammatory arthritides known as seronegative spondyloarthropathies (SpA), which also includes idiopathic ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, and undifferentiated SpA. The articular involvement in IBD significantly affects the patients' quality of the life. Although magnetic resonance imaging (MRI) is still the gold standard for assessing entheseal involvement, ultrasonography (US) is a non-invasive and easily reproducible means of detecting early pathological changes in SpA patients. It can identify characteristic features of SpA such as enthesitis, bone erosions, synovitis, bursitis, and tenosynovitis and is therefore helpful for diagnostic purposes. Anti-TNF drugs should be used to treat AS patients with axial and peripheral symptoms (arthritis and enthesitis) who have persistently high levels of disease activity despite conventional treatment, and adalimumab and infliximab can also be beneficially used in patients with IBD.

  10. 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.

  11. Biological therapy induces expression changes in Notch pathway in psoriasis.

    PubMed

    Skarmoutsou, Evangelia; Trovato, Chiara; Granata, Mariagrazia; Rossi, Giulio A; Mosca, Ambra; Longo, Valentina; Gangemi, Pietro; Pettinato, Maurizio; D'Amico, Fabio; Mazzarino, Maria Clorinda

    2015-12-01

    Psoriasis is a chronic inflammatory skin disease, characterized by hyperproliferation of keratinocytes and by skin infiltration of activated T cells. To date, the pathophysiology of psoriasis has not yet been fully elucidated. The Notch pathway plays a determinant role in cell fate determination, proliferation, differentiation, immune cell development and function. Many biological agents, used in the treatment of psoriasis, include TFN-α inhibitors, such as etanercept, adalimumab, and anti IL-12/IL-23 p40 antibody, such as ustekinumab. This study aimed to determine mRNA expression levels by real-time RT-PCR, and protein expression levels, analysed by Western blot and immunohistochemistry, of some components of the Notch pathway, such as NOTCH1, NOTCH2, JAGGED1, and HES1 after biological treatments in psoriatic patients. mRNA and protein levels of NOTCH1, NOTCH2, JAGGED1 and HES1 were upregulated in skin samples from untreated psoriatic patients compared with normal controls. Biological therapy showed to downregulate differently the protein expression levels of the molecules under study. Our study suggests that Notch pathway components might be a potential therapeutic target against psoriasis.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. [ANTI-TUBERCULOSIS THERAPY AND PARADOXICAL RESPONSE WHEN TUBERCULOSIS DEVELOPS UNDER THE INFLUENCE OF BIOLOGICS FOR RHEUMATOID ARTHRITIS].

    PubMed

    Matsumoto, Tomoshige

    2015-01-01

    A paradoxical response is designated as the clinical or radiological worsening of pre-existing TB lesions or the development of new lesions during appropriate anti-TB treatment. Tuberculosis bacilli have no toxin and the organism apparently does not produce any toxins, so the virulence depends on a response to the host immune reaction. According to our report, the annual reported numbers of tuberculosis cases and death did not decrease during biologics treatment in Japan. We have been monitoring and analyzing all the TB cases activated during adalimumab treatments in Japan. According to the analysis, there was no TB related death and severe sequelae in patients with lung tuberculosis without extra pulmonary TB; TB related deaths were caused not by delays of diagnosis and therapy but by the paradoxical response following miliary TB. Paradoxical response after abrupt cessation of anti-TB treatment is caused by immune activation to cell components despite TB bacilli are alive or dead. So, we concluded that the abrupt cessation of anti-TNF agents after TB development could activate immune response causing paradoxical response, which lead to severe sequelae and death, and that continuation of anti-TNF therapy for rheumatoid arthritis in patients with active tuberculosis reactivated during anti-TNF medication is more beneficial than its cessation concerning not only clinical and radiological but also bacteriological outcomes.

  20. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate.

    PubMed

    Farhangian, Michael E; Feldman, Steven R

    2015-08-01

    The five biologic agents approved for the treatment of psoriasis-etanercept, infliximab, adalimumab, ustekinumab, and secukinumab-have been transformative in the clinical management of severe forms of the disease. However, a significant number of patients fail to respond to these agents or experience a loss of efficacy over time, which may be attributable to the development of antidrug antibodies (ADAs). Increasing evidence, primarily in the context of rheumatoid arthritis or other chronic inflammatory diseases, suggests that concomitant administration of methotrexate may prevent or diminish the development of ADAs, thereby improving response rates. However, methotrexate is infrequently coadministered with biologic agents in patients with psoriasis, and the potential benefits of this strategy in the context of psoriasis are largely unexplored. In this review, we discuss clinical studies regarding the development and consequences of antibodies targeting biologic agents used in the treatment of psoriasis and present key findings describing the potential role of methotrexate as an inhibitor of immunogenicity. We also discuss clinical considerations pertaining to the use of methotrexate as a tool to reduce immunogenicity, and encourage further investigation into potential techniques to optimize this treatment approach in patients with psoriasis.

  1. Bioboosters in the treatment of rheumatic diseases: a comprehensive review of currently available biologics in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis

    PubMed Central

    Cantini, Fabrizio; Nannini, Carlotta; Niccoli, Laura

    2009-01-01

    Immunologic research has clarified many aspects of the pathogenesis of inflammatory rheumatic disorders. Biologic drugs acting on different steps of the immune response, including cytokines, B- and T-cell lymphocytes, have been marketed over the past 10 years for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). Randomized controlled trials (RCTs) of anti-cytokine agents in RA (including the anti-tumor necrosis factor alpha (TNFα) drugs infliximab, etanercept, adalimumab, golimumab, certolizumab, anti-interleukin (IL)-1 anakinra, and anti-IL-6 tocilizumab) demonstrated a significant efficacy compared to traditional therapies, if combined with methotrexate (MTX), as measured by ACR 20, 50 and 70 response criteria. The new therapies have also been demonstrated to be superior to MTX in slowing or halting articular damage. RCTs have shown the efficacy of anti-TNFα in AS patients through significant improvement of symptoms and function. Trials of anti-TNFα in PsA patients showed marked improvement of articular symptoms for psoriasis and radiological disease progression. More recent studies have demonstrated the efficacy of B-cell depletion with rituximab, and T-cell inactivation with abatacept. All these drugs have a satisfactory safety profile. This paper reviews the different aspects of efficacy and tolerability of biologics in the therapy of RA, AS, and PsA.

  2. 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

  3. 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

  4. 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

  5. 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.

  6. Gateways to clinical trials.

    PubMed

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

    2006-04-01

    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, alemtuzumab, AMG-531, anakinra, armodafinil, asenapine maleate, atazanavir sulfate, atorvastatin; Bortezomib, bosentan; CEB-1555, cetuximab, ciclesonide, clodronate, CT-011; Darifenacin hydrobromide, desloratadine; E-7010, ecallantide, eculizumab, efalizumab, eltrombopag, erlotinib hydrochloride, eslicarbazepine acetate, eszopiclone, ezetimibe; Febuxostat, fosamprenavir calcium, fulvestrant; Gefitinib, genistein; Haemophilus influenzae B vaccine, human papillomavirus vaccine; Imatinib mesylate, insulin glargine; Lenalidomide, liposomal cisplatin; MAb G250, mapatumumab, midostaurin, MP4, mycophenolic acid sodium salt; Natalizumab, neridronic acid, NSC-330507; Oblimersen sodium, ofatumumab, omalizumab, oral insulin, oregovomab; Paliperidone, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pegylated arginine deiminase 20000, pemetrexed disodium, pimecrolimus, pitavastatin, pneumococcal 7-valent conjugate vaccine, prasterone, pregabalin, pumosetrag hydrochloride; Recombinant malaria vaccine, retigabine, rivaroxaban, Ro-26-9228, romidepsin, rosuvastatin calcium, rotavirus vaccine; SGN-30, sitaxsentan sodium, solifenacin succinate, sorafenib, sunitinib malate; Tadalafil, tegaserod maleate, temsirolimus, TER-199, tifacogin, tiludronic acid, tiotropium bromide; Vildagliptin, VNP-40101M, vorinostat; YM-150, yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zoledronic acid monohydrate. PMID:16810345

  7. 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

  8. 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

  9. Gateways to Clinical Trials.

    PubMed

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

    2002-09-01

    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: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil

  10. 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

  11. Can biologic treatment induce cutaneous focal mucinosis?

    PubMed Central

    Włodarczyk, Marcin; Sobolewska, Aleksandra; Sieniawska, Joanna; Rogowski-Tylman, Michał; Sysa-Jedrzejowska, Anna; Olejniczak-Staruch, Irmina; Narbutt, Joanna

    2014-01-01

    Skin mucinosis is a rare skin disease which clinically manifests as firm papules and waxy nodules. We report a case of a 66-year-old female psoriatic patient who developed skin mucinosis during biological therapy. Because of a previous lack of response to the local and conventional systemic treatment of psoriasis, the patient received biological therapy (infliximab from June 2008 to May 2009 – initial clinical improvement and loss of treatment effectiveness in the 36th week of the therapy; adalimumab from June 2009 to January 2010 – lack effectiveness; ustekinumab from March 2012 to the present). Throughout 2 months we observed a manifestation of the skin mucinosis as well-demarcated, yellow and brown, papulo-nodular lesions of 5–10 mm in diameter, localized on the back. Histopathological examination with alcian blue staining demonstrated mucin deposits in the dermis. On the basis of clinical and histopathological findings, the diagnosis of cutaneous focal mucinosis was established. We present the case because of the extremely rare occurrence of the disease. Scarce literature and data suggest that there is an association between focal mucinosis and thyroid dysfunction, as well as possible adverse effects of biological therapy with TNF-α antagonists. PMID:25610359

  12. 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

  13. Vulval Crohn's disease: a clinical study of 22 patients.

    PubMed

    Laftah, Zainab; Bailey, Clare; Zaheri, Shirin; Setterfield, Jane; Fuller, Lucinda Claire; Lewis, Fiona

    2015-04-01

    Vulval Crohn's disease [VCD] is a challenging condition that can occur without gastrointestinal Crohn's disease [GCD]. We reviewed the clinical features and effects of therapy in a cohort of 22 patients with VCD to determine whether the presence of GCD affected the clinical presentation and treatment response. Of these, 64% had GCD and 65% of these presented with GCD prior to VCD. Fissuring, ulceration, and scarring were more common in those with VCD alone. Potent and ultra-potent topical steroids showed benefit in most patients. There was no clear evidence of sustained remission with metronidazole. Azathioprine was the most commonly used oral immunosuppressive agent, with an efficacy of 57%. Patients with both VCD and GCD had a better clinical response compared with those with VCD alone [70% and 25%, respectively]. Infliximab and adalimumab were effective in 56% and 71% of patients, respectively. Excision of redundant tissue was helpful in four patients. The absence of GCD may delay the diagnosis in women who present with vulval symptoms alone. The more active clinical features in those with VCD alone may represent a more aggressive condition, or the severity of the cutaneous disease may have been reduced by immunosuppression taken for GCD. Several patients obtained sustained remission in their GCD with anti-tumor necrosis factor alpha [anti-TNFα] agents while the VCD remained active.

  14. Improved Efficacy of a pegylated interferon-α-2a stepwise optimization treatment strategy in the treatment of hepatitis B e antigen-positive chronic hepatitis B patients.

    PubMed

    Zhou, Pu; Yang, Feifei; Wang, Jinyu; Mao, Richeng; Qi, Xun; Huang, Yuxian; Zhang, Jiming

    2015-05-01

    Current pegylated interferon-α (PEG-IFN) treatment for chronic hepatitis B (CHB) e-antigen (HBeAg)-positive patients are suboptimal, and effective ways of improving PEG-IFN treatment efficacy are needed.This retrospective cohort study compared the efficacy of a PEG-IFN stepwise optimization treatment (PEG-IFN SOT) strategy with that of a 48-week PEG-IFN standard therapy (PEG-IFN ST) in HBeAg-positive CHB patients.A total of 110 patients were included in our study. Of these, 70 received the PEG-IFN SOT and 40 received the PEG-IFN ST (control group). We based the decision whether to add adefovir and/or extend the PEG-IFN-based treatment to 96 weeks on the patients' 12-week or 24-week early virological response (12W EVR, at least a 2 log10 reduction in HBV DNA copies/mL at week 12; 24W EVR, at least 1 log10 reduction in HBsAg IU/mL or HBsAg <1500 IU/mL at week 24) and their 48-week partial response (48W PR, 1.0 ≤HBeAg ≤10.0 S/CO or HBeAg >10.0 S/CO but HBsAg <1000 IU/mL).The HBeAg seroconversion rate 24 weeks post-PEG-IFN treatment was significantly higher in the PEG-IFN SOT than the PEG-IFN ST group (50% vs 22.5%, P = 0.005). The HBsAg clearance rates in the PEG-IFN SOT and ST groups were 10% and 0% (P = 0.04), respectively. Receiving PEG-IFN SOT (OR = 0.26, P = 0.01), ALT × ULN at baseline (OR = 0.74, P = 0.003), and achieving 12 and 24W EVR (OR = 0.29, P = 0.03) were independent factors associated with HBeAg seroconversion.PEG-IFN SOT is a promising strategy for achieving high rates of serological response in HBeAg-positive CHB patients.

  15. 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

  16. Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China

    PubMed Central

    2012-01-01

    Background Several rescue therapies have been used in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB); however, the economic outcome of these therapies is unclear. The object of the current analysis was to evaluate the lifetime cost-effectiveness of rescue therapies among patients with LAM-resistant CHB. Methods A Markov model was developed to simulate the clinical course of patients with LAM-resistant CHB. From the perspective of Chinese health care, a lifetime cost-utility analysis was performedfor 4 rescue strategies: adefovir (ADV), entecavir (ETV) or tenofovir (TDF) monotherapy and combination therapy using LAM and ADV. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model, and the beginning health state was LAM-resistant CHB without other complications. The transition probabilities, efficacy and resistance data for each rescue therapy as well as the costs and utility data were estimated from the literature. The discount rate (3%) utilized for costs and benefits. Sensitivity analyses were used to explore the impact of uncertainty on the results. Results In LAM-resistant HBeAg-positive and HBeAg-negative CHB cohorts, TDF monotherapy and combination therapy were on the efficiency frontier for both positive and negative populations. Compared with no treatment, the use of combination therapy cost an additional $6,531.7 to gain 1 additional quality-adjusted life year (QALY) for HBeAg-positive patients and $4,571.7 to gain 1 additional QALY for HBeAg-negative patients. TDF monotherapy for HBeAg-positive patients, shows greater increase in QALYs but higher incremental cost-effectiveness ratio (ICER) in comparison with combination therapy. In probabilistic sensitivity analyses, combination therapy was the preferred option for health care systems with limited health resources, such as Chinese health care system. Conclusion In Chinese patients with LAM-resistant CHB, combination therapy is a more

  17. 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

  18. Association of serum gamma-glutamyl transferase with treatment outcome in chronic hepatitis B patients

    PubMed Central

    Huang, Rui; Yang, Chen-Chen; Liu, Yong; Xia, Juan; Su, Ran; Xiong, Ya-Li; Wang, Gui-Yang; Sun, Zhen-Hua; Yan, Xiao-Min; Lu, Shan; Wu, Chao

    2015-01-01

    AIM: To investigate the association of serum gamma-glutamyl transferase (GGT) levels with chronic hepatitis B infection and hepatitis B e antigen (HBeAg) seroconversion. METHODS: A retrospective study was performed on clinical data collected from patients who had been positive for hepatitis B surface antigen for > 6 mo and who were antiviral-treatment naïve (n = 215) attending the Hepatitis Clinic at Nanjing Drum Tower Hospital between August 2010 and December 2013. Healthy individuals without liver disease (n = 83) were included as controls. Patients were categorized into four groups based on disease status as recommended by the European Association for the Study of the Liver: immune tolerance (IT; n = 47), HBeAg-positive hepatitis (EPH; n = 93), HBeAg-negative hepatitis (ENH; n = 20), and inactive carrier (IC; n = 55). Prediction of complete response (CR) based on serum GGT was also examined in EPH patients (n = 33) treated for 48 wk with nucleos(t)ide analogue (NA) therapy, including lamivudine plus adefovir combination therapy (n = 20) or entecavir monotherapy (n = 13). CR was defined as a serum hepatitis B virus DNA level < 500 copies/mL and HBeAg seroconversion by 48 wk of treatment. RESULTS: Serum GGT levels were significantly increased in EPH and ENH patients relative to the IT, IC, and healthy control groups (P < 0.01 for all). However, no significant difference in serum GGT levels was found between the EPH and ENH groups. Baseline serum GGT levels were significantly higher in patients who achieved CR (7/33; 21.2%) compared to patients in the non-CR group (26/33; 78.8%; P = 0.011). In addition, the decline in serum GGT was greater in CR patients compared to non-CR patients after 24 wk and 48 wk of treatment (P = 0.012 and P = 0.008, respectively). The receiver operating characteristic curve yielded a sensitivity of 85.71% and a specificity of 61.54% at a threshold value of 0.89 times the upper limit of normal for baseline serum GGT in the prediction of CR

  19. Golimumab for the treatment of psoriatic arthritis.

    PubMed

    Yang, H; Epstein, D; Bojke, L; Craig, D; Light, K; Bruce, I; Sculpher, M; Woolacott, N

    2011-05-01

    from controlled studies in other conditions, such as rheumatoid arthritis and ankylosing spondylitis. Although the adverse effect profile of golimumab appears similar to other anti-tumour necrosis factor (TNF) agents, the longer-term safety profile of golimumab remains uncertain. The manufacturer's submission presented a decision model to compare etanercept, infliximab, golimumab and adalimumab versus palliative care for patients with PsA. In the base-case model, 73% of the cohort of patients were assumed to have significant psoriasis (> 3% of body surface area). Estimates of the effectiveness of anti-TNF agents in terms of PsARC, HAQ change and PASI change were obtained from an MTC analysis of RCT data. The manufacturer failed to calculate incremental cost-effectiveness ratios (ICERs) correctly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab is a cost-effective treatment option, the manufacturer's own model showed that golimumab is not cost-effective compared with other biologics when the ICERs are correctly calculated. None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost-effectiveness of anti-TNF agents is whether they should be treated as a class. If all anti-TNF agents are considered equally effective then etanercept, adalimumab and golimumab have very nearly equal costs and equal quality-adjusted life-years (QALYs), and all have an ICER of about £ 15,000 per QALY versus palliative care, whereas infliximab with a higher acquisition cost is dominated by the other biologics.

  20. Biotherapies in inflammatory ocular disorders: Interferons, immunoglobulins, monoclonal antibodies.

    PubMed

    Saadoun, D; Bodaghi, B; Bienvenu, B; Wechsler, B; Sene, D; Trad, S; Abad, S; Cacoub, P; Kodjikian, L; Sève, P

    2013-05-01

    Biotherapies used in clinical practice for the treatment of ophthalmologic manifestations of systemic diseases include interferons (IFN), intravenous immunoglobulins (IVIG) and monoclonal antibodies (anti-TNF, anakinra, tocilizumab and rituximab). Several open prospective studies have shown the effectiveness of IFN-α (78 to 98% complete remission) for the treatment of severe uveitis in Behcet's disease. IFN is capable of inducing prolonged remission and continued after his arrest, in 20-40% of patients. Side effects (flu-like, psychological effects) limit its use in practice. Anti-TNFα (infliximab and adalimumab) represents an attractive alternative therapeutic in severe uveitis refractory to immunosuppressants, especially in Behcet's disease. They are almost always (>90% of cases) and rapidly effective but their action is often suspensive. Anti-TNFα requires an extended prescription or takes over from another immunosuppressant once ocular inflammation has been controlled. IVIG are used for the treatment of Kawasaki disease and Birdshot disease. Several open or retrospective studies showed their effectiveness for the treatment of severe and refractory cicatricial pemphigoid. Tolerance of IVIG is good but their efficacy is transient. Rituximab showed an efficacy in few observations of various inflammatory eye diseases (uveitis, scleritis and idiopathic inflammatory pseudo-tumors or associated with granulomatosis with polyangiitis) and cicatricial pemphigoid. The risk of infection associated with this biotherapy limits its use in refractory diseases to conventional therapy. Anakinra (a soluble antagonist of IL-1R) showed interesting results in terms of efficiency in one small open study in Behcet's disease. Its safety profile is good and with a quick action that could be interesting for the treatment of severe uveitis.

  1. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  2. Management of Inflammatory Bowel Disease during Pregnancy and Breastfeeding Varies Widely: A Need for Further Education

    PubMed Central

    Goodman, Karen Jean; Hegadoren, Kathleen M.; Dieleman, Levinus Albert; Fedorak, Richard Neil

    2016-01-01

    Background. Inflammatory bowel disease (IBD) affects patients in their young reproductive years. Women with IBD require maintenance therapies during pregnancy and breastfeeding. However, physician management of IBD during pregnancy and breastfeeding has not been well characterized. Objective. To characterize physician perceptions and management of IBD during pregnancy and breastfeeding. Methods. A cross-sectional survey of Canadian physicians who are involved in the care of women with IBD was conducted. The survey included multiple-choice and Likert scale questions about perceptions and practice patterns regarding the management of IBD during pregnancy and breastfeeding. Results. 183 practicing physicians completed the questionnaire: 97/183 (53.0%) gastroenterologists; 75/183 (41.0%) general practitioners; and 11/183 (6.0%) other physicians. Almost half (87/183, 47.5%) of the physicians felt comfortable managing pregnant IBD patients. For specified IBD medications, proportions of physicians who indicated they would continue them during pregnancy were as follows: sulfasalazine, 47.4%; oral mesalamine, 67.0%; topical mesalamine, 70.3%; oral prednisone, 68.0%; topical prednisone, 78.0%; oral budesonide, 61.6%; topical budesonide, 75.0%; ciprofloxacin, 15.3%; metronidazole, 31.4%; azathioprine, 57.1%; methotrexate, 2.8%; infliximab, 55.6%; adalimumab, 78.1%. Similar proportions of physicians would continue these medications during breastfeeding. A higher proportion of gastroenterologists than nongastroenterologists indicated appropriate use of these IBD medications during pregnancy and breastfeeding. Conclusions. Physician management of IBD during pregnancy and breastfeeding varies widely. Relative to other physicians, responses of gastroenterologists more frequently reflected best practices pertaining to medications for control of IBD during pregnancy and breastfeeding. There is a need for further education regarding the management of IBD during pregnancy and

  3. 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.

  4. 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

  5. Melanoma Associated with TNFα Inhibitors: a Research on Adverse Drug events And Reports (RADAR) Project

    PubMed Central

    Nardone, B.; Hammel, J.A.; Raisch, D.W.; Weaver, L.L.; Schneider, D.; West, D.P.

    2014-01-01

    Background Tumor necrosis factor-alpha inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out of five TNFαIs the Food and Drug Administration (FDA) label states, “melanoma has been reported in patients treated with these agents.” Objectives Determine whether a statistically-significant association exists between administration of TNFαIs and development of malignant melanoma. Methods We searched the FDA Adverse Events Reporting System (FAERS) database for terms related to melanoma and TNFαIs for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFαIs vs. non-exposed subjects. Results There were 972 reports of melanoma associated with a TNFαIs identified in the FAERS database, with 69 reports among individuals using more than one TNFαI. A safety signal was detected for infliximab (I) golimumab (G), etanercept (E), and adalimumab (A). Cetrolizumab pegol (CP) had no detectible safety signal. For TNFαIs as a class of drugs, a safety signal was detectable in the FAERS database, and RR was significant in the EMR database. For the EMR cohort, 6,045 patients were exposed to TNFαIs and 35 cases of melanoma were detected. Significance for RR was detected for A (RR = 1.8, p = 0.02) and E (RR 2.35, p = 0.0004). Conclusions We identified a significant association between exposure to TNFαIs and malignant melanoma in two different analyses. Our findings add to existing evidence linking these agents with the occurrence of malignant melanoma. Additional investigations are required to further explore this association and the risk of melanoma with TNFαI therapy. PMID:24328939

  6. Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

    PubMed

    Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin C; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Lee, Joo Yeon; Liu, Jiang; Mulugeta, Yeruk; Yu, Jingyu; Zhao, Ping; Sinha, Vikram

    2016-07-01

    Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy. PMID:27079249

  7. Comparison of combination therapies in the treatment of rheumatoid arthritis: leflunomide-anti-TNF-alpha versus methotrexate-anti-TNF-alpha.

    PubMed

    De Stefano, Renato; Frati, Elena; Nargi, Fernando; Baldi, Caterina; Menza, Luana; Hammoud, Mohammed; Galeazzi, Mauro

    2010-05-01

    To compare the efficacy and safety of leflunomide (LEF)-anti-TNF-alpha combination therapy to methotrexate (MTX)-anti-TNF-alpha combination therapy in a group of patients with active rheumatoid arthritis (RA). We have recruited 120 patients with RA with a high disease activity despite being treated with MTX (15 mg/week) or LEF (20 mg/die) for 3 months, without side effects. In each of these patients, therapy with either MTX or LEF was continued and randomly combined with an anti-TNF-alpha drug: etanercept, infliximab, or adalimumab. Patients were assessed at study entry and at 4, 12, and at 24 weeks. The efficacy endpoints included variations in the DAS28-ESR and the ACR20, ACR50, and ACR70 responses. At each visit, any side-effect was recorded. There were no statistically significant differences in the DAS28 variations and in the ACR responses between the two groups or among the six subgroups. The number of discontinuation due to the appearance of serious side effects was higher, but not statistically significant, in the LEF-anti-TNF-alpha group than in the MTX-anti-TNF-alpha group. Other adverse events that did not necessitate the discontinuation of therapy occurred much more frequently in patients treated with MTX than in those treated with LEF. Anti-TNF-alpha drugs can be used in combination not only with MTX, but also with LEF, with the same probability of achieving significant clinical improvement in RA patients and without a significantly greater risk of serious adverse events. In contrast, it seems that combination therapy with LEF-anti-TNF-alpha is more readily tolerated than combination therapy with MTX-anti-TNF-alpha.

  8. Validation of the cantharidin-induced skin blister as an in vivo model of inflammation

    PubMed Central

    Dinh, Phong Huy Duc; Corraza, Francis; Mestdagh, Kristel; Kassengera, Zaina; Doyen, Virginie; Michel, Olivier

    2011-01-01

    AIM Pharmacological profiling techniques, such as the cantharidin-induced skin blister, may be used to assess the anti-inflammatory properties of novel drugs. However, no data are available on the reproducibility of this technique or on the blocking effect of anti-inflammatory drugs, such as anti-TNF and corticosteroids. METHODS A group of 30 healthy subjects were randomized into three parallel groups treated with placebo, oral methylprednisolone 20 mg day−1 for 7 days or anti-tumour necrosis factor (TNF) (adalimumab, Humira®, Abbott) 40 mg s.c. single dose. A first blister was induced at baseline and collected, immediately before the start of treatment and a second blister was obtained 7 days after the start of treatment. The total number of cells, the cell viability and the differential cell count were evaluated by two independent observers, who were blind to treatment. anova was used to compare change from baseline among the three groups before pairwise comparisons. RESULTS Among the placebo group, there was no significant difference in the total cell count, neutrophils, eosinophils and monocytes between day 1 and day 7. Methylprednisolone inhibited the eosinophil influx in mean % (95% CI) (−1.0 (−1.7, −0.3); P < 0.02) and absolute (P < 0.02) values, while anti-TNF inhibited the neutrophil influx in mean % (95% CI) (−19.3 (−29.5, −9.1); P < 0.01) and absolute (P < 0.05) values. CONCLUSIONS The cantharidin-induced skin blister is a safe, well tolerated and reproducible procedure. Pre-treatment with anti-TNF or methylprednisolone inhibited the neutrophilic or eosinophilic trafficking, respectively. It could be useful in profiling anti-inflammatory drugs regarding their effects on the cellular inflammatory response. PMID:21595743

  9. 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.

  10. Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis

    PubMed Central

    Martínez-Santana, Virginia; González-Sarmiento, E; Calleja-Hernández, MA; Sánchez-Sánchez, T

    2013-01-01

    Background Persistence of anti-tumor necrosis factor (TNF) therapy in rheumatoid arthritis (RA) is an overall marker of treatment success. Objective To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. Design An observational, descriptive, longitudinal, retrospective study. Setting The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. Patients RA patients treated with anti-TNF therapy between January 2011 and January 2012. Measurements Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations) for quantitative variables and frequency distribution for qualitative variables. Kaplan–Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. Results In total, 126 treatment series with infliximab (n = 53), etanercept (n = 51) or adalimumab (n = 22) were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. Limitation The small sample size. Conclusion The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with RA should be reconsidered in order to achieve disease control with a reduction in costs. PMID:24023512

  11. Are American College of Rheumatology 50% response criteria superior to 20% criteria in distinguishing active aggressive treatment in rheumatoid arthritis clinical trials reported since 1997? A meta‐analysis of discriminant capacities

    PubMed Central

    Chung, C P; Thompson, J L; Koch, G G; Amara, I; Strand, V; Pincus, T

    2006-01-01

    Objective To carry out a meta‐analysis designed to compare the discriminant capacities of American College of Rheumatology 50% (ACR50) with 20% (ACR20) responses in clinical trials on rheumatoid arthritis reported after 1997 and to analyse whether ACR50 can be as informative as ACR20 in distinguishing active from control treatments in more recent trials. Methods Clinical trials on rheumatoid arthritis reported since 1997 were identified, which included aggressive combinations of disease‐modifying antirheumatic drugs and glucocorticoids, as well as powerful new agents—leflunomide, etanercept, infliximab, anakinra, adalimumab, abatacept, tacrolimus and rituximab. A meta‐analysis of ACR20 compared with ACR50 responses for 21 clinical trials was carried out on differences in proportions of responders for active and control treatments and corresponding odds ratios (ORs). Results In all but one clinical trial on rheumatoid arthritis published since 1997 with data available on ACR20 and ACR50, more than 50% of patients who were ACR20 responders among those randomised to active treatment were also ACR50 responders. This phenomenon was seen for control groups in 38% of trials, many of which included treatment with methotrexate. A meta‐analysis of the clinical trials indicated a slight advantage to ACR50 for quantifying treatment comparisons, not significant for differences in proportions but significant for ORs. Conclusion ACR20 and ACR50 seem to be similar in distinguishing active from control treatments in clinical trials on rheumatoid arthritis reported since 1997. As ACR50 represents a considerably stronger clinical response, ACR50 may be a preferred end point for contemporary clinical trials on rheumatoid arthritis. PMID:16504992

  12. First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy

    PubMed Central

    Atreya, Raja; Billmeier, Ulrike; Rath, Timo; Mudter, Jonas; Vieth, Michael; Neumann, Helmut; Neurath, Markus F

    2015-01-01

    We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling. PMID:26668517

  13. EndoS and EndoS2 hydrolyze Fc-glycans on therapeutic antibodies with different glycoform selectivity and can be used for rapid quantification of high-mannose glycans

    PubMed Central

    Sjögren, Jonathan; Cosgrave, Eoin F J; Allhorn, Maria; Nordgren, Maria; Björk, Stephan; Olsson, Fredrik; Fredriksson, Sarah; Collin, Mattias

    2015-01-01

    Enzymes that affect glycoproteins of the human immune system, and thereby modulate defense responses, are abundant among bacterial pathogens. Two endoglycosidases from the human pathogen Streptococcus pyogenes, EndoS and EndoS2, have recently been shown to hydrolyze N-linked glycans of human immunoglobulin G. However, detailed characterization and comparison of the hydrolyzing activities have not been performed. In the present study, we set out to characterize the enzymes by comparing the activities of EndoS and EndoS2 on a selection of therapeutic monoclonal antibodies (mAbs), cetuximab, adalimumab, panitumumab and denosumab. By analyzing the glycans hydrolyzed by EndoS and EndoS2 from the antibodies using matrix-assisted laser desorption ionization time of flight, we found that both the enzymes cleaved complex glycans and that EndoS2 hydrolyzed hybrid and oligomannose structures to a greater extent compared with EndoS. A comparison of ultra-high-performance liquid chromatography (LC) profiles of the glycan pool of cetuximab hydrolyzed with EndoS and EndoS2 showed that EndoS2 hydrolyzed hybrid and oligomannose glycans, whereas these peaks were missing in the EndoS chromatogram. We utilized this difference in glycoform selectivity, in combination with the IdeS protease, and developed a LC separation method to quantify high mannose content in the Fc fragments of the selected mAbs. We conclude that EndoS and EndoS2 hydrolyze different glycoforms from the Fc-glycosylation site on therapeutic mAbs and that this can be used for rapid quantification of high mannose content. PMID:26156869

  14. Performance of ultrasound to monitor Achilles enthesitis in patients with ankylosing spondylitis during TNF-a antagonist therapy.

    PubMed

    Wang, Cong-hua; Feng, Yuan; Ren, Zhen; Yang, Xichao; Jia, Jun-feng; Rong, Meng-yao; Li, Xue-yi; Wu, Zhen-biao

    2015-06-01

    Enthesitis is considered as the primary anatomical lesion in ankylosing spondylitis (AS). We aimed to investigate the potential of ultrasound to detect early changes after TNF-a antagonist therapy of Achilles enthesitis of AS patients. One hundred AS patients with active disease, requiring TNF-a antagonist therapy, were included (etanercept n = 25, infliximab n = 25, adalimumab n = 25, non-biologic disease-modifying antirheumatic drugs (DMARDs) n = 25). Physical examination was performed to evaluate disease activity and detect Achilles enthesitis and/or retrocalcaneal bursitis. Ultrasound of the Achilles enthesitis was performed bilaterally. Follow-up examinations were performed 3 months after the initiation of therapy. Gray scale (GS) scores, Power Doppler (PD) scores, and total additive scores (TS) decreased significantly during TNF-a antagonist therapy but not in traditional non-biologic traditional DMARDs group. The bath ankylosing spondylitis disease activity index (BASDAI), bath ankylosing spondylitis metrology index (BASMI), bath ankylosing spondylitis functional index (BASFI), and Maastricht ankylosing spondylitis enthesitis score (MASES) all showed significant improvements. When three different TNF-a antagonists were analyzed separately, no significant difference was observed in GS, PD, and total scores. Subclinical Achilles enthesitis, detected only with GS ultrasound, is present in a subset of AS patients and a significant improvement can be demonstrated after 3 months of TNF-a antagonist therapy. Doppler ultrasound provides a reliable estimation to monitor the therapeutic response to TNF antagonists in AS patients with Achilles enthesitis. TNF-a antagonists have been shown to be effective in decreasing ultrasound signs of enthesitis after 3 months of therapy in AS patients.

  15. The Future is Now – Biologics for Non-Infectious Pediatric Anterior Uveitis

    PubMed Central

    Lerman, Melissa A.; Rabinovich, C. Egla

    2015-01-01

    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 reduce 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

  16. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis.

    PubMed

    Krishnan, Asha; Stobaugh, Derrick J; Deepak, Parakkal

    2015-04-01

    The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score.

  17. A proposal of simple calculation (ERI calculator) to predict the early response to TNF-α blockers therapy in rheumatoid arthritis.

    PubMed

    Bazzichi, Laura; Rossi, Paolo; Giacomelli, Camillo; De Feo, Francesca; Bobbio-Pallavicini, Francesca; Rossi, Alessandra; Baldini, Chiara; Consensi, Arianna; Doveri, Marica; Bonino, Claudia; Mazzantini, Maurizio; Della Rossa, Alessandra; Montecucco, Carlomaurizio; Bombardieri, Stefano

    2012-02-01

    Increasing evidence has been accumulated for treating rheumatoid arthritis (RA) with TNF-α blocking agents. The formulation and definition of an early indicator of patient's reactivity during therapy may be extremely simplified by a mathematical model of clinical response. We analyzed the most significant clinical and laboratory parameters of response of 35 homogeneous patients (30 women, 5 men mean age ± SD: 52.31 ± 12.30 years) treated with adalimumab 40 mg every 2 weeks associated with methotrexate (MTX) 10-15 mg/week and with a stable dosage of steroids for 30 weeks. The over time trend of the studied parameters showed a linear response, which has allowed the realization of a simple mathematical model. The formula derived from this mathematical model was then applied and therefore validated in a group of 121 patients previously treated with several anti-TNF-alpha agents for at least 6 months. We drafted a mathematical model (early response indicator, ERI) that, by using a simple calculation, allows us to identify a high percentage of responder patients after only 2 weeks of treatment. ERI identified a high percentage (88%) of patients responding after only 2 weeks, as was confirmed at weeks 30; the use of ERI calculation after 6 weeks increases the proportion of responding patients to 92% with a percentage of false negatives of only 12%. ERI could be a useful tool to early differentiate the responder from the non-responder patients.

  18. Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

    PubMed

    Hero, M; Suomalainen, A; Hagström, J; Stoor, P; Kontio, R; Alapulli, H; Arte, S; Toiviainen-Salo, S; Lahdenne, P; Mäkitie, O

    2013-01-01

    Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism. PMID:23069372

  19. Tailored treatment options for patients with psoriatic arthritis and psoriasis: review of established and new biologic and small molecule therapies.

    PubMed

    Elyoussfi, Sarah; Thomas, Benjamin J; Ciurtin, Coziana

    2016-05-01

    The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed to classify the available biologic agents and new small molecule inhibitors (licensed and nonlicensed) based on their proven efficacy in treating different clinical manifestations associated with psoriasis and PsA. This review presents the level of evidence of efficacy of different biologic treatments and small molecule inhibitors for certain clinical features of treatment of PsA and psoriasis, which was graded in categories I-IV. The literature searches were performed on the following classes of biologic agents and small molecules: TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab), anti-IL12/IL23 (ustekinumab), anti-IL17 (secukinumab, brodalumab, ixekizumab), anti-IL6 (tocilizumab), T cell modulators (alefacept, efalizumab, abatacept, itolizumab), B cell depletion therapy (rituximab), phosphodiesterase 4 inhibitor (apremilast) and Janus kinase inhibitor (tofacitinib). A comprehensive table including 17 different biologic agents and small molecule inhibitors previously tested in psoriasis and PsA was generated, including the level of evidence of their efficacy for each of the clinical features included in our review (axial and peripheral arthritis, enthesitis, dactylitis, and nail and skin disease). We also proposed a limited set of recommendations for a sequential biologic treatment algorithm for patients with PsA who failed the first anti-TNF therapy, based on the available literature data. There is good evidence that many of the biologic treatments initially tested in psoriasis are also effective in PsA. Further research into both prognostic biomarkers and patient stratification is required to allow clinicians the possibility to make better use of the various biologic treatment options available. This review showed that there are many potentially new treatments that are

  20. An appraisal of golimumab in the treatment of severe, active nonradiographic axial spondyloarthritis.

    PubMed

    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.

  1. 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

  2. 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.

  3. 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

  4. A general strategy for generating intact, full-length IgG antibodies that penetrate into the cytosol of living cells.

    PubMed

    Choi, Dong-Ki; Bae, Jeomil; Shin, Seung-Min; Shin, Ju-Yeon; Kim, Sunghoon; Kim, Yong-Sung

    2014-01-01

    Full-length IgG antibodies cannot cross cell membranes of living cells; this limits their use for direct targeting of cytosolic proteins. Here, we describe a general strategy for the generation of intact, full-length IgG antibodies, herein called cytotransmabs, which internalize into living cells and localize in the cytosol. We first generated a humanized light chain variable domain (VL) that could penetrate into the cytosol of living cells and was engineered for association with various subtypes of human heavy chain variable domains (VHs). When light chains with humanized VL were co-expressed with 3 heavy chains (HCs), including 2 HCs of the clinically approved adalimumab (Humira®) and bevacizumab (Avastin®), all 3 purified IgG antibodies were internalized into the cytoplasm of living cells. Cytotransmabs primarily internalized into living cells by the clathrin-mediated endocytic pathway through interactions with heparin sulfate proteoglycan that was expressed on the cell surface. The cytotransmabs escaped into the cytosol from early endosomes without being further transported into other cellular compartments, like the lysosomes, endoplasmic reticulum, Golgi apparatus, and nucleus. Furthermore, we generated a cytotransmab that co-localized with the targeted cytosolic protein when it was incubated with living cells, demonstrating that the cytotransmab can directly target cytosolic proteins. Internalized cytotransmabs did not show any noticeable cytotoxicity and remained in the cytosol for more than 6 h before being degraded by proteosomes. These results suggest that cytotransmabs, which efficiently enter living cells and reach the cytosolic space, will find widespread uses as research, diagnostic, and therapeutic agents.

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

    PubMed

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

    2013-01-01

    Objetivo: analizar la relación costo-efectividad del etanercept en comparación con otras terapias biológicas para tratar la artritis reumatoide moderada o severa en pacientes con falla previa a fármacos antirreumáticos modificadores de la enfermedad. Métodos: se empleó un modelo farmacoeconómico basado en el análisis de decisiones para valorar la evolución clínica con etanercept, infliximab, adalimumab o tocilizumab para tratar artritis reumatoide moderada o severa. Los parámetros de efectividad fueron las tasas de mejoría igual o superior a 20 % (ACR 20) y de mejoría igual o superior a 70 % (ACR 70). Resultados: etanercept tuvo la mayor efectividad terapéutica: en 79.7 % de los pacientes se observó una ACR 20 y en 31.4 %, una ACR 70. También tuvo el menor costo asociado ($149 629.1 por paciente) y fue más costo-efectiva ($187 740.4 por éxito clínico para obtener ACR 20 y $476 525.8 por éxito clínico para obtener ACR 70) que las demás terapias biológicas. Conclusiones: el etanercept fue el fármaco más efectivo y menos costoso, por lo que resulta la opción terapéutica más eficiente, desde el punto de vista de la relación costo-efectividad media y en términos incrementales para el tratamiento de la artritis reumatoide.

  6. Drug-induced Depression: a Case/Non Case Study in the French Pharmacovigilance Database.

    PubMed

    Lafay-Chebassier, Claire; Chavant, François; Favrelière, Sylvie; Pizzoglio, Véronique; Pérault-Pochat, Marie-Christine

    2015-01-01

    Depression is a complex disorder with heterogeneous clinical anomalies whose neurobiological understanding still remains unclear. Medications have been implicated as potential causes of depression but for many of them, data are controversial. The present study aims to investigate association bet ween drugs and reports of depression. We used the case/non case method in the French pharmacovigilance database (FPVD) to identify drugs associated with depression. Cases were reports of depression in the FPVD between January 2007 and December 2011. Non cases were all other reports during the same period. Data were expressed as reporting odds ratio (ROR) with their 95% confidence interval. Of the 114,692 reports recorded in the FPVD during the studied period, we identified 474 cases of depression. For the majority of the patients, they were considered as "non serious" (56%) and evolution was favorable (64%). Significant RORs were found for antiepileptics (topiramate, levetiracetam), anti-infective and especially anti-retroviral drugs (efavirenz, emtricitabine, tenofovir, etravirine, raltegravir), interferons and other agents including isotretinoin, methylphenidate, sodium oxybate, varenicline, montelukast, flunarizine, adalimumab, anastrozole. Taking into account the limits of the methodology, the present study described associations with mainly expected drugs belonging to various therapeutic classes but it also found a signal with some anti-retrovirals. On the contrary, we did not find some assumed associations like cardiovascular medications, antimalarial. For most of the drugs, one or more mechanisms were found to explain these depressogenic effects on the basis of animal and human literature. Even if such associations need to be confirmed by further prospective studies, cautions are necessary for many drugs to early detect depressive symptoms. PMID:26056040

  7. Relative efficiencies of the 7 rheumatoid arthritis Core Data Set measures to distinguish active from control treatments in 9 comparisons from clinical trials of 5 agents.

    PubMed

    Pincus, T; Richardson, B; Strand, V; Bergman, M J

    2014-01-01

    The 7 Core Data Set measures to assess rheumatoid arthritis (RA) were analysed for their relative efficiencies to distinguish active from control treatments in 9 comparisons of 5 agents, methotrexate, leflunomide, infliximab, adalimumab, and abatacept, in 8 clinical trials. Among the 7 measures, levels of relative efficiencies were in a similar range, highest for the physician global estimate, followed by, in order, patient global estimate, physical function on a health assessment questionnaire (HAQ), pain, swollen joint count (SJC), an acute phase reactant laboratory test - erythrocyte sedimentation (ESR) or C-reactive protein (CRP), and tender joint count (TJC). Comparisons of only 3 measures, SJC and ESR/CRP (regarded as optimal indicators of inflammation) and HAQ function (regarded as most likely to be affected by joint damage and therefore least reversible) indicated relative efficiencies for HAQ function at least as great as for SJC or ESR/CRP, although 8 of the nine comparisons involved patients with disease duration > 6.9 years. The findings indicate a strong rationale for a Core Data Set of 7 measures, as no single measure was clearly superior in relative efficiency in all clinical trials. At the same time, 'objective' laboratory ESR/CRP, TJC and SJC were not superior to 'subjective' global estimates of the physician or patient or patient self-report measures of physical function or pain, to differentiate active from control treatments. The findings challenge a traditional view that laboratory and clinical examination findings are more robust than patient self-report scores and physician global estimates to assess and monitor RA patients.

  8. European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.

    PubMed

    Zouboulis, C C; Desai, N; Emtestam, L; Hunger, R E; Ioannides, D; Juhász, I; Lapins, J; Matusiak, L; Prens, E P; Revuz, J; Schneider-Burrus, S; Szepietowski, J C; van der Zee, H H; Jemec, G B E

    2015-04-01

    Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. A mean disease incidence of 6.0 per 100,000 person-years and an average prevalence of 1% has been reported in Europe. HS has the highest impact on patients' quality of life among all assessed dermatological diseases. HS is associated with a variety of concomitant and secondary diseases, such as obesity, metabolic syndrome, inflammatory bowel disease, e.g. Crohn's disease, spondyloarthropathy, follicular occlusion syndrome and other hyperergic diseases. The central pathogenic event in HS is believed to be the occlusion of the upper part of the hair follicle leading to a perifollicular lympho-histiocytic inflammation. A highly significant association between the prevalence of HS and current smoking (Odds ratio 12.55) and overweight (Odds ratio 1.1 for each body mass index unit) has been documented. The European S1 HS guideline suggests that the disease should be treated based on its individual subjective impact and objective severity. Locally recurring lesions can be treated by classical surgery or LASER techniques, whereas medical treatment either as monotherapy or in combination with radical surgery is more appropriate for widely spread lesions. Medical therapy may include antibiotics (clindamycin plus rifampicine, tetracyclines), acitretin and biologics (adalimumab, infliximab). A Hurley severity grade-relevant treatment of HS is recommended by the expert group following a treatment algorithm. Adjuvant measurements, such as pain management, treatment of superinfections, weight loss and tobacco abstinence have to be considered.

  9. Four cases of Japanese patients with psoriatic arthritis in whom effective treatments by anti-tumor necrosis factor-α drugs were evaluated by magnetic resonance imaging together with improvement of skin lesions.

    PubMed

    Yonenaga, Takenori; Saeki, Hidehisa; Nakagawa, Hidemi; Fukuchi, Osamu; Umezawa, Yoshinori; Hayashi, Mitsuha; Ito, Toshihiro; Yanaba, Koichi; Tojyo, Shinjiro; Fukuda, Kunihiko

    2015-01-01

    Because psoriatic skin lesions of psoriatic arthritis (PsA) usually precede the onset of joint symptom, dermatologists are in an ideal position to screen and find individuals with PsA early in the disease course. There have been no reports from the dermatology field evaluating the effect of anti-tumor necrosis factor (TNF)-α drugs on joint disorders using magnetic resonance imaging (MRI) in PsA patients. The purpose of this study was to elucidate the effectiveness of MRI in the evaluation of anti-TNF-α drugs on joint disease of Japanese PsA patients. Data were collected from four adult Japanese male PsA patients. MRI of the affected hand was performed at baseline and 1-7 months after infliximab or adalimumab treatment. T1 -weighted gadolinium-enhanced images with fat suppression were acquired in the coronal, sagittal and/or axial planes. We determined the apparent improvement of synovitis, periarticular inflammation, tenosynovitis and/or bone marrow edema by MRI after anti-TNF-α treatments in all the patients together with the improvement of skin lesions. We also determined in one patient that these symptoms detected by MRI before treatment were alleviated within 1 month and had disappeared 6 months after treatment, suggesting the potentially early detection of the effect of anti-TNF-α drugs on joint disease. We present four cases of Japanese patients with PsA in whom effective treatments by anti-TNF-α drugs were evaluated by contrast-enhanced MRI. This imaging enables dermatologists and radiologists to assess and monitor early inflammatory changes, and to grant PsA patients earlier access to modern treatment such as biologics.

  10. 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

  11. An appraisal of golimumab in the treatment of severe, active nonradiographic axial spondyloarthritis.

    PubMed

    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

  12. Reactivation of human polyomavirus JC in patients affected by psoriasis vulgaris and psoriatic arthritis and treated with biological drugs: preliminary results.

    PubMed

    Nardis, Chiara; Anzivino, Elena; Bellizzi, Anna; Rodio, Donatella M; De Pità, Ornella; Chiarini, Fernanda; Pietropaolo, Valeria

    2012-12-01

    Psoriasis vulgaris (PsV) and psoriatic arthritis (PSA) are inter-related heritable inflammatory skin diseases. Psoriatic lesions develop as a result of abnormal immune responses, hyperproliferation and altered differentiation of keratinocytes, and a notable subset of psoriatic patients develops PsA, characterized by joints inflammation. Recently, biological drugs were introduced to treat these diseases. However, this therapy has already been associated with the development of serious life-threatening infections, such as the reactivation of human polyomavirus JC (JCV), responsible for the progressive multifocal leukoencephalopathy (PML), a lethal demyelinating disease caused by oligodendrocytes lytic infection. Therefore, the aims of our study were the investigation of the possible JCV reactivation in PsV and PsA patients treated with adalimumab, etanercept, and methotrexate, performing quantitative real-time PCR in sera and skin biopsies at the time of recruitment (T0) and after 3 (T3) and 6 (T6) months of treatment, and the sequencing analysis of the JCV non-coding control region (NCCR). We found JCV DNA in 5/15 PsV patients and in 2/15 PsA patients and JCV NCCR sequence analysis always showed a structure similar to non-pathogenic CY archetype, with random occurrence of a few irrelevant point mutations. Nevertheless the poor number of patients analyzed, our preliminary data can pave the way for taking into account that the follow-up of JCV DNA detection and the JCV NCCR sequence analysis in psoriatic patients may be important to evaluate the risk of PML onset, considering that patients affected by autoimmune diseases and treated with biologics continue to rise. PMID:22422468

  13. Phage display-derived human antibodies in clinical development and therapy

    PubMed Central

    Frenzel, André; Schirrmann, Thomas; Hust, Michael

    2016-01-01

    ABSTRACT Over the last 3 decades, monoclonal antibodies have become the most important class of therapeutic biologicals on the market. Development of therapeutic antibodies was accelerated by recombinant DNA technologies, which allowed the humanization of murine monoclonal antibodies to make them more similar to those of the human body and suitable for a broad range of chronic diseases like cancer and autoimmune diseases. In the early 1990s in vitro antibody selection technologies were developed that enabled the discovery of “fully” human antibodies with potentially superior clinical efficacy and lowest immunogenicity. Antibody phage display is the first and most widely used of the in vitro selection technologies. It has proven to be a robust, versatile platform technology for the discovery of human antibodies and a powerful engineering tool to improve antibody properties. As of the beginning of 2016, 6 human antibodies discovered or further developed by phage display were approved for therapy. In 2002, adalimumab (Humira®) became the first phage display-derived antibody granted a marketing approval. Humira® was also the first approved human antibody, and it is currently the best-selling antibody drug on the market. Numerous phage display-derived antibodies are currently under advanced clinical investigation, and, despite the availability of other technologies such as human antibody-producing transgenic mice, phage display has not lost its importance for the discovery and engineering of therapeutic antibodies. Here, we provide a comprehensive overview about phage display-derived antibodies that are approved for therapy or in clinical development. A selection of these antibodies is described in more detail to demonstrate different aspects of the phage display technology and its development over the last 25 years. PMID:27416017

  14. EndoS and EndoS2 hydrolyze Fc-glycans on therapeutic antibodies with different glycoform selectivity and can be used for rapid quantification of high-mannose glycans.

    PubMed

    Sjögren, Jonathan; Cosgrave, Eoin F J; Allhorn, Maria; Nordgren, Maria; Björk, Stephan; Olsson, Fredrik; Fredriksson, Sarah; Collin, Mattias

    2015-10-01

    Enzymes that affect glycoproteins of the human immune system, and thereby modulate defense responses, are abundant among bacterial pathogens. Two endoglycosidases from the human pathogen Streptococcus pyogenes, EndoS and EndoS2, have recently been shown to hydrolyze N-linked glycans of human immunoglobulin G. However, detailed characterization and comparison of the hydrolyzing activities have not been performed. In the present study, we set out to characterize the enzymes by comparing the activities of EndoS and EndoS2 on a selection of therapeutic monoclonal antibodies (mAbs), cetuximab, adalimumab, panitumumab and denosumab. By analyzing the glycans hydrolyzed by EndoS and EndoS2 from the antibodies using matrix-assisted laser desorption ionization time of flight, we found that both the enzymes cleaved complex glycans and that EndoS2 hydrolyzed hybrid and oligomannose structures to a greater extent compared with EndoS. A comparison of ultra-high-performance liquid chromatography (LC) profiles of the glycan pool of cetuximab hydrolyzed with EndoS and EndoS2 showed that EndoS2 hydrolyzed hybrid and oligomannose glycans, whereas these peaks were missing in the EndoS chromatogram. We utilized this difference in glycoform selectivity, in combination with the IdeS protease, and developed a LC separation method to quantify high mannose content in the Fc fragments of the selected mAbs. We conclude that EndoS and EndoS2 hydrolyze different glycoforms from the Fc-glycosylation site on therapeutic mAbs and that this can be used for rapid quantification of high mannose content.

  15. Nocardia infections among immunomodulated inflammatory bowel disease patients: A review

    PubMed Central

    Abreu, Cândida; Rocha-Pereira, Nuno; Sarmento, António; Magro, Fernando

    2015-01-01

    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

  16. A general strategy for generating intact, full-length IgG antibodies that penetrate into the cytosol of living cells

    PubMed Central

    Choi, Dong-Ki; Bae, Jeomil; Shin, Seung-Min; Shin, Ju-Yeon; Kim, Sunghoon; Kim, Yong-Sung

    2014-01-01

    Full-length IgG antibodies cannot cross cell membranes of living cells; this limits their use for direct targeting of cytosolic proteins. Here, we describe a general strategy for the generation of intact, full-length IgG antibodies, herein called cytotransmabs, which internalize into living cells and localize in the cytosol. We first generated a humanized light chain variable domain (VL) that could penetrate into the cytosol of living cells and was engineered for association with various subtypes of human heavy chain variable domains (VHs). When light chains with humanized VL were co-expressed with 3 heavy chains (HCs), including 2 HCs of the clinically approved adalimumab (Humira®) and bevacizumab (Avastin®), all 3 purified IgG antibodies were internalized into the cytoplasm of living cells. Cytotransmabs primarily internalized into living cells by the clathrin-mediated endocytic pathway through interactions with heparin sulfate proteoglycan that was expressed on the cell surface. The cytotransmabs escaped into the cytosol from early endosomes without being further transported into other cellular compartments, like the lysosomes, endoplasmic reticulum, Golgi apparatus, and nucleus. Furthermore, we generated a cytotransmab that co-localized with the targeted cytosolic protein when it was incubated with living cells, demonstrating that the cytotransmab can directly target cytosolic proteins. Internalized cytotransmabs did not show any noticeable cytotoxicity and remained in the cytosol for more than 6 h before being degraded by proteosomes. These results suggest that cytotransmabs, which efficiently enter living cells and reach the cytosolic space, will find widespread uses as research, diagnostic, and therapeutic agents. PMID:25484049

  17. Effectiveness and Safety of Immunomodulators with Anti-TNF Therapy in Crohn's Disease

    PubMed Central

    Osterman, Mark T.; Haynes, Kevin; Delzell, Elizabeth; Zhang, Jie; Bewtra, Meenakshi; Brensinger, Colleen M.; Chen, Lang; Xie, Fenglong; Curtis, Jeffrey R.; Lewis, James D.

    2015-01-01

    Background & Aims The benefit of continuing immunomodulators when “stepping up” to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD. Methods We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared using 3 metrics of effectiveness – surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery – and 2 metrics of safety – serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses. Results Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as “step up” after thiopurine therapy. The rates of surgery (hazard ratio [HR] 1.20, 95% CI 0.73-1.96), hospitalization (HR 0.82 [0.57-1.19]), discontinuation of anti-TNF therapy or surgery (HR 1.09, [0.88-1.34]), and serious infection (HR 0.93 [0.88-1.34]) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risk of opportunistic infection (HR 2.64 [1.21-5.73]) and herpes zoster (HR 3.16 [1.25-7.97]) were increased with combination therapy. Conclusions We found that continuation of immunomodulators after “stepping up” to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection. PMID:25724699

  18. A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations

    PubMed Central

    Wells, Alvin F; Jodat, Nicole; Schiff, Michael

    2014-01-01

    There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept’s mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient

  19. 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

  20. Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: systematic literature review and analysis of a monocentric cohort.

    PubMed

    Piga, Matteo; Chessa, Elisabetta; Ibba, Valentina; Mura, Valentina; Floris, Alberto; Cauli, Alberto; Mathieu, Alessandro

    2014-08-01

    The use of biologic drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. The aim of this study was to describe the features of biologics-induced autoimmune renal disorders (AIRD) through a systematic review and a cohort study of 707 adult patients affected with Rheumatoid Arthritis (RA), Ankylosing Spondylitis (SA) and Psoriatic Arthritis (PsA). The literature search identified 2687 articles of which 21 were considered relevant for the present study, accounting for 26 case reports. The cohort analysis retrieved 3 cases. According to clinical manifestations and kidney histology the identified AIRD cases were classified as: a) glomerulonephritis associated with systemic vasculitis (GNSV), b) glomerulonephritis in lupus-like syndrome (GNLS), c) isolated autoimmune renal disorders (IARD). Twenty-two out of 29 cases with AIRD were reported in patients affected by RA, 5 in AS and 2 in PsA. The biologic drug most frequently associated with development of AIRD was Etanercept (15 cases, 51.7%), followed by Adalimumab (9 cases, 31.0%) and Infliximab (3 cases, 10.3%) while Tocilizumab and Abatacept were reported in 1 case (3.4%) for each. Thirteen out of 29 (44.8%) cases were classified as affected by IARD, 12 (41.3%) as GNSV and 4 (13.9%) as GNLS. Worse prognosis was associated with GNSV and lack of biologic withdrawal. Although rare, AIRD may be life-threatening and may lead to renal failure and death. If AIRD occurs, biologic drugs must be stopped and patient should be treated according to clinical manifestations and kidney biopsy findings.

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

    PubMed Central

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

    2015-01-01

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

  2. Infliximab-Associated Psoriasiform Dermatitis: Case Report and Review of a Seemingly Paradoxical Inflammatory Response

    PubMed Central

    Cohen, Philip R

    2016-01-01

    Background: Tumor necrosis factor-α (TNF-α) inhibitors, such as infliximab, adalimumab, and certolizumab pegol are effective agents in the treatment of inflammatory bowel disease. Some individuals undergoing anti-TNF-α therapy for Crohn’s disease or ulcerative colitis develop psoriasiform lesions. This is a paradoxical finding, as classical psoriasis is known to respond to these agents. Purpose: The clinical features of anti-TNF-α-induced psoriatic dermatitis are described. Method: A 60-year-old man with Crohn’s disease treated with infliximab, who developed anti-TNF-α-induced psoriasiform dermatitis, is described. Results: The man developed erythematous skin lesions in the bilateral axillae two years after beginning infliximab treatment for Crohn’s disease. Biopsy revealed psoriasiform dermatitis, consistent with a diagnosis of anti-TNF-α-induced psoriasiform dermatitis. He was treated with clobetasol 0.05% ointment twice daily for two weeks and had significant improvement. Subsequently, he used the corticosteroid ointment two days per week and calcipotriene 0.005% ointment twice daily for five days per week to achieve and maintain clear skin. Conclusions: Anti-TNF-α-induced psoriasiform dermatitis is an infrequent complication of infliximab therapy. However, the condition may require discontinuation of the anti-TNF-α agent. Anti-TNF-α-induced psoriasiform dermatitis should be considered in the differential diagnosis when evaluating a new erythematous skin condition in an individual with a history of inflammatory bowel disease who is being treated with a TNF-α inhibitor. PMID:27738572

  3. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies

    PubMed Central

    Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn’s disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn’s disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon’s signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients. PMID:27636201

  4. Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

    PubMed

    Hero, M; Suomalainen, A; Hagström, J; Stoor, P; Kontio, R; Alapulli, H; Arte, S; Toiviainen-Salo, S; Lahdenne, P; Mäkitie, O

    2013-01-01

    Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

  5. Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients.

    PubMed

    Scheinfeld, Noah

    2013-01-01

    Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients' lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients. PMID:24021361

  6. Distinctive histopathologic phenotype in resection specimens from patients with Crohn's disease receiving anti-TNF-α therapy.

    PubMed

    Schaeffer, David F; Walsh, Joanna C; Kirsch, Richard; Waterman, Matti; Silverberg, Mark S; Riddell, Robert H

    2014-09-01

    Anti-tumor necrosis factor α (anti-TNF-α) therapy can result in endoscopic healing, reduction of symptoms, and reduced need for surgery and hospitalization in many patients with Crohn's disease (CD). Earlier data suggested that anti-TNF-α therapy may be associated with fibrosis and stricturing. We sought to determine whether anti-TNF-α therapy affects histologic inflammation, fibrosis, and granuloma formation. Hematoxylin and eosin sections from 62 patients with CD treated with either infliximab or adalimumab and 80 controls undergoing the same surgery but without prior exposure to anti-TNF-α therapy were compared. All patients with CD had undergone surgery within 6 months of therapy; CD controls were matched for steroid exposure, procedure, and indication for surgery and were subcategorized and case matched. Blinded histologic assessment of all slides was performed using a semiquantitative scoring system to assess inflammatory changes and fibrosis in all bowel layers. Compared with controls, the group treated with anti-TNF-α showed a reduction in mucosal and submucosal inflammation (P < .05), a decrease in granuloma formation (P < .05), and an increase in duplication of the muscularis mucosae (P < .05). A notable feature was a distinct pattern of hyalinizing submucosal fibrosis that was often devoid of inflammatory cells and that started directly below the muscularis mucosae; this pattern was not observed in the control group (P < .05). Resection specimens from patients with CD treated with anti-TNF-α therapy showed (a) reduced mucosal and submucosal inflammation; (b) a decrease in granuloma formation; and (c) a distinct pattern of submucosal hyaline fibrosis, with increased fibrosis in the muscularis mucosae and muscularis propria.

  7. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER

    PubMed Central

    Carmona, Loreto; Gómez-Reino, Juan J

    2006-01-01

    The aim of the present work is to compare drug survival and safety of infliximab, etanercept, and adalimumab (tumor necrosis factor [TNF] antagonists) in spondylarthritis (SpA) with those of rheumatoid arthritis (RA). To this purpose, we analysed the data in BIOBADASER (2000–2005), a drug registry launched in 2000 for long-term follow-up of the safety of these biologics in rheumatic diseases. The rates of drug discontinuation and adverse events (AEs) in SpA (n = 1,524) were estimated and compared with those of RA (n = 4,006). Cox regression analyses were used to adjust for independent factors. Total exposure to TNF antagonists for SpA was 2,430 patient-years and 7,865 for RA. Drug survival in SpA was significantly greater than in RA at 1, 2, and 3 years. The hazard ratio (HR) for discontinuation in SpA compared with RA was 0.66 (95% confidence interval [CI], 0.57–0.76) after adjustment for age, gender, and use of infliximab. The difference remained after controlling for the individual medication and its place in the sequence of treatment. There were fewer SpA patients with AEs (17%) than RA patients (26%; p < 0.001). The HR for AEs in SpA was 0.80 (95% CI, 0.70–0.91) compared with RA after adjustment for age, disease duration, and use of infliximab. In conclusion, due in part to a better safety profile, survival of TNF antagonists in SpA is better than in RA. TNF antagonists are at present a safe and effective therapeutic option for long-term treatment of patients with SpA failing to respond to traditional drugs. Because chronic therapy is necessary, continual review of this issue is necessary. PMID:16620398

  8. Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period

    PubMed Central

    Gomez-Reino, Juan J; Carmona, Loreto

    2006-01-01

    The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34–0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97–2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13–4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. PMID:16507128

  9. 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

  10. Gateways to clinical trials.

    PubMed

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

    2005-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials reported 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:[188Re]-HDD; A-179578, adalimumab, AK-602, albumin interferon alfa, alfimeprase, amelubant, anakinra, anti-CD2 MAb, APD-356, aripiprazole, atvogen; Bimatoprost, bimosiamose, BLP-25, brivaracetam; Caspofungin acetate, cilansetron, CMV vaccine (bivalent), conivaptan hydrochloride, Cypher; Darbepoetin alfa, darifenacin hydrobromide, D-D4FC, decitabine, dnaJP1, doranidazole, dronedarone hydrochloride; Efalizumab, efaproxiral sodium, emtricitabine, Endeavor, entecavir, erlotinib hydrochloride, escitalopram oxalate, etoricoxib, etravirine, ezetimibe; Fampridine, fenretinide, ferumoxtran-10, forodesine hydrochloride; Gantacurium chloride, gemi-floxacin mesilate, Glyminox, GW-501516; HBV-ISS, hepavir B, human insulin, HuMax-CD20, hyaluronic acid, HyCAMP; Icatibant, IDEA-070, IGN-311, imatinib mesylate, insulin detemir, insulin glargine, insulin glulisine; Lapatinib, lasofoxifene tartrate, LB-80380, liarozole fumarate, liposome encapsulated doxorubicin, lumiracoxib, LY-570310; MC-1, melatonin, merimepodib, metanicotine, midostaurin; Natalizumab, nicotine conjugate vaccine, NYVAC-HIV C; Patupilone, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pelitinib, Peru-15, pexelizumab, PHP, pimecrolimus, prednisolone sodium metasulfobenzoate; Recombinant alfa1-antitrypsin (AAT), retigabine, rHA influenza vaccine, rifalazil, rofecoxib, rosiglitazone maleate/Metformin hydrochloride, rostaporfin, rosuvastatin calcium, rubitecan; Selenite sodium, semilente insulin, SMP-797, sorafenib; Talampanel, tenofovir disoproxil fumarate, TER-199, tiotropium bromide, torcetrapib, treprostinil sodium, TTA

  11. 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

  12. Gateways to clinical trials.

    PubMed

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

    2005-04-01

    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 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: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort

  13. 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

  14. 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

  15. 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

  16. Growth and Adult Height in Patients with Crohn's Disease Treated with Anti-Tumor Necrosis Factor α Antibodies.

    PubMed

    Bamberger, Sarah; Martinez Vinson, Christine; Mohamed, Damir; Viala, Jérôme; Carel, Jean-Claude; Hugot, Jean-Pierre; Simon, Dominique

    2016-01-01

    Inflammation contributes to growth failure associated with inflammatory bowel diseases. Anti-TNFα therapy induces sustained remission and short-term improvements in height velocity and/or height standard deviation score (H-SDS) patients with Crohn's disease. The purpose of this study was to evaluate growth and adult height in patients with Crohn's disease taking maintenance infliximab or adalimumab therapy.This university-hospital based retrospective study included 61 patients, with a median follow-up of 2.6 years (2.0; 3.3). 38 patients (62%) reached their adult height. H-SDS was collected at diagnosis and together with disease activity markers (Harvey-Bradshaw Index, albumin, and C-reactive protein) at treatment initiation (baseline), and follow-up completion. Wilcoxon's signed-rank test was chosen for comparisons. Median H-SDS decreased from diagnosis to baseline (-0.08 [-0.73; +0.77] to -0.94 [-1.44; +0.11], p<0.0001) and then increased to follow-up completion (-0.63 [-1.08; 0.49], p = 0.003 versus baseline), concomitantly with an improvement in disease activity. Median adult H-SDS was within the normal range (-0.72 [-1.25; +0.42]) but did not differ from baseline H-SDS and was significantly lower than the target H-SDS (-0.09 [-0.67; +0.42], p = 0.01). Only 2 (6%) males had adult heights significantly below their target heights (10.5 and -13.5 cm [-1.75 and -2.25 SD]). In conclusion, anti-tumor necrosis factor α (TNF) therapy prevented loss of height without fully restoring the genetic growth potential in this group of patients with CD. Earlier treatment initiation might improve growth outcomes in these patients.

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

    PubMed

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

    2012-04-01

    several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice. No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics. The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer's claim that golimumab was a cost-effective treatment option, the manufacturer's own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally

  18. Management of psoriasis patients with hepatitis B or hepatitis C virus infection

    PubMed Central

    Bonifati, Claudio; Lora, Viviana; Graceffa, Dario; Nosotti, Lorenzo

    2016-01-01

    The systemic therapies available for the management of Psoriasis (PsO) patients who cannot be treated with more conservative options, such as topical agents and/or phototherapy, with the exception of acitretin, can worsen or reactivate a chronic infection. Therefore, before administering immunosuppressive therapies with either conventional disease-modifying drugs (cDMARDs) or biological ones (bDMARDs) it is mandatory to screen patients for some infections, including hepatitis B virus (HBV) and hepatitis C virus (HCV). In particular, the patients eligible to receive an immunosuppressive drug must be screened for the following markers: antibody to hepatitis B core, antibody to hepatitis B surface antigen (anti-HBsAg), HBsAg, and antibody to HCV (anti-HCV). In case HBV or HCV infection is diagnosed, a close collaboration with a consultant hepatologist is needed before and during an immunosuppressive therapy. Concerning therapy with immunosuppressive drugs in PsO patients with HBV or HCV infection, data exist mainly for cyclosporine a (CyA) or bDMARDs (etanercept, adalimumab, infliximab, ustekinumab). The natural history of HBV and HCV infection differs significantly as well as the effect of immunosuppression on the aforementioned infectious diseases. As a rule, in the case of active HBV infection, systemic immunosuppressive antipsoriatic therapies must be deferred until the infection is controlled with an adequate antiviral treatment. Inactive carriers need to receive antiviral prophylaxis 2-4 wk before starting immunosuppressive therapy, to be continued after 6-12 mo from its suspension. Due to the risk of HBV reactivation, these patients should be monitored monthly for the first 3 mo and then every 3 mo for HBV DNA load together with transaminases levels. Concerning the patients who are occult HBV carriers, the risk of HBV reactivation is very low. Therefore, these patients generally do not need antiviral prophylaxis and the sera HBsAg and transaminases dosing can

  19. Comparison of low-field dedicated extremity magnetic resonance imaging with articular ultrasonography in patients with rheumatoid arthritis.

    PubMed

    Horikoshi, Masanobu; Suzuki, Takeshi; Sugihara, Makoto; Kondo, Yuya; Tsuboi, Hiroto; Uehara, Takeaki; Hama, Maasa; Takase, Kaoru; Ohno, Shigeru; Ishigatsubo, Yoshiaki; Yoshida, Yuri; Sagawa, Akira; Ikeda, Kei; Ota, Toshiyuki; Matsumoto, Isao; Ito, Satoshi; Sumida, Takayuki

    2010-12-01

    To compare magnetic resonance imaging (MRI) and ultrasonography (US) in the detection of joint inflammation of rheumatoid arthritis (RA), 6 patients with RA were examined by US and low-field 0.3-T nonenhanced dedicated extremity MRI (compacTscan). All patients were females, with mean age of 50.2 years, mean disease duration of 13.5 years, and mean disease activity score (DAS)28-CRP of 1.78. Each patient was treated with either infliximab, etanercept, adalimumab, or tocilizumab. Intercarpal joints, radioulnar joints, second through fifth proximal interphalangeal (PIP) joints, and first through fifth metacarpophalangeal (MCP) joints (a total of 132 joints, 22 joints in each patient) were assessed by MRI for presence of joint inflammation. A total of 156 joints (24 first interphalangeal and radiocarpal joints plus the above 132 joints), were assessed by grayscale US (GS-US) and power Doppler US (PD-US) for presence of joint inflammation by two trained ultrasonographers. We assessed correlations between joint inflammations on MRI and GS-US/PD-US, and also interobserver correlation between the two ultrasonographers by calculating intraclass correlation coefficients (ICC). Synovial hypertrophy and/or synovial fluid was detected in 74/156 joints on GS-US, and synovitis was detected in 10/156 joints on PD-US and in 38/132 joints on MRI. Using PD-US as a reference, sensitivity of MRI in detection of synovitis was 80%. Using MRI as a reference, sensitivity of PD-US was 21%. Specificity of PD-US was higher than that of MRI. Overall agreement between GS-US and MRI and between PD-US and MRI was 0.56 and 0.76, respectively, suggesting that results of PD-US are close to those of MRI. ICC was 0.545 for GS-US and 0.807 for PD-US, suggesting specificity of PD-US in detecting joint inflammation. Our results show that findings of PD-US correlated with those of MRI. Low-field MRI and PD-US are useful tools for assessment of patients with RA.

  20. Gateways to clinical trials.

    PubMed

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

    2005-01-01

    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: (-)-Epigallocatechin gallate; ACP-103, Ad.Egr.TNF.11 D, adalimumab, AF-IL 12, AIDSVAX gp120 B/B, alefacept, alemtuzumab, a-Galactosylceramide, ALVAC vCP 1452, alvimopan hydrate, alvocidib hydrochloride, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anidulafungin, antarelix, aprepitant, aripiprazole, arsenic sulfide, asoprisnil, atazanavir sulfate, atomoxetine hydrochloride; Bevacizumab, bimatoprost, BMS-184476, bortezomib, bosentan, botulinum toxin type B, BrachySil, brivudine; Caffeine, calcipotriol/betamethasone dipropionate, cannabidiol, capsaicin for injection, caspofungin acetate, CC-4047, cetuximab, CGP-36742, clofazimine, CpG-7909, Cypher; Darbepoetin alfa, dextromethorphan/quinidine sulfate, dimethylfumarate, dronabinol/cannabidiol, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecogramostim, efalizumab, eletriptan, emtricitabine, enfuvirtide, eplerenone, esomeprazole magnesium, estradiol acetate, eszopiclone, etoricoxib, exenatide, ezetimibe, ezetimibe/simvastatin; Fampridine, fondaparinux sodium, fosamprenavir calcium; Gefitinib, GPI-0100; hA 20, HTU-PA, human insulin, HuOKT 3 gamma 1(Ala 234-Ala 235), hyaluronic acid; Icatibant, imatinib mesylate, Indiplon, INKP-100, INKP-102, iodine (I131) tositumomab, istradefylline, IV gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, landiolol, lanthanum carbonate, lasofoxifene tartrate, LB-80380, lenalidomide, lidocaine/tetracaine, linezolid, liposomal doxorubicin, liposomal vincristine sulfate, lopinavir, lopinavir/ritonavir, lumiracoxib, lurtotecan; Maribavir, morphine glucuronide, MVA-5 T

  1. Biological drugs for the treatment of psoriasis in a public health system

    PubMed Central

    Lopes, Luciane Cruz; Silveira, Miriam Sanches do Nascimento; de Camargo, Iara Alves; Barberato, Silvio; Del Fiol, Fernando de Sá; Osorio-de-Castro, Claudia Garcia Serpa

    2014-01-01

    OBJECTIVE To analyze the access and utilization profile of biological medications for psoriasis provided by the judicial system in Brazil. METHODS This is a cross-sectional study. We interviewed a total of 203 patients with psoriasis who were on biological medications obtained by the judicial system of the State of Sao Paulo, from 2004 to 2010. Sociodemographics, medical, and political-administrative characteristics were complemented with data obtained from dispensation orders that included biological medications to treat psoriasis and the legal actions involved. The data was analyzed using an electronic data base and shown as simple variable frequencies. The prescriptions contained in the lawsuits were analyzed according to legal provisions. RESULTS A total of 190 lawsuits requesting several biological drugs (adalimumab, efalizumab, etanercept, and infliximab) were analyzed. Patients obtained these medications as a result of injunctions (59.5%) or without having ever demanded biological medication from any health institution (86.2%), i.e., public or private health services. They used the prerogative of free legal aid (72.6%), even though they were represented by private lawyers (91.1%) and treated in private facilities (69.5%). Most of the patients used a biological medication for more than 13 months (66.0%), and some patients were undergoing treatment with this medication when interviewed (44.9%). Approximately one third of the patients discontinued treatment due to worsening of their illness (26.6%), adverse drug reactions (20.5%), lack of efficacy, or because the doctor discontinued this medication (13.8%). None of the analyzed medical prescriptions matched the legal prescribing requirements. Clinical monitoring results showed that 70.3% of the patients had not undergone laboratory examinations (blood work, liver and kidney function tests) for treatment control purposes. CONCLUSIONS The plaintiffs resorted to legal action to get access to biological medications

  2. Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy

    PubMed Central

    Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

    2013-01-01

    Objective Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. Methods A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with