Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. 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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 : To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis ( RA ) despite sulfasalazine therapy . Methods : Patients were r and omly assigned to etanercept ( 25 mg twice weekly ; sulfasalazine was discontinued at baseline ) , etanercept plus sulfasalazine ( unchanged regimen of 2–3 g/day ) or sulfasalazine in a double-blind , r and omised , 2-year study in adult patients with active RA despite sulfasalazine therapy .  Efficacy was assessed using the American College of Rheumatology criteria , disease activity scores ( DAS ) and patient-reported outcomes ( PRO ) . Results : Demographic variables and baseline disease characteristics were comparable among treatment groups ; mean DAS 5.1 , 5.2 and 5.1 for etanercept ( n = 103 ) , etanercept plus sulfasalazine ( n = 101 ) and sulfasalazine ( n = 50 ) , respectively . Withdrawal due to lack of efficacy was highest with sulfasalazine ( 26 ( 52 % ) vs 6 ( 6 % ) for either etanercept group , p<0.001 ) . Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response , which was sustained at 2 years , than those receiving sulfasalazine : mean DAS 2.8 , 2.5 versus 4.5 , respectively ( p<0.05 ) ; ACR 20 response was achieved by 67 % , 77 % versus 34 % of patients , respectively ( p<0.01 ) Overall , PRO followed a similar pattern ; a clinical ly significant improvement in health assessment question naire was achieved by 76 % , 78 % versus 40 % of patients , respectively ( p<0.01 ) . Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis ( p<0.01 ) . Conclusion : Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA . The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine Objective : To compare patient reported measures of function , health related quality of life ( QoL ) , and satisfaction with medication among patients with rheumatoid arthritis ( RA ) treated with methotrexate ( MTX ) , etanercept , or both for up to 1 year . Methods : In a 52 week , double blind , clinical trial , patients with active RA were r and omised to receive etanercept 25 mg twice weekly , methotrexate up to 20 mg weekly , or combination therapy .  The Health Assessment Question naire ( HAQ ) disability index , EuroQoL health status visual analogue scale ( EQ-5D VAS ) , patient global assessment , and patient general health VAS were administered at baseline and weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 32 , 40 , 48 , and 52 . Satisfaction with the medication was compared at 52 weeks . Results : Of 682 enrolled patients , 522 completed 52 weeks of treatment . Mean improvement from baseline in HAQ score was 0.65 , 0.70 , and 1.0 for MTX , etanercept , and the combination , respectively . The mean percentage and absolute improvement in the HAQ was significantly higher ( p<0.01 ) for combination therapy than for either of the monotherapies . Combination therapy produced significantly more rapid achievement of HAQ ⩽0.5 sustained for 6 months than either of the monotherapies ( p<0.01 ) . Compared with patients receiving monotherapy , those receiving combination therapy achieved a significantly better ( p<0.05 ) health state as measured by the EQ-5D VAS ( mean ( SD ) 63.7 ( 3.2 ) , 66.8 ( 3.2 ) , 72.7 ( 3.1 ) for MTX , etanercept , and the combination , respectively ) . Results were similar for other assessment s ( p<0.01 ) . Patients in combination and etanercept groups were significantly more likely ( p<0.0001 , p = 0.0009 , respectively ) to report satisfaction with the medication . Conclusions : Combination therapy with etanercept and methotrexate improved function , QoL , and satisfaction with the medication significantly more than monotherapy 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 Introduction The objective of this study was to assess the impact of certolizumab pegol ( CZP ) treatment on health-related quality of life ( HRQoL ) , fatigue and other patient-reported outcomes ( PROs ) in patients with rheumatoid arthritis ( RA ) . Methods Patients with active RA ( N = 982 ) were r and omized 2:2:1 to subcutaneous CZP  ( 400 mg at weeks 0 , 2 and 4 ; followed by CZP 200 mg or 400 mg ) plus methotrexate ( MTX ) every other week , or placebo ( PBO ) plus MTX . PRO assessment s included HRQoL , fatigue , physical function , arthritis pain and disease activity . Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance ( ANCOVA ) applying last observation carried forward ( LOCF ) imputation . The proportion of patients achieving clinical ly meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal . The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation . Results Patients treated with CZP plus MTX reported significant ( P < 0.001 ) , clinical ly meaningful improvements in HRQoL at the first assessment ( week 12 ) ; reductions in fatigue , disease activity and pain and improvements in physical function were reported at week 1 . In particular , CZP-treated patients reported improvements in mental health . Mean changes from baseline in the SF-36 Mental Component Summary ( MCS ) at week 52 for CZP 200 mg and 400 mg plus MTX , and PBO plus MTX were 6.4 , 6.4 and 2.1 , respectively ( P < 0.001 ) . In addition , mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms . Improvements in all PROs were sustained . Similar benefits were reported with both CZP doses . Changes in SF-36 MCS scores had the lowest correlation with disease activity scores ( DAS28 ) and American College of Rheumatology 20 % improvement ( ACR20 ) response rates , while improvements in pain showed the highest correlation . Conclusions Treatment with CZP plus MTX result ed in rapid and sustained improvements in all PROs , indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis . Trial Registration Clinical Trials.gov NCT00152386 BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX )  were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX .  Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 OBJECTIVE To assess the efficacy and safety of 100 mg daily anakinra ( Kineret ) , a recombinant form of the naturally occurring interleukin 1 receptor antagonist , plus methotrexate ( MTX ) in reducing the signs and symptoms of rheumatoid arthritis ( RA ) . METHODS Patients with active RA ( n = 506 ) despite current treatment with MTX  were enrolled in this multicentre , double blind , r and omised , placebo controlled study . Patients received subcutaneous injections of anakinra 100 mg/day or placebo . They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events . The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24 . RESULTS Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 ( 38 % v 22 % ; p<0.001 ) , ACR50 ( 17 % v 8 % ; p<0.01 ) , and ACR70 ( 6 % v 2 % ; p<0.05 ) responses . The response to anakinra was rapid ; the proportion of patients with an ACR20 response at the first study assessment ( 4 weeks ) was twice as high with anakinra as with placebo ( p<0.005 ) . Clinical ly meaningful and statistically significant responses were also seen in individual components of the ACR response ( for example , Health Assessment Question naire , pain , C reactive protein levels , and erythrocyte sedimentation rate ) . Anakinra was well tolerated , with a safety profile , similar to that of placebo with one exception : mild to moderate injection site reactions were more common with anakinra than with placebo ( 65 % v 24 % ) . CONCLUSIONS This study confirms previous observations from a dose-ranging study showing that anakinra , in combination with MTX , is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig  per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo  ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate  , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX .  METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy  in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ;  etanercept  , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated 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 Recent r and omized controlled trials ( RCTs ) in rheumatoid arthritis ( RA ) have used patient- and physician-reported outcomes , ESR and /or CRP as components of ACR response criteria to assess efficacy . OBJECTIVES Mean changes from baseline in patient- and physician-reported outcome measures , ESR and CRP were compared in two RCTs in patients with active RA . Comparisons between active and placebo treatment used mean percentage improvements and st and ard effect sizes ( SESs ) . RESULTS In both protocol s , patient-reported assessment s of disease activity , pain and physical function reflected little or no improvement with placebo , best discriminating between active and placebo therapy , as did ESR and CRP . CONCLUSION Improvements in signs and symptoms of active RA in placebo RCTs appear to be best reflected by patient-reported measures of physical function , as long as reported changes in global assessment s of disease activity and /or pain reflect similar benefit . Patient-reported outcome measures should be considered objective ; treatment-associated changes are congruent with measures of inflammation , and appear less susceptible to the placebo response Objective To evaluate the effect of different concomitant disease modifying antirheumatic drugs ( DMARDs ) on the persistence with antitumour necrosis factor ( anti-TNF ) therapies  in patients with rheumatoid arthritis ( RA ) . Method This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register , a prospect i ve observational cohort study , who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline : no DMARD  ( n=3339 ) , methotrexate ( MTX ) ( n=4418 ) , leflunomide ( LEF ) ( n=610 ) , sulfasalazine ( SSZ ) ( n=308 ) , MTX+SSZ ( n=902 ) , MTX+ hydroxychloroquine ( HCQ ) ( n=401 ) or MTX+SSZ+HCQ ( n=418 ) . Kaplan – Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years . Multivariate Cox proportional hazard models , stratified by anti-TNF used and start year and adjusted for a number of potential confounders , were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups , using MTX as reference . Results One-year drug survival ( 95 % CI ) for the first anti-TNF therapy was 71 % ( 71 % to 72 % ) but this dropped to 42 % ( 41 % to 43 % ) at 5 years . Compared with MTX , patients receiving no DMARD , LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence . Conclusions These results support the continued use of background DMARD combinations which include MTX . Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started , with the possible exception of the SSZ+ETN combination We investigated the frequency of remission according to the disease activity score ( DAS28 ) definition , modified American Rheumatology Association ( ARA ) criteria , and the frequency of an achievement of a functional status above defined thresholds ( ' functional remission ' , ' physical independence ' ) in rheumatoid arthritis ( RA ) patients treated with either biologics or conventional DMARDs .  We used the data of a prospect i ve cohort study , the German biologics register RABBIT ( German acronym for Rheumatoid Arthritis – Observation of Biologic Therapy ) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics ( BIOL ; n = 818 ) or a conventional DMARD ( n = 265 ) .  Logistic regression analysis was applied to adjust for differences in baseline risks . Taking risk indicators such as previous DMARD failures or baseline clinical status into account , we found that biologics doubled the chance of remission compared to conventional DMARD therapies ( DAS28 remission , adjusted odds ratio ( OR ) 1.95 ( 95 % confidenece interval ( CI ) 1.2–3.2 ) ) ; ARA remission , OR 2.05 ( 95 % CI 1.2–3.5 ) ) . High remission rates ( DAS28 remission , 30.6 % ; ARA remission , 16.9 % ) were observed in BIOL patients with a moderate disease activity ( DAS28 , 3.2 to 5.1 ) at the start of treatment . These rates decreased to 8.5 % in patients with DAS28 > 6 . Sustained remission at 6 and 12 months was achieved in < 10 % of the patients . Severely disabled patients ( ≤50 % of full function ) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence ( ≥67 % of full function ) than controls ( OR 3.88 ( 95 % CI 1.7–8.8 ) ) . ' Functional remission ' ( ≥83 % of full function ) was more often achieved in BIOL than in controls ( OR 2.18 ( 95 % CI 1.04–4.6 ) ) . In conclusion , our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence . However , temporary or even sustained remission remain ambitious aims , which are achieved in a minority of patients only OBJECTIVE To examine correlations between clinical improvement as defined by the American College of Rheumatology ( ACR ) responder analysis and clinical improvement as determined by 4 function and /or health-related quality of life measures , and to estimate the sensitivity and relative efficiency of these measures compared with changes in the tender joint count in patients with rheumatoid arthritis ( RA ) . METHODS A 52-week , multicenter , double-blind controlled trial was conducted to compare treatment with leflunomide ( n = 182 ) , methotrexate ( n = 180 ) , or placebo ( n = 118 ) in patients with active RA .  ACR response rates and improvement in scores on the  Health Assessment Question naire ( HAQ ) , Problem Elicitation Technique ( PET ) , and Medical Outcomes Survey Short Form 36 ( SF-36 ) were compared in 438 of the patients . RESULTS In comparing leflunomide with placebo , the patient global assessment , HAQ disability index , and SF-36 bodily pain scale were most responsive to treatment group differences . The modified HAQ ( M-HAQ ) , PET Top 5 , SF-36 physical component score , physician global assessment , pain intensity scale , and SF-36 physical functioning scale were more responsive to treatment group differences than was the tender joint count . In comparing methotrexate with placebo , the patient and physician global assessment s were most responsive . These 2 measures , as well as the pain intensity scale and the C-reactive protein level , were more responsive to treatment group differences than was the tender joint count , while the SF-36 mental health component score was least responsive . A close correlation between changes in the M-HAQ and HAQ scores indicated that the M-HAQ was similarly responsive to change over time . Improvements in the PET , SF-36 physical component score , bodily pain , and physical functioning scales correlated with the ACR responder status . CONCLUSION Both disease-specific and generic measures of function and health-related quality of life detect improvements in RA patients . Using both types of measures for evaluating therapies will identify discernible changes that are important to patients , and will facilitate comparisons across different disease states OBJECTIVE To determine the minimal clinical ly important differences ( MCID ) in the patient-reported outcomes of activity ( 0 - 30 , number of days of limitation ) , fatigue ( 0 = none , 100 = complete ) , and sleep quality ( 0 = no problems , 100 = worst case ) for patients with rheumatoid arthritis ( RA ) . METHODS Two r and omized controlled trials comparing abatacept to placebo  in RA patients were considered : ATTAIN ( n = 391 ) and AIM ( n = 652 ) . An internal anchor-based approach was used to derive the MCID using the Health Assessment Question naire , patient global assessment , and pain as anchors . Minimal important change in activity , fatigue , and sleep were determined by estimating mean changes in these outcomes in patients showing change in a narrow range about the MCID of the internal anchor . Correlation analysis was used to determine the consistency of the changes in the outcomes and anchors , and a Delphi process was used to determine the final MCID values . RESULTS For the 2 trials , consistent patterns of change for activity , fatigue , and sleep and the internal anchors were found with correlations in the range of 0.5 , 0.7 , and 0.4 , respectively . The mean changes for activity , fatigue , and sleep in a narrow range about the MCID of the 3 internal anchors corresponding to the 2 trials were : 3.4 to 4.3 for activity ; 6.7 to 17.0 for fatigue ; and 4.1 to 7.3 for sleep . Following the Delphi process the MCID determined were 4 for activity , 10 for fatigue , and 6 for sleep . CONCLUSION These MCID for activity limitation , fatigue , and sleep problems can be used in design ing clinical trials and providing benchmarks in assessing patient improvement STUDY OBJECTIVE To compare the efficacy of biologic disease-modifying antirheumatic drugs ( DMARDs ) versus placebo with or without methotrexate , in treating rheumatoid arthritis . DESIGN Comparative effectiveness analysis using an indirect treatment comparison ( ITC ) method in a Bayesian framework . PATIENTS Adults with rheumatoid arthritis who had been enrolled in r and omized controlled trials ( RCTs ) and had never failed biologic DMARD therapy . MEASUREMENTS AND MAIN RESULTS Two r and om-effects logistic regression models , representing 6 and 12 months of treatment , were created using RCTs identified in a literature search . Twenty-three RCTs ( 11,589 patients ) were included in the 6-month model and 10 RCTs ( 6051 patients ) in the 12-month model . Nine biologic DMARDs in five therapeutic drug classes were included in the 6-month model , and six biologic DMARDs in three classes were included in the 12-month model . Our efficacy end point was the American College of Rheumatology 50 % improvement criteria . In the 6-month model , all biologic DMARDs and methotrexate were significantly more efficacious than placebo and ranked in the following order : certolizumab ( median log odds ratio [ OR ] 2.6 ) , tocilizumab ( 1.7 ) , rituximab ( 1.6 ) , infliximab ( 1.6 ) , etanercept ( 1.4 ) , adalimumab ( 1.4 ) , golimumab ( 1.4 ) , abatacept ( 1.2 ) , anakinra ( 1.0 ) , and methotrexate ( 0.8 ) . Of 45 pairwise comparisons , certolizumab was significantly more efficacious than methotrexate , but no other comparisons were significant . The rank order in the 12-month analysis was certolizumab ( median log OR 2.0 ) , rituximab ( 2.0 ) , adalimumab ( 1.4 ) , infliximab ( 1.4 ) , etanercept ( 0.9 ) , abatacept ( 0.6 ) , and methotrexate ( 0.8 ) . Of the 21 pairwise comparisons , none were significant . The results of the model using therapeutic class revealed that each class was more efficacious than placebo . In pairwise comparisons , each class was more efficacious than methotrexate , but none was more efficacious than another . CONCLUSION Use of emerging ITC methods enabled us to compare the efficacy of biologic DMARDs for the treatment of rheumatoid arthritis in the absence of direct head-to-head comparison trials . Our methods enabled us to rank order these treatments . Further analyses by drug and by therapeutic class suggest that biologic DMARDs are similarly efficacious 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 compare the functional status and well-being of patients with rheumatoid arthritis ( RA ) who were r and omly assigned to receive placebo , etanercept  10 mg , or etanercept 25 mg during a 26-week , phase III , double-blind clinical trial . BACKGROUND No single indicator of disease activity , severity , or therapeutic efficacy has been established for RA . During the past decade , health-related quality of life , a multidimensional way to assess physical , emotional , and social aspects of a disease or its treatment , has become an important outcome in RA studies and in assessment s of RA drug therapies . METHODS A total of 234 patients completed the Health Assessment Question naire ( HAQ )  , the  Short-Form 36 ( SF-36 ) ( n = 48 patients ) , items assessing energy and mental health from the Medical Outcomes Study ( MOS ) , and a single-item rating scale assessing current health ( feeling thermometer ) at baseline and several times during 6 months . RESULTS Significant improvements from baseline to last assessment were reported with etanercept versus placebo and in the HAQ Disability Index score ( ie , the total HAQ score ) and all 8 HAQ categories ( P < 0.05 ) , with the exception of grip . Significant improvements with etanercept in the MOS energy and mental health subscales , current health ( from the feeling thermometer ) , and mental and physical function components of the SF-36 were reported ( P < 0.05 ) . CONCLUSIONS Patients receiving 10- or 25-mg doses of etanercept reported significantly better functional status and well-being than did patients receiving placebo 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 Objective : To examine the impact of added abatacept treatment on health related quality of life ( HRQoL ) in patients with rheumatoid arthritis ( RA ) who have inadequate response to methotrexate ( MTX ) .  Methods : The impact of abatacept treatment on HRQoL was examined in a longitudinal , r and omised double blind , placebo controlled clinical trial . Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups . The relationship between American College of Rheumatology ( ACR ) clinical markers and disease duration with changes in HRQoL indicators was also examined . Finally , a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population . Results : Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures , including physical function , fatigue , all eight domains of the SF-36 , and the physical and mental component summaries ( PCS and MCS ) . Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains . By day 169 , all HRQoL measures were significantly better with abatacept than with placebo .  HRQoL gains were associated with greater ACR clinical improvement , and the effects were consistent for patients with different disease duration . A significantly greater percentage of patients treated with abatacept reached normative levels of PCS , MCS , physical functioning , and fatigue compared with patients treated with MTX alone . Conclusion : Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA OBJECTIVES Fatigue is an important systemic symptom of rheumatoid arthritis ( RA ) but has rarely been evaluated consistently after initiation of treatment in RA patients . This study examined the effects of adalimumab ( HUMIRA , Abbott Laboratories , Abbott Park , IL , USA ) , a fully human , anti-tumor necrosis factor ( anti-TNF ) monoclonal antibody , on reducing fatigue in patients with RA . METHODS A total of 1526 patients with RA were enrolled in 3 r and omized , placebo-controlled clinical trials of adalimumab versus placebo plus methotrexate ( MTX ) or placebo plus st and ard antirheumatic therapies .  Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy ( FACIT ) fatigue scale question naire ( which has been vali date d in RA ) at baseline , mid- study , and at the end of the study . Logistic regression models were constructed using baseline demographic variables to test for treatment effect . In addition , sensitivity analyses were performed to determine the robustness of the data . RESULTS At baseline in the 3 trials , patients ' fatigue ranged from 27.9 - 29.7 , representing considerable fatigue on the FACIT fatigue scale . Fatigue was significantly and consistently reduced in adalimumab-treated patients in the 3 clinical trials . Relative to placebo plus MTX , the adalimumab 40-mg-every-other-week dosage group reported statistically significantly less fatigue at all time points post-baseline . Improvements between adalimumab and placebo ranged from 3 - 7 points across all 3 trials , with a 3 - 4-point change representing a minimum clinical ly important difference . CONCLUSION Adalimumab treatment was shown to significantly reduce fatigue  in patients with moderate to severe RA . Changes in fatigue in all 3 trials were found to be clinical ly important 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 BACKGROUND Neutralization of tumor necrosis factor a ( TNF-alpha ) for three to six months reduces the symptoms and signs of rheumatoid arthritis . However , the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known . METHODS We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab , a chimeric monoclonal antibody against TNF-alpha  , in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks . We assessed clinical responses with use of the criteria of the American College of Rheumatology , the quality of life with a health-status question naire , and the effect on joint damage radiographically . RESULTS The combination of infliximab and methotrexate was well tolerated and result ed in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone ( clinical response , 51.8 percent vs. 17.0 percent ; P<0.001 ) . The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone . Radiographic evidence of joint damage increased in the group given methotrexate , but not in the groups given infliximab and methotrexate ( mean change in radiographic score , 7.0 vs. 0.6 , P<0.001 ) . Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response . CONCLUSIONS In patients with persistently active rheumatoid arthritis despite methotrexate therapy , repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate  , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo .  Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for  adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities  , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the OBJECTIVE To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs ( DMARDs ) in patients with active rheumatoid arthritis ( RA ) . METHODS A total of 1,220 patients were r and omized ( 2:1 ratio ) in the phase III , double-blind , placebo-controlled , multicenter TOWARD ( Tocilizumab in Combination With Traditional DMARD Therapy ) study . Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo ( control group ) every 4 weeks for 24 weeks . RESULTS At week 24 , the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) was significantly greater in the tocilizumab plus DMARD group than in the control group ( 61 % versus 25 % ; P<0.0001 ) . Secondary end points including 50 % or 70 % improvement ( ACR50/70 ) , the Disease Activity Score in 28 joints ( DAS28 ) , DAS28 remission responses ( DAS28<2.6 ) , European League Against Rheumatism responses , and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone . Seventy-three percent of patients in the tocilizumab group had > or=1 adverse event ( AE ) , compared with 61 % of patients in the control group . AEs leading to withdrawal from the study were infrequent ( 4 % of patients in the tocilizumab group and 2 % of those in the control group ) . Serious AEs occurred in 6.7 % and 4.3 % of patients in the tocilizumab and control groups , respectively , and serious infections occurred in 2.7 % and 1.9 % , respectively . Elevations in the alanine aminotransferase level , from normal at baseline to > 3-fold the upper limit of normal , occurred in 4 % of patients in the tocilizumab group and 1 % of those in the control group , and elevated total cholesterol levels were observed in 23 % and 6 % of patients , respectively . Sixteen patients started lipid-lowering therapy during the study . Grade 3 neutropenia occurred in 3.7 % of patients receiving tocilizumab and none of the patients in the control group , and no grade 4 neutropenia was reported . CONCLUSION Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents
Objective To compare biologics as monotherapy or in combination with methotrexate ( MTX ) in terms of patient reported outcomes ( PROs ) in RA patients with an inadequate response to conventional DMARDs ( DMARD-IR ) .