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Tocilizumab Monotherapy Reduces Arterial Stiffness as Effectively as Etanercept or Adalimumab Monotherapy in Rheumatoid Arthritis: An Open-label Randomized Controlled Trial Less Radiographic Progression with Adalimumab Plus Methotrexate Versus Methotrexate Monotherapy Across the Spectrum of Clinical Response in Early Rheumatoid Arthritis Significant improvement in synovitis, osteitis, and bone erosion following golimumab and methotrexate combination therapy as compared with methotrexate alone: a magnetic resonance imaging study of 318 methotrexate-naive rheumatoid arthritis patients. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Estimating the cost-effectiveness of 54 weeks of infliximab for rheumatoid arthritis. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: continued observations. Monte Carlo probabilistic sensitivity analysis for patient level simulation models: efficient estimation of mean and variance using ANOVA. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. 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Biologic drugs for rheumatoid arthritis in the Medicare program: a cost-effectiveness analysis. Continuation of Methotrexate Resulted in Better Clinical and Radiographic Outcomes Than Discontinuation upon Starting Etanercept in Patients with Rheumatoid Arthritis: 52-week Results from the JESMR Study Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Filtration leukocytapheresis therapy in rheumatoid arthritis: a randomized, double-blind, placebo-controlled trial. 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). 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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 Objectives This r and omised , double-blind , placebo-controlled phase IIIb study evaluated the impact of abatacept on MRI pathology as a primary outcome in  methotrexate (MTX)-refractory patients with rheumatoid arthritis . Methods Patients received intravenous abatacept ( ∼10 mg/kg ) or placebo , on background MTX , for 4 months , followed by an 8-month open-label extension ( OLE ; all patients received abatacept plus MTX ) . Patients had 1.5 T MRI with intravenous contrast at baseline , Months 4 and 12 ; wrist synovitis ( three locations assessed ) , and wrist and h and ( 15 and eight locations assessed , respectively ) osteitis and erosion were scored using OMERACT-RAMRIS . Results 26/27 abatacept- and 23/23 placebo-r and omised patients completed Month 4 and entered the OLE ; 26 and 21 completed Month 12 . The primary endpoint was not achieved ; mean change ( SD ) from baseline in synovitis was −0.44 ( 1.47 ) for abatacept versus 0.52 ( 1.38 ) for placebo ( p=0.103 ) at Month 4 . For mean change in synovitis adjusted for baseline score ( sensitivity analysis ) , the difference between groups was −0.69 , p=0.078 . Adjusted mean changes ( SE ) in osteitis and erosion were −1.94 ( 0.86 ) and 0.45 ( 0.43 ) for abatacept , and 1.54 ( 0.90 ) and 0.95 ( 0.45 ) for placebo . Further MRI improvements were observed up to Month 12 for abatacept and from Months 4 to 12 for placebo-treated patients switched to abatacept at Month 4 . Clinical efficacy was shown with abatacept and sustained to Month 12 . Conclusions Despite small patient numbers , MRI detected structural and synovial benefit , sustained to Month 12 in abatacept+MTX-treated patients , and improvements in structural and inflammatory outcomes for placebo+MTX-treated patients following addition of abatacept . Clinical trial registration Clinical trials.gov NCT00420199 OBJECTIVE To determine the efficacy , toxicity , utilities , and costs of 4 treatment strategies for patients with recent-onset rheumatoid arthritis ( RA ) . METHODS 508 patients with recent-onset active RA [ mean Disease Activity Score ( DAS ) 4.4 , mean Health Assessment Question naire score 1.4 ] were r and omized into 4 strategy groups : ( 1 ) sequential monotherapy ; ( 2 ) step-up to combination therapy [ both starting with methotrexate ( MTX ) ] ; ( 3 ) initial combination therapy with MTX , sulfasalazine , and prednisone ; ( 4 ) initial combination therapy with MTX and infliximab . Treatment adjustments were based on 3-monthly calculations of the DAS ( target DAS ? 2.4 ) , by research nurses who were blinded to the strategy group . They also collected data on treatment toxicity , functional ability , costs , and utilities . Yearly anonymized radiographs of h and s and feet were scored in r and om order by 2 independent physicians , using the Sharp/van der Heijde score . RESULTS Functional ability improved significantly earlier in Groups 3 and 4 than in Groups 1 and 2 , but was comparable among the groups at the end of the first year of treatment . Radiographic joint damage progression was significantly lower in Groups 3 and 4 than in Groups 1 and 2 , but low in all groups compared to other RA population s , probably due to DAS-driven treatment adjustments in all groups . More patients in Groups 3 and 4 than in Groups 1 and 2 achieved clinical remission ( DAS 1.6 ) , and patients who achieved early continued remission in Groups 3 and 4 had significantly less joint damage progression than those who achieved the same in Groups 1 and 2 . More patients could taper and stop all antirheumatic drugs and still retained remission in Group 4 ( 17 % at t = 3 years ) than in the other groups ( 10 % , 5 % , 9 % , respectively ) . Toxicity was comparable between groups . Quality of life measures were significantly higher in Group 4 than in the other groups , but costs of treatment were also the highest in Group 4 . Depending on the method used , higher productivity in Group 4 compensated for the higher medical costs . CONCLUSION In patients with recent-onset RA , initial combination therapy including prednisone or infliximab results in earlier clinical improvement and less joint damage progression than initial monotherapy . Initial treatment with infliximab result ed in the highest quality of life , highest productivity , and highest medical costs . DAS-driven treatment adjustments were effective to suppress disease activity and damage progression in all groups 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 OBJECTIVES To describe the changes in functional ability ( FA ) taking place over 5 yr in patients with rheumatoid arthritis ( RA ) starting disease-modifying anti-rheumatic drug ( DMARD ) therapy  , to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment . METHODS Three hundred and sixty-six patients with active RA were studied as part of a 5-yr r and omized controlled study of DMARD therapy . FA was assessed by  Health Assessment Question naire  ( HAQ )  score every 6 months . Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr . The independent variables used were age , sex , visual analogue scale ( VAS ) pain , Ritchie articular index , C-reactive protein ( CRP ) , Larsen score and log-transformed morning stiffness ( EMS ) . RESULTS Mean HAQ score was 1.64 at baseline , improved by 21 % at 1 yr and gradually returned towards baseline levels by 5 yr . At baseline only 34 % of variance in HAQ score could be explained ; the most significant explanatory variables were the Ritchie articular index and CRP . At 5 yr the variance explained was 60 % . The Ritchie articular index remained the strongest factor followed by VAS pain , log(10 ) EMS and Larsen score . CONCLUSIONS Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr . The most consistent factor affecting function was joint tenderness . Global pain and duration of EMS were of lesser importance . Disease activity measures such as the CRP exerted an influence in the earlier , more active stages of disease : radiographic damage assumed greater importance as the arthritis progressed Objective : To evaluate the ability of tocilizumab ( a humanised anti-IL-6 receptor antibody ) monotherapy to inhibit progression of structural joint damage in patients with RA . Methods : In a multi-centre , x ray reader-blinded , r and omised , controlled trial , 306 patients with active RA of < 5 years ’ duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs ( DMARDs ) for 52 weeks . Radiographs of h and s and forefeet were scored by the van der Heijde modified Sharp method . Results : Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline .  Mean total modified Sharp score ( TSS ) was 29.4 , which was very high despite the relatively short disease duration . At week 52 , the tocilizumab group showed statistically significantly less radiographic change in TSS ( mean 2.3 ; 95 % CI 1.5 to 3.2 ) than the DMARD group ( mean 6.1 ; 95 % CI 4.2 to 8.0 ; p<0.01 ) . Tocilizumab monotherapy also improved signs and symptoms . The overall incidences of AEs were 89 % and 82 % ( serious AEs : 18 % and 13 % ; serious infections : 7.6 % and 4.1 % ) in the tocilizumab and DMARD groups , respectively . Conclusion : Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA Objective In patients with active rheumatoid arthritis ( RA ) despite methotrexate  , to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy . Methods Double-blind , 2-year study in which adults with active RA ( DAS28 > 4.4 ) despite methotrexate were r and omly assigned either to continue methotrexate with the addition of tocilizumab ( MTX+TCZ ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo ( TCZ+PBO ) . The primary endpoint was the DAS28–erythrocyte sedimentation rate ( ESR ) remission rate at week 24 . Secondary objectives included other symptomatic outcomes , quality of life and progression of structural damage . Results Of 556 r and omly assigned patients , 512 ( 92 % ) completed 24 weeks . DAS28–ESR remission rates were 40.4 % for TCZ+MTX and 34.8 % for TCZ+PBO ( p=0.19 ) ; American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8 % ( TCZ+MTX ) and 70.3%/40.2%/25.4%/5.1 % ( TCZ+PBO ; differences not significant ) . A significant difference between groups was seen for low DAS28 ( 61.7 % vs 51.4 % ) . Radiographic progression was small and not different between groups ( Genant – Sharp score progression ≤ smallest detectable change in 91 % ( TCZ+MTX ) and 87 % ( TCZ+PBO ) ) . Rates per 100 patient-years of serious adverse events and serious infections were 21 and six , respectively , for TCZ+MTX and 18 and six , respectively , for TCZ+PBO  . Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8 % and 1.2 % of TCZ+MTX and TCZ+PBO patients , respectively . Conclusion No clinical ly relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed . The combination was more commonly associated with transaminase increases . Meaningful clinical and radiographic responses were achieved with both strategies , suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients Objective : To evaluate the safety and effectiveness of adalimumab alone or in combination with st and ard disease-modifying antirheumatic drugs ( DMARDs ) for the treatment of rheumatoid arthritis ( RA ) . Methods : Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre , open-label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase . Patients were allowed to continue with pre-existing traditional DMARDs .  Long-term safety results are reported for all patients ( 4210 patient-years ( PYs ) of adalimumab  exposure ) . The observed effectiveness results at week 12 are reported using American College of Rheumatology ( ACR ) and European League Against Rheumatism ( EULAR ) response criteria . Results : Among the 6610 treated patients , adalimumab was generally well tolerated . Serious infections occurred in 3.1 % of patients ( 5.5/100 PYs , including active tuberculosis , 0.5/100 PYs ) . Demyelinating disease ( 0.06 % ) and systemic lupus erythematosus ( 0.03 % ) were rare serious adverse events . The st and ardised incidence ratio of malignancy was 0.71 ( 95 % CI 0.49 to 1.01 ) . The st and ardised mortality ratio was 1.07 ( 95 % CI 0.75 to 1.49 ) . At week 12 , 69 % of patients achieved an ACR20 response , 83 % a moderate , and 33 % a good EULAR response .  Adalimumab was effective in combination with a variety of DMARDs . The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate . Conclusions : Considering the limitations of an open-label study , adalimumab alone or in combination with st and ard DMARDs appeared to be well tolerated and effective in 6610 difficult-to-treat patients with active RA treated in clinical practice Background Patient reported outcomes ( PROs ) are especially useful in assessing treatments for rheumatoid arthritis ( RA ) since they measure dimensions of health-related quality of life that can not be captured using strictly objective physiological measures . The aim of this study was to compare the effects of combination etanercept and methotrexate ( ETN + MTX ) versus combination synthetic disease modifying antirheumatic drugs ( DMARDs ) and methotrexate ( DMARD + MTX ) on PRO measures among RA patients from the Asia-Pacific region , a population not widely studied to date . Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate  were studied . Methods Patients were r and omized to either ETN + MTX ( N = 197 ) or DMARD + MTX ( N = 103 ) in an open-label , active-comparator , multicenter study , with PRO measures design ed as prospect i ve secondary endpoints . The Health Assessment Question naire ( HAQ ) , Functional Assessment of Chronic Illness Therapy Fatigue Scale ( FACIT-Fatigue ) , Medical Outcomes Short Form-36 Health Survey ( SF-36 ) , Hospital Anxiety and Depression Scale ( HADS ) and the Work Productivity and Activity Impairment Question naire : General Health ( WPAI : GH ) were used . Results Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5 , compared to patients in the DMARD + MTX group . SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group ; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms . Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue , HADS , and WPAI : GH mean scores . Conclusion Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures , compared to combination therapy with usual st and ard of care DMARDs plus MTX  in patients with established rheumatoid arthritis from the Asia-Pacific region . Trial registration clintrials.gov # Objectives : To evaluate the safety and efficacy of 5-year , long-term tocilizumab monotherapy for patients with rheumatoid arthritis . Methods : In an open-label , long-term extension trial following an initial 3-month r and omised phase II trial , 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy ( 8 mg/kg ) every 4 weeks . Concomitant therapy with non-steroidal anti-inflammatory drugs and /or oral prednisolone ( 10 mg daily maximum ) was permitted . All patients were evaluated with American College of Rheumatology ( ACR ) improvement criteria , disease activity score ( DAS ) in 28 joints , and the European League Against Rheumatism response , as well as for safety issues . Results : 143 patients were enrolled in the open-label , long-term extension trial and 94 ( 66 % ) patients had completed 5 years as of March 2007 . 32 patients ( 22 % ) withdrew from the study due to adverse events and one patient ( 0.7 % ) due to unsatisfactory response . 14 patients withdrew because of the patient ’s request or other reasons . The serious adverse event rate was 27.5 events per 100 patient-years , with 5.7 serious infections per 100 patient-years , based on a total tocilizumab exposure of 612 patient-years . Of the 88 patients receiving corticosteroids at baseline , 78 ( 88.6 % ) were able to decrease their corticosteroid dose and 28 ( 31.8 % ) discontinued corticosteroids . At 5 years , 79/94 ( 84.0 % ) , 65/94 ( 69.1 % ) and 41/94 ( 43.6 % ) of the patients achieved ACR20 , ACR50 , and ACR70 improvement criteria , respectively . Remission defined as DAS28 less than 2.6 was achieved in 52/94 ( 55.3 % ) of the patients . Conclusion : In this 5-year extension study , tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile Objective : To estimate the cost effectiveness of combination treatment with etanercept plus methotrexate in comparison with monotherapies in patients with active rheumatoid arthritis ( RA ) using a new model that incorporates both functional status and disease activity . Methods : Effectiveness data were based on a 2 year trial in 682 patients with active RA ( TEMPO ) . Data on re source consumption and utility related to function and disease activity were obtained from a survey of 616 patients in Sweden . A Markov model was constructed with five states according to functional status ( Health Assessment Question naire ( HAQ ) ) subdivided into high and low disease activity . The cost for each quality adjusted life year ( QALY ) gained was estimated by Monte Carlo simulation . Results : Disease activity had a highly significant effect on utilities , independently of HAQ . For re source consumption , only HAQ was a significant predictor , with the exception of sick leave . Compared with methotrexate alone , etanercept plus methotrexate over 2 years increased total costs by € 14 221 and led to a QALY gain of 0.38 . When treatment was continued for 10 years , incremental costs were € 42 148 for a QALY gain of 0.91 . The cost per QALY gained was € 37 331 and € 46 494 , respectively . The probability that the cost effectiveness ratio is below a threshold of € 50 000/QALY is 88 % . Conclusion : Incorporating the influence of disease activity into this new model allows better assessment of the effects of anti-tumour necrosis factor treatment on patients ’ general wellbeing . In this analysis , the cost per QALY gained with combination treatment with etanercept plus methotrexate compared with methotrexate alone falls within the acceptable range Objective : The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis ( RA ) despite methotrexate therapy . Methods : Patients were r and omly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules ( group 1 , n = 133 ) , golimumab 100 mg injections plus placebo capsules ( group 2 , n = 133 ) , golimumab 50 mg injections plus methotrexate capsules ( group 3 , n = 89 ) , or golimumab 100 mg injections plus methotrexate capsules ( group 4 , n = 89 ) . Injections were administered subcutaneously every 4 weeks . The co- primary endpoints were the proportion of patients with 20 % or greater improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 and the change from baseline in the health assessment question naire-disability index ( HAQ-DI ) score at week 24 . Results : The proportion of patients who achieved an ACR20 response at week 14 was 33.1 % in the placebo plus methotrexate group , 44.4 % ( p = 0.059 ) in the golimumab 100 mg plus placebo group , 55.1 % ( p = 0.001 ) in the golimumab 50 mg plus methotrexate group and 56.2 % ( p<0.001 ) in the golimumab 100 mg plus methotrexate group . At week 24 , median improvements from baseline in HAQ-DI scores were 0.13 , 0.13 ( p = 0.240 ) , 0.38 ( p<0.001 ) and 0.50 ( p<0.001 ) , respectively . During the placebo-controlled portion of the study ( to week 16 ) , serious adverse events occurred in 2.3 % , 3.8 % , 5.6 % and 9.0 % of patients and serious infections occurred in 0.8 % , 0.8 % , 2.2 % and 5.6 % , respectively . Conclusion : The addition of golimumab to methotrexate  in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) .  Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX  were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX Objective The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis ( RA ) who discontinued previous tumour necrosis factor alpha ( TNFα ) inhibitor(s ) for any reason . Methods Results through week 24 of this multicentre , r and omised , double-blind , placebo-controlled study of active RA ( ≥4 tender , ≥4 swollen joints ) were previously reported . Patients received placebo ( Group 1 ) , 50 mg golimumab ( Group 2 ) or 100 mg golimumab ( Group 3 ) subcutaneous injections every 4 weeks . Patients from Groups 1 and 2 with < 20 % improvement in tender/swollen joints at week 16 early escaped to golimumab 50 mg and 100 mg , respectively . At week 24 , Group 1 patients crossed over to golimumab 50 mg , Group 2 continued golimumab 50/100 mg per escape status and Group 3 maintained dosing . Data through week 160 are reported . Results 459 of the 461 r and omised patients were treated ; 236/459 ( 51 % ) continued treatment through week 160 . From week 24 to week 100 , ACR20 ( ≥20 % improvement in American College of Rheumatology criteria ) response and ≥0.25 unit HAQ ( Health Assessment Question naire ) improvement were sustained in 70–73 % and 75–81 % of responding patients , respectively . Overall at week 160 , 63 % , 67 % and 57 % of patients achieved ACR20 response and 59 % , 65 % and 64 % had HAQ improvement ≥0.25 unit in Groups 1 , 2 and 3 , respectively . Adjusted for follow-up duration , adverse event incidences ( 95 % CI ) per 100 patient-years among patients treated with golimumab 50 mg and 100 mg were 4.70 ( 2.63 to 7.75 ) and 8.07 ( 6.02 to 10.58 ) for serious infection , 0.95 ( 0.20 to 2.77 ) and 2.04 ( 1.09 to 3.49 ) for malignancy and 0.00 ( 0.00 to 0.94 ) and 0.62 ( 0.17 to 1.59 ) for death , respectively . Conclusion In patients with active RA who discontinued previous TNF-antagonist treatment  , golimumab 50 and 100 mg injections every 4 weeks yielded sustained improvements in signs/symptoms and physical function in ∼57–67 % of patients who continued treatment . Golimumab safety was consistent with other anti-TNF agents , although definitive conclusions regarding long-term safety require further monitoring We compared the validity of the American College of Rheumatology ( ACR ) and the European League of Associations for Rheumatology ( EULAR ) definitions of response in rheumatoid arthritis ( RA ) clinical trials . US : ACR and EULAR improvement criteria were calculated in 7 large r and omized RA clinical trials . The discriminant validity of the response criteria between treatment groups was studied using the Mantel-Haenszel chi-squared value . To compare both sets of criteria the chi-squared ratio was determined for each trial . Europe : In 2 large r and omized RA clinical trials , ACR and EULAR criteria were calculated , once with extensive and once with 28 joint counts . The classification of patients with these 4 criteria were compared with each other using cross tables . We further studied the difference in response between treatment groups per trial , the association of response with patient and investigator assessment of improvement , and the association of response with radiological progression . US : The chi-squared ratio for most trials was close to 1 . There was no clear pattern suggesting that the discriminant validity of the ACR criteria was stronger than the discriminant validity of the EULAR definition of response or vice versa . Europe : Conflicting results between ACR and EULAR were present in only 3 % of patients in both trials . The discriminant validity of all 4 criteria ( ACR and EULAR with reduced and extensive joint counts ) was comparable . All criteria were related with the overall assessment of improvement by both investigator and patient . The association with radiographic progression was comparable for EULAR and ACR improvement criteria . There is a high level of agreement between ACR and EULAR improvement classification , and their validity is equivalent . The discriminating potential of the criteria between treatment groups is comparable , as is the association with patient 's and investigator 's overall assessment and with radiographic progression BACKGROUND Tumor necrosis factor ( TNF ) is an important mediator of cachexia , and its blockade prevents catabolism in animal models . However , little evidence shows that anti-TNF therapy is effective in treating cachexia in humans . OBJECTIVE The main aim of this study was to investigate the effect of etanercept , a synthetic soluble TNF receptor , on body composition in patients with early rheumatoid arthritis ( RA ) . DESIGN Twenty-six patients were r and omly assigned to 24 wk of treatment with  etanercept or methotrexate ; the latter is the first-line therapy for RA . Body composition , physical function , disease activity , systemic inflammation , and the circulating insulin-like growth factor ( IGF ) system were measured at baseline ( week 0 ) and at follow-up ( weeks 12 and 24 ) . Twelve patients in each treatment group ( 9 F , 3 M ) completed the study . RESULTS Overall , no important changes in body composition were observed , despite a transient increase in IGF-I at week 12 ( P < 0.01 ) . However , the secondary analysis of those patients ( 6/treatment group ) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained : 44 % of weight gained in the etanercept group was fat-free mass , as compared with only 14 % in the methotrexate group ( P = 0.04 ) . Etanercept and methotrexate were equally effective in controlling the disease and improving physical function . CONCLUSIONS Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo . However , TNF blockade seems to normalize the anabolic response to overfeeding and , if these findings are confirmed , may be useful in conditions characterized by anorexia and weight loss Objective . To investigate the effect of tocilizumab on patient-reported outcomes ( PROs ) in RA patients with inadequate responses to TNF inhibitors ( TNFis ) . Methods . In a Phase III r and omized controlled trial , 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks . Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinical ly important differences ( MCIDs ) in PROs were analyzed . Results . At week 24 , 8 mg/kg result ed in significantly greater improvements vs placebo in pain , global assessment of disease activity ( P = 0.001 ) , Health Assessment Question naire-Disability Index ( HAQ-DI ; P < 0.0001 ) , Functional Assessment of Chronic Illness Therapy-Fatigue ( P = 0.0150 ) and Medical Outcomes Survey Short Form 36 ( SF-36 v2 ) Physical Component Summary ( PCS ; P = 0.0003 ) scores , all greater than MCID ; 4 mg/kg result ed in greater improvements in pain ( P = 0.0100 ) , HAQ-DI ( P = 0.0030 ) and SF-36 PCS ( P = 0.0020 ) scores . Tocilizumab-associated improvements were evident as early as week 2 . At week 24 , more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs ( 50.9–84.9 % vs 35.0–51.7 % ) and achieved ACR50 responses and /or Disease Activity Score 28 ( DAS28 ) remission with PRO improvements greater than or equal to MCID ( 36.2–51.2 % vs 10–20.7 % and 10.7–37.5 % vs 0.0–3.4 % , respectively ) . Conclusion . Tocilizumab treatment in patients with inadequate responses to TNFis result ed in rapid and sustained improvements in multiple PROs that were statistically significant and clinical ly meaningful , consistent with previous efficacy reports . Trial Registration . Clinical Trials.gov , http:// clinical trials.gov/ , NCT00106522 Background : The anti-interleukin ( IL ) 6 receptor antibody tocilizumab inhibits signalling of IL6 , a key cytokine in rheumatoid arthritis ( RA ) pathogenesis . Objective : To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed . Methods : This 24-week , double-blind , double-dummy , parallel-group study , r and omised 673 patients to either tocilizumab 8 mg/kg every 4 weeks , or methotrexate , starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks , or placebo for 8 weeks followed by tocilizumab 8 mg/kg . The primary end point was the proportion of patients achieving American College of Rheumatology ( ACR ) 20 response at week 24 . Results : The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response ( 69.9 vs 52.5 % ; p<0.001 ) , and 28-joint Disease Activity Score ( DAS28 ) < 2.6 rate ( 33.6 vs 12.1 % ) at week 24 . Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab , whereas levels remained elevated with methotrexate . The incidence of serious adverse events  with tocilizumab was 3.8 % versus 2.8 % with methotrexate ( p = 0.50 ) , and of serious infections , 1.4 % versus 0.7 % , respectively . There was a higher incidence of reversible grade 3 neutropenia ( 3.1 % vs 0.4 % ) and increased total cholesterol ⩾240 mg/dl ( 13.2 % vs 0.4 % ) , and a lower incidence of alanine aminotransferase elevations > 3 × –<5 × upper limit of normal ( 1.0 % vs 2.5 % ) , respectively . Conclusion : Tocilizumab monotherapy is better than methotrexate monotherapy , with rapid improvement in RA signs and symptoms , and a favourable benefit – risk , in patients for whom treatment with methotrexate or biological agents has not previously failed . Trial registration number : Objective . To determine the efficacy of methotrexate ( MTX ) with infliximab ( IFX ) compared with MTX alone in the prevention of atherosclerosis and arterial stiffness in patients with early rheumatoid arthritis ( RA ) . Methods . A r and omized , open-label study in which early RA patients with active disease were treated with MTX alone ( n = 20 ) and MTX plus IFX ( n = 20 ) for 6 months . Patients were assessed every 3 months . Patients from the MTX-alone group who failed to achieve 28-joint Disease Activity Score remission ( DAS28 ≤ 2.6 ) at 6 months were permitted to escape to open-label IFX . Intima-media thickness ( IMT ) , pulse wave velocity ( PWV ) , and augmentation index ( AIx ) were measured at baseline , 6 months , and 12 months . Results . At 6 months , there was a significantly greater reduction in PWV in the MTX-alone group ( 0.18 ± 1.59 m/s ) compared with the MTX plus IFX group ( −0.78 ± 1.13 m/s ; p = 0.044 ) , accompanied by significantly greater reduction in patient ’s global assessment , number of swollen joints , C-reactive protein , and DAS28 in the MTX plus IFX group compared to the MTX-alone group . The changes in IMT and AIx were similar between the 2 groups . At 12 months , there was a trend favoring early combination treatment with regard to the reduction in PWV ( p = 0.06 ) . Conclusion . MTX plus IFX causes a more significant reduction in PWV than MTX alone in patients with early RA after 6-month treatment , and further improvement may be achieved in patients who continued on longterm tumor necrosis factor-α blockers , suggesting that early , effective suppression of inflammation may prevent progression of atherosclerosis by improving vascular function Objective To compare the efficacy and safety of subcutaneous ( SC ) and intravenous ( IV ) abatacept . Methods In this phase IIIb double-blind , double-dummy , 6-month study , patients with rheumatoid arthritis ( RA ) and inadequate responses to methotrexate were r and omized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter ( plus an IV loading dose [ ∼10 mg/kg ] on day 1 ) or IV abatacept ( ∼10 mg/kg ) on days 1 , 15 , and 29 and every 4 weeks thereafter . The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at month 6 . Other efficacy end points , immunogenicity , and safety were also assessed . Results Of 1,457 patients , 693 of 736 ( 94.2 % ) treated with SC abatacept and 676 of 721 ( 93.8 % ) treated with IV abatacept completed 6 months . At month 6 , 76.0 % ( 95 % confidence interval 72.9 , 79.2 ) of SC abatacept – treated patients versus 75.8 % ( 95 % confidence interval 72.6 , 79.0 ) of IV abatacept – treated patients achieved an ACR20 response ( estimated difference between groups 0.3 % [ 95 % confidence interval –4.2 , 4.8 ] ) , confirming noninferiority of SC abatacept to IV abatacept . Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept – treated groups . The proportions of adverse events ( AEs ) and serious AEs over 6 months were 67.0 % and 4.2 % , respectively , in the SC abatacept – treated group and 65.2 % and 4.9 % , respectively , in the IV abatacept – treated group , with comparable frequencies of serious infections , malignancies , and autoimmune events between groups . SC injection site reactions ( mostly mild ) occurred in 19 SC abatacept ( IV placebo)–treated patients ( 2.6 % ) and 18 IV abatacept ( SC placebo)–treated patients ( 2.5 % ) . Abatacept-induced antibodies occurred in 1.1 % of SC abatacept – treated patients and 2.3 % of IV abatacept – treated patients . Conclusion SC abatacept provides efficacy and safety comparable with that of IV abatacept , with low immunogenicity and high retention rates , consistent with the established IV abatacept profile . Rates of injection site reactions were low . SC abatacept will provide additional treatment options , such as an alternative route of administration , for patients with RA 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 ascertain whether a 1-year remission induction therapy with an infliximab-MTX ( INF-MTX ) combination in patients with early RA provided sustained benefit after INF cessation compared with conventional treatment . METHODS Twenty patients with poor prognosis RA of < 1 year of disease duration were r and omized to receive either INF and MTX or placebo infusions and MTX for 1 year . They then stepped down to MTX monotherapy and were treated according to st and ard clinical care . After 8 years , disease activity , function and quality of life ( QoL ) data were collected . RESULTS At follow-up , data were available for 18 patients ( 1 in each group had died ) . Median 28-joint DAS was significantly lower in the INF-MTX group compared with placebo-MTX group ( 2.7 vs 4.3 , P = 0.02 ) . Four patients in the INF-MTX group were in remission vs none in the placebo-MTX group . One patient in the INF-MTX group achieved drug-free remission . Both RAQoL and HAQ median scores were lower in the INF-MTX group ; however , this did not reach statistical significance ( median RAQoL 3 vs 8 , P = 0.18 ; median HAQ 1.0 vs 1.5 , P = 0.12 ) . CONCLUSION A remission induction regime with an INF-MTX combination for 1 year in early RA can improve long-term clinical outcomes . Larger studies will be required to confirm the implication s of these findings Objectives : To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis ( RA ) and poor prognostic factors . Methods : In this double-blind , phase IIIb study , patients with RA for 2 years or less were r and omly assigned 1 : 1 to receive abatacept ( ∼10 mg/kg ) plus methotrexate , or placebo plus methotrexate .  Patients were methotrexate-naive and seropositive for rheumatoid factor ( RF ) , anti-cyclic citrullinated protein ( CCP ) type 2 or both and had radiographic evidence of joint erosions . The co- primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission ( C-reactive protein ) and joint damage progression ( Genant-modified Sharp total score ; TS ) at year 1 . Safety was monitored throughout . Results : At baseline , patients had a mean DAS28 of 6.3 , a mean TS of 7.1 and mean disease duration of 6.5 months ; 96.5 % and 89.0 % of patients were RF or anti-CCP2 seropositive , respectively . At year 1 , a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission ( 41.4 % vs 23.3 % ; p<0.001 ) and there was significantly less radiographic progression ( mean change in TS 0.63 vs 1.06 ; p = 0.040 ) versus methotrexate alone . Over 1 year , the frequency of adverse events ( 84.8 % vs 83.4 % ) , serious adverse events ( 7.8 % vs 7.9 % ) , serious infections ( 2.0 % vs 2.0 % ) , autoimmune disorders ( 2.3 % vs 2.0 % ) and malignancies ( 0.4 % vs 0 % ) was comparable for abatacept plus methotrexate versus methotrexate alone . Conclusions : In a methotrexate-naive population with early RA and poor prognostic factors , the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable , favourable safety profile 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 Objective . Patients with rheumatoid arthritis ( RA ) are at increased risk of death . Modern RA therapy has been shown to improve health status , but the relationship of such improvements to mortality risk is unknown . We assessed the relationship between health status and all-cause mortality in patients with RA , using the Health Assessment Question naire ( HAQ ) and the Medical Outcomes Study Short Form-36 question naire ( SF-36 ) physical and mental component summary scores ( PCS , MCS ) . Methods . Subjects ( n = 10,319 ) were selected from the National Data Bank for Rheumatic Diseases , a prospect i ve longitudinal observational US study with semiannual assessment s of HAQ , PCS , and MCS .  Risk of death up to 7 years through 2006 was obtained from the US National Death Index . Relationship of HAQ , PCS , and MCS to mortality was assessed using Cox regression models ; prediction accuracy was compared using Harrell ’s concordance coefficient ( C ) . Results . Over 64,888 patient-years of followup , there were 1317 deaths . Poorer baseline health status was associated with greater mortality risk . Adjusting for age , sex , and baseline PCS and MCS , declines in PCS and HAQ were associated with higher risk of death . HAQ improvement was associated with reduced mortality risk from 6 months through 3 years ; a similar relationship was not observed for PCS or MCS improvement . Controlling for baseline values , change in PCS or HAQ did not improve prediction accuracy . Conclusion . The HAQ and the SF-36 PCS are similarly and strongly associated with mortality risk in patients with RA . Change in these measures over time does not appear to add to predictive accuracy over baseline levels Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX )  were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX .  Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 Objectives : This study assessed the relative efficacy of etanercept ( ETN ) or etanercept and methotrexate ( ETN+MTX ) for patients with rheumatoid arthritis ( RA ) who had an unsatisfactory response to MTX  , using patient-reported outcomes ( PROs ) of function , pain , general health , disease activity and morning stiffness . Methods : The PROs were secondary assessment s in a 16-week , prospect i ve , r and omised , parallel-group study conducted at 60 European centres . Patients with RA were r and omly assigned either to monotherapy with ETN or combination therapy with ETN+MTX . PRO instruments administered included the Stanford Health Assessment Question naire , the pain visual analogue scale , the EuroQoL assessment of current health state ( EQ-5D ) , the EQ-5D visual analogue scale , a patient global assessment of disease activity and an assessment of morning stiffness . Treatment groups were compared by percentage of patients within clinical ly meaningful categories . The primary endpoint for all PROs was comparison of mean improvement from baseline to week 16 between ETN and ETN+MTX groups . Results : Three hundred and fifteen patients were r and omised to ETN or ETN+MTX . Both treatment arms had similar Health Assessment Question naire Disability Index DI , EQ-5D , patient global assessment of disease activity , pain or morning stiffness scores and improvement from baseline to week 16 . Conclusions : For patients with active RA and intolerance or unsatisfactory response to MTX  , substituting ETN for MTX and adding ETN to MTX are both effective ways of reducing disability , pain , disease activity , morning stiffness , and improving general health 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 OBJECTIVE To document the burden of early rheumatoid arthritis ( RA ) on health-related quality of life ( HQL ) and compare changes in HQL across 2 treatments . STUDY DESIGN Analysis of HQL scores among patients enrolled in a multicenter , double-blind , r and omized control trial of early RA treatment . PATIENTS AND METHODS A total of 424 patients with early RA were r and omized to 1 of 2 treatment groups : etanercept or methotrexate .  Patients were treated and followed for 52 weeks . Health-related quality of life was assessed before and throughout treatment using the Medical Outcomes Study Short Form 36 Health Survey ( SF-36 ) and the Health Assessment Question naire ( HAQ ) . The HQL burden of RA was established by comparing SF-36 scale scores to general US population norms . The impact of treatment on HQL was determined by comparing scores on both SF-36 and HAQ scales . RESULTS Before treatment , RA patients showed significant decrements in scores on all SF-36 scales and summary measures in comparison with age- and sex-matched general US population norms , multivariate analysis of variance ( MANOVA ) F(8,2815 ) = 204.6 , P < .0001 . After 52 weeks of treatment , 7 of 8 SF-36 scales and the physical summary measure remained significantly below the general US population norm , MANOVA F(8,2815 ) = 41.9 , P < .0001 . Patients r and omized to etanercept showed significantly better HQL improvement earlier in treatment than patients r and omized to methotrexate on the SF-36 physical summary , MANOVA F(10,4230 ) = 6.1 , P < .0001 , the SF-36 arthritis-specific health index , MANOVA F(10,4230 ) = 8.5 , P < .0001 , and the HAQ , MANOVA F(10,4230 ) = 14.7 , P < .0001 . At 52 weeks , there were no significant differences between treatment groups . CONCLUSIONS Rheumatoid arthritis places tremendous disease burden on patients ' HQL . Successful treatment of early RA improved HQL . Etanercept showed a rapid HQL response OBJECTIVES To compare the short term clinical and biological effects of intravenous ( i.v . ) pulse methylprednisolone ( MP ) and infliximab ( IFX ) in patients with severe active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) treatment . METHODS Patients with active RA despite MTX treatment were r and omly allocated to receive a single i.v . infusion of MP ( 1 g ) or three i.v . infusions of IFX ( 3 mg/kg ) on weeks 0 , 2 , and 6 . Patients were " blindly " evaluated for disease activity measures . Quality of life ( QoL ) was evaluated through the SF-36 health survey . Serum matrix metalloproteinase-3 ( MMP-3 ) titres were measured at baseline , weeks 2 and 6 . RESULTS Compared with baseline , significant improvement was noted in all activity measures , including serum C reactive protein ( CRP ) titres , in the IFX group only . At week 14 , 6/9 ( 67 % ) and 4/9 ( 44 % ) IFX patients met the ACR20 and 50 response criteria , while this was the case in only 1/12 ( 8 % ) and 0/12 ( 0 % ) MP patients , respectively ( p<0.05 ) . None of the QoL scales improved with MP treatment , whereas some did so in the IFX group . Serum MMP-3 titres significantly decreased ( 41 % drop ) at week 6 in the IFX group , while no changes were seen in patients given MP . CONCLUSION This short term r and omised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA , with improvement in not only clinical parameters of disease activity but also biological inflammatory indices , such as serum CRP and MMP-3 titres BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig  per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo  ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate  , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis BACKGROUND It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis ( RA ) for the UK were published . Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA , especially in women . OBJECTIVES To estimate the age- and sex-specific point prevalence of RA ( defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment ) . The estimate was made in the primary care setting in Norfolk , UK . METHODS A stratified r and om sample was drawn from seven age and gender b and s. The 7050 individuals selected were mailed a screening question naire . Positive responders were invited to attend for a clinical examination . The sample was matched against the names in the Norfolk Arthritis Register ( NOAR ) , a register of incident cases of inflammatory polyarthritis which has been in existence since 1990 . RESULTS The overall response rate was 82 % . Sixty-six cases of RA were identified . Extrapolated to the population of the UK , the overall minimum prevalence of RA is 1.16 % in women and 0.44 % in men . A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission . In addition , some cases who failed to attend for examination had significant disability . These prevalence figures are therefore an underestimate . CONCLUSIONS The prevalence of RA in women , but not in men , in the UK may have fallen since the 1950s Due to the unknown etiology of RA , specific treatment is not available . Recently , in a double-blinded , placebo-controlled clinical trial , in vivo blockade of TNF-alpha by a single infusion of a chimeric TNF-alpha-blocking mAb , cA2 , has proven to be highly effective in the treatment of RA . In parallel to this trial , we tested the consequences of cA2 infusion in ex vivo and in vitro experiments . In this paper , we describe an increase in CD4 + and CD8 + T lymphocyte counts on day 1 and a marked decrease in monocyte counts preferentially on day 7 after cA2 treatment , without major changes in B lymphocyte or NK cell counts . In addition , we found an increased responsiveness of P BMC to CD28 mAb/PMA , but not to CD3 mAb , superantigen staphylococcus enterotoxin B , or PHA on day 1 after infusion . The increase in DNA synthesis of P BMC was paralleled by increased IL-2 mRNA and IL-4 mRNA expression and IL-2 protein secretion in culture supernatants after in vitro stimulation of P BMC with CD28 mAb/PMA . In P BMC , we did not find any significant changes in mRNA or protein expression of CD28 Ag or CD28 lig and s , B7 - 1 and B7 - 2 . Serum concentrations of IL-1 beta , IL-6 , and soluble CD14 were significantly diminished after in vivo TNF-alpha blockade . We did not see relevant changes in granulocyte function in vitro after cA2 infusion . Finally , we observed a statistically significant decrease in slCAM-1 molecules in the serum of patients treated with verum  compared with that in the serum of subjects given placebo .  This change in slCAM-1 concentration was evident on days 1 and 7 after the infusion of 10 mg/kg cA2 , whereas it occurred only on day 7 in the serum of patients treated with the low dose ( 1 mg/kg ) of cA2 Objective . To evaluate the effect of golimumab on physical function , general health , and fatigue in patients with active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) therapy . Methods . In the multicenter , r and omized , placebo-controlled GO-FORWARD study , 444 adults with active RA despite MTX received subcutaneous placebo + MTX  ( crossover to golimumab 50 mg at Week 24 ) , golimumab 100 mg + placebo , golimumab 50 mg + MTX , or golimumab 100 mg + MTX every 4 weeks . Physical function and general health were assessed using the Health Assessment Question naire-Disability Index ( HAQ-DI ) and Physical and Mental Component Summary ( PCS , MCS ) scores of the Medical Outcomes Study Short Form-36 question naire ( SF-36 ) , respectively , through Week 52 . Fatigue was measured through Week 24 using the Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-Fatigue ) question naire . Results . Mean improvements from baseline in HAQ-DI , SF-36 PCS , and FACIT-Fatigue scores ( Weeks 14 and 24 ) were significantly greater for golimumab 50 mg + MTX and 100 mg + MTX versus placebo + MTX . Significantly greater proportions of patients treated with golimumab + MTX achieved clinical ly meaningful improvements from baseline to Weeks 14 and 24 in HAQ-DI , PCS , and FACIT-Fatigue scores . Mean improvements in SF-36 PCS ( Week 14 ) , MCS ( Week 24 ) , and FACIT-Fatigue ( Weeks 14 and 24 ) scores were significantly greater for golimumab 100 mg + placebo versus placebo + MTX . Mean improvements from baseline in HAQ-DI , SF-36 PCS , and MCS scores through Week 24 were sustained through Week 52 . Conclusion . Patients with active RA despite MTX had significant improvement in physical function , general health , and fatigue following golimumab + MTX therapy ; improvements in physical function and general health were maintained through Week 52 . ( Clinical Trials Registration NCT00264550 Objectives To compare over 2 years the safety , efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab , in combination with methotrexate ( MTX ) , in patients with rheumatoid arthritis ( RA ) . Methods AMPLE is a phase IIIb , 2-year , r and omised , investigator-blinded study with a 1-year primary endpoint . Biologic-naive patients with active RA and an inadequate response to MTX  were r and omised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly , both with a stable dose of MTX . Results Of 646 patients r and omised , 79.2 % abatacept and 74.7 % adalimumab  patients completed year 2 . At year 2 , efficacy outcomes , including radiographic , remained comparable between groups and with year 1 results . The American College Rheumatology 20 , 50 and 70 responses at year 2 were 59.7 % , 44.7 % and 31.1 % for abatacept and 60.1 % , 46.6 % and 29.3 % for adalimumab . There were similar rates of adverse events ( AEs ) and serious adverse events ( SAEs ) . More serious infections occurred with adalimumab ( 3.8 % vs 5.8 % ) including two cases of tuberculosis with adalimumab . There were fewer discontinuations due to AEs ( 3.8 % vs 9.5 % ) , SAEs ( 1.6 % vs 4.9 % ) and serious infections ( 0/12 vs 9/19 patients ) in the abatacept group . Injection site reactions ( ISRs ) occurred less frequently with abatacept ( 4.1 % vs 10.4 % ) . Conclusions Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX , subcutaneous abatacept and adalimumab were similarly efficacious based on clinical , functional and radiographic outcomes . Overall , AE frequency was similar in both groups but there were less discontinuations due to AEs , SAEs , serious infections and fewer local ISRs with abatacept . Clinical Trials.gov Identifier NCT00929864 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 Objectives : The phase III RADIATE study examined the efficacy and safety of tocilizumab , an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis ( RA ) refractory to tumour necrosis factor ( TNF ) antagonist therapy . Methods : 499 patients with inadequate response to one or more TNF antagonists were r and omly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo ( control ) intravenously every 4 weeks with stable methotrexate for 24 weeks . ACR20 responses , secondary efficacy and safety endpoints were assessed . Results : ACR20 was achieved at 24 weeks by 50.0 % , 30.4 % and 10.1 % of patients in the 8 mg/kg , 4 mg/kg and control groups , respectively ( less than p<0.001 both tocilizumab groups versus control ) . At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls ( less than p = 0.001 ) . Patients responded regardless of most recently failed anti-TNF or the number of failed treatments . DAS28 remission ( DAS28 < 2.6 ) rates at week 24 were clearly dose related , being achieved by 30.1 % , 7.6 % and 1.6 % of 8 mg/kg , 4 mg/kg and control groups ( less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control ) . Most adverse events were mild or moderate with overall incidences of 84.0 % , 87.1 % and 80.6 % , respectively . The most common adverse events with higher incidence in tocilizumab groups were infections , gastrointestinal symptoms , rash and headache . The incidence of serious adverse events was higher in controls ( 11.3 % ) than in the 8 mg/kg ( 6.3 % ) and 4 mg/kg ( 7.4 % ) groups . Conclusion : Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile . Trial registration number : NCT00106522 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 assess the efficacy and safety of golimumab + methotrexate ( MTX ) in Japanese patients with active rheumatoid arthritis ( RA ) . Methods 269 Japanese patients with active RA despite treatment with MTX  were r and omised ( 1:1:1 ) to placebo + MTX ( Group 1 ) , golimumab 50 mg + MTX ( Group 2 ) or golimumab 100 mg + MTX ( Group 3 ) . Subcutaneous golimumab/placebo was injected every 4 weeks ; stable doses of oral MTX ( 6–8 mg/week ) were continued . Patients were allowed to enter early escape ( Group 1 added golimumab 50 mg , Group 2 increased golimumab to 100 mg , Group 3 continued golimumab 100 mg ) based on swollen/tender joint counts at week 14 . The primary study endpoint was achievement of at least 20 % improvement in the American College of Rheumatology ( ACR20 ) response criteria at week 14 . To control for multiplicity of testing , treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1 , followed by comparisons of Group 2 and Group 3 versus Group 1 . Results The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 ( 73.4 % , 127/173 ) and in each of Group 2 ( 72.1 % , 62/86 ) and Group 3 ( 74.7 % , 65/87 ) compared with Group 1 ( 27.3 % , 24/88 ; p<0.0001 for all comparisons ) . Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters , including disease activity score ( DAS28 ) response/remission and radiographic assessment s. During the 16-week fixed treatment regimen study period , 72.7 % , 75.6 % and 78.2 % of patients had adverse events and 1.1 % , 1.2 % and 2.3 % had serious adverse events in Groups 1 , 2 and 3 , respectively . Conclusion In Japanese patients with active RA despite MTX therapy , golimumab + MTX was significantly more effective  than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves 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 Objective To assess the efficacy and safety of adalimumab plus methotrexate ( ADA+MTX ) compared with methotrexate monotherapy in achieving stable low disease activity ( LDA ; disease activity score ( DAS28(CRP ) ) < 3.2 at weeks 22 and 26 ) and clinical , radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis ( RA ) . Methods 1032 patients with active RA were r and omly assigned 1:1 to ADA+MTX or placebo plus methotrexate ( PBO+MTX ) for 26 weeks . Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP ) < 3.2 at weeks 22 and 26 . Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission . Results Among patients completing 6 months , 44 % ( 207/466 ) ADA+MTX versus 24 % ( 112/460 ) PBO+MTX patients achieved stable LDA at weeks 22 and 26 ( p<0.001 ) . Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses , more clinical remissions , greater mean reductions in DAS28(CRP ) , no radiographic progression , and normal functional status at week 26 ( p<0.001 for all ) . The only factor predicting stable LDA was disease activity at week 12 . Patients achieving ACR/EULAR remission , particularly in the PBO+MTX group , had some advantage in radiographic outcomes compared with patients who only achieved LDA ( but not remission ) . The overall frequency of adverse events was comparable between groups . There were more serious infections and deaths in the ADA+MTX group , with a possible age effect . Conclusions Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical , radiographic and functional outcomes in patients with early active RA . Before initiating treatment with adalimumab , individual patient evaluation of the benefit/risk ratio should be carefully considered The superiority of the combination therapy of methotrexate ( MTX ) and anti-tumor necrosis factor ( TNF ) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis ( RA ) has been demonstrated . We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept ( ETN ) in patients with active RA despite MTX therapy .  In total , 151 patients with active RA despite treatment with MTX  were r and omized to either ETN 25 mg twice a week and MTX 6–8 mg/week ( the E + M group ) or ETN alone ( the E group ) . Co- primary endpoints included the European League Against Rheumatism ( EULAR ) good response rate and the American College of Rheumatology ( ACR ) 50 response rate at week 24 . Demographic and clinical features between groups at baseline were similar . The EULAR good response rates were significantly higher in the E + M group ( 52 % ) than in the E group ( 33 % ) at week 24 ( p = 0.0001 ) . Although the ACR50 response rate , one of the co- primary endpoints , and the ACR70 response rate at week 24 were not significantly greater in the E + M group ( 64 and 38 % , respectively ) than in the E group ( 48 and 26 % , respectively ) , the ACR20 response rate was significantly greater in the E + M group ( 90 % ) than in the E group ( 64 % ; p = 0.0002 ) . Safety profiles were similar for the groups . Thus , MTX should be continued at the commencement of ETN therapy , even in RA patients who show an inappropriate response to MTX OBJECTIVE Rheumatoid arthritis ( RA ) patients who have inadequate response to anti-tumour necrosis factor ( TNF ) therapy  currently have treatment options that are limited and less than optimal in their risk-to-benefit ratio . Abatacept provides a new generation of RA medications that has previously been demonstrated to have positive clinical outcomes with this population . The current study sought to demonstrate the efficacy of abatacept on quality of life ( QoL ) for RA patients with inadequate response to anti-TNF therapy . METHODS Patients were entered into a double-blind , placebo-controlled , multicentre r and omized clinical trial , with 258 patients r and omized to abatacept + disease-modifying anti-rheumatic drugs ( DMARDs ) and 133 patients r and omized to placebo + DMARDS . The QoL was measured with the Short Form Health Survey ( SF-36 ) , Health Assessment Question naire ( HAQ ) and fatigue visual analogue scale , and was analysed with basic ( ANOVA , chi-square ) and multigroup growth curve techniques to assess differential change over time . RESULTS Treatment group QoL improved significantly more than placebo on the HAQ and fatigue indices , as well as seven of the eight SF-36 scales and SF-36 physical and mental summary scores . Improvement rate was faster for abatacept than for placebo on the QoL measures , and the improvements from abatacept related to normal levels of QoL on many domains . CONCLUSION Clinical ly relevant benefits of abatacept over placebo are discussed regarding improving QoL. Importantly , the larger rate of change for abatacept over placebo provides clinicians with a medication that can lead to meaningful changes in a patient 's life within a few weeks , even when the patient previously failed anti-TNF therapy OBJECTIVE To assess cost-effectiveness of abatacept in patients with moderately to severely active RA and inadequate response to MTX .  METHODS We developed a simulation model to depict progression of disability [ in terms of the HAQ Disability Index ( HAQ-DI ) ] in women aged 55 - 64 yrs with moderately to severely active RA and inadequate response to MTX .  At model entry , patients were assumed to receive either only MTX or MTX plus abatacept . Patients were then tracked from model entry until death . Future health-state utilities and medical-care costs ( except study therapy ) were estimated based on predicted values of the HAQ-DI . The model was estimated using data from a Phase III clinical trial of abatacept plus various secondary sources . Cost-effectiveness was expressed in terms of incremental cost ( 2006 US$ ) per quality -adjusted life-year ( QALY ) gained over alternatively 10 yrs and a lifetime . Costs and health effects were both discounted at 3 % annually . RESULTS Over 10 yrs , abatacept would yield 1.2 additional QALYs ( undiscounted ) per patient ( 4.6 vs 3.4 for MTX ) at an incremental ( discounted ) cost of $ 51,426 ( $ 103,601 vs $ 52,175 , respectively ) ; over a lifetime , corresponding figures were 2.0 QALYS ( 6.8 vs 4.8 ) and $ 67,757 ( $ 147,853 vs $ 80,096 ) . Cost-effectiveness was [ mean ( 95 % CI ) ] $ 47,910 ( $ 44,641 , $ 52,136 ) per QALY gained over 10 yrs and $ 43,041 ( $ 39,070 , $ 46,725 ) per QALY gained over a lifetime . Findings were robust in sensitivity analyses . CONCLUSION Abatacept is cost-effective by current st and ards of medical practice in patients with moderately to severely active RA and inadequate response to MTX We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) .  In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX Objective To 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 OBJECTIVES In early and active RA despite MTX , continuous treatment with TNF blockers in combination with MTX is recommended . To compare this strategy with an initial combination of MTX and adalimumab ( ADA ) given for 3 months and then adjusted based on the disease activity status . METHODS Prospect i ve unblinded r and omized multicentre controlled 1-year trial in which 65 patients with early ( < 6 months ) and active [ disease activity score ( DAS28(ESR ) ) > 5.1 ] RA were assigned to Group 1 ( 32 patients ):  MTX ( 0.3 mg/kg/week , maximum of 20 mg/week , without escalating dose regimen ) or to Group 2 ( 33 patients ): initial combination therapy with MTX ( as in Group 1 ) and ADA ( 40 mg eow ) . In both groups , treatment was adjusted every 3 months . The aim was to achieve a low DAS ( DAS28(ESR ) < 3.2 ) . RESULTS From Week 12 until Week 52 , seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy ( P = 0.28 ) . The 1-year area under the curve ( AUC ) of DAS28 was lower in Group 2 owing to an initial better response . The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups . CONCLUSIONS Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX Objective To evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate . Methods Patients were r and omly assigned to receive placebo plus methotrexate ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus methotrexate ( group 3 ) and golimumab 100 mg plus methotrexate ( group 4 ) . At week 16 , patients in groups 1 , 2 and 3 who had less than 20 % improvement in tender and swollen joints entered early escape . At week 24 , patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate . Results At week 16 , 31 % , 27 % and 17 % of patients in groups 1 , 2 and 3 , respectively , entered early escape . At week 52 , 44 % , 45 % , 64 % and 58 % of patients in groups 1 , 2 , 3 and 4 , respectively , achieved 20 % improvement in the American College of Rheumatology criteria ; and 34 % , 31 % , 42 % and 53 % , respectively , achieved low disease activity ( ≤3.2 ) according to the 28-joint disease activity score . Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections . Conclusion The results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks . The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors BACKGROUND Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy . Tocilizumab -- an inhibitor of interleukin 6 receptor signalling -- has been studied as monotherapy in several clinical trials . We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis . METHODS We did this r and omised , double-blind , parallel-group , phase 4 superiority study in 76 centres in 15 countries in North and South America , Australasia , and Europe . We enrolled patients who were aged at least 18 years , had severe rheumatoid arthritis for 6 months or more , and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment . Patients were r and omly assigned ( 1:1 ; block size of four ) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks . Investigators , patients , and sponsor personnel were masked to assignment . The primary endpoint was change in disease activity score using 28 joints ( DAS28 ) from baseline to week 24 . This trial is registered with Clinical Trials.gov , number NCT01119859 . FINDINGS We screened 452 patients and enrolled 326 patients . The intention-to-treat population contained 325 patients ( 163 assigned to tocilizumab , 162 assigned to adalimumab ) . Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group ( -3·3 ) than in the adalimumab group ( -1·8 ) patients ( difference -1·5 , 95 % CI -1·8 to -1·1 ; p<0·0001 ) . 16 of 162 ( 10 % ) patients in the adalimumab group versus 19 of 162 ( 12 % ) in the tocilizumab group had serious adverse events . More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol , increased alanine aminotransferase concentrations , and reduced platelet and neutrophil counts . INTERPRETATION Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate . The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings . FUNDING F Hoffmann-La Roche OBJECTIVE To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis ( RA ) who previously discontinued tumour necrosis factor ( TNF ) antagonists for any reason in clinical practice . METHODS ReAct ( Research in Active Rheumatoid Arthritis ) was a large , open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers . Patients self-administered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase . Measures of adalimumab effectiveness included American College of Rheumatology ( ACR ) and European League Against Rheumatism ( EULAR ) response criteria , Disease Activity Score 28 ( DAS28 ) and the Health Assessment Question naire Disability Index ( HAQ DI ) . RESULTS Of 6610 patients , 899 had a history of etanercept and /or infliximab therapy ; these patients experienced substantial clinical benefit from adalimumab treatment . At week 12 , 60 % of patients had an ACR20 and 33 % had an ACR50 response ; 76 % had a moderate and 23 % had a good EULAR response . In addition , 12 % achieved a DAS28 < 2.6 , indicating clinical remission , and 13 % achieved a HAQ DI score < 0.5 . The allergic adverse event rate , regardless of relationship to adalimumab , was 6.5/100-patient-years ( PYs ) in previously TNF-antagonist-exposed patients and 4.3/100-PYs in TNF-antagonist-naive patients . A multiple regression analysis indicated no statistically significantly increased risk of serious infections in patients who received prior TNF antagonists compared with TNF-antagonist-naive patients . CONCLUSION In typical clinical practice , adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and /or infliximab OBJECTIVE Anti-tumor necrosis factor alpha agents are among the most effective therapies for rheumatoid arthritis ( RA ) . However , their optimal use is yet to be determined . This 12-month double-blind study attempted remission induction using st and ard therapy with or without infliximab in patients with early , poor-prognosis RA . The primary end point was synovitis ( measured by magnetic resonance imaging [ MRI ] ) . Clinical observations continued to 24 months . METHODS All patients had fewer than 12 months of symptoms . Assessment s included full metrologic evaluation , laboratory tests , radiographs , functional evaluation using the Health Assessment Question naire ( HAQ ) , and quality of life measurement using the RA Quality of Life ( RAQoL ) question naire . MRI was performed at 0 , 4 , 14 , and 54 weeks ; MR images were scored blindly . Patients received methotrexate ( MTX ) and were r and omized to receive either infliximab or placebo for 12 months . RESULTS Twenty patients were recruited ( mean age 52 years , mean symptom duration 6 months , mean C-reactive protein level 42 mg/liter , and 65 % rheumatoid factor positive ) . At 1 year , all MRI scores were significantly better , with no new erosions in the infliximab plus MTX group ; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology ( ACR ) 50 % and 70 % improvement criteria ( 78 % versus 40 % in the placebo plus MTX group and 67 % versus 30 % , respectively ) and had a greater functional benefit ( P < 0.05 for all comparisons ) . Importantly , at 1 year after stopping induction therapy , response was sustained in 70 % of the patients in the infliximab plus MTX group , with a median Disease Activity Score in 28 joints ( DAS28 ) of 2.05 ( remission range ) . At 2 years , there were no significant between-group differences in the DAS28 , ACR response , or radiographic scores , but differences in the HAQ and RAQoL scores were maintained ( P < 0.05 ) . CONCLUSION Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year . At 2 years , functional and quality of life benefits were sustained , despite withdrawal of infliximab therapy . These data may have significant implication s for the optimal use of expensive biologic therapies 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 Recent years have seen many exciting developments in the treatment of inflammatory arthritis .  Tocilizumab ( TCZ ) is a compound that inhibits the IL-6 receptor . Following initial studies in Japan , it has been extensively studied in five multicenter clinical trials . This report concentrates on the Actemra Versus Methotrexate Double-blind Investigative Trial in Monotherapy ( AMBITION ) , which compared TCZ monotherapy ( 8 mg/kg every 4 weeks ) with methotrexate monotherapy over 24 weeks . TCZ was shown to be the first biologic agent that is superior to methotrexate across a whole range of clinical outcomes measures with a rapid onset of effect . Significant liver toxicity was less common in the  TCZ group . However , increases in lipids and decreases in neutrophils and skin infections were more common in the TCZ arm . Long-term efficacy and safety follow-up is ongoing . This trial supports the use of TCZ as monotherapy and suggests it should be regarded as a first-line biologic therapy OBJECTIVES To examine the effectiveness and cost-effectiveness of symptomatic versus aggressive treatment in patients with established , stable rheumatoid arthritis ( RA ) . DESIGN A r and omised observer-blinded controlled trial and economic evaluation with an initial assessment at r and omisation and follow-ups at 12 , 24 and 36 months . SETTING Five rheumatology centres in Engl and . The ' symptomatic care ' patients were managed predominantly in primary care with regular visits by a rheumatology specialist nurse . The ' aggressive care ' patients were managed predominantly in the hospital setting . PARTICIPANTS Patients with RA for more than 5 years were screened in rheumatology clinics . INTERVENTIONS The symptomatic care patients were seen at home every 4 months by a rheumatology specialist nurse and annually by the rheumatologist . The aim of treatment was symptom control . The aggressive care patients were seen at least every 4 months in hospital . Their treatment was altered ( following predefined algorithms ) with the aim of suppressing both clinical and laboratory evidence of joint inflammation . MAIN OUTCOME MEASURES The main outcome measure was the Health Assessment Question naire ( HAQ ) . Others included the patient and physician global assessment , pain , tender and swollen joint counts , the erythrocyte sedimentation rate and the OSRA ( Overall Status in Rheumatoid Arthritis ) score . X-rays of the h and s and feet were performed at the beginning and end of the study . The EQ-5D was used in the health economic evaluation . Comprehensive costs were also estimated and were combined with measures of outcome to examine between-group differences . RESULTS A total of 466 patients were recruited ; 399 patients completed the 3 years of follow-up . There was a significant deterioration in physical function ( HAQ ) in both arms . There was no significant difference between the groups for any of the clinical outcome measures except the physician global assessment [ adjusted mean difference 3.76 ( 95 % CI 0.03 to 7.52 ) ] and the OSRA disease activity component [ adjusted mean difference 0.41 ( 95 % CI 0.01 to 0.71 ) ] , both in favour of the aggressive arm . During the trial , second-line drug treatment was changed in 77.1 % of the aggressive arm and 59.0 % of the symptomatic arm . There were instances when the rheumatologist should have changed treatment but did not do so , usually because of mild disease activity . The symptomatic arm was associated with higher costs and higher quality -adjusted life-years ( QALYs ) . There was a net cost of 1517 Pounds Sterling per QALY gained for the symptomatic arm . Overall , the primary economic analysis and sensitivity analyses of the cost and QALY data indicate that symptomatic treatment is likely to be more cost-effective than aggressive treatment in 58 - 90 % of cases . CONCLUSIONS This trial showed no benefit of aggressive treatment in patients with stable established RA . However , it was difficult to persuade the rheumatologist and /or the patient to change treatment if the evidence of disease activity was minimal . Patients in the symptomatic arm were able to initiate changes of therapy when their symptoms deteriorated , without frequent hospital assessment . Approximately one-third of current clinic attenders with stable RA could be managed in a shared care setting with annual review by a rheumatologist and regular contact with a rheumatologist nurse . Further research is needed into disease progression and the use of biological agents , minimum disease activity level below which disease progression does not occur , cost-effectiveness through shared care modelling , the development of a robust and fail-safe system of primary -care based disease-modifying anti-rheumatic drug ( DMARD ) monitoring , and predicting response to DMARDs OBJECTIVE To compare work disability and job loss in early rheumatoid arthritis ( RA ) patients receiving adalimumab plus methotrexate ( adalimumab + MTX ) versus MTX alone .  METHODS In this multicenter , r and omized , controlled trial , patients with RA for < 2 years who had never taken MTX and who self-reported work impairment were r and omized to  adalimumab + MTX or placebo + MTX for 56 weeks . Primary outcome was job loss of any cause and /or imminent job loss at or after week 16 . Secondary outcomes included disease activity , function ( Health Assessment Question naire [ HAQ ] score ) , and RA quality of life ( RAQoL ) question naire score . Work was evaluated with work diaries and the RA Work Instability Scale . RESULTS Although job loss during the 56-week study was significantly lower with adalimumab + MTX ( 14 of 75 patients ) compared with MTX alone ( 29 of 73 patients ; P=0.005 ) , the primary end point was not met ( 12 of 75 versus 20 of 73 patients ; P=0.092 ) , likely owing to early drop out in the MTX group . There were significant improvements in American College of Rheumatology 20 % response criteria , 28-joint Disease Activity Score , DeltaHAQ , DeltaRAQoL , and working time lost in the adalimumab + MTX group . Twenty-four serious adverse events were reported in 17 participants , with no differences between groups . CONCLUSION Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone , which supports the early use of anti-tumor necrosis factor therapy and suggests its cost efficacy 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 R and omized clinical trials ( RCTs ) evaluate the efficacy of treatments in selected groups of patients defined by strict inclusion criteria . The value of these trials in predicting therapeutic effectiveness in " real world " patients is limited . This observational cohort study was design ed to complement the knowledge obtained in RCTs by evaluating the effectiveness of tumor necrosis factor ( TNF ) inhibitors in patients with rheumatoid arthritis ( RA ) according to their eligibility for the major trials . METHODS Using the data from the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy ( RABBIT [ in German ] ) , we investigated how many of the RA patients who were treated with a TNF inhibitor ( infliximab , etanercept , or adalimumab )  would have been eligible for the major clinical trials that led to approval of the drugs . In addition , therapeutic effectiveness was compared in the eligible and ineligible patients using the American College of Rheumatology 20 % ( ACR20 ) and 50 % ( ACR50 ) improvement response criteria . RESULTS Only 21 - 33 % of the patients in the RABBIT register would have been eligible for the major trials . In these patients , the ACR20 and ACR50 improvement responses , indicating therapeutic effectiveness , were comparable with the response rates in the published trials . ACR response rates were lower in those patients considered ineligible for the trials ; however , absolute improvement was similar to that in eligible patients . Ineligible patients had lower baseline disease activity , more comorbidity , and lower functional status . CONCLUSION RCT cohorts reflect only a minor proportion of the patients treated with biologic agents in routine care . In the clinic setting , the indications for treatment with biologic agents are not identical to the inclusion criteria for trials . Despite the smaller relative improvement achieved in these patients with longst and ing , severe RA who would not fulfill the inclusion criteria of a major trial , the majority of such patients would nevertheless benefit from biologic therapy 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 OBJECTIVE To demonstrate the efficacy of etanercept to reduce synovitis as measured by magnetic resonance imaging ( MRI ) as early as 6 weeks after starting treatment in patients with active rheumatoid arthritis ( RA ) . METHODS Twenty-two patients with active RA despite disease modifying antirheumatic drug ( DMARD ) treatment were included in this prospect i ve , controlled study . Patients were r and omized in 2 groups . In the treatment group , etanercept was added at usual doses during 6 weeks . In the control group , patients continued with prior DMARD therapy . MRI of the dominant wrist and 2nd-5th MCP joints were obtained at baseline and at 6 weeks and evaluated according to OMERACT recommendations . Results of changes in synovitis in the treatment group were compared with changes in the control group . RESULTS Changes in synovitis measured by MRI of the h and ( OMERACT evaluation ) in the etanercept group showed a significant reduction after 6 weeks of treatment compared with no changes in the control group . Reduction of synovitis in the treatment group also showed good correlation with decrease of various clinical and laboratory measures . CONCLUSION In patients with active RA despite DMARD therapy , etanercept , but not placebo , reduced synovitis as measured by MRI after 6 weeks Abstract Objectives . This 24-week , multicenter , double-blind , r and omized , placebo-controlled study ( NCT00791999 ) compared efficacy and safety of certolizumab pegol ( CZP ) in combination with methotrexate ( MTX ) vs placebo plus MTX in Japanese rheumatoid arthritis ( RA ) patients with inadequate response to MTX .  Methods . In total , 316 patients were r and omized 1:1:1:1 to subcutaneous CZP 100 , 200 , or 400 mg ( induction dose : 200 mg or 400 mg CZP at Weeks 0 , 2 , and 4 ) plus MTX or placebo plus MTX every 2 weeks . Primary endpoint was ACR20 response at Week 12 . Results . ACR20 response rates were 62.5 % , 76.8 % , 77.6 % , and 28.6 % at Week 12 , and 61.1 % , 73.2 % , 71.8 % , and 24.7 % at Week 24 for CZP 100 , 200 , and 400 mg , and placebo groups , respectively , with statistical significance between each CZP group and placebo . Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo . Improvements in health-related quality of life ( HRQoL ) were observed in all three CZP groups vs placebo . Incidence of adverse events was similar between CZP groups . Conclusions . CZP plus MTX result ed in rapid , sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX  , with significant inhibition of radiographic progression and improved 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 safety of abatacept , a selective costimulation modulator , in patients with active rheumatoid arthritis ( RA ) who had been receiving > or = 1 traditional nonbiologic and /or biologic disease-modifying antirheumatic drugs ( DMARDs ) approved for the treatment of RA for at least 3 months prior to entry into the study . METHODS This was a 1-year , multicenter , r and omized , double-blind , placebo-controlled trial . Patients were r and omized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range  , or placebo . RESULTS The abatacept and placebo groups exhibited similar frequencies of adverse events ( 90 % and 87 % , respectively ) , serious adverse events ( 13 % and 12 % , respectively ) , and discontinuations due to adverse events ( 5 % and 4 % , respectively ) . Five patients ( 0.5 % ) in the abatacept group and 4 patients ( 0.8 % ) in the placebo group died during the study . Serious infections were more frequent in the abatacept group than in the placebo group ( 2.9 % versus 1.9 % ) . Fewer than 4 % of patients in either group experienced a severe or very severe infection . The incidence of neoplasms was 3.5 % in both groups . When evaluated according to background therapy , serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent ( 22.3 % ) than in the other subgroups ( 11.7 - 12.5 % ) . CONCLUSION Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes . However , abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events . Therefore , abatacept is not recommended for use in combination with biologic therapy OBJECTIVE To calculate mortality rate associated with rheumatoid arthritis ( RA ) , to estimate the effect of initial functional status and of change in functional status on mortality among persons with RA , and to compare the mortality experience of such persons to that of the US population . METHODS The study used a prospect i ve panel of 1269 persons followed for a mean of 8.4 years ( median 7 yrs , interquartile range 3 - 12 , maximum 18 ) . Mortality status was ascertained from contacts with next of kin , study physicians , and search of the National Death Index . The Kaplan-Meier method was used to calculate the proportion dying in each time interval , with and without stratification for initial functional status [ Health Assessment Question naire ( HAQ ) score ] or average change in functional status . Cox proportional hazards regression was used to establish the effect of functional status , demographic characteristics , and health status on mortality risk . RESULTS There were 270 deaths among the 1269 persons with RA . After 18 years of followup the overall death rate was 39 % . The death rates in the best through worst initial quartiles of HAQ score were 29 , 33 , 44 , and 54 % . The death rate was 51 % among persons with declining HAQ score versus 31 and 32 % among those with no change or improvement in this measure , respectively . Demographic and health status did not reduce the effect of HAQ or average change in HAQ on mortality risk . Compared to the US population , the persons with RA had a st and ardized mortality rate of 1.32 . CONCLUSION The persons with RA in this study had elevated mortality rates . Poor initial functional status and declining functional status significantly increased mortality risk among these persons with RA Objective . To evaluate the efficacy and safety of initial combination treatment with adalimumab ( ADA ) and methotrexate ( MTX ) versus monotherapy with ADA or MTX during an open-label extension of PREMIER . Methods . Patients with early rheumatoid arthritis ( RA ) received blinded ADA plus MTX , ADA alone , or MTX alone for 2 years in PREMIER . At Year 2 , patients could enroll in an open-label extension and receive ADA monotherapy ; MTX could be added at the investigator ’s discretion . Longterm efficacy results are presented as observed data . Results . In the open-label period , 497 of the original 799 r and omized patients had ≥ 1 dose of ADA  ( by original r and omization : ADA plus MTX , n = 183 ; ADA , n = 159 ; MTX , n = 155 ) . In the completers cohort [ patients with available Year-5 ACR responses and modified total Sharp scores ( mTSS ) ] , the Year-5 mean change from baseline in mTSS for the ADA+MTX arm ( n = 124 ) was 2.9 , compared with 8.7 and 9.7 in the ADA ( n = 115 ) and MTX ( n = 115 ) arms . Comprehensive disease remission , defined as the combination of DAS28 remission , normal function ( Health Assessment Question naire ≤ 0.5 ) , and radiographic nonprogression ( ΔmTSS ≤ 0.5 ) , was achieved by more patients in the initial ADA+MTX arm ( 35 % ) than in the ADA ( 13 % ) or MTX ( 14 % ) arms . Conclusion . Initial combination treatment with ADA plus MTX , followed by open-label ADA , led to better longterm clinical , functional , and radiographic outcomes than either initial ADA or MTX monotherapy during 5 years of treatment Objective The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis ( RA ) with an inadequate clinical response to methotrexate ( MTX ) .  Methods In this multicenter , placebo-controlled , double-blind , parallel-group , dose – response study , 195 Japanese patients with active RA with an inadequate response to MTX were r and omized 1:1:1 to receive 10 mg/kg or 2 mg/kg abatacept plus MTX , or placebo plus MTX , for 24 weeks . Results Abatacept demonstrated a dose – response relationship when given at 2 and 10 mg/kg . Based on the American College of Rheumatology criteria ( 20 , 50 , and 70 % ) , the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 ( p < 0.001 ) . Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group . Overall rates of adverse events , serious adverse events , and treatment discontinuations because of adverse events were comparable in all three groups . Conclusions Abatacept ( 2 mg/kg and 10 mg/kg ) showed a dose – response relationship in Japanese patients with active RA with an inadequate clinical response to MTX . Administration of abatacept in combination with MTX for 24 weeks was well tolerated BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied .  ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis OBJECTIVE To evaluate the safety , efficacy , and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis ( RA ) . METHODS Four hundred twenty RA patients were r and omized to receive , in a blinded manner , the study drug for up to 16 weeks : 214 patients received 50 mg etanercept once weekly , 153 received 25 mg etanercept twice weekly , and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks . Efficacy and safety were assessed at weeks 8 and 16 . Pharmacokinetic analyses were performed on serum sample s from patients at selected study sites . The primary efficacy end point was achievement of the American College of Rheumatology ( ACR ) 20 % improvement criteria ( ACR20 response ) at week 8 . RESULTS An ACR20 response was achieved at week 8 by 50 % of the patients receiving 50 mg etanercept once weekly , by 49 % of the patients receiving 25 mg etanercept twice weekly , and by 19 % of the patients in the placebo group ( P < /= 0.0001 for each etanercept group versus placebo ) . Similarly , achievement of the ACR50 response was attained by 18 % of patients in each of the 2 etanercept groups , compared with 6 % of patients in the placebo group ( P < 0.03 for each comparison ) . Pharmacokinetics of the 2 etanercept regimens were similar at steady state . No clinical ly significant differences in efficacy or safety were observed between the 2 etanercept groups . CONCLUSION Safety , efficacy , and pharmacokinetics were comparable between the 2 etanercept dosing regimens . Thus , comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX )  were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab  dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 OBJECTIVE To compare the efficacy , safety , and tolerability of 6 dosages of oral tofacitinib ( CP-690,550 ) with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients receiving a stable background regimen of methotrexate ( MTX ) who have an inadequate response to MTX monotherapy . METHODS In this 24-week , double-blind , phase IIb study , patients with active RA ( n = 507 ) were r and omized to receive placebo or tofacitinib ( 20 mg/day , 1 mg twice daily , 3 mg twice daily , 5 mg twice daily , 10 mg twice daily , or 15 mg twice daily ) . All patients continued to receive a stable dosage of MTX . The primary end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at week 12 . RESULTS At week 12 , ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily ( 52.9 % for 3 mg twice daily , 50.7 % for 5 mg twice daily , 58.1 % for 10 mg twice daily , 56.0 % for 15 mg twice daily , and 53.8 % for 20 mg/day ) were significantly ( P ≤ 0.05 ) greater than those for placebo ( 33.3 % ) . Improvements were sustained at week 24 for the ACR20 , ACR50 , and ACR70 responses , scores for the Health Assessment Question naire disability index , the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level ( DAS28-CRP ) , and a 3-variable DAS28-CRP of < 2.6 . The most common treatment-emergent adverse events occurring in > 10 % of patients in any tofacitinib group were diarrhea , upper respiratory tract infection , and headache ; 21 patients ( 4.1 % ) experienced serious adverse events . Sporadic increases in transaminase levels , increases in cholesterol and serum creatinine levels , and decreases in neutrophil and hemoglobin levels were observed . CONCLUSION In patients with active RA in whom the response to MTX has been inadequate , the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks 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 Peripheral blood mononuclear cells ( P BMC ) from patients with rheumatoid arthritis ( RA ) have increased expression of nitric oxide synthase type 2 ( NOS2 ) protein and enhanced formation of nitric oxide ( NO ) that correlate with disease activity . NO may play a role in the inflammation of RA . Treatment of RA patients with a chimeric monoclonal antibody against tumor necrosis factor alpha ( TNFalpha ; cA2 ) results in clinical improvement in the majority of patients . The present study was design ed to determine if cA2 therapy decreases P BMC NOS2 protein expression and NOS enzyme activity in RA patients . METHODS RA patients receiving background oral methotrexate  participated in a double-blind , placebo-controlled clinical trial in which they were r and omly assigned to receive a single infusion of either placebo or cA2 at 5 , 10 , or 20 mg/kg . NOS2 protein and NOS enzyme activity were measured in P BMC at baseline and 4 weeks following cA2 therapy . These results were compared with the degree of clinical change in disease activity . RESULTS At baseline , elevated levels of NOS2 protein and NOS enzyme activity were more frequently detected in P BMC from RA patients than in those from healthy controls . Treatment of the RA patients with cA2 significantly reduced NOS2 protein expression and NOS enzyme activity . Changes in NOS activity following treatment correlated significantly with changes in the number of tender joints . CONCLUSION These results indicate that TNFalpha likely plays an important role in enhancing NOS2 expression in RA , and that the antiinflammatory effects of cA2 treatment may be mediated by a reduction of NO overproduction 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 Objectives : To compare the effects of etanercept ( ETN ) 50 mg once weekly plus methotrexate ( MTX ) versus MTX alone on patient-reported outcomes ( PROs ) and the relationship between remission and PRO improvement . Methods : In this double-blind , r and omised clinical trial ( COMET ) , PROs included : the Health Assessment Question naire ( HAQ ) , EuroQoL health status , fatigue and pain visual analogue scales , Hospital Anxiety and Depression Scale , and Medical Outcomes Short-Form-36 . Mean changes from baseline were analysed by analysis of covariance using the last observation carried forward method . Results from week 52 are presented . Results : Most PROs demonstrated significantly greater improvements with ETN+MTX than MTX alone , including physical functioning , pain , fatigue and overall health status . A significantly greater improvement in HAQ score was observed in the ETN+MTX than the MTX group ( −1.02 vs −0.72 ; p<0.001 ) and a greater proportion reached the minimal clinical ly important difference of 0.22 ( 88 % vs 78 % ; p<0.006 ) . The relationship between PRO score and clinical status indicated that improvement was greatest among patients achieving remission . Conclusions : Early treatment with ETN+MTX leads to significantly greater improvements in multiple dimensions of PROs than MTX alone . The close relationship between disease activity and PRO improvement suggests that early treatment , with remission as a goal , should maximise the chance of restoring normal functioning and 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 assess the efficacy , safety , and biologic activity of atacicept in tumor necrosis factor antagonist-naive patients with rheumatoid arthritis ( RA ) in whom the response to methotrexate treatment was inadequate . METHODS In this phase II study , patients with active RA ( n = 311 ) were r and omized 1:1:1:1 to receive placebo , atacicept 150 mg weekly with or without a 4-week loading period ( twice-weekly dosing ) , or open-label adalimumab 40 mg every other week , for 25 weeks . The primary end point was 20 % improvement in disease severity according to the American College of Rheumatology criteria , assessed using the C-reactive protein level ( ACR20-CRP ) , at week 26 . Secondary end points included additional assessment s of efficacy , biologic activity , and safety . RESULTS The proportion of patients meeting the primary end point ( ACR20-CRP response ) did not differ significantly in the atacicept groups and the placebo group ( 46 % in the placebo group , 45 % in the atacicept loading group , and 58 % in the atacicept nonloading group ) . In contrast , an ACR20-CRP response was observed in 71 % of patients in the adalimumab group ( P < 0.001 versus placebo ) . ACR50-CRP response rates were significantly higher in all active-treatment groups compared with placebo , but ACR70-CRP response rates were superior only in the adalimumab group . Atacicept treatment reduced the levels of serum IgG , IgA , and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells . The effects of treatment were similar with and without loading . Immunoglobulin levels returned toward baseline values during the treatment-free followup period ( week 38 ) . The most frequent adverse events associated with atacicept represented common illnesses . No serious infections occurred among patients treated with atacicept . CONCLUSION The primary end point ( ACR20-CRP response ) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action . Modest effects of atacicept were seen for some secondary efficacy end points . Treatment with atacicept raised no new safety concerns 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 investigate the longterm consequences of tumor necrosis factor-alpha ( TNF-alpha ) blockade in patients with rheumatoid arthritis ( RA ) , to compare changes after repeated infusion of cA2 monoclonal antibody with those occurring after the initial treatment , and to investigate significant correlations of cellular or serological changes to the duration of clinical benefit for each patient . METHODS A clinical trial testing TNF-alpha monoclonal antibody cA2 in treatment of RA showed this therapeutic agent is highly effective . A dosage of 1 mg/kg or 10 mg/kg cA2 , given in a single infusion , was compared to placebo . After clinical relapse all patients were (re)treated with 3 or 10 mg/kg cA2 . In parallel to this clinical study , we investigated cellular and molecular changes induced by in vivo blockade of TNF-alpha . RESULTS After an initial transient increase , T lymphocyte counts were not significantly different from starting values throughout the observation period . Monocyte counts as well as serum interleukin 6 ( IL-6 ) and soluble intercellular adhesion molecule 1 ( sICAM-1 ) concentrations remained decreased for several weeks after infusion . After a repeated infusion , increases in numbers of T cells and decreases in monocytes and IL-6 and sICAM-1 concentrations were evident again . Changes in cell counts , however , were smaller , especially in the group initially treated with the low dose ( 1 mg/kg ) , despite a higher retreatment dosage of 3 or 10 mg/kg cA2 . Similarly , in this group decrease of IL-6 and sICAM-1 concentrations was less pronounced , was delayed to Day 7 after infusion , and lasted for a shorter period than seen after initial treatment . CONCLUSION We conclude that in vivo TNF-alpha blockade leads to prolonged cellular and serological changes . This effect appears to be less pronounced after repeated infusion of cA2 compared to the initial treatment , mainly in the low dose group OBJECTIVE Biological products that neutralize tumour necrosis factor alpha ( TNF-alpha ) are beneficial in rheumatoid arthritis ( RA ) . We studied the effects of CDP870 , a novel anti-TNF-alpha antibody fragment modified to obtain a prolonged plasma half-life ( approximately 14 days ) . METHODS Thirty-six patients were r and omized in a double-blind , ascending-dose group study to a single intravenous infusion of placebo ( n = 12 ) or 1 , 5 or 20 mg/kg CDP870 ( each n = 8) . The patients were predominantly female ( 30/36 ) , had a mean age of 56 yr and a mean duration of RA of 13 years . They had received a mean of five DMARDs or experimental therapies ( with 1 month washout before the study started ) and had active disease . Continuation of NSAIDs and up to 7.5 mg prednisolone daily was allowed . Following the blinded dosing period , 32 patients received a single open-label infusion of either 5 or 20 mg/kg CDP870 . RESULTS In the blinded dosing period , 6/12 placebo patients withdrew from the study ( for deteriorating RA < or = 4 weeks after dosing ) . Two of 24 CDP870-treated patients withdrew , both in the 1 mg/kg group ( for deteriorating RA or lost to follow up > 4 weeks after dosing ) . The proportion of patients with ACR20 improvement for the per- protocol population with the last observation carried forward was 16.7 , 50 , 87.5 and 62.5 % after 0 , 1 , 5 and 20 mg/kg CDP870 respectively ( combined treatment effect , P = 0.012 , primary analysis ) at 4 weeks and 16.7 , 25 , 75 and 75 % ( P = 0.032 ) at 8 weeks . The proportion of patients with ACR50 improvement for the per- protocol population with the last observation carried forward was 0 , 12.5 , 12.5 and 50 % after 0 , 1 , 5 and 20 mg/kg CDP870 respectively ( combined treatment effect , P = 0.079 ) at 4 weeks and 0 , 12.5 , 12.5 and 50 % ( P = 0.079 ) at 8 weeks . Following the open-label dose of CDP870 , similar beneficial effects were achieved . CONCLUSION CDP870 is effective , was very well tolerated in this small study , and has an extended duration of action following one or more intravenous doses 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 abatacept treatment over 3 years in patients with rheumatoid arthritis ( RA ) refractory to methotrexate ( MTX ) . Methods Patients r and omised to abatacept or placebo ( + MTX ) during the 1-year double-blind period of the Abatacept in Inadequate responders to Methotrexate ( AIM ) trial received open-label abatacept ( + MTX ) in the long-term extension ( LTE ) . Safety was assessed for patients who received ≥1 dose of abatacept , regardless of r and omisation group . Efficacy was assessed for patients r and omised to abatacept who entered the LTE . Results 433 and 219 patients were r and omised and treated with abatacept or placebo , respectively ; 378 and 161 entered the LTE . At year 3 , 440/539 patients were ongoing . No unexpected safety events were observed in the LTE . By year 3 , incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years , respectively . Incidence rates were generally stable over time . At year 3 , 84.8 % , 63.4 % and 37.5 % of patients achieved American College of Rheumatology ( ACR ) criteria of 20 , 50 and 70 , respectively , compared with 82.3 % , 54.3 % and 32.4 % of patients at year 1 . Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years , with significantly greater inhibition during year 3 compared with year 2 ( p=0.022 for total score ) . Conclusion In MTX-inadequate responders with RA , abatacept  provided consistent safety and sustained efficacy over 3 years . The data suggest an increasing inhibitory disease-modifying effect on radiographic progression OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE OBJECTIVE To determine whether there is a relation between disease duration and functional outcome in patients with rheumatoid arthritis ( RA ) treated with intramuscular sodium aurothiomolate ( gold ) for five years . METHODS 440 patients with RA were enrolled in a prospect i ve trial of gold treatment . Initial demographic details were recorded . Disease activity was assessed at yearly intervals using a combination of clinical ( pain score , Ritchie articular index , duration of morning stiffness ) and laboratory ( erythrocyte sedimentation rate , C reactive protein ) parameters . Change in functional status was assessed using the health status question  naire ( HAQ ) . Patients were stratified according to disease duration at outset ( group 1= 0–2 years n=106 , group 2 = > 2–5 years n=93 , and group 3= > 5 years n=235 ) . RESULTS There were no significant differences between the groups at outset . A total of 160 patients completed five years of treatment ( group 1 n=44 ( 42 % ) , group 2 n=37 ( 40 % ) , and group 3 n=79 ( 34 % ) ) . Patients in group 1 had a significantly lower HAQ from year 1 to year 5 with a mean improvement of 30 % at the end of the study ( p<0.001 ) . Neither group 2 nor group 3 had a significant change in their HAQ at study end . There were significant improvements in all other variables ( p<0.05 ) in each group apart from pain in group 2 . CONCLUSION Patients with early RA have a larger reversible component to their HAQ . Only patients with disease duration of up to two years have a longlasting improvement in their functional ability after starting intramuscular gold treatment This paper provides the first data on the incidence of RA  based on a prospect i ve population -based register . All new cases of inflammatory polyarthritis in the Norwich Health Authority are notified by general practitioners to the Norfolk Arthritis Register . The patients are then clinical ly evaluated by metrologists and blood taken for RF estimation . Cases of RA were defined as all those notified with an onset of symptoms in 1990 ; who presented by 31 December 1991 ; and who satisfied the 1987 ARA criteria for RA at the time of presentation . Two hundred and ten patients were notified in the defined time-frame , of whom 104 were classified as having RA . The annual incidence rate was 36/100,000 for women and 14/100,000 for men .  RA was rare in men aged under 45 yr . The incidence in men rose steeply with age . The incidence in women rose up to age 45 yr , plateaued to age 75 yr , and fell in the very elderly BACKGROUND Rheumatoid arthritis ( RA ) is initially treated with methotrexate and other disease-modifying antirheumatic drugs ( DMARDs ) .  Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors ( TNFis ) , which are effective but expensive . OBJECTIVE We assessed whether or not combination DMARDs ( cDMARDs ) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis . DESIGN An open-label , 12-month , pragmatic , r and omised , multicentre , two-arm trial [ Tumour necrosis factor inhibitors Against Combination Intensive Therapy ( TACIT ) ] compared these treatment strategies . We then systematic ally review ed all comparable published trials . SETTING The TACIT trial involved 24 English rheumatology clinics . PARTICIPANTS Active RA patients eligible for TNFis . INTERVENTIONS The TACIT trial compared cDMARDs with TNFis plus methotrexate or another DMARD ; 6-month non-responders received ( a ) TNFis if in the cDMARD group ; and ( b ) a second TNFi if in the TNFi group . MAIN OUTCOME MEASURES The Heath Assessment Question naire ( HAQ ) was the primary outcome measure . The European Quality of Life-5 Dimensions ( EQ-5D ) , joint damage , Disease Activity Score for 28 Joints ( DAS28 ) , withdrawals and adverse effects were secondary outcome measures . Economic evaluation linked costs , HAQ changes and quality -adjusted life-years ( QALYs ) . RESULTS In total , 432 patients were screened ; 104 started on cDMARDs and 101 started on TNFis . The initial demographic and disease assessment s were similar between the groups . In total , 16 patients were lost to follow-up ( nine in the cDMARD group , seven in the TNFi group ) and 42 discontinued their intervention but were followed up ( 23 in the cDMARD group and 19 in the TNFi group ) . Intention-to-treat analysis with multiple imputation methods used for missing data showed greater 12-month HAQ score reductions with initial cDMARDs than with initial TNFis [ adjusted linear regression coefficient 0.15 , 95 % confidence interval ( CI ) -0.003 to 0.31 ; p = 0.046 ] . Increases in 12-month EQ-5D scores were greater with initial cDMARDs ( adjusted linear regression coefficient -0.11 , 95 % CI -0.18 to -0.03 ; p = 0.009 ) whereas 6-month changes in HAQ and EQ-5D scores and 6- and 12-month changes in joint damage were similar between the initial cDMARD group and the initial TNFi group . Longitudinal analyses ( adjusted general estimating equations ) showed that the DAS28 was lower in the initial TNFi group in the first 6 months ( coefficient -0.63 , 95 % CI -0.93 to -0.34 ; p < 0.001 ) but there were no differences between the groups in months 6 - 12 . In total , 36 patients in the initial cDMARD group and 44 in the initial TNFi group achieved DAS28 remission . The onset of remission did not differ between groups ( p = 0.085 on log-rank test ) . In total , 10 patients in the initial cDMARD group and 18 in the initial TNFi group experienced serious adverse events ; stopping therapy because of toxicity occurred in 10 and six patients respectively . Economic evaluation showed that the cDMARD group had similar or better QALY outcomes than TNFi with significantly lower costs at 6 and 12 months . In the systematic review s we identified 32 trials ( including 20 - 1049 patients ) on early RA and 19 trials ( including 40 - 982 patients ) on established RA that compared ( 1 ) cDMARDs with DMARD monotherapy ; ( 2 ) TNFis/methotrexate with methotrexate monotherapy ; and ( 3 ) cDMARDs with TNFis/methotrexate . They showed that cDMARDs and TNFis had similar efficacies and toxicities .  CONCLUSIONS Active RA patients who have failed methotrexate and another DMARD achieve equivalent clinical benefits at a lower cost from starting cDMARDs or from starting TNFis ( reserving TNFis for non-responders ) . Only a minority of patients achieve sustained remission with cDMARDs or TNFis ; new strategies are needed to maximise the frequency of remission . TRIAL REGISTRATION Current Control Trials IS RCT N37438295 . FUNDING This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 66 . See the NIHR Journals Library website for further project information Objective . To compare the respective effects of tocilizumab ( TCZ ) monotherapy , etanercept ( ETN ) monotherapy , and adalimumab ( ADA ) monotherapy on arterial stiffness in patients with rheumatoid arthritis ( RA ) in an open-label , r and omized controlled trial . Methods . Patients with RA were eligible if they had active disease ( 28-joint Disease Activity Score > 3.2 ) and no prior treatment with methotrexate or biologics .  All 64 patients had no history of cardiovascular disease or steroid treatment . Patients were r and omly assigned to receive TCZ alone ( n = 22 ) , ETN alone ( n = 21 ) , or ADA alone ( n = 21 ) . Arterial stiffness was assessed with cardio-ankle vascular index ( CAVI ) and aortic augmentation index normalized to a fixed heart rate of 75 bpm ( AIx@75 ) at baseline and 24 weeks ’ followup . Clinical data were collected at regular visits . Results . The characteristics of each group at baseline were not significantly different . In all groups there was significant attenuation from baseline to 24 weeks in CAVI ( Week 0-Week 24 , TCZ : 0.85 ± 0.15 m/s , p = 0.02 ; ETN : 0.81 ± 0.18 m/s , p = 0.03 ; ADA : 0.90 ± 0.21 m/s , p = 0.02 ) and in AIx@75 . There were no significant differences among the groups in measures of CAVI or AIx@75 . The 3 therapies made no difference to carotid intima-media thickness and carotid artery plaque .  Only TCZ  increased fasting serum total cholesterol from baseline to 24 weeks . Conclusion . The 3 types of monotherapy limited arterial stiffness in patients with RA to a similar extent Objective . To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate ( MTX ) versus either monotherapy in patients with early rheumatoid arthritis ( RA ) in the PREMIER study . Methods . Patients with early RA who received adalimumab plus MTX ( n = 240 ) , adalimumab ( n = 222 ) , or MTX ( n = 216 ) were grouped by American College of Rheumatology ( ACR ) response , 28-joint Disease Activity Score ( DAS28 ) , or remission-like state [ tender joint count ( TJC ) = 0 ; DAS28 < 2.6 ; swollen joint count = 0 ; ACR100 ] at 26 and 104 weeks . Radiographic progression was assessed by cumulative probability plots , mean changes in total Sharp score ( ΔTSS ) , and percentages of progressors ( ΔTSS > 0.5 ) . Results . Across the spectrum of clinical outcomes , including ACR20 nonresponses and remission-like responses , therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy . Adalimumab monotherapy was generally intermediate . A strong , proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy . The monotherapies approximated the radiographic efficacy  of adalimumab plus MTX only among remission-like responders , although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0 . Concurrent clinical ( DAS28 < 2.6 ) and radiographic ( ΔTSS ≤ 0.5 ) remission was significantly more frequent at Week 104 with adalimumab plus MTX ( 45 % ) than with adalimumab ( 25 % ) or MTX ( 18 % ) monotherapy . Conclusion . In patients with early RA  , adalimumab plus MTX result ed in less radiographic progression  than MTX monotherapy across the spectrum of clinical response , including ACR20 non-responses and remission-like responses OBJECTIVE To evaluate the effects of golimumab on inflammation/structural damage detected by magnetic resonance imaging ( MRI ) in patients with rheumatoid arthritis ( RA ) . METHODS  Methotrexate (MTX)-naive RA patients ( n = 637 ) were r and omized to placebo plus MTX , golimumab 100 mg plus placebo , golimumab 50 mg plus MTX , or golimumab 100 mg plus MTX ( subcutaneous golimumab every 4 weeks ) . Of these , 318 patients participated in an MRI sub study . MRIs ( contrast-enhanced ; 1.5 T ) of the wrist and second through fifth metacarpophalangeal joints of the dominant h and were obtained at baseline and weeks 12 and 24 . MRIs were scored by 2 independent readers ( blinded to image sequence/chronology , patient identity , and treatment group ) for synovitis , bone edema/osteitis , and bone erosions using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring ( RAMRIS ) system . Radiographs ( h and s , wrists , forefeet at baseline and week 28 ) were scored by 2 other readers ( blinded as above ) using the modified Sharp/van der Heijde ( SvdH ) scoring system . Changes from baseline were compared between treatment groups ( two-sided analysis of variance on van der Waerden normal scores ) . RESULTS At weeks 12 and 24 , combined therapy with golimumab plus MTX versus placebo plus MTX significantly improved RAMRIS scores for synovitis ( mean -1.92 versus 0.14 [ P < 0.001 ] at week 12 ; -2.45 versus -1.04 [ P < 0.001 ] at week 24 ) , osteitis ( mean -1.82 versus 0.56 [ P < 0.001 ] at week 12 ; -2.27 versus -0.32 [ P < 0.001 ] at week 24 ) , and bone erosion ( mean -0.40 versus 0.24 [ P = 0.016 ] at week 12 ; -0.40 versus -0.24 [ P = 0.010 ] at week 24 ) . Results of sensitivity analyses ( no missing doses/ data and using linear extrapolation ) were generally consistent with results of the primary analyses . Changes in SvdH scores among the MRI sub study patients at week 28 showed no significant difference between golimumab plus MTX therapy and placebo plus MTX ( mean 0.49 versus 0.92 ; P = 0.19 ) . Radiographic SvdH scores demonstrated inhibition of structural damage progression by treatment with golimumab plus MTX as compared with placebo plus MTX in the overall study population but required double the number of patients ( 637 versus 318 ) and double the length of followup ( 28 versus 12 weeks ) as needed for MRI to demonstrate this . CONCLUSION Improvements in inflammation ( synovitis and osteitis ) and erosions with golimumab plus MTX therapy exceeded those with placebo plus MTX therapy from week 12 onward , confirming the overall clinical /radiologic findings . MRI was more sensitive than conventional radiography in detecting the progression of erosions BACKGROUND Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis . Although moderately active rheumatoid arthritis is common , treatment effects in moderate disease have not been well studied . Additionally , optimum use of biologics needs further investigation , including the use of induction , maintenance , and withdrawal treatment strategies . The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease . METHODS In a r and omised controlled trial , patients aged between 18 and 70 years with moderately active rheumatoid arthritis ( disease activity score in 28 joints [ DAS28 ] > 3.2 and ≤5.1 ) despite treatment with methotrexate were enrolled at 80 centres in Europe , Latin America , Asia , and Australia between March 6 , 2008 , and Sept 9 , 2009 . To be eligible , patients had to have been receiving 15 - 25 mg of methotrexate every week for at least 8 weeks . In an open-label period of 36 weeks , all patients were given 50 mg etanercept plus methotrexate every week . To be eligible for a subsequent double-blind period of 52 weeks , participants had to have achieved sustained low disease activity . These patients were r and omly assigned ( 1:1:1 ) by an interactive voice-response system to one of three treatment groups : 50 mg etanercept plus methotrexate , 25 mg etanercept plus methotrexate , or placebo plus methotrexate . Patients were stratified in blocks of three by DAS28 response ( low disease activity or remission ) at week 36 . Patients , investigators , data analysts , and study staff were all masked to treatment allocation . The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period . A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity . Modified intention-to-treat population s were used for analyses . This trial is registered with Clinical Trials.gov , number NCT00565409 . FINDINGS 604 ( 72.4 % ) of 834 enrolled patients were eligible for the double-blind period , of whom 202 were assigned to 50 mg etanercept plus methotrexate , 202 to 25 mg etanercept plus methotrexate , and 200 to placebo plus methotrexate . At week 88 , 166 ( 82.6 % ) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity , compared with 84 ( 42.6 % ) of 197 who had received placebo ( mean difference 40.8 % , 95 % CI 32.5 - 49.1 % ; p<0.0001 ) . Additionally , 159 ( 79.1 % ) of 201 patients given 25 mg etanercept had low disease activity at week 88 ( mean difference from placebo 35.9 % , 27.0 - 44.8 % ; p<0.0001 ) . INTERPRETATION Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept . FUNDING Pfizer PURPOSE To estimate the cost-effectiveness of infliximab plus methotrexate for active , refractory rheumatoid arthritis . METHODS We projected the 54-week results from a r and omized controlled trial of infliximab into lifetime economic and clinical outcomes using a Markov computer simulation model . Direct and indirect costs , quality of life , and disability estimates were based on trial results ; Arthritis , Rheumatism , and Aging Medical Information System ( ARAMIS ) data base outcomes ; and published data . Results were discounted using the st and ard 3 % rate . Because most well-accepted medical therapies have cost-effectiveness ratios below $ 50,000 to $ 100,000 per quality -adjusted life-year ( QALY ) gained , results below this range were considered to be " cost-effective . " RESULTS At 3 mg/kg , each infliximab infusion would cost $ 1393 . When compared with methotrexate alone , 54 weeks of infliximab plus methotrexate decreased the likelihood of having advanced disability from 23 % to 11 % at the end of 54 weeks , which projected to a lifetime marginal cost-effectiveness ratio of $ 30,500 per discounted QALY gained , considering only direct medical costs . When applying a societal perspective and including indirect or productivity costs , the marginal cost-effectiveness ratio for infliximab was $ 9100 per discounted QALY gained . The results remained relatively unchanged with variation of model estimates over a broad range of values . CONCLUSIONS Infliximab plus methotrexate for 54 weeks for rheumatoid arthritis should be cost-effective with its clinical benefit providing good value for the drug cost , especially when including productivity losses . Although infliximab beyond 54 weeks will likely be cost-effective , the economic and clinical benefit remains uncertain and will depend on long-term results of clinical trials BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis . METHODS In this 12-month , phase 3 trial , 717 patients who were receiving stable doses of methotrexate were r and omly assigned to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , 40 mg of adalimumab once every 2 weeks , or placebo . At month 3 , patients in the placebo group who did not have a 20 % reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily ; at month 6 , all patients still receiving placebo were switched to tofacitinib in a blinded fashion . The three primary outcome measures were a 20 % improvement at month 6 in the American College of Rheumatology scale ( ACR 20 ) ; the change from baseline to month 3 in the score on the Health Assessment Question naire-Disability Index ( HAQ-DI ) ( which ranges from 0 to 3 , with higher scores indicating greater disability ) ; and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity ) . RESULTS At month 6 , ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib ( 51.5 % and 52.6 % , respectively ) and among those receiving adalimumab ( 47.2 % ) than among those receiving placebo ( 28.3 % ) ( P<0.001 for all comparisons ) . There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28 - 4(ESR ) below 2.6 at month 6 in the active-treatment groups than in the placebo group . Adverse events occurred more frequently with tofacitinib than with placebo , and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group . Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts . CONCLUSIONS In patients with rheumatoid arthritis receiving background methotrexate , tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy . ( Funded by Pfizer ; ORAL St and ard Clinical Trials.gov number , NCT00853385 . ) OBJECTIVE To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis ( RA ) receiving infliximab + methotrexate ( MTX ) versus placebo + MTX over 18 weeks , and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the h and s and feet at 54 weeks . METHODS Patients with early RA ( duration <3 years ) receiving stable dosages of MTX  were r and omly assigned to receive blinded infusions of 5 mg/kg infliximab ( n = 12 ) or placebo ( n = 12 ) at weeks 0 , 2 , 6 , and then every 8 weeks until week 46 . At baseline and week 18 , clinical assessment s were performed , and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements . Radiographs of the h and s and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method ( vdH-Sharp score ) . RESULTS Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks , we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX . Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54 . Infliximab + MTX treatment abolished these relationships . CONCLUSION The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks OBJECTIVE To assess the efficacy and safety of tocilizumab plus methotrexate ( MTX ) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX .  METHODS A total of 1,196 patients were enrolled in a 2-year , r and omized , double-blind , placebo-controlled trial . Patients received tocilizumab ( 8 mg/kg or 4 mg/kg ) or placebo every 4 weeks plus MTX . Rescue treatment was available from week 16 . Results from year 1 are presented . RESULTS Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX , respectively , versus 1.13 with placebo plus MTX ( P < 0.0001 for both comparisons ) . Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Question naire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg ( -144.1 and -128.4 units , respectively ) than with placebo ( -58.1 units ; P < 0.0001 for both comparisons ) . Proportions of patients with American College of Rheumatology 20 % , 50 % , and 70 % improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo ( P < 0.0001 for all comparisons ) . The safety profile of tocilizumab was consistent with the profiles in previous studies . Infections were the most common adverse and serious adverse events . CONCLUSION The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone . Tocilizumab has a well-characterized safety profile OBJECTIVE To observe the long-term safety and efficacy of combination therapy with etanercept and methotrexate in patients with rheumatoid arthritis ( RA ) , and to determine whether the addition of etanercept allowed reductions in methotrexate or corticosteroid dosages while maintaining a clinical response . METHODS Patients with RA who received methotrexate plus etanercept in a previous r and omized , placebo-controlled trial were offered the opportunity to enroll in an open-label extension study for further evaluation of treatment with etanercept and methotrexate . RESULTS Seventy-nine of the 89 patients in the original blinded study enrolled in the extension study , and 65 of these patients continue in the study . Patients have received etanercept therapy  for up to 47 months ( median 44 months ) . The types and rate of adverse events noted during the extension trial were similar to those observed in the controlled trial . At the 3-year assessment , 77 % of the 57 patients available for evaluation met American College of Rheumatology 20 % ( ACR20 ) criteria for improvement in RA , 47 % met the ACR50 criteria , and 23 % met the ACR70 criteria . Of the 36 patients assessed at 3 years in the extension study , 30 ( 83 % ) were able to decrease their dosages of corticosteroids , and 20 ( 56 % ) were able to discontinue corticosteroid therapy . At 3 years , the dosage of methotrexate  was decreased in 41 of 66 patients ( 62 % ) , and methotrexate therapy was discontinued in 19 patients ( 29 % ) . CONCLUSION In this observational continuation study , the addition of etanercept to background methotrexate provided sustained clinical benefit over a median period of 44 months . With etanercept therapy , there were trends toward dosage reduction or discontinuation of methotrexate and corticosteroids , without apparent worsening of ACR response rates . Compared with the controlled trial , no increases in the rate of adverse events were observed Probabilistic sensitivity analysis ( PSA ) is required to account for uncertainty in cost-effectiveness calculations arising from health economic models . The simplest way to perform PSA in practice is by Monte Carlo methods , which involves running the model many times using r and omly sample d values of the model inputs . However , this can be impractical when the economic model takes appreciable amounts of time to run . This situation arises , in particular , for patient-level simulation models ( also known as micro-simulation or individual-level simulation models ) , where a single run of the model simulates the health care of many thous and s of individual patients . The large number of patients required in each run to achieve accurate estimation of cost-effectiveness means that only a relatively small number of runs is possible . For this reason , it is often said that PSA is not practical for patient-level models . We develop a way to reduce the computational burden of Monte Carlo PSA for patient-level models , based on the algebra of analysis of variance . Methods are presented to estimate the mean and variance of the model output , with formulae for determining optimal sample sizes . The methods are simple to apply and will typically reduce the computational dem and very substantially 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 BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly . We aim ed to compare addition of conventional disease-modifying antirheumatic drugs ( sulfasalazine and hydroxychloroquine ) with addition of a tumour necrosis factor antagonist ( infliximab ) to methotrexate in patients with early rheumatoid arthritis . METHODS We undertook a r and omised trial in 15 rheumatology units in Sweden . We enrolled patients with early rheumatoid arthritis ( symptom duration < 1 year ) and administered methotrexate ( up to 20 mg per week ) . After 3 - 4 months , those who had not achieved low disease activity but who could tolerate methotrexate were r and omly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab . Primary outcome was achievement of a good response according to European League Against Rheumatism ( EULAR ) criteria at 12 months . Patients were followed up to 24 months ; here , we present findings at 12 months . Analysis was by intention to treat and we used non-responder imputation . The Swefot ( Swedish Pharmacotherapy ) study is registered in the WHO data base at the Karolinska University Hospital , number CT20080004 . FINDINGS 487 patients were initially enrolled . Of 258 who had not achieved low disease activity with methotrexate  , 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab . 32 of 130 ( 25 % ) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 ( 39 % ) assigned infliximab ( risk ratio 1.59 [ 95 % CI 1.10 - 2.30 ] , p=0.0160 ) . Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used . No deaths occurred in either group . INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed , addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinical ly superior to addition of conventional disease-modifying antirheumatic drugs . FUNDING Swedish Rheumatism Association , Schering-Plough 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 The P2X7 purinergic receptor antagonist AZD9056 was evaluated in a phase IIa study and subsequently in a phase IIb study to assess the effects of orally administered AZD9056 on the signs/symptoms of  rheumatoid arthritis ( RA ) , with American College of Rheumatology 20 % response criteria ( ACR20 ) as the primary outcome . Methods Both studies were r and omised , double-blind , placebo-controlled , parallel-group studies in patients with RA receiving methotrexate or sulphasalazine .  Phase IIa was an ascending-dose trial in two cohorts ( n=75 ) using AZD9056 administered daily over 4 weeks . Phase IIb included an open-label etanercept treatment group . Patients were r and omised to receive treatment for 6 months with 50 , 100 , 200 or 400 mg AZD9056 ( oral , once a day ) or matching placebo ( oral , once a day ) , or subcutaneous etanercept ( 50 mg once a week ) . Results In phase IIa , 65 % of AZD9056 recipients at 400 mg/day responded at the ACR20 level compared with 27 % of placebo-treated patients . A significant reduction in swollen and tender joint count was observed in the actively treated group compared with placebo , whereas no effect on acute-phase response was observed . Of 385 r and omised patients in the phase IIb study , 383 received treatment .  AZD9056 ( all doses ) had no clinical ly or statistically significant effect on RA relative to placebo as measured by the proportion of patients meeting the ACR20 criteria at 6 months and further supported by secondary end points . In both studies AZD9056 was well tolerated up to 400 mg/day . Conclusions AZD9056 does not have significant efficacy in the treatment of RA , and the P2X7 receptor does not appear to be a therapeutically useful target in RA . Trial registration number Clinical Trials.gov NCT00520572 OBJECTIVE To evaluate the efficacy , radiographic changes , and safety of abatacept and methotrexate therapy through 2 years in a long-term extension of a previously published 1-year study . METHODS Patients who received placebo during year 1 were switched to abatacept . Patients taking abatacept continued to take it . Efficacy and safety were assessed through 2 years . RESULTS Of 539 patients enrolled in the initial 1-year study , 488 completed 1 year of the long-term extension ( 2 % discontinued for lack of efficacy ) . At 2 years , patients taking abatacept had maintained their responses on the American College of Rheumatology ( ACR ) improvement criteria and the Disease Activity Score in 28 joints ( DAS28 ; using the C-reactive protein [ CRP ] level ) , as well as their physical function ( according to the Health Assessment Question naire [ HAQ ] disability index [ DI ] ) and health-related quality of life ( HRQOL ; assessed with the Short Form 36 [ SF-36 ] health survey ) , that were observed at the end of the double-blind period ( year 1 versus year 2 values were 81.9 % versus 80.3 % for ACR 20 % improvement , 25.4 % versus 30.9 % for a DAS28 [ CRP ] of < 2.6 , 71.8 % versus 66.8 % for the HAQ DI , and 9.7 versus 10.6 and 7.3 versus 7.2 , respectively , for the mean change in the physical and mental components summary scores of the SF-36 ) . In the abatacept group , post hoc analysis demonstrated further inhibition of radiographic progression during year 2 ( 57 % reduction in mean change of total score in year 2 versus year 1 ; P<0.0001 ) , and minimal radiographic progression was observed ( mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2 , respectively ) . Rates of adverse events ( AEs ) and severe AEs were consistent throughout the cumulative period . CONCLUSION The improvements in signs and symptoms , physical function , and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment . This durability was accompanied by a safety profile consistent with that in the double-blind portion of the study . Radiographic progression was further inhibited in year 2 compared with year 1 , suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2 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 Context It remains unclear whether the optimal treatment strategy for early rheumatoid arthritis ( RA ) is to step care from nonsteroidal anti-inflammatory drugs and other symptomatic treatments to glucocorticoids and then to disease-modifying antirheumatic drugs ( DMARDs ) only after 1 year , or to use more aggressive therapy early after diagnosis . Contribution The investigators used available data to estimate the cost-effectiveness of initial treatment strategies for RA . Compared with stepped care , early DMARDs or early biologic agents seem to improve outcomes , but only DMARDs do so at a cost per year of life saved that society typically considers acceptable . Caution Assumptions were based on limited data on early RA treatment with DMARDs and biologics . The Editors The treatment of rheumatoid arthritis ( RA ) has changed dramatically in the past decade with the introduction of new biologic therapies , particularly tumor necrosis factor inhibitors . Growing evidence suggests a benefit of aggressive treatment very early in the course of the disease and the existence of a critical therapeutic window of opportunity within which antirheumatic therapy is more effective and has a more durable effect than later in the course of the disease ( 1 , 2 ) . Very early initiation of disease-modifying antirheumatic drug ( DMARD ) or biologic therapy has a demonstrated prolonged benefit on RA progression and may permanently modify the disease to a milder course ( 1 , 3 ) . Emerging data also suggest that if RA is detected and treated very early , long-term control or remission may be possible and continuing treatment may not be necessary ( 46 ) . Although antirheumatic therapy should be initiated as early as possible after disease onset , the optimal strategy has not been determined . Early treatment with  biologics  seems to be superior to treatment with conventional DMARDs  in terms of hard outcomes , such as radiographic structural joint damage , but not necessarily in terms of disease activity ( 7 ) . Biologics are generally prescribed only after therapy with 1 or more conventional DMARDs has failed . However , r and omized , controlled trials ( RCTs ) have demonstrated improved efficacy of biologics in early disease ( 811 ) , and the pharmaceutical industry promotes early initiation of biologic therapy for RA . Because early therapy may change the natural course of the disease ( 4 ) , biologics could be most useful in early RA ( 4 , 12 , 13 ) . Although evidence supports the cost-effectiveness of biologic therapy  in DMARD-resistant severe RA ( 14 , 15 ) , its long-term cost-effectiveness in very early RA is unknown . The diagnosis of RA can be problematic very early in the course of disease ( 16 ) . An early diagnosis carries the risk for prescribing expensive and potentially toxic drugs to patients who might have spontaneous remission . Patients may incur time lost from work because of treatment or drug-related toxicities or may die because of treatment ( 13 ) . In addition , early antirheumatic therapy increases treatment costs ; in particular , biologics cost up to 10 times more than conventional DMARDs . However , patients may benefit from early therapy , endure fewer disability days , have less productivity loss , require fewer days in the hospital , and need fewer subsequent joint replacements ( 13 ) . It is therefore important to consider the total long-term costs associated with various therapeutic strategies . Health policy analyses use the incremental cost effectiveness ratio ( ICER ) to compare a particular treatment or strategy with competing treatment strategies to inform the allocation of health care re sources ( 17 ) . To determine whether the increased costs of treatment strategies that involve biologics in very early RA are warranted by health gains , we assessed the cost-effectiveness of major therapeutic strategies by examining different scenarios based on emerging data . Methods Decision Model Structure Our base-case analysis considers adults with very early RA , operationally defined as symptoms of less than 3 months in duration a definition commonly used in the literature for very early RA ( 18 , 19 ) . The classification criteria for RA require that signs and symptoms be present for at least 6 weeks ( 20 ) , and studies of patients with early RA suggest a median duration of illness of 11 to 23 weeks at diagnosis ( 21 , 22 ) . However , RA can not be reliably diagnosed at an early stage in all patients with inflammatory polyarthritis . A significant proportion of patients with undifferentiated arthritis will have spontaneous remission or receive diagnoses of other conditions ( 23 , 24 ) . Evolving diagnostic techniques , such as biomarkers ( 25 ) or improved clinical prediction rules for identifying which patients who present with undifferentiated polyarthritis will progress to RA , enable individualized decisions about initiation of treatment with DMARDs ( 23 , 26 ) . We used an individual sampling model ( 27 ) to track the course of disease over time , with changes in important variables ( principally radiographic joint damage and functional disability ) at time points at which events ( toxicities , treatment initiation , treatment discontinuation , or death ) occur . We estimated the expected lifetime costs and benefits for U.S. patients , expressed as quality -adjusted life-years ( QALYs ) , from both a health care provider and a societal perspective . Our models explore 5 conceivable strategies , but we focus on the 3 most plausible and clinical ly relevant strategies for very early RA . Although these may vary in actual practice , we simplified the choices to model the problem . In the pyramid strategy , initial nonsteroidal anti-inflammatory drugs , patient education , joint protection and therapeutic exercise , pain management , and low-dose glucocorticoids are administered as needed , followed by DMARDs at 1 year for nonresponders . This is still the most common pattern of therapy because of delayed consultation and diagnosis ( 2830 ) . In the early DMARD strategy , conventional DMARDs ( such agents as leflunomide , sulfasalazine , hydroxychloroquine , or methotrexate ) are given within 12 weeks of symptom onset . Methotrexate is the current st and ard of care in U.S. rheumatology ( 30 ) and also has the most evidence for its effectiveness in very early RA ( 6 ) . The early biologic strategy involves very early use of biologics , defined as use of 3 sequential tumor necrosis factor inhibitors , in combination with methotrexate . In the first 2 strategies , patients initially receive conventional DMARDs ; those who do not respond to therapy with 3 conventional DMARDs , alone or in combination , then receive agents from the third strategy . We modified a published model ( 31 ) for this analysis . We tracked hypothetical patient cohorts through the model , one at a time , in 6-month cycles from symptom onset until death . The exact route a simulated patient takes through the model depends on the therapeutic strategy used and the patient 's disease characteristics ( type of disease progression , age , sex , education level , race , income , duration of disease , comorbid conditions , baseline and current Health Assessment Question naire [ HAQ ] Disability Index score , and type and number of previously received DMARDs ) . Figure 1 shows model pathways . Figure 1 . Model schematic . Patients can change disease state every 6 months , depending on the underlying disease type and the treatment strategy received . The time spent in a particular disease state determines the probability of transition and the ultimate outcome . DMARD = disease-modifying antirheumatic drug ;  HAQ = Health Assessment Question naire ; RA = rheumatoid arthritis . * See Appendix for discussion of this strategy . Appendix . Technical Appendix We assume that patients follow 1 of 3 disease courses : drug-free remission , a mild course with slow disease progression , or rapid disease progression . At presentation , we assume that a patient 's future course can not be predicted . The patients ' disease characteristics are representative of the U.S. population with RA ( 32 ) . The model synthesizes data from RCTs ( 33 ) ; the National Data Bank for Rheumatic Diseases ( NDB ) , a longitudinal data base of semi-annual , self-reported patient data ( 32 ) ; and other literature . Details on disease progression , treatment effect , estimates for QALYs , and costs are provided in the following sections . Table 1 ( 3445 ) describes input variables , and the Appendix details our methods . We used R project statistical software ( www.R-project.org ) for all decision analyses . Table 1 . Key Model Parameters and Assumptions Disease Progression We modeled the course of the disease by using functional disability and radiographic evidence of structural joint damage . Functional disability , measured by the HAQ ( 46 ) , is a primary outcome in most RA clinical studies . Structural joint damage can be assessed by several radiographic scoring methods . We used the percentage of the maximum score of each measure to include all sources of information ( 39 ) . We applied the rate of disease progression to each disease course pattern . Because these rates are often unknown over an extended period , we first assumed that all patients present with a HAQ score of 1 and no radiographic damage . We then used the literature as a guide for the mean progression rates in each disease course . Finally , we calibrated the overall progression for all disease courses . We calibrated the HAQ with data from the NDB that show increases during early disease to an annual HAQ score progression of around 0.03 in patients with established disease , similar to previous estimates ( 47 ) . We assumed that radiographic damage increased linearly over time and calibrated it with rates of approximately 2 % per year ( 48 ) . We computed the relationship between radiographic damage and HAQ score . Estimates indicate that a 1percentage point change in radiographic progression is equivalent to a 0.04 change in HAQ score ( 38 ) . However , the effect of radiographic progression on functional disability in early phases of disease is only 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 OBJECTIVES To assess the impact of rheumatoid arthritis ( RA ) on function and how this affects major aspects of patients ' lives . METHODS The inception cohort of RA patients was recruited from rheumatology out-patient departments in nine National Health Service ( NHS ) hospital trusts in Engl and . All consecutive patients with RA of less than 2 yr duration , prior to any second-line ( disease-modifying ) drug treatment  were recruited and followed-up for 5 yr . St and ard clinical , laboratory and radiological assessment s , and all hospital-based interventions were recorded prospect ively at presentation and yearly . The outcome measures were clinical remission and extra-articular features , functional ability [ functional grade s I-IV and Health Assessment Question naire ( HAQ ) ] , use of aids , appliances and home adaptations , orthopaedic interventions , and loss of paid work . RESULTS A total of 732 patients completed 5 yr of follow-up , of whom 84 % received second-line drugs . Sixty-nine ( 9.4 % ) had marked functional loss at presentation , compared with normal function in 243 ( 33 % ) , and by 5 yr these numbers had increased in each group , respectively , to 113 ( 16 % ) and 296 ( 40 % ) . Home adaptations and /or wheelchair use by 5 yr were seen in 74 ( 10 % ) . Work disability was seen in 27 % of those in paid employment at onset . One hundred and seventeen ( 17 % ) patients underwent orthopaedic surgery for RA , 55 ( 8 % ) for major joint replacements . Marked functional loss at 5 yr was more likely in women [ odds ratio ( OR ) 1.63 , 95 % confidence interval ( CI ) 1.04 - 2.5 ] , patients older than 60 yr ( OR 1.94 , 95 % CI 1.3 - 2.9 ) , and with HAQ > 1.0 at presentation ( OR 4.4 , 95 % CI 2.8 - 7.0 ) . CONCLUSIONS Clinical profiles of RA patients treated with conventional drug therapy over 5 yr showed that a small proportion of patients ( around 16 % ) do badly functionally and in terms of life events , whereas around 40 % do relatively well . The details and exact figures of cumulative disability are likely to be useful to clinicians , health professionals and patients . The rate of progression and outcome in these patients can be compared against future therapies with any disease-modifying cl aims Objective . Rheumatoid arthritis ( RA ) is associated with significant impairments in health-related quality of life ( HRQOL ) . We evaluated patient-reported outcomes including HRQOL outcomes following adalimumab plus methotrexate ( MTX ) therapy in patients with early RA . Methods . PREMIER was a phase III , multicenter , r and omized , double-blind , active-comparator clinical trial in early RA . Patients aged ≥ 18 years were r and omly assigned to receive adalimumab 40 mg every other week ( eow ) plus weekly MTX , weekly MTX , or adalimumab 40 mg eow for 104 weeks . American College of Rheumatology ( ACR ) criteria were used to evaluate clinical efficacy and response . Outcomes were assessed using the Health Assessment Question naire Disability Index ( HAQ-DI ) , Short-Form 36 Health Survey ( SF-36 ) , Short-Form 6 Dimension ( SF-6D ) , visual analog scale ( VAS ) assessment s of global disease activity ( patient ’s global assessment ; PtGA ) and pain , Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-F ) , and Health Utility Index Mark 3 ( HUI-3 ) . Results . Of 799 patients enrolled , 268  received adalimumab plus MTX , 257 received MTX monotherapy , and 274 received adalimumab monotherapy . Patients treated with adalimumab plus MTX demonstrated significant baseline to Week 104 improvements in HAQ-DI ( p < 0.0001 ) , SF-36 Physical Component Summary ( p < 0.0001 ) , 4 SF-36 domains [ physical function ( p < 0.0001 ) , bodily pain ( p < 0.0001 ) , vitality ( p = 0.0139 ) , role limitations -physical ( p = 0.0005 ) ] , SF-6D ( p = 0.0152 ) , VAS-PtGA ( p < 0.0001 ) , VAS-pain ( p < 0.0001 ) , FACIT-F ( p < 0.0001 ) , and HUI-3 ( p = 0.0034 ) scores versus patients treated with MTX monotherapy . Both SF-6D and HUI-3 were found to be sensitive preference-based measures for assessing the effects of treatment on multidimensional function . No clinical ly meaningful differences between adalimumab and MTX monotherapy groups were observed for most measures . For each measure , there was significant association between HRQOL improvement and ACR clinical response . Conclusion . Adalimumab plus MTX significantly improved physical functioning and HRQOL in patients with early RA over 2 years of treatment . ( Clinical Trials.gov identifier NCT00195663 ) OBJECTIVE To investigate the safety and efficacy of MRA , a recombinant human anti-interleukin-6 ( anti-IL-6 ) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6 , in patients with established rheumatoid arthritis ( RA ) . METHODS A r and omized , double-blind , placebo-controlled , dose-escalation trial was conducted in 45 patients with active RA , as defined by the American College of Rheumatology ( ACR ) revised criteria . Patients were sequentially allocated to receive a single intravenous dose of either 0.1 , 1 , 5 , or 10 mg/kg of MRA or placebo . The primary efficacy end point was meeting the ACR 20 % response criteria at week 2 after treatment . RESULTS Demographic features were similar between treatment groups . At week 2 , a significant treatment difference was observed between the 5 mg/kg of MRA and placebo , with 5 patients ( 55.6 % ) in the MRA cohort and none in the placebo cohort achieving ACR 20 % improvement . There was no statistically significant difference in the ACR 20 % response between the other 3 MRA cohorts and placebo at week 2 . The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 ( P < 0.001 and P < 0.001 by analysis of variance ) , respectively . These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts ( 6.4 , 6.2 , and 7.0 , respectively ) . The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment . Seventeen patients ( 5 , 4 , 6 , 2 , and 0 patients in the placebo , 0.1- , 1- , 5- , and 10-mg/kg MRA cohorts , respectively ) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end . They were regarded as nonresponders from the time they received these treatments . Diarrhea was the most common adverse event , occurring in 8 % of patients . Seven patients ( 15.6 % ) reported a severe adverse event ( 3 , 1 , 2 , and 2 patients in the placebo , 0.1- , 1- , and 10-mg/kg MRA cohorts ) . There were no serious adverse events that were thought to be related to the study drug . CONCLUSION This is the first r and omized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants . Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA BACKGROUND Analysis of the Swedish Farmacotherapy ( Swefot ) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis . Here we report the 2 year follow-up assessment . METHODS In this r and omised , non-blinded , parallel-group trial , we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December , 2002 and December , 2006 . All patients were started on methotrexate .  After 3 - 4 months , those who failed treatment were r and omly assigned ( 1:1 ) to group A ( conventional treatment ; additional sulfasalazine and hydroxychloroquine ) or group B ( biological treatment ; additional infliximab ) . R and omisation was done with a computer-generated sequence . We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism , and radiographs of patients ' h and s and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score . Analysis was by intention to treat . This trial is registered with www . Clinical Trials.gov , number NCT00764725 . FINDINGS Of 493 screened individuals , we enrolled 487 , of whom 258 were r and omly allocated to treatment . The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months ( 49 of 128 [ 38 % ] vs 38 of 130 [ 29 % ] ) and at 24 months ( 49 of 128 [ 38 % ] vs 40 of 130 [ 31 % ] ; p=0·204 ) . After 24 months , radiological disease progression was greater in patients in group A than it was in those in group B ( mean 7·23 [ SD 12·72 ] vs 4·00 [ 10·0 ] ; p=0·009 ) . We recorded three serious adverse events : an extended generalised illness in group A , an extended febrile episode in group B , and a generalised illness in group B. INTERPRETATION Additional biological treatment is a valid option for patients who fail initial methotrexate treatment . However , improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs . Therefore , for many patients who fail initial methotrexate treatment , add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option . FUNDING Swedish Rheumatism Association , Stockholm County , and Schering-Plough/Merck Sharp and Dohme Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate  , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo .  Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for  adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities  , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the OBJECTIVE To assess safety , clinical response , and pharmacokinetics of subcutaneous ( SC ) and intramuscular ( IM ) doses of an experimental formulation of infliximab [ including experimental SC doses following administration of commercially-formulated intravenous ( IV ) infliximab ] in patients with rheumatoid arthritis ( RA ) refractory to methotrexate . METHODS In this r and omized , open-label , 3-stage design , 43 subjects were enrolled in 7 dose groups . In Stage I , 15 subjects received single SC doses of 0.5 , 1.5 , or 3.0 mg/kg . In Stage II , 21 subjects received one of 3 regimens : 100 mg SC every 2 weeks ( 3 injections ) ; 3 mg/kg commercially-formulated IV infliximab every 2 weeks ( 2 infusions ) followed by 100 mg SC every 2 weeks ( 3 injections ) ; or 100 mg IM every 2 weeks ( 3 injections ) . In Stage III , 7 subjects received 100 mg SC every 4 weeks ( 3 injections ) . RESULTS No treatment-related serious adverse events were observed , and there were no serious injection site reactions . A low-titer infliximab antibody response was detected in 27 % of subjects receiving single SC doses , 5 % receiving multiple SC doses , and 43 % receiving IM doses . SC administration yielded roughly dose-proportional increases in Cmax and AUC . American College of Rheumatology 20 % response ( ACR20 ) was achieved 2 weeks after the last injection by 86.7 % of subjects receiving single SC doses , 85.7 % receiving SC doses every 2 weeks , 85.7 % receiving both IV and SC doses , 57.1 % receiving multiple IM doses , and 80.0 % receiving SC doses every 4 weeks . CONCLUSION SC and IM treatment with this experimental infliximab formulation was well tolerated and was associated with a favorable ACR response Objective To estimate the comparative lifetime cost-effectiveness of sequenced therapy with tumor necrosis factor ( TNF ) antagonists as the initial therapeutic intervention for patients with early rheumatoid arthritis ( RA ) . Methods Because patients with RA switch regimens many times throughout the course of disease , sequenced therapeutic interventions were modeled , continuing until the last effective agent failed or death occurred . The model used published clinical outcomes from short-term , r and omized controlled trials . Direct treatment costs and costs of lost productivity were modeled for each of 5 alternative treatment sequences . Incremental cost-effectiveness ratios are expressed as quality -adjusted lifeyears ( QALY ) gained . Results Treatment sequences that included TNF antagonists produced a greater number of QALY than conventional disease modifying antirheumatic drug regimens alone . The cost-effectiveness of sequenced therapy initiated with adalimumab plus methotrexate ( MTX ) extendedly dominated both infliximab-plus-MTX – initiated and etanercept sequences . The cost of adalimumab plus MTX per QALY was US $ 47,157 excluding productivity losses , and $ 19,663 including productivity losses . A supplementary sequence that incorporated adalimumab-plus-MTX – initiated first-line therapy followed by another TNF antagonist as second-line therapy was modeled ; this sequence result ed in additional QALY gained and extendedly dominated all single-TNF strategies . Conclusion Of the 3 single-TNF antagonist sequences , the adalimumab-plus-MTX – initiated sequence was cost-effective in producing the greatest number of QALY . Multiple TNF strategies , such as the supplementary sequence modeled in this analysis , may be cost-effective in producing even greater health gain AIM The aim of this study was to evaluate the differences between infliximab and etanercept , in terms of clinical efficacy and rapidity of action . METHODS We selected 32 patients with rheumatoid arthritis ( RA ) with an incomplete response to disease modifying anti-rheumatic drugs ( DMARDs ) , and r and omly assigned them to etanercept or infliximab . We evaluated the efficacy after 14 , 22 , 54 weeks of treatment , using the American College of Rheumatology ( ACR ) 20 , 50 and 70 criteria , and the improvement of quality of life using the Health Assessment Question -naire ( HAQ ) . RESULTS After 14 weeks , the 54.4 % of patients was considered ACR-responders in the etanercept group , whereas , in the infliximab group , the percentage of responders was 74.4 % : infliximab gave better results for the tender joint count and for physician 's global assessment . After 22 weeks , no significant difference was present . After 54 weeks , etanercept result ed more effective than infliximab for tender joint count ( TJC ) value , for visual analogic scale ( VAS ) for pain score , for global disease assessment value , with 74.4 % of patients considered ACR-responders in the group treated with etanercept and 60 % in the group treated with infliximab . As regards HAQ , patients in the infliximab group presented higher scores at week 14 , but in weeks 22 and 54 , patients in the etanercept group showed better results . Therefore , both infliximab and etanercept are efficacious in RA , but infliximab is more efficacious than etanercept in week 14 . Vice versa , in week 54 etanercept is the most efficacious drug . CONCLUSIONS Physicians have 2 weapons in their armamentarium , with the same target but distinct clinical , pharmacokinetic and pharmacodynamic properties 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 Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project , coverage of selected biologic drugs has been exp and ed for Medicare beneficiaries . For rheumatoid arthritis , coverage was extended to etanercept , adalimumab , and anakinra in addition to the previously covered infliximab . We undertook to develop a model to compare the costs and quality -adjusted life years ( QALYs ) generated by each of the 4 biologic agents . METHODS Data were drawn from meta- analysis of r and omized controlled trials and from a large longitudinal outcomes data bank . Uncertainty was addressed using probabilistic and one-way sensitivity analyses . A lifetime horizon and Medicare viewpoint were adopted . RESULTS In the base case analysis , anakinra was the least effective and least costly strategy . Etanercept , adalimumab , and infliximab were similar in terms of effectiveness , but infliximab was more costly . If decision makers are willing to pay a maximum of $ 50,000/QALY , the probability that infliximab is cost-effective is < 1 % . Findings were robust to a range of sensitivity analyses . Only if the dose of infliximab remains constant over time is this likely to be a cost-effective strategy . CONCLUSION Infliximab is unlikely to be cost-effective in the Medicare population compared with either etanercept or adalimumab . Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor alpha inhibitors Objective . The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan ( JESMR ) study is to compare the efficacy of continuation versus discontinuation of methotrexate ( MTX ) when starting etanercept ( ETN ) in patients with active rheumatoid arthritis ( RA ) . Methods . In total , 151 patients with active RA who had been taking MTX were r and omized to either ETN 25 mg twice a week with 6–8 mg/week MTX ( the E+M group ) , or ETN alone ( the E group ) . The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score . Results . The mean progression in total score at Week 52 was not significantly different , statistically , between the E+M group and the E group ( 0.8 vs 3.6 , respectively ; p = 0.06 ) . However , a significant difference was observed in radiographic progression between Weeks 24 and 52 ( 0.3 vs 2.5 ; p = 0.03 ) , and the mean progression of the erosion score was negative in the E+M group , which was significantly better than the E group at Week 52 ( –0.2 vs 1.8 ; p = 0.02 ) . Clinical ly , the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group . ACR20 , 50 , and 70 response rates at Week 52 in the E+M group ( 86.3 % , 76.7 % , and 50.7 % ) were significantly greater than those in the E group ( 63.8 % ; p = 0.003 , 43.5 % ; p < 0.0001 and 29.0 % ; p = 0.01 , respectively ) . Conclusion . MTX should be continued when starting ETN in patients with active RA . ( Clinical Trials.gov : NCT00688103 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 determine the efficacy and safety of filtration leukocytapheresis ( LCP ) for the treatment of rheumatoid arthritis ( RA ) . METHODS Twenty-five patients with drug-resistant RA were r and omly assigned to undergo filtration LCP and 7 to undergo sham apheresis ( control group ) in a r and omized , double-blind , placebo-controlled study . Three apheresis procedures were performed , with 1-week intervals between procedures . The efficacy of filtration LCP was evaluated according to the American College of Rheumatology definition of improvement in RA . Medications for each patient were unchanged for at least 6 months prior to enrollment and throughout the study . RESULTS Tender joint counts , swollen joint counts , patient assessment of pain and global severity , physician assessment of global severity , and Health Assessment Question naire Disability Index were significantly improved in the LCP group compared with the control group ( P < 0.05 for patient assessment of pain ; P < 0.01 for all others ) . Seventy-nine percent of the patients in the LCP group exhibited significant overall improvement , while none of the patients in the control group were improved ( P < 0.001 ) . CONCLUSION The results indicate that filtration LCP is an effective and well-tolerated treatment for patients with drug-resistant RA 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 OBJECTIVE To evaluate societal costs and quality -adjusted life years ( QALYs ) of treatment strategies for patients with recent-onset active rheumatoid arthritis ( RA ) . METHODS Patients ( n = 508 ) were r and omly allocated to 1 of 4 treatment strategy groups : sequential monotherapy , step-up combination therapy , initial combination therapy with prednisone , or initial combination therapy with infliximab . For 2 years , patients reported cost and utility measures . RESULTS Average QALYs ( ideally 2.00 ) for groups 1 - 4 were 1.29 , 1.31 , 1.32 , and 1.41 , respectively , for the British EuroQol ( P < or= 0.05 for group 4 versus groups 1 - 3 ) ; 1.41 , 1.43 , 1.44 , and 1.52 , respectively , for the Dutch EuroQol ( P < or= 0.05 for group 4 versus groups 1 - 3 ) ; and 1.38 , 1.38 , 1.39 , and 1.44 , respectively , for the Short Form 6D ( P < or= 0.05 for group 4 versus groups 1 - 3 ) . The Time Trade-Off showed no significant differences . In the primary analysis , using the friction cost method to value productivity , the cost-utility ratio for group 4 against the next best alternative was estimated at euro 130,000 ( 95 % confidence interval euro 27,000 , euro 3,000,000 ) per QALY . Using the human capital method , the value of sustained productivity in group 4 largely compensated for the extra medication costs . CONCLUSION Initial combination therapy with infliximab for patients with recent-onset active RA result ed in significantly better quality of life than other strategies . Using the friction cost method , costs to achieve this improvement are generally considered too high , and initial combination therapy with prednisone should be preferred . However , depending on the extent to which productivity is valued , infliximab costs could be largely compensated for by savings on productivity . Since patterns of infliximab use had not yet stabilized after 2 years , longer followup may change the economic conclusions BACKGROUND Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs , but a minority of patients achieve a good response . We aim ed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis -- for sustained , tight control of disease activity -- compared with routine outpatient care . METHODS We design ed a single-blind , r and omised controlled trial in two teaching hospitals . We screened 183 patients for inclusion . 111 were r and omly allocated either intensive management or routine care . Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response ( defined as a disease activity score < 2.4 and a fall in this score from baseline by > 1.2 ) . Analysis was by intention-to-treat . FINDINGS One patient withdrew after r and omisation and seven dropped out during the study . Mean fall in disease activity score was greater in the intensive group than in the routine group ( -3.5 vs -1.9 , difference 1.6 [ 95 % CI 1.1 - 2.1 ] , p<0.0001 ) . Compared with routine care , patients treated intensively were more likely to have a good response ( definition , 45/55 [ 82 % ] vs 24/55 [ 44 % ] , odds ratio 5.8 [ 95 % CI 2.4 - 13.9 ] , p<0.0001 ) or be in remission ( disease activity score < 1.6 ; 36/55 [ 65 % ] vs 9/55 [ 16 % ] , 9.7 [ 3.9 - 23.9 ] , p<0.0001 ) . Three patients assigned routine care and one allocated intensive management died during the study ; none was judged attributable to treatment . INTERPRETATION A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity , radiographic disease progression , physical function , and quality of life at no additional cost Objective : To examine the effect of infliximab plus methotrexate ( MTX ) compared with placebo plus MTX on bone loss in patients with early rheumatoid arthritis ( RA ) in a double-blind r and omised study design . Further , to explore the associations between bone loss and markers of RA disease . Methods : All 20 patients with RA ( 10 patients in each treatment group ) had active , early RA .  Bone mineral density ( BMD ) was assessed at the h and , lumbar spine ( L2–4 ) and hip by dual energy x-ray absorptiometry at baseline and 12 months ’ follow-up . Clinical data were collected at regular visits . Results : BMD loss was significantly reduced in the infliximab group compared with the placebo group at the femoral neck ( −0.35 % vs −3.43 % , p = 0.01 ) and total hip ( −0.23 % vs −2.62 % , p = 0.03 ) but not at the h and ( −2.09 % vs −2.82 % , p = 0.82 ) and spine ( −0.75 % vs −1.77 % , p = 0.71 ) . Measures of disease process and joint damage were found to be independently associated with bone loss . Conclusions : This study provides strong evidence of a causal link between inflammation and bone loss in RA . The anti-inflammatory effect of infliximab was potent enough to arrest inflammatory bone loss at the hip but not at the spine and h and Objective . This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy , radiographic response , and safety of rituximab ( RTX ) in patients with rheumatoid arthritis ( RA ) who had an inadequate response to tumor necrosis factor ( TNF ) inhibitors .  Methods . Patients in REFLEX were originally r and omized to placebo ( PBO ) + methotrexate ( MTX ; PBO-r and omized ) or RTX + MTX ( RTX-r and omized ) . PBO-r and omized patients were rescued with RTX as appropriate . Patients responding to initial RTX treatment could receive further RTX courses . For clinical efficacy and safety analyses , PBO-r and omized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-r and omized patient data . Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline . Radiographic outcomes were assessed relative to r and omization baseline for both PBO-r and omized and RTX-r and omized groups . Results . A total of 480 patients received ≥ 1 RTX course . At 24 weeks , American College of Rheumatology 20/50/70 responses were 62.0 % , 30.8 % , and 13.0 % , respectively at course 1 ( n = 400 ) and 70.3 % , 41.8 % , and 22.0 % at course 5 ( n = 91 ) . European League Against Rheumatism good/moderate responses were 77.2 % and 84.4 % at courses 1 ( n = 390 ) and 5 ( n = 90 ) . Rates of adverse events ( AE ) , serious AE , and infections generally remained stable . Rate of progressive joint damage ( PJD ; change in mean Total Sharp Score ) decreased over time in both PBO-r and omized ( n = 79 ) and RTX-r and omized ( n = 105 ) groups . Mean change from baseline in PJD over 5 years was greater in PBO-r and omized versus RTX-r and omized patients ( 5.51 vs 3.21 ) . Conclusion . RTX re-treatment over 5 years is associated with maintained or improved efficacy , continued inhibition of PJD , and a safety profile consistent with that previously reported . A delay in initiating RTX treatment may result in increased PJD
OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic inflammatory disease associated with increasing disability , reduced quality of life and substantial costs ( as a result of both intervention acquisition and hospitalisation ) .
The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs ( bDMARDs ) compared with each other and conventional disease-modifying antirheumatic drugs ( cDMARDs ) .
Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient .