Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab bef Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial 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 A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Role of adalimumab in the treatment of early rheumatoid arthritis. [Therapeutic effect of infliximab on moderate and severe active rheumatoid arthritis]. 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 Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. 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. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. 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. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled 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 Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Aiming at low disease activity in rheumatoid arthritis with initial combination therapy or initial monotherapy strategies: the BeSt study. 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. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE 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. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment 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. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. A placebo-controlled, randomized, double-blinded study evaluating the safety of etanercept in patients with rheumatoid arthritis and concomitant comorbid diseases. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Etanercept and methotrexate combination therapy. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. 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. [Efficacy and safety of infliximab in patients with rheumatoid arthritis]. [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. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). 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.
BACKGROUND Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate , a st and ard treatment for this disease . There is evidence that antitumour necrosis factor alpha ( TNFalpha ) is efficacious in relief of signs and symptoms . We therefore investigated whether infliximab , a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate .  METHODS In an international double-blind placebo-controlled phase III clinical trial , 428 patients who had active rheumatoid arthritis , who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks , were r and omised to placebo ( n=88 ) or one of four regimens of  infliximab  at weeks 0 , 2 , and 6 . Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate ( median 15 mg/week for > or = 6 months , range 10 - 35 mg/wk ) . Patients were assessed every 4 weeks for 30 weeks . FINDINGS At 30 weeks , the American College of Rheumatology ( 20 ) response criteria , representing a 20 % improvement from baseline , were achieved in 53 , 50 , 58 , and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks , respectively , compared with 20 % of patients receiving placebo plus methotrexate ( p<0.001 for each of the four infliximab regimens vs placebo ) . A 50 % improvement was achieved in 29 , 27 , 26 , and 31 % of infliximab plus methotrexate in the same treatment groups , compared with 5 % of patients on placebo plus methotrexate ( p<0.001 ) . Infliximab was well-tolerated ; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group . INTERPRETATION During 30 weeks , treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns 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 : 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 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 Infliximab , a chimeric anti-TNF alpha antibody , showed in two double-blind placebo-controlled trials efficacy in combination with methotrexate ( MTX ) in patients with severe rheumatoid arthritis ( RA ) . Whereas in the first trial low-dose MTX or placebo was compared to infliximab alone and in combination , the second trial compared infliximab to placebo in patients with active RA despite maximal tolerated MTX treatment . Infliximab showed synergistic effects in combination with MTX . The immunogenicity of infliximab  was reduced by the combination . Infliximab in combination with high-dose MTX  is effective and safe in long-term treatment up to 54 weeks 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 OBJECTIVE To evaluate the efficacy , pharmacokinetics , immunogenicity , and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody ( cA2 ) ( infliximab ; Remicade , Centocor , Malvern , PA ) given alone or in combination with low-dose methotrexate ( MTX ) in rheumatoid arthritis ( RA ) patients . METHODS In a 26-week , double-blind , placebo-controlled , multicenter trial , 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were r and omized to 1 of 7 groups of 14 - 15 patients each . The patients received either intravenous cA2 at 1 , 3 , or 10 mg/kg , with or without MTX 7.5 mg/week , or intravenous placebo plus MTX 7.5 mg/week at weeks 0 , 2 , 6 , 10 , and 14 and were followed up through week 26 . RESULTS Approximately 60 % of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20 % Paulus criteria for response to treatment , for a median duration of 10.4 to > 18.1 weeks ( P < 0.001 versus placebo ) . Patients receiving cA2 at 1 mg/kg without MTX became unresponsive to repeated infusions of cA2 ( median duration 2.6 weeks ; P=0.126 versus placebo ) . However , coadministration of cA2 at 1 mg/kg with MTX appeared to be synergistic , prolonging the duration of the 20 % response in > 60 % of patients to a median of 16.5 weeks ( P < 0.001 versus placebo ; P=0.006 versus no MTX ) and the 50 % response to 12.2 weeks ( P < 0.001 versus placebo ; P=0.002 versus no MTX ) . Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease , with a Paulus response lasting a median of 0 weeks . A 70 - 90 % reduction in the swollen joint count , tender joint count , and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX . In general , treatment was well tolerated and stable blood levels of cA2 were achieved in all groups , except for the group receiving 1 mg/kg of cA2 alone , at which dosage antibodies to cA2 were observed in approximately 50 % of the patients . CONCLUSION Multiple infusions of cA2 were effective and well tolerated , with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60 % of patients with active RA despite therapy with low-dose MTX . When cA2 at 1 mg/kg was given with low-dose MTX , synergy was observed . The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2 Adalimumab , a recent addition to the therapeutic armamentarium in rheumatoid arthritis ( RA ) , has been evaluated in patients with early RA . The DE019 study , a double blind r and omized placebo controlled trial of adalimumab given 20 mg once a week or 40 mg every other week demonstrated both clinical and radiographic efficacy . A subset analysis of patients with early disease revealed that early treatment with adalimumab may be more efficacious than therapy later in the course of disease , particularly with regard to radiographic progression . The findings support early aggressive intervention in RA OBJECTIVE To evaluate the clinical efficacy of infliximab in the treatment of moderate and severe active rheumatoid arthritis ( RA ) . METHODS This r and omized double-blind II/III clinical trial involved 30 patients with moderate and severe active RA , who were r and omly allocated into 3 groups ( groups A , B , and C ) at the ratio of 3:1:1 . At weeks 0 , 2 , 6 , and 14 , the patients in groups A and C received infliximab or placebo , and those in group B had placebo at week 14 with a stable background dose of methotrexate . The indicators for efficacy evaluation included the proportions of ACR20/50/70 of the responders and DAS28 . The sharp scores of the h and joints were recorded before and after the treatment . RESULTS Twenty-nine patients completed the clinical trial ( 18 in group A , 5 in group B , and 6 in group C ) . At week 14 , the proportions of ACR20/50/70 in the 3 groups reached 83.33 % , 60 % , and 33.33 % , respectively ( P<0.05 ) , as compared to 100 % , 100 % , and 33.33 % at week 18 ( P<0.05 ) . The other indicators for clinical efficacy evaluation also suggested similar clinical improvement of the patients ( P=0.000 ) . The proportions of the patients with DAS28<3.2 and DAS28<2.6 were significantly different . Compared to the baseline , the Sharp scores in group A showed no significant changes at week 18 ( P>0.930 ) , while those in group C exhibited significant radiographic progression ( P<0.044 ) . CONCLUSION Infliximab produces good short-term therapeutic effect against moderate and severe active RA and may help arrest the radiographic progression of the diseases , which can be more obvious in patients with moderate severity 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 OBJECTIVE To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate ( MTX ) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early , active rheumatoid arthritis . METHODS Subjects were r and omized at baseline for the entire 2-year period ; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2 . The original combination group either continued combination therapy ( the EM/EM group ; n = 111 ) or received etanercept monotherapy ( the EM/E group ; n = 111 ) in year 2 ; the original MTX monotherapy group either received combination therapy ( the M/EM group ; n = 90 ) or continued monotherapy ( the M/M group ; n = 99 ) in year 2 . Efficacy end points included remission ( a Disease Activity Score in 28 joints [ DAS28 ] < 2.6 ) and radiographic nonprogression ( change in the modified Sharp/van der Heijde score < or = 0.5 ) at year 2 . A last observation carried forward analysis from the modified intention-to-treat population ( n = 398 ) and a post hoc nonresponder imputation ( NRI ) analysis ( n = 528 ) were performed for remission . RESULTS At year 2 , DAS28 remission was achieved by 62/108 , 54/108 , 51/88 , and 33/94 subjects in the EM/EM , EM/E , M/EM , and M/M groups , respectively ( P < 0.01 for the EM/EM and M/EM groups versus the M/M group ) . This effect was corroborated by a more conservative post hoc 2-year NRI analysis , with remission observed in 59/131 , 50/134 , 48/133 , and 29/130 of the same respective groups ( P < 0.05 for each of the EM/EM , EM/E , and M/EM groups versus the M/M group ) . The proportions of subjects achieving radiographic nonprogression ( n = 360 ) were 89/99 , 74/99 , 59/79 , and 56/83 in the EM/EM ( P < 0.01 versus each of the other groups ) , EM/E , M/EM , and M/M groups , respectively . No new safety signals or between-group differences in serious adverse events were seen . CONCLUSION Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy . Combination therapy result ed in important clinical and radiographic benefits over 2 study years , without significant additional safety risk 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 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 safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody ( infliximab ) in patients with rheumatoid arthritis ( RA ) who had active disease despite therapy with methotrexate ( MTX ) .  METHODS Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX  were r and omized to receive a single , blinded infusion of either placebo or 5 , 10 , or 20 mg/kg infliximab .  Twenty-three patients who completed the blinded study entered an open , multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12 , 20 , and 28 . Safety , efficacy , and pharmacokinetics were evaluated during the blinded and open trial . RESULTS There were no serious infusion related reactions . In the blinded phase , 17 ( 81.0 % ) of 21 patients receiving infliximab achieved an American College of Rheumatology ( ACR ) 20 % response at some point during the 12 weeks of followup compared to one ( 14.3 % ) of 7 patients receiving placebo ( p = 0.003 ) . Clinical improvement was evident by the first week and was sustained through Week 12 . For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial , 53 % maintained an ACR 20 % response with multiple infusions of 10 mg/kg infliximab through Week 40 . Three patients withdrew from the trial during the open continuation phase because of adverse events : cellulitis , infusion related dizziness and headache , and vasculitic rash .  Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing . CONCLUSION Infliximab is generally well tolerated during 40 weeks of therapy . A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX . Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks 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 Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy 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 BACKGROUND Tumour necrosis factor alpha ( TNFalpha ) inhibitors are frequently used to treat rheumatoid arthritis , but whether use of a different TNFalpha inhibitor can improve patient response is unknown . We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors . METHODS 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were r and omly allocated by interactive voice response system , stratified by study site and methotrexate use , to receive subcutaneous injections of placebo ( n=155 ) , 50 mg golimumab ( n=153 ) , or 100 mg golimumab ( n=153 ) every 4 weeks between Feb 21 , 2006 , and Sept 26 , 2007 . Allocation was double-blind . Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously . Patients continued stable doses of methotrexate , sulfasalazine , hydroxychloroquine , oral corticosteroids , and non-steroidal anti-inflammatory drugs . The primary endpoint was achievement at week 14 of 20 % or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis ( ACR20 ) . At week 16 , patients who had less than 20 % improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab , or from 50 mg to 100 mg golimumab .  Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given . This study is registered with Clinical Trials.gov , number NCT00299546 . FINDINGS Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness ( 269 [ 58 % ] patients ) or reasons unrelated to effectiveness ( 246 [ 53 % ] patients ) , such as intolerance and accessibility issues . Patients had active disease , which was indicated by a median of 14.0 ( IQR 9.0 - 22.0 ) swollen and 26.0 ( 16.0 - 41.0 ) tender joints for the whole group . 28 ( 18 % ) patients on placebo , 54 ( 35 % ) patients on 50 mg golimumab ( odds ratio 2.5 [ 95 % CI 1.5 - 4.2 ] , p=0.0006 ) , and 58 ( 38 % ) patients on 100 mg golimumab ( 2.8 [ 1.6 - 4.7 ] , p=0.0001 ) achieved ACR20 at week 14 . Two patients were never treated , and 57 patients did not complete the study because of adverse events , unsatisfactory treatment effect , loss to follow-up , death , or other reasons .  155 patients on placebo , 153 on 50 mg golimumab , and 153 on 100 mg golimumab  were assessed for drug efficacy . For weeks 1 - 16 , serious adverse events were recorded in 11 ( 7 % ) patients on placebo , 8 ( 5 % ) on 50 mg golimumab , and 4 ( 3 % ) on 100 mg golimumab . For weeks 1 - 24 , after some patients were given rescue therapy , serious adverse events were recorded in 15 ( 10 % ) patients on placebo , 14 ( 5 % ) on 50 mg golimumab , and 8 ( 4 % ) on 100 mg golimumab . INTERPRETATION Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors . FUNDING Centocor Research and Development and Schering-Plough Research Institute OBJECTIVE To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis ( RA ) who received monotherapy with either etanercept or methotrexate ( MTX ) for 2 years and to assess the safety of this therapy . METHODS In the Enbrel ERA ( early rheumatoid arthritis ) trial , 632 patients with early , active RA were r and omized to receive either twice-weekly subcutaneous etanercept ( 10 mg or 25 mg ) or weekly oral MTX ( mean dosage 19 mg per week ) for at least 1 year in a double-blind manner . Following the blinded phase of the trial , 512 patients continued to receive the therapy to which they had been r and omized for up to 1 additional year , in an open-label manner . Radiograph readers remained blinded to treatment group assignment and the chronologic order of images . RESULTS At 24 months , more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20 % improvement criteria ( 72 % and 59 % , respectively ; P = 0.005 ) , and more had no increase in total score and erosion scores on the Sharp scale ( P = 0.017 and P = 0.012 , respectively ) . The mean changes in total Sharp score and erosion score in the 25-mg etanercept group ( 1.3 and 0.66 units , respectively ) were significantly lower than those in the MTX group ( 3.2 and 1.86 units , respectively ; P = 0.001 ) . Significantly more patients in the 25-mg etanercept group ( 55 % ) than in the MTX group ( 37 % ) had at least 0.5 units of improvement in the Health Assessment Question naire disability index ( P < 0.001 ) . Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events . CONCLUSION Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity , arresting structural damage , and decreasing disability over 2 years in patients with early , aggressive RA AIM To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis ( RA ) . METHODS In the BeSt study , 508 patients with newly diagnosed ( < 2 years ) active RA were r and omised to be treated according to four treatment strategies : 1 . sequential monotherapy , 2 . step up to combination therapy ( both starting with methotrexate ) , 3 . initial combination therapy with methotrexate , sulphasalazine , and a tapered high dose of prednisone , and 4 . initial combination therapy with methotrexate and infliximab . Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score ( DAS ) , with the goal to achieve and maintain a DAS < or= 2.4 . Functional ability was measured every 3 months with the Health Assessment Question naire . Radiographs of h and s and feet were assessed yearly , blinded for patient identity and treatment , and in r and om order , to measure joint damage progression ( Sharp/van der Heijde score ) . RESULTS After 2 years of treatment , 80 % of all patients achieved the goal of DAS < or= 2.4 , and 42 % reached clinical remission ( DAS < 1.6 ) . Initial combination therapy , either with prednisone ( group 3 ) or with infliximab ( group 4 ) , result ed in earlier improvement in functional ability , more continuous clinical remission ( DAS < 1.6 ) , and less joint damage progression than initial monotherapy ( groups 1 and 2 ) . Patients in groups 1 and 2 needed more therapy adjustments , including introduction of combination therapy with prednisone or infliximab , to achieve a DAS < or= 2.4 , whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate , respectively , monotherapy . The adverse events profile was comparable in all groups . The presence or absence of rheumatoid factor , HLA DR4 , or anti-CCP was not associated with radiologic damage progression . CONCLUSION In patients with early , active RA , remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent , objective ly steered treatment adjustments . The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate , sulphasalazine and prednisone or with methotrexate and infliximab , which can be tapered to DMARD monotherapy once low disease activity is achieved 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 To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone Tumour necrosis factor alpha ( TNF alpha ) is a critical inflammatory mediator in rheumatoid arthritis , and may therefore be a useful target for specific immunotherapy . In support of this hypothesis , we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a  chimeric monoclonal antibody to TNF alpha ( cA2 ) . We now report the results of a four-centre , r and omised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis . The primary endpoint of the study was the achievement at week 4 of a Paulus 20 % response , an amalgam of six clinical , observational , and laboratory variables . Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time , compared with 11 of 25 patients treated with low-dose cA2 ( p = 0.0083 ) and 19 of 24 patients treated with high-dose cA2 ( p < 0.0001 ) . Over half of the high-dose cA2 patients responded by the more stringent 50 % Paulus criteria at this time ( p = 0.0005 ) . The magnitude of these responses was impressive , with maximum mean improvements in individual disease-activity assessment s , such as tender or swollen-joint counts and in serum C-reactive protein , exceeding 60 % for patients on high-dose treatment . There were two severe adverse events . 1 patient on 1 mg/kg cA2 developed pneumonia ( " possibly " treatment-related ) and 1 on 10 mg/kg had a fracture ( " probably not " treatment-related ) . The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis OBJECTIVE To assess the relationship between inflammation and joint destruction in rheumatoid arthritis ( RA ) patients who have not responded clinical ly to treatment . METHODS Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab ( 3 mg/kg or 10 mg/kg every 4 or 8 weeks ) plus methotrexate ( MTX ) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial . RESULTS At week 54 , patients who did not show 20 % improvement by American College of Rheumatology criteria ( ACR20 nonresponders ) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables , including the 28-joint Disease Activity Score ( DAS28 ) ( P < 0.001 ) , tender joint count ( P = 0.014 ) , swollen joint count ( P < 0.001 ) , and C-reactive protein ( CRP ) level ( P < 0.001 ) . Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment , radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited ( P < 0.001 ) compared with ACR20 nonresponders to MTX plus placebo .  Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX , irrespective of ACR response status ( mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group , versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group ) . Furthermore , among patients who were ACR20 nonresponders through week 54 , patients who were DAS nonresponders at weeks 30 and 54 , and patients without any improvement in individual clinical variables , those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo ( P < 0.05 to P < 0.001 ) . CONCLUSION Even in patients without clinical improvement , treatment with infliximab plus MTX provided significant benefit with regard to the destructive process , suggesting that in such patients these 2 measures of disease are dissociated 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 identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis ( RA ) treated with methotrexate ( MTX )  versus those treated with infliximab plus MTX . METHODS Patients who had not previously been treated with MTX with active RA were r and omly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . Radiographic joint damage was assessed using the modified Sharp/van der Heijde score ( SHS ) . The relationship between disease activity measures at baseline and week 14 , as well as those averaged over time , were examined in relation to the change in SHS from baseline through week 54 . RESULTS C-reactive protein ( CRP ) levels , erythrocyte sedimentation rate ( ESR ) , and swollen joint count were associated with greater joint damage progression in the MTX-only group , while none of these parameters was associated with progression in the infliximab plus MTX group . Mean changes in SHS among patients in the highest CRP ( > or = 3 mg/dl ) and ESR ( > or = 52 mm/hour ) tertiles in the MTX-only group were 5.62 and 5.89 , respectively , compared with 0.73 and 1.12 in the infliximab plus MTX group ( P < 0.001 ) . Patients with greater joint damage at baseline ( SHS > or = 10.5 ) showed less progression with infliximab plus MTX compared with MTX alone ( -0.39 versus 4.11 ; P < 0.001 ) . Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab . CONCLUSION High CRP level , high ESR , or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone , while little radiographic progression was seen in patients receiving both MTX and infliximab , regardless of the abnormal levels of these traditional predictors 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 BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268  methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research 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 OBJECTIVE To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate ( MTX ) over a 2-year period in patients with rheumatoid arthritis ( RA ) who previously experienced an incomplete response to MTX .  METHODS Four hundred twenty-eight patients were r and omly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks , with an additional year of followup . The protocol was later amended to allow for continued treatment during the second year . Of 259 patients who entered the second year of treatment , 216 continued to receive infliximab plus MTX for 102 weeks . Ninety-four of these 259 patients experienced a gap in therapy of > 8 weeks before continuing therapy . Infusions were administered at weeks 0 , 2 , and 6 , followed by treatment every 4 weeks or every 8 weeks ( alternating with placebo infusions in the interim 4-week visits ) at a dose of 3 or 10 mg/kg for a total of 102 weeks ( including the gap in therapy ) . For safety and efficacy assessment s , data on the patients who were r and omized to receive treatment , irrespective of whether treatment was administered for 102 weeks , were evaluated using all actual observations available . The efficacy measures included the Health Assessment Question naire ( HAQ ) ( physical function ) , Short Form 36 health survey ( SF-36 ) ( health-related quality of life ) , total radiographic scores ( structural damage ) , and the American College of Rheumatology 20 % improvement criteria ( ACR20 ) ( signs and symptoms ) . RESULTS The infliximab plus MTX regimens result ed in significantly greater improvement in HAQ scores ( P < or = 0.006 ) and SF-36 physical component summary scores ( P < or = 0.011 ) compared with the MTX-only group . There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens . Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen . The proportion of patients achieving an ACR20 response at week 102 varied from 40 % to 48 % for the infliximab plus MTX groups compared with 16 % for the MTX-only group . CONCLUSION Throughout 102 weeks of therapy , infliximab plus MTX provided significant , clinical ly relevant improvement in physical function and quality of life , accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone OBJECTIVE To compare the effects of methotrexate ( MTX ) , alone or in combination with intravenous ( IV ) methylprednisolone ( MP ) or infliximab , on magnetic resonance imaging (MRI)-detected synovitis , bone edema , and erosive changes in patients with early rheumatoid arthritis ( RA ) . METHODS Forty-four patients with early RA were r and omized to receive MTX alone ( MTX group ) , MTX plus IV MP ( IV MP group ) , or MTX plus infliximab ( infliximab group ) , infused on day 0 and weeks 2 , 6 , 14 , 22 , 30 , 38 , and 46 . Gadolinium-enhanced MRI scans of the metacarpophalangeal joints , wrists , and metatarsophalangeal joints were performed at baseline , week 18 , and week 52 . RESULTS Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups , with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups . Scores for MRI-detected erosion significantly increased over time in all groups . There were no differences in erosion scores between the MTX group and the other groups . It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab . At week 22 , response rates according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the ACR50 , and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group . At week 52 , remission was achieved in 40 % of patients in the MTX group and in 70 % of patients in the IV MP and infliximab groups . Health Assessment Question naire scores improved significantly over time in all groups , with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone . No severe side effects were observed , except 1 case of MTX-related pneumonitis . CONCLUSION The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA . Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab OBJECTIVE To evaluate the safety of etanercept in patients with rheumatoid arthritis ( RA ) and concomitant comorbidities . METHODS The safety of etanercept ( 25 mg twice weekly ) in RA patients with at least one comorbidity ( i.e. diabetes mellitus , chronic pulmonary disease , recent pneumonia , recurrent infections ) was evaluated in a 16-week placebo-controlled , r and omized , double-blinded study . The primary endpoint was the incidence of medically important infections ( MIIs ; defined as those result ing in hospitalization or treatment with intravenous antibiotics ) . RESULTS Data from 535 patients were analysed ; the study was terminated early because of slow enrolment and lower than predicted incidence of infections . Serious adverse events ( 5.9 % placebo , 8.6 % etanercept ) were most commonly observed in the cardiovascular system . Six patients ( 1 placebo ; 5 etanercept )  died during the study ; four deaths were attributed to cardiovascular events . The numerically higher mortality in the etanercept group was not statistically significant [ relative risk ( 95 % CI ) = 5.06 ( 0.59 , 42.99 ) ] but remains unexplained . No etanercept-related increase in the incidence of MIIs ( 3.7 % placebo , 3.0 % etanercept ) or overall infections was observed in the total study population or in subgroups of patients who were > or = 65 yrs of age , had diabetes or had chronic pulmonary disease . CONCLUSIONS Etanercept was generally well tolerated by RA patients with comorbidities .  Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad , preventing reliable conclusions from being drawn . Although the study had limited statistical power , the incidence of MIIs in these patients was not increased by etanercept treatment 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 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 Tumor necrosis factor ( TNF ) is a major proinflammatory cytokine in the rheumatoid joint . TNF activity can be neutralized by administration of a recombinant version of its soluble p75 TNF receptor linked to the Fc portion of human immunoglobulin IgG1 ( etanercept ) . The present study examined the combination of etanercept with methotrexate ( MTX ) in a group of patients with rheumatoid arthritis ( RA ) who had persistent activity despite monotherapy with MTX .  The etanercept-MTX group had a significantly better outcome than the placebo-MTX group using American College of Rheumatology ( ACR ) criteria . At 6 months , 71 % of the patients in the etanercept-MTX group had an ACR 20 % response ( versus 27 % in the placebo-MTX group ) . In the etanercept-MTX group , 39 % had an ACR 50 % response ( versus 3 % in the placebo-MTX group ) , and 15 % in the etanercept-MTX group versus 0 % in the placebo-MTX group met the robust ACR 70 % response . The present study indicates that etanercept is a novel and robust drug in combination with MTX for the treatment of RA BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept  ( 10 or 25 mg ) or weekly  oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis OBJECTIVE Tumor necrosis factor ( TNF ) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis ( RA ) . We investigated the ability of adalimumab , a human anti-TNF monoclonal antibody , to inhibit the progression of structural joint damage , reduce the signs and symptoms , and improve physical function in patients with active RA receiving concomitant treatment with methotrexate ( MTX ) .  METHODS In this multicenter , 52-week , double-blind , placebo-controlled study , 619 patients with active RA who had an inadequate response to MTX were r and omized to receive adalimumab 40 mg subcutaneously every other week ( n = 207 ) , adalimumab 20 mg subcutaneously every week ( n = 212 ) , or placebo ( n = 200 ) plus concomitant MTX . The primary efficacy end points were radiographic progression at week 52 ( total Sharp score by a modified method [ TSS ] ) , clinical response at week 24 ( improvements of at least 20 % in the American College of Rheumatology core criteria [ ACR20 ] ) , and physical function at week 52 ( disability index of the Health Assessment Question naire [ HAQ ] ) . RESULTS At week 52 , there was statistically significantly less radiographic progression , as measured by the change in TSS , in the patients receiving adalimumab either 40 mg every other week ( mean + /- SD change 0.1 + /- 4.8 ) or 20 mg weekly ( 0.8 + /- 4.9 ) as compared with that in the placebo group ( 2.7 + /- 6.8 ) ( P < or = 0.001 for each comparison ) . In addition , there were statistically significant changes in the components of the TSS . At week 24 , ACR20 responses were achieved by 63 % and 61 % of patients in the adalimumab 40 mg every other week and 20 mg weekly groups , respectively , versus 30 % of patients in the placebo group ( P < or = 0.001 for each comparison ) . At week 52 , ACR20 responses were achieved by 59 % and 55 % of patients taking adalimumab 40 mg every other week and 20 mg weekly , respectively , versus 24 % of patients taking placebo ( P < or = 0.001 for each comparison ) . At week 52 , physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo ( mean change in HAQ score -0.59 and -0.61 , respectively , versus -0.25 ; P < or = 0.001 for each comparison ) . A total of 467 patients ( 75.4 % ) completed 52 weeks of treatment . Adalimumab was generally well tolerated . Discontinuations occurred in 22.0 % of adalimumab-treated patients and in 30.0 % of placebo-treated patients . The rate of adverse events ( both serious and nonserious ) was comparable in the adalimumab and placebo groups , although the proportion of patients reporting serious infections was higher in patients receiving adalimumab ( 3.8 % ) than in those receiving placebo ( 0.5 % ) ( P < or = 0.02 ) , and was highest in the patients receiving 40 mg every other week . CONCLUSION In this 52-week trial , adalimumab was more effective than placebo at inhibiting the progression of structural joint damage , reducing the signs and symptoms , and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX OBJECTIVE The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes ( TEMPO ) is a 3-year , double-blind , multicenter study evaluating the efficacy and safety of etanercept , methotrexate , and the combination of etanercept plus methotrexate in patients with active rheumatoid arthritis ( RA ) . The results after 1 and 2 years of the study have been previously reported . Here we provide the 3-year clinical and radiographic outcomes and safety of etanercept , methotrexate , and the combination in patients with RA . METHODS In this r and omized , double-blind , multicenter TEMPO study , 682 patients received etanercept 25 mg twice weekly , methotrexate < or = 20 mg weekly , or the combination . Key efficacy assessment s included the Disease Activity Score ( DAS ) and the DAS in 28 joints . RESULTS Combination therapy result ed in significantly greater improvement in the DAS and in more patients with disease in remission than either monotherapy . This finding was confirmed by longitudinal analysis ; patients receiving combination therapy were more than twice as likely to have disease in remission than those receiving either monotherapy . Independent predictors of remission included male sex , lower disease activity , lower level of joint destruction , and /or better physical function .  Combination and etanercept therapy both result ed in significantly less radiographic progression than did methotrexate ( P < 0.05 ) . Etanercept and combination treatment were well tolerated , with no new safety findings . CONCLUSION Etanercept plus methotrexate showed sustained efficacy through 3 years and remained more effective than either monotherapy , even after adjustment for patient withdrawal . Combination therapy for 3 years led to disease remission and inhibition of radiographic progression , 2 key goals for treatment of patients with RA 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 OBJECTIVE To investigate the efficacy and safety of Infliximab ( IFX ) plus methotrexate ( MTX ) combination therapy in patients with rheumatoid arthritis ( RA ) . METHODS Prospect ively observe refractory RA patients who were treated with combination therapy of MTX and IFX . IFX was infused at the dosage of 3 mg/kg , in week 0 , 2 , 6 , and then every 8 weeks . During treatment , clinical variables , disease activity and adverse effects were evaluated . RESULTS After treatment , 69.8 % , 52.4 % , 29.5 % and 7.2 % RA patients achieved ACR20 , ACR50 , ACR70 and ACR90 respectively . There were significant statistical differences in the changes of swollen joint counts , tender joint counts , VAS scale , patient ' s global assessment , and physician 's global assessment before and after therapy . CONCLUSION Infliximab plus MTX achieved significant efficacy and safety in refractory RA 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 This study , known as STAR ( Safety Trial of Adalimumab in Rheumatoid Arthritis ) , evaluated the safety and efficacy of adalimumab ( Humira ) , a fully human monoclonal tumor necrosis factor-alpha ( TNF-a ) antibody , when given with st and ard antirheumatic therapy in patients with active rheumatoid arthritis ( RA ) not adequately responding to such therapies .  St and ard antirheumatic therapy included traditional disease modifying antirheumatic drugs ( DMARD ) , low dose corticosteroids , nonsteroidal antiinflammatory drugs ( NSAID ) , and /or analgesics . METHODS In this 24-week , double-blind , placebo-controlled study , 636 patients with RA were r and omly assigned to receive adalimumab 40 mg subcutaneously ( sc ) every other week ( n = 318 ) or placebo ( n = 318 ) while continuing st and ard antirheumatic therapy . The frequencies of adverse events , serious adverse events , severe or life-threatening adverse events , adverse events leading to withdrawal , infection , or serious infection were the primary endpoints . Secondary endpoints were determined by American College of Rheumatology ( ACR ) response criteria . RESULTS During the study , the majority of patients received concomitant traditional DMARD ( 83.5 % ) and /or corticosteroids , NSAID , and /or analgesics ( 97.3 % ) . Overall , 56.0 % of patients continued treatment with one , 23.6 % with 2 , and 3.9 % with > or = 3 traditional DMARD . At 24 weeks , there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events ( 86.5 % vs 82.7 % ) , serious adverse events ( 5.3 % vs 6.9 % ) , severe or life-threatening adverse events ( 11.9 % vs 15.4 % ) , or those leading to withdrawal ( 2.8 % vs 2.2 % ) . There were also no statistically significant differences in the rates of infections ( 52.2 % vs 49.4 % ) or serious infections ( 1.3 % vs 1.9 % ) between the groups . The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD ( 0 , 1 , or 2 ) . Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 ( 52.8 % vs 34.9 % ) , ACR50 ( 28.9 % vs 11.3 % ) , and ACR70 ( 14.8 % vs 3.5 % ) response rates at Week 24 ( p < or = 0.001 ) . CONCLUSION This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant st and ard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA . The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to st and ard antirheumatic therapy , including one or more traditional DMARD  , corticosteroids , NSAID , and analgesics 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
BACKGROUND AND OBJECTIVES Five-tumour necrosis factor (TNF)-blockers ( infliximab , etanercept , adalimumab , certolizumab pegol and golimumab ) are available for treatment of rheumatoid arthritis .
Only few clinical trials compare one TNF-blocker to another .
Hence , a systematic review is required to indirectly compare the substances .
The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis ( RA ) and indirectly compare all five currently available blockers by combining the results from included r and omized clinical trials ( RCT ) .