Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)) Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment Comparison of health-related quality of life in rheumatoid arthritis, psoriatic arthritis and psoriasis and effects of etanercept treatment Combination of direct and indirect evidence in mixed treatment comparisons. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: a randomized trial Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Indirect comparisons of competing interventions. Randomized, double-blind, placebo-controlled, comparative study of human anti-TNF antibody adalimumab in combination with methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis. Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Comparison of 2 doses of etanercept (50 vs 100 mg) in active rheumatoid arthritis: a randomized double blind study. [Adalimumab plus methotrexate for the treatment of rheumatoid arthritis: a multi-center randomized, double-blind, placebo-controlled clinical study.]. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study. Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study.
Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response  versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function  versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : Objectives : To evaluate the safety and efficacy of 5-year , long-term tocilizumab monotherapy for patients with rheumatoid arthritis . Methods : In an open-label , long-term extension trial following an initial 3-month r and omised phase II trial , 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy ( 8 mg/kg ) every 4 weeks . Concomitant therapy with non-steroidal anti-inflammatory drugs and /or oral prednisolone ( 10 mg daily maximum ) was permitted . All patients were evaluated with American College of Rheumatology ( ACR ) improvement criteria , disease activity score ( DAS ) in 28 joints , and the European League Against Rheumatism response , as well as for safety issues . Results : 143 patients were enrolled in the open-label , long-term extension trial and 94 ( 66 % ) patients had completed 5 years as of March 2007 . 32 patients ( 22 % ) withdrew from the study due to adverse events and one patient ( 0.7 % ) due to unsatisfactory response . 14 patients withdrew because of the patient ’s request or other reasons . The serious adverse event rate was 27.5 events per 100 patient-years , with 5.7 serious infections per 100 patient-years , based on a total tocilizumab exposure of 612 patient-years . Of the 88 patients receiving corticosteroids at baseline , 78 ( 88.6 % ) were able to decrease their corticosteroid dose and 28 ( 31.8 % ) discontinued corticosteroids . At 5 years , 79/94 ( 84.0 % ) , 65/94 ( 69.1 % ) and 41/94 ( 43.6 % ) of the patients achieved ACR20 , ACR50 , and ACR70 improvement criteria , respectively . Remission defined as DAS28 less than 2.6 was achieved in 52/94 ( 55.3 % ) of the patients . Conclusion : In this 5-year extension study , tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile Objective : The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis ( RA ) despite methotrexate therapy . Methods : Patients were r and omly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules ( group 1 , n = 133 ) , golimumab 100 mg injections plus placebo capsules ( group 2 , n = 133 ) , golimumab 50 mg injections plus methotrexate capsules ( group 3 , n = 89 ) , or golimumab 100 mg injections plus methotrexate capsules ( group 4 , n = 89 ) . Injections were administered subcutaneously every 4 weeks . The co- primary endpoints were the proportion of patients with 20 % or greater improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 and the change from baseline in the health assessment question naire-disability index ( HAQ-DI ) score at week 24 . Results : The proportion of patients who achieved an ACR20 response at week 14 was 33.1 % in the placebo plus methotrexate group , 44.4 % ( p = 0.059 ) in the golimumab 100 mg plus placebo group , 55.1 % ( p = 0.001 ) in the golimumab 50 mg plus methotrexate group and 56.2 % ( p<0.001 ) in the golimumab 100 mg plus methotrexate group . At week 24 , median improvements from baseline in HAQ-DI scores were 0.13 , 0.13 ( p = 0.240 ) , 0.38 ( p<0.001 ) and 0.50 ( p<0.001 ) , respectively . During the placebo-controlled portion of the study ( to week 16 ) , serious adverse events occurred in 2.3 % , 3.8 % , 5.6 % and 9.0 % of patients and serious infections occurred in 0.8 % , 0.8 % , 2.2 % and 5.6 % , respectively . Conclusion : The addition of golimumab to methotrexate  in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) who had an inadequate response to MTX and who were naïve to prior biological treatment . Methods Patients with active disease on stable MTX ( 10–25 mg/week ) were r and omised to rituximab 2 × 500 mg ( n=168 ) , rituximab 2 × 1000 mg ( n=172 ) , or placebo ( n=172 ) . From week 24 , patients not in remission ( Disease Activity Score ( 28 joints ) ≥2.6 ) received a second course of rituximab ; patients initially assigned to placebo switched to rituximab 2 × 500 mg . The primary end point was American College of Rheumatology 20 ( ACR20 ) response at week 24 . All patients were followed until week 48 . Results At week 24 , both doses of rituximab showed statistically superior efficacy ( p<0.0001 ) to placebo ( ACR20 : 54 % , 51 % and 23 % ; rituximab ( 2 × 500 mg ) + MTX , rituximab ( 2 × 1000 mg ) + MTX and placebo + MTX , respectively ) . Secondary end points were also significantly improved for both rituximab groups compared with placebo . Further improvements in both rituximab arms were observed from week 24 to week 48 . Rituximab + MTX was well tolerated , demonstrating comparable safety to placebo + MTX through to week 24 , and between rituximab doses through to week 48 . Conclusions Rituximab ( at 2 × 500 mg and 2 × 1000 mg ) plus MTX  significantly improved clinical outcomes at week 24 , which were further improved by week 48 . No significant differences in either clinical or safety outcomes were apparent between the rituximab doses This multicenter , double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis ( RA ) . Patients were r and omized to placebo ( n = 87 ) or adalimumab 20 mg ( n = 87 ) , 40 mg ( n = 91 ) , or 80 mg ( n = 87 ) every other week for 24 weeks . The primary efficacy endpoint was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at Week 24 . At Week 24 , all adalimumab treatment groups achieved statistically significantly better ACR20 response rates ( 20 mg : 28.7 % , P < 0.05 ; 40 mg : 44.0 % , P < 0.001 ; and 80 mg : 50.6 % , P < 0.001 ) versus placebo ( 13.8 % ) , as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo . Rates of adverse events were comparable between the adalimumab groups and the placebo group , except for injection-site reactions , which occurred in more adalimumab-treated patients . Adalimumab 20 , 40 , and 80 mg were safe and effective in Japanese patients ; however , the greatest responses occurred with the 40 and 80 mg doses . These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients Tumour necrosis factor alpha ( TNF-α ) and interlekin-6 ( IL-6 ) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis ( RA ) , a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules . As relationships between these processes and molecules are unclear , we tested the hypotheses ( a ) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules , and ( b ) that intensive anti-inflammatory treatment improves levels of these indices . We recruited 66 patients with RA , 48 community controls ( CC ) , and 25 disease controls ( DC ) .  Plasma TNF-α and IL-6 were compared to markers of vascular biology ( vWF , sE-sel ) , soluble adhesion molecules ( sICAM , sVCAM ) and routine inflammatory markers ( CRP and ESR ) . Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA . With the exception of sE-selectin , RA patients had increased levels of all plasma markers compared to the HCs , whilst levels in the DCs were largely intermediate between RA and the CCs . Within the RA group , sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM ( all r > 0.32 , P < 0.01 ) . After 1 week of combined anti-inflammatory therapy , only CRP , ESR , sEsel and sVCAM were significantly reduced ( all P < 0.05 ) . In RA , endothelial activation ( as sEsel ) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications Objectives To compare health-related quality of life ( HRQoL ) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis ( RA ) , psoriatic arthritis ( PsA ) and psoriasis using spydergram representations . Methods Data from r and omised , controlled trials of etanercept in patients with RA , PsA and psoriasis were analysed . HRQoL was assessed by the medical outcomes survey short form 36 ( SF-36 ) physical ( PCS ) and mental ( MCS ) component summary and domain scores . Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure . Results Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA , but near normative values in patients with psoriasis ; MCS scores at baseline were near normal in PsA and psoriasis but low in RA . Treatment with etanercept result ed in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications . Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA ; clinical ly meaningful improvements in SF-6D were observed in all three patient population s following treatment with etanercept . Conclusions Patients with RA , PsA and psoriasis demonstrated unique HRQoL profiles at baseline . Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA , PsA and psoriasis Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX )  were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX .  Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 OBJECTIVES To compare the short term clinical and biological effects of intravenous ( i.v . ) pulse methylprednisolone ( MP ) and infliximab ( IFX ) in patients with severe active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) treatment . METHODS Patients with active RA despite MTX treatment were r and omly allocated to receive a single i.v . infusion of MP ( 1 g ) or three i.v . infusions of IFX ( 3 mg/kg ) on weeks 0 , 2 , and 6 . Patients were " blindly " evaluated for disease activity measures . Quality of life ( QoL ) was evaluated through the SF-36 health survey . Serum matrix metalloproteinase-3 ( MMP-3 ) titres were measured at baseline , weeks 2 and 6 . RESULTS Compared with baseline , significant improvement was noted in all activity measures , including serum C reactive protein ( CRP ) titres , in the IFX group only . At week 14 , 6/9 ( 67 % ) and 4/9 ( 44 % ) IFX patients met the ACR20 and 50 response criteria , while this was the case in only 1/12 ( 8 % ) and 0/12 ( 0 % ) MP patients , respectively ( p<0.05 ) . None of the QoL scales improved with MP treatment , whereas some did so in the IFX group . Serum MMP-3 titres significantly decreased ( 41 % drop ) at week 6 in the IFX group , while no changes were seen in patients given MP . CONCLUSION This short term r and omised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA , with improvement in not only clinical parameters of disease activity but also biological inflammatory indices , such as serum CRP and MMP-3 titres BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig  per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo  ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate  , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis BACKGROUND It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis ( RA ) for the UK were published . Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA , especially in women . OBJECTIVES To estimate the age- and sex-specific point prevalence of RA ( defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment ) . The estimate was made in the primary care setting in Norfolk , UK . METHODS A stratified r and om sample was drawn from seven age and gender b and s. The 7050 individuals selected were mailed a screening question naire . Positive responders were invited to attend for a clinical examination . The sample was matched against the names in the Norfolk Arthritis Register ( NOAR ) , a register of incident cases of inflammatory polyarthritis which has been in existence since 1990 . RESULTS The overall response rate was 82 % . Sixty-six cases of RA were identified . Extrapolated to the population of the UK , the overall minimum prevalence of RA is 1.16 % in women and 0.44 % in men . A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission . In addition , some cases who failed to attend for examination had significant disability . These prevalence figures are therefore an underestimate . CONCLUSIONS The prevalence of RA in women , but not in men , in the UK may have fallen since the 1950s OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX .  METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy  in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ;  etanercept  , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated The superiority of the combination therapy of methotrexate ( MTX ) and anti-tumor necrosis factor ( TNF ) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis ( RA ) has been demonstrated . We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept ( ETN ) in patients with active RA despite MTX therapy .  In total , 151 patients with active RA despite treatment with MTX  were r and omized to either ETN 25 mg twice a week and MTX 6–8 mg/week ( the E + M group ) or ETN alone ( the E group ) . Co- primary endpoints included the European League Against Rheumatism ( EULAR ) good response rate and the American College of Rheumatology ( ACR ) 50 response rate at week 24 . Demographic and clinical features between groups at baseline were similar . The EULAR good response rates were significantly higher in the E + M group ( 52 % ) than in the E group ( 33 % ) at week 24 ( p = 0.0001 ) . Although the ACR50 response rate , one of the co- primary endpoints , and the ACR70 response rate at week 24 were not significantly greater in the E + M group ( 64 and 38 % , respectively ) than in the E group ( 48 and 26 % , respectively ) , the ACR20 response rate was significantly greater in the E + M group ( 90 % ) than in the E group ( 64 % ; p = 0.0002 ) . Safety profiles were similar for the groups . Thus , MTX should be continued at the commencement of ETN therapy , even in RA patients who show an inappropriate response to MTX Background : Tumour necrosis factor α ( TNFα ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis ( RA ) . Treatment with TNFα inhibitors reduces disease activity and improves outcomes for patients with RA . This study evaluated the efficacy and safety of certolizumab pegol 400 mg , a novel , poly-(ethylene glycol ) (PEG)ylated , Fc-free TNFα inhibitor , as monotherapy in patients with active RA . Methods : In this 24-week , multicentre , r and omised , double-blind , placebo-controlled study , 220 patients previously failing ⩾1 disease-modifying antirheumatic drug ( DMARD ) were r and omised 1:1 to receive subcutaneous certolizumab pegol 400 mg ( n = 111 ) or placebo ( n = 109 ) every 4 weeks . The primary endpoint was 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) at week 24 . Secondary endpoints included ACR50/70 response , ACR component scores , 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 ( DAS28(ESR)3 ) , patient-reported outcomes ( including physical function , health-related quality of life ( HRQoL ) , pain and fatigue ) and safety . Results : At week 24 , the ACR20 response rates were 45.5 % for certolizumab pegol 400 mg every 4 weeks vs 9.3 % for placebo ( p<0.001 ) . Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 ( p<0.001 ) . Significant improvements in ACR50 , ACR components , DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study . Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported . Conclusions : Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing ⩾1 DMARD compared with placebo , and demonstrated an acceptable safety profile . Trial registration number : NCT00548834 We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) .  In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX OBJECTIVE To establish the safety and efficacy of repeat infusions of tocilizumab ( previously known as MRA ) , a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , alone and in combination with methotrexate ( MTX ) , for the treatment of rheumatoid arthritis ( RA ) . METHODS The study group comprised 359 patients with active RA in whom the response to MTX was inadequate . During a stabilization period , these patients received their current dose of MTX for at least 4 weeks . Following stabilization , they were r and omized to 1 of 7 treatment arms , as follows : tocilizumab at doses of 2 mg/kg , 4 mg/kg , or 8 mg/kg either as monotherapy or in combination with MTX , or MTX plus placebo . RESULTS A 20 % response ( improvement ) according to the American College of Rheumatology criteria ( ACR20 response ) was achieved by 61 % and 63 % of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy , respectively , and by 63 % and 74 % of patients receiving those doses of tocilizumab plus MTX , respectively , compared with 41 % of patients receiving placebo plus MTX . Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX ( P < 0.05 ) . A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward , in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab . In the majority of patients who received 8 mg/kg of tocilizumab , the C-reactive protein level/erythrocyte sedimentation rate normalized , while placebo plus MTX had little effect on these laboratory parameters . Tocilizumab was mostly well tolerated , with a safety profile similar to that of other biologic and immunosuppressive therapies . Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern ( rising and falling between infusions ) . There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels . There were 2 cases of sepsis , both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX . CONCLUSION These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA OBJECTIVE To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol ( a novel PEGylated anti-tumor necrosis factor agent ) as adjunctive therapy to methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) with an inadequate response to MTX therapy alone . METHODS In this 52-week , phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial , 982 patients were r and omized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0 , 2 , and 4 , with a subsequent dosage of 200 mg or 400 mg given every 2 weeks , plus MTX , or placebo plus MTX . Co- primary end points were the response rate at week 24 according to the American College of Rheumatology 20 % criteria for improvement ( ACR20 ) and the mean change from baseline in the modified total Sharp score at week 52 . RESULTS At week 24 , ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8 % and 60.8 % , respectively , as compared with 13.6 % for the placebo group . Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 ( P < 0.001 ) . At week 52 , mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg ( 0.4 Sharp units ) or 400 mg ( 0.2 Sharp units ) as compared with that in placebo-treated patients ( 2.8 Sharp units ) ( P < 0.001 by rank analysis ) . Improvements in all ACR core set of disease activity measures , including physical function , were observed by week 1 with both certolizumab pegol dosage regimens . Most adverse events were mild or moderate . CONCLUSION Treatment with certolizumab pegol 200 or 400 mg plus MTX result ed in a rapid and sustained reduction in RA signs and symptoms , inhibited the progression of structural joint damage , and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX OBJECTIVE Interleukin-6 ( IL-6 ) is a pleiotropic cytokine that regulates the immune response , inflammation , and hematopoiesis . Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis ( RA ) , and the blockade of IL-6 may be therapeutically effective for the disease . This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody , MRA , in patients with RA . METHODS In a multicenter , double-blind , placebo-controlled trial , 164 patients with refractory RA were r and omized to receive either MRA ( 4 mg/kg body weight or 8 mg/kg body weight ) or placebo . MRA was administered intravenously every 4 weeks for a total of 3 months . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria . RESULTS Treatment with MRA reduced disease activity in a dose-dependent manner . At 3 months , 78 % of patients in the 8-mg group , 57 % in the 4-mg group , and 11 % in the placebo group achieved at least a 20 % improvement in disease activity according to the ACR criteria ( an ACR20 response ) ( P < 0.001 for 8-mg group versus placebo ) . Forty percent of patients in the 8-mg group and 1.9 % in the placebo group achieved an ACR50 response ( P < 0.001 ) . The overall incidences of adverse events were 56 % , 59 % , and 51 % in the placebo , 4-mg , and 8-mg groups , respectively , and the adverse events were not dose dependent . A blood cholesterol increase was observed in 44.0 % of the patients . Liver function disorders and decreases in white blood cell counts were also observed , but these were mild and transient . There was no increase in antinuclear antibodies or anti-DNA antibodies . Anti-MRA antibodies were detected in 2 patients . CONCLUSION Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied .  ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis OBJECTIVE To evaluate the safety , efficacy , and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis ( RA ) . METHODS Four hundred twenty RA patients were r and omized to receive , in a blinded manner , the study drug for up to 16 weeks : 214 patients received 50 mg etanercept once weekly , 153 received 25 mg etanercept twice weekly , and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks . Efficacy and safety were assessed at weeks 8 and 16 . Pharmacokinetic analyses were performed on serum sample s from patients at selected study sites . The primary efficacy end point was achievement of the American College of Rheumatology ( ACR ) 20 % improvement criteria ( ACR20 response ) at week 8 . RESULTS An ACR20 response was achieved at week 8 by 50 % of the patients receiving 50 mg etanercept once weekly , by 49 % of the patients receiving 25 mg etanercept twice weekly , and by 19 % of the patients in the placebo group ( P < /= 0.0001 for each etanercept group versus placebo ) . Similarly , achievement of the ACR50 response was attained by 18 % of patients in each of the 2 etanercept groups , compared with 6 % of patients in the placebo group ( P < 0.03 for each comparison ) . Pharmacokinetics of the 2 etanercept regimens were similar at steady state . No clinical ly significant differences in efficacy or safety were observed between the 2 etanercept groups . CONCLUSION Safety , efficacy , and pharmacokinetics were comparable between the 2 etanercept dosing regimens . Thus , comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life .  Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX )  were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab  dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX  group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX  result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis OBJECTIVE A placebo controlled , double-blind trial ( DBT ) was conducted for Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with low dose methotrexate ( MTX ) to evaluate the efficacy and safety of infliximab . Extended treatment with infliximab was conducted in an open-label trial ( OLT ) . METHODS In the DBT , 147 patients were r and omly assigned and treated with a placebo or 3 mg/kg or 10 mg/kg infliximab at Weeks 0 , 2 and 6 , combined with MTX . In the OLT , 129 patients from the DBT received 3 mg/kg infliximab  every 8 weeks . RESULTS The mean dose of MTX was 7.2 + /- 2.0 mg/week . Significantly more patients receiving 3 mg/kg ( 61.2 % ) and 10 mg/kg (52.9%)infliximab achieved a 20 % improvement according to the American College of Rheumatology ( ACR ) criteria at Week 14 , compared to placebo ( 23.4 % ) ( p < 0.001 ) . There was no significant difference in incidence of adverse events among the treatment groups . In patients receiving infliximab in the DBT , 11.6 % of patients with serum infliximab just before the OLT developed antibodies to infliximab ( ATI ) in the OLT , whereas 62.2 % of patients without serum infliximab did . In patients receiving placebo in the DBT , 43.9 % developed ATI . CONCLUSION The efficacy and safety of infliximab combined with low dose MTX were similar to those of the ATTRACT study . The data from the DBT and OLT also supported the importance of an induction treatment of infliximab , followed by a maintenance treatment without a long interval , giving stable serum concentrations in order to prevent formation of ATI BACKGROUND Tumor necrosis factor ( TNF ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis , and antagonism of TNF may reduce the activity of the disease . This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor ( p75 ) linked to the Fc portion of human IgG1 ( TNFR : Fc ) . METHODS In this multicenter , double-blind trial , we r and omly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR : Fc ( 0.25 , 2 , or 16 mg per square meter of body-surface area ) twice weekly for three months . The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria . RESULTS Treatment with TNFR : Fc led to significant reductions in disease activity , and the therapeutic effects of TNFR : Fc were dose-related . At three months , 75 percent of the patients in the group assigned to 16 mg of TNFR : Fc per square meter had improvement of 20 percent or more in symptoms , as compared with 14 percent in the placebo group ( P<0.001 ) . In the group assigned to 16 mg per square meter , the mean percent reduction in the number of tender or swollen joints at three months was 61 percent , as compared with 25 percent in the placebo group ( P<0.001 ) . The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms . There were no dose-limiting toxic effects , and no antibodies to TNFR : Fc were detected in serum sample s. CONCLUSIONS In this three-month trial TNFR : Fc was safe , well tolerated , and associated with improvement in the inflammatory symptoms of rheumatoid arthritis OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo :  ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin  and  heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful BACKGROUND / PURPOSE Adalimumab is a fully humanized monoclonal antibody that blocks tumor necrosis factor (TNF)-alpha , which is effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of adalimumab plus methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS Forty-seven patients with active RA who were maintained on MTX therapy at a stable dose of 10 - 15 mg/week for 4 weeks were r and omized blindly to receive adalimumab 40 mg ( n = 35 ) or placebo ( n = 12 ) by subcutaneous injection every other week over a period of 12 weeks . The primary endpoint was a reduction in tender and swollen joint counts of 20 % ( ACR20 ) , 50 % ( ACR50 ) and 70 % ( ACR70 ) , as determined by the American College of Rheumatology criteria in week 12 . The occurrence of treatment-emergent adverse events ( TEAEs ) was the primary safety variable . RESULTS Addition of adalimumab to MTX result ed in a significant reduction in the number of swollen joints ( 12.6 vs. 5.6 ; p = 0.011 ) , patients ' global assessment of disease activity ( 18.0 vs. 4.8 ; p = 0.040 ) , pain visual analog scale ( 18.3 vs. 1.3 ; p = 0.015 ) , and disability indices of the Health Assessment Question naire ( 0.6 vs. 0.2 ; p = 0.031 ) , compared with MTX alone after 12 weeks of therapy . Overall improvement in disease activity was assessed by ACR20 ( 54.3 % vs. 33.3 % ) , ACR50 ( 34.3 % vs. 16.7 % ) and ACR70 ( 14.3 % vs. 0 % ) , and all favored the adalimumab plus MTX group . TEAEs were comparable between the treatment groups , except for a slightly higher incidence of severe infection in the adalimumab plus MTX group . CONCLUSION Adalimumab in combination with MTX is well tolerated and provides significantly more clinical benefits than MTX alone in Taiwanese patients with active RA Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate  , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo .  Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for  adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities  , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the OBJECTIVE To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha ( TNF-alpha ) blocker-naäve active rheumatoid arthritis ( RA ) . METHODS Seventy-seven patients with RA were r and omized in an unequal allocation ( 2:1 ) in a blinded fashion to receive either 50 mg ( 51 patients ) or 25 mg ( 26 patients ) of etanercept twice a week for 24 weeks . RESULTS The primary outcome measure , the ACR-N AUC at 24 weeks , showed no difference between the 2 dose groups . In addition , there was no difference in ACR 20 , 50 , and 70 responses or in EULAR response criteria by Week 24 . There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event . The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg  etanercept compared with those receiving 25 mg ( 26 % vs 4 % , p = 0.027 ) . CONCLUSION Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the st and ard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients OBJECTIVE To investigate the efficacy and safety of adalimumab plus methotrexate ( MTX ) for the treatment of rheumatoid arthritis ( RA ) . METHODS This is a multi-center , r and omized , double-blind , parallel-group , and placebo-controlled clinical study , included a total of 302 cases of active rheumatoid arthritis , r and omized into three groups of observation : 40 mg adalimumab ( 121 cases ) , 80 mg adalimumab ( 121 cases ) , or placebo ( 60 cases ) . Upon enrollment , all subjects had been previously treated with MTX for at least 3 months , and their doses of drug had remained stable for at least 28 days . The double-blind phase lasted for 12 weeks , during which the subjects were administered with adalimumab or placebo subcutaneously every other week . Then the subjects entered into another 12 weeks of open-label study , which included subcutaneous injection of 40 mg adalimumab every other week . In both the double-blind and the open-label periods , all subjects were maintained concomitantly with MTX that had already been used before this study . The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12 . The secondary efficacy variables included : ACR20 response rate at week 24 ; ACR50 and ACR70 response rates at weeks 12 and 24 ; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts , as well as the assessment of pain with visual analog scale ( VAS ) , the physician 's and the patient 's global assessment of disease activity ( VAS ) , and the analysis on health assessment question naire ( HAQ ) and health related quality of life ( HRQL ) measured by Short Form-36 ( SF-36 ) ; The safety variables mainly included adverse events ( AE ) . RESULT During the double-blind period , subjects treated with 40 mg of adalimumab , 57.0 % achieved ACR20 response at week 12 ( P = 0.004 versus placebo ) , and subjects treated with 80 mg of adalimumab , 51.2 % achieved ACR20 response at week 12 ( P = 0.026 versus placebo ) , and only 35.0 % of subjects treated with placebo achieved ACR20 response at week 12 . On the other h and , 32.2 % of subjects receiving 40 mg of adalimumab achieved ACR50 response ( P = 0.009 versus placebo ) , and 15.7 % achieved ACR70 response ( P = 0.007 versus placebo ) at week 12 . Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count , swollen joint count , and improvement in C-reactive protein ; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count , and improvement in C-reactive protein ; all of these findings were statistically significant in differences . During the open-label period all subjects received 40 mg of adalimumab , and response rates for ACR20 , ACR50 , and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 ( being 73.1 % , 40.3 % and 17.6 % respectively for 40 mg group ; 71.1 % , 39.5 % and 17.5 % respectively for 80 mg group ) ; while response in the original placebo group ( being 67.8 % , 44.1 % and 18.6 % ) increased during the 12-week open-label period to match that of the original adalimumab treatment groups . While for changes in tender and swollen joint counts , VAS , HAQ , SF-36 , a significant improvement was seen at week 24 when compared with baseline and week 12 values . Throughout the double-blind and open-label period , adverse events reported in > /= 5 % of subjects at least possibly associated with the study drug were upper respiratory tract infection , nasopharyngitis , and injection site itching , mostly being mild to moderate in severity . There were 3 cases of tuberculosis reported during this study . And 3 cases of serious adverse event ( SAE ) were reported among the adalimumab subjects during the double-blind period , which were determined as unrelated or probably unrelated to the study drug . And 8 cases ( 2.7 % ) of SAE were seen among the adalimumab subjects during the open-label period , 3 of which were at least possibly unrelated with the study drug . All SAEs reported were consistent to those seen in other adalimumab trials . No other unexpected safety signals were reported . CONCLUSION Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA . Being generally safe and well tolerated , adalimumab plus MTX can significantly increase the response rate , continuously reduce the arthritic signs , symptoms and the inflammatory factors in patients , and also be helpful for reducing disabilities and improving the global quality of life for the patients OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) .  METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX OBJECTIVE To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs ( DMARDs ) in patients with active rheumatoid arthritis ( RA ) . METHODS A total of 1,220 patients were r and omized ( 2:1 ratio ) in the phase III , double-blind , placebo-controlled , multicenter TOWARD ( Tocilizumab in Combination With Traditional DMARD Therapy ) study . Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo ( control group ) every 4 weeks for 24 weeks . RESULTS At week 24 , the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) was significantly greater in the tocilizumab plus DMARD group than in the control group ( 61 % versus 25 % ; P<0.0001 ) . Secondary end points including 50 % or 70 % improvement ( ACR50/70 ) , the Disease Activity Score in 28 joints ( DAS28 ) , DAS28 remission responses ( DAS28<2.6 ) , European League Against Rheumatism responses , and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone . Seventy-three percent of patients in the tocilizumab group had > or=1 adverse event ( AE ) , compared with 61 % of patients in the control group . AEs leading to withdrawal from the study were infrequent ( 4 % of patients in the tocilizumab group and 2 % of those in the control group ) . Serious AEs occurred in 6.7 % and 4.3 % of patients in the tocilizumab and control groups , respectively , and serious infections occurred in 2.7 % and 1.9 % , respectively . Elevations in the alanine aminotransferase level , from normal at baseline to > 3-fold the upper limit of normal , occurred in 4 % of patients in the tocilizumab group and 1 % of those in the control group , and elevated total cholesterol levels were observed in 23 % and 6 % of patients , respectively . Sixteen patients started lipid-lowering therapy during the study . Grade 3 neutropenia occurred in 3.7 % of patients receiving tocilizumab and none of the patients in the control group , and no grade 4 neutropenia was reported . CONCLUSION Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents BACKGROUND AND PURPOSE Etanercept ( Enbrel ) , a recombinant tumor necrosis factor receptor fusion protein , has been shown to be effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS In this double-blind study , 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were r and omized to receive either etanercept 25 mg ( n = 29 ) or placebo ( n = 29 ) by subcutaneous injection twice weekly over a period of 12 weeks . The primary endpoint was the reduction of tender and swollen joint counts by 20 % ( ACR 20 ) , 50 % ( ACR 50 ) , and 70 % ( ACR 70 ) as determined by the American College of Rheumatology criteria at the 12th week . RESULTS The addition of etanercept to MTX result ed in a greater reduction in the number of tender ( 7.00 vs 2.45 , p = 0.012 ) and swollen joints ( 8.55 vs 3.86 , p = 0.017 ) , and in serum levels of C-reactive protein ( 1.26 mg/dL vs 0.45 mg/dL , p = 0.014 ) compared to MTX alone after 12 weeks of therapy . In addition , the global assessment of disease activity by both physicians and patients , duration of morning stiffness , pain visual analog scale score , and Health Assessment Question naire were all improved by etanercept plus MTX therapy . Results for the overall improvement in disease activity assessed by ACR 20 ( 90 % vs 34 % ) , ACR 50 ( 66 % vs 10 % ) and ACR 70 ( 24 % vs 0 % ) all favored the etanercept plus MTX group . However , the adverse events were comparable between the 2 treatment groups . CONCLUSION Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA OBJECTIVE To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis ( RA ) . METHODS Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate ( MTX ) at a dosage of 15 - 25 mg/week for > or = 4 weeks were r and omized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg , with or without MTX , every 12 weeks through week 48 . Patients with < 20 % improvement in the swollen and tender joint counts  could enter early escape and receive additional active treatment ( week 16 ) or could have their dose regimen adjusted ( week 24 ) . The primary end point was the proportion of patients achieving a 50 % response according to the American College of Rheumatology improvement criteria ( ACR50 ) at week 14 . RESULTS The primary study end point was not met ( at week 14 , an ACR50 response was observed in 21 % of the patients treated with golimumab plus MTX compared with 13 % of the patients treated with placebo plus MTX [ P = 0.051 ] ) . By week 24 , significantly more patients treated with golimumab plus MTX had achieved an ACR50 response . Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 ( 16 % versus 13 % ) or week 24 ( 10 % versus 9 % ) . At week 48 , the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX ( 70 % and 48 % , respectively ) . Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab . The most commonly reported adverse events through week 48 were infections ( 48 % of patients treated with golimumab with or without MTX and 41 % of patients receiving placebo plus MTX ) . CONCLUSION The primary end point was not met . However , intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients , with no unexpected safety concerns
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 .