A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naïve patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study Patient-reported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-contro Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The BeSt way of withdrawing biologic agents. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Discontinuation of infliximab in rheumatoid arthritis patients in clinical remission Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Sustained remission with etanercept tapering in early rheumatoid arthritis.
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 To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) OBJECTIVE To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis ( RA ) on 2-year patient-reported outcomes , including functioning and quality of life . METHODS A total of 508 patients with recent-onset RA were r and omly assigned to 1 ) sequential monotherapy , 2 ) step-up combination therapy , both starting with methotrexate , 3 ) initial combination therapy , including a tapered high-dose prednisone , or 4 ) initial combination therapy with methotrexate and infliximab . Treatment was adjusted every 3 months if the Disease Activity Score ( DAS ) remained > 2.4 . The McMaster Toronto Arthritis Patient Preference Disability Question naire , the Short Form 36 ( SF-36 ) , and scores for pain , global health , and disease activity measured on a 100-mm visual analog scale ( VAS ) were compared between groups at baseline and every 3 months thereafter for 2 years . RESULTS After 2 years , all patient-reported outcomes had improved significantly from baseline , irrespective of the treatment strategy . SF-36 subscale scores approached population norms for 3 physical components , and achieved population norms ( P > 0.05 ) for bodily pain and 4 mental components . Improvement in functioning , VAS scores , and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies ( all comparisons after 3 months : overall P < 0.001 ; P < 0.05 for groups 1 and 2 versus groups 3 and 4 ) . CONCLUSION All 4 DAS-driven treatment strategies result ed in substantial improvements in functional ability , quality of life , and self-assessed VAS scores after 2 years . Initial combination therapy led to significantly faster improvement in all patient-reported measures OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy 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 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 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 OBJECTIVES Treat-to-target strategies in the management of patients with rheumatoid arthritis ( RA ) involve intensifying medication as long as low disease activity or remission is not achieved . Our aim was to discuss reasons and opportunities for tapering and discontinuing medication when the target is achieved , in particular of biological agents . METHODS Data from the Beh and el Strategieën ( BeSt ) study are presented , a multicentre r and omised clinical trial comparing 4 treatment strategies in patients with recent onset active RA ( 1987 criteria ): 1 . Sequential monotherapy , 2 . Step up to combination therapy ( both starting with methotrexate ( MTX ) monotherapy ) , 3 . Initial combination therapy with MTX , sulfasalazine and prednisone and 4 . Initial combination therapy with MTX and infliximab . Treatment adjustments involving dose increases , drug changes or expansion to combination therapy occurred based on three-monthly calculations of the Disease Activity Score ( DAS ) , with a target of ≤2.4 . If this was achieved for 2 consecutive evaluations , treatment was tapered ( combinations to monotherapy , monotherapy to maintenance dose ) . Prednisone and infliximab ( either as part of initial treatment or as delayed treatment after failure on earlier therapies in arms 1 , 2 and -for infliximab- 3 ) were always tapered and discontinued before other drugs . The outcomes of discontinuation of infliximab  are presented . RESULTS 77/120 ( 64 % ) of patients who started initial infliximab were able to discontinue infliximab , whereas 27/109 ( 25 % ) of patients who started delayed infliximab in arms 1 - 3 could discontinue infliximab . Discontinuation was independent of previous dose increases in order to achieve low DAS . After discontinuation of infliximab , 16 of 27 patients ( 59 % ) in arms 1 - 3 and 34 of 77 patients ( 44 % ) in arm 4 suffered a DAS flare > 2.4 and had to restart treatment . Median time without infliximab  treatment was 17 ( IQR 3 - 47 ) months , and 29 of the 61 patients ( 58 % ) who needed to restart had been at least 1 year without infliximab . Restarting infliximab result ed in DAS ≤2.4 in all patients , and there was no progression of radiological damage . Presence of shared epitope , smoking , and a long treatment with infliximab  were independent predictors of infliximab restart . CONCLUSIONS Data on infliximab discontinuation in the BeSt study suggest that this possible in 1 in 4 patients , or more if infliximab was the initial treatment , who have had at least 6 consecutive months of low disease activity . While MTX is continued , about 50 % of patients can permanently stop infliximab without radiological damage progression , the others regain low disease activity after restarting infliximab . Treat to target strategies using biologic agents should include strategies for discontinuation 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 BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life .  Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis BACKGROUND Biological agents offer good control of rheumatoid arthritis , but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear . The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining ( or not ) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy . METHODS This trial was done at 161 sites worldwide . Patients with early ( < 1 year duration ) rheumatoid arthritis naive to methotrexate  were r and omly allocated ( by interactive voice response system , in a 1:1 ratio , block size four ) to adalimumab ( 40 mg every other week ) plus methotrexate ( initiated at 7·5 mg/week , increased by 2·5 mg every 1 - 2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks ( period 1 ) . Patients in the  adalimumab plus methotrexate  group who completed period 1 and achieved the stable low disease activity target ( 28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26 ) were r and omised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks ( period 2 ) . Patients achieving the target with initial methotrexate continued methotrexate-monotherapy . Inadequate responders were offered adalimumab plus methotrexate . All patients and investigators were masked to treatment allocation in period 1 . During period 2 , treatment reallocation of patients who achieved the target was masked to patients and investigators ; patients who did not achieve the target remained masked to original r and omisation , but were aware of the subsequent assignment . The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78 , compared between adalimumab-continuation and methotrexate-monotherapy  . Adverse events were monitored throughout period 2 . This trial is registered with Clinical Trials.gov , number NCT00420927 . FINDINGS The study was done between Dec 28 , 2006 , and Aug 3 , 2010 . 1636 patients were assessed and 1032 were r and omised in period 1 ( 515 to adalimumab plus methotrexate ; 517 to placebo plus methotrexate ) . 466 patients in the adalimumab plus methotrexate group completed period 1 ; 207 achieved the stable low disease activity target , of whom 105 were rer and omised to adalimumab-continuation . 460 patients in the placebo plus methotrexate group completed period 1 ; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy . 73 of 105 ( 70 % ) patients in the adalimumab-continuation group and 61 of 112 ( 54 % ) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 ( mean difference 15 % [ 95 % CI 2 - 28 % ] , p=0·0225 ) . Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses . Overall , 706 of 926 patients in period 2 had an adverse event , of which 82 were deemed serious ; however , distribution of adverse events did not differ between groups . INTERPRETATION Treatment to a stable low disease activity target result ed in improved clinical , functional , and structural outcomes , with both adalimumab-continuation and methotrexate-monotherapy . However , a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone . Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate . FUNDING AbbVie 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 Biologic drugs are effective but are also expensive , and it is difficult to evaluate the duration of treatment . Infliximab , an anti-TNFα antibody , suppresses arthritic activity and inhibits bone destruction in patients with rheumatoid arthritis ( RA ) . Here , we document that infliximab could be discontinued after clinical remission in RA patients . Among 172 patients with RA who reached clinical remission following infliximab ( 3 mg/kg ) and methotrexate ( MTX , > 6 mg/w ) , nine patients with sustained remission discontinued it . Clinical assessment was based on a disease activity score ( DAS ) that included a 28-joint count/erythrocyte sedimentation rate ( DAS28-ESR ) . The disease was assessed before and after the start of infliximab treatment , and concomitant drug treatment — in the order of corticosteroid , nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and disease-modifying anti-rheumatic drugs ( DMARDs ) other than MTX — was gradually discontinued . We considered patients for discontinuation of infliximab treatment after remission ( DAS28-ESR < 2.6 ) had been sustained for more than 24 weeks . The nine patients able to discontinue treatment were all females , with a mean age of 53.8 years ; eight patients were at stage I or II .  The mean duration of disease was 28.7 months , and these patients were on corticosteroid treatment equivalent to a mean of 2.28 mg prednisolone ( PSL ) . These nine patients all met the remission st and ard — that DAS28-ESR < 2.6 for ≥24 weeks ) — and so their treatment with concomitant drugs was discontinued . After the discontinuation of infliximab , the mean period of sustained remission was 14.2 months and the longest period was 29 months . The duration of disease was significantly shorter and the points from Steinbrocker ’s stage-classification were significantly lower in the infliximab-discontinued group than in the infliximab-continued group . Strategic reductions and /or discontinuations of concomitant treatment were performed in RA patients who attained clinical remission ( DAS28 < 2.6 ) through treatment with infliximab and MTX . Nine patients successfully discontinued infliximab after maintaining clinical remission for more than 24 weeks . After infliximab was discontinued , clinical remission and suppression of joint destruction were maintained with MTX alone , especially in early RA patients Objectives To study clinical and radiographic outcomes after withdrawing 1 year 's adalimumab induction therapy for early rheumatoid arthritis ( eRA ) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy ( NCT00660647 ) . Methods Disease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate ( 20 mg/week ) and intra-articular triamcinolone ( 20 mg/ml ) for 2 years . In addition , they were r and omised to receive  placebo adalimumab ( DMARD group , n=91 ) or adalimumab (  40 mg/every other week ) ( DMARD+adalimumab group , n=89 ) during the first year . Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months . During year 2 , synthetic DMARDs continued . Adalimumab was (re)initiated if active disease reoccurred . Clinical response , remission , disability , quality of life and radiographic changes were assessed . Results One year after adalimumab withdrawal , treatment profiles and clinical responses did not differ between groups . In the DMARD/DMARD+adalimumab groups , the median 2-year methotrexate dose was 20/20 mg/week ( p=0.45 ) , triple DMARD therapy had been initiated in 33/27 patients ( p=0.49 ) , adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg ( p=0.15 ) . The treatment target ( disease activity score , 4 variables , C-reactive protein ( DAS28CRP ) ≤3.2 or DAS28>3.2 without swollen joints ) was achieved at all visits in ≥85 % of patients in year 2 ; remission rates were DAS28CRP<2.6:69%/66 % ; Clinical Disease Activity Index ≤2.8:55%/57 % ; Simplified Disease Activity Index < 3.3:54%/49 % ; American College of Rheumatology/European League against Rheumatism ( 28 joints):44%/45 % ( p=0.66–1.00 ) . Radiographic progression ( Δtotal Sharp score/year ) was similar 1.31/0.53 ( p=0.12 ) . Erosive progression ( Δerosion score (ES)/year ) was year 1:0.57/0.06 ( p=0.02 ) ; year 2:0.38/0.05 ( p=0.005 ) . Proportion of patients without erosive progression ( ΔES≤0 ) was year 1 : 59%/76 % ( p=0.03 ) ; year 2:64%/79 % ( p=0.04 ) . Conclusions An aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy . ES progression was slightly less during and following adalimumab induction therapy . Trial registration number NCT00660647 BACKGROUND Neutralization of tumor necrosis factor a ( TNF-alpha ) for three to six months reduces the symptoms and signs of rheumatoid arthritis . However , the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known . METHODS We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab , a chimeric monoclonal antibody against TNF-alpha  , in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks . We assessed clinical responses with use of the criteria of the American College of Rheumatology , the quality of life with a health-status question naire , and the effect on joint damage radiographically . RESULTS The combination of infliximab and methotrexate was well tolerated and result ed in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone ( clinical response , 51.8 percent vs. 17.0 percent ; P<0.001 ) . The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone . Radiographic evidence of joint damage increased in the group given methotrexate , but not in the groups given infliximab and methotrexate ( mean change in radiographic score , 7.0 vs. 0.6 , P<0.001 ) . Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response . CONCLUSIONS In patients with persistently active rheumatoid arthritis despite methotrexate therapy , repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage 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 BACKGROUND We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy .  METHODS Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks ( open-label phase ) . We then r and omly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate ( combination-therapy group ) , methotrexate alone , or placebo for 39 weeks ( double-blind phase ) . Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 ( treatment-withdrawal phase ) . The primary end point was the proportion of patients with sustained remission in the double-blind phase . RESULTS Of 306 patients enrolled , 193 underwent r and omization in the double-blind phase ; 131 qualified for the treatment-withdrawal phase . More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point ( 40 of 63 [ 63 % ] vs. 26 of 65 [ 40 % ] and 15 of 65 [ 23 % ] , respectively ; P=0.009 for combination therapy vs. methotrexate alone ; P<0.001 for combination therapy vs. placebo ) . At 65 weeks , 28 patients ( 44 % ) who had received combination therapy , 19 ( 29 % ) who had received methotrexate alone , and 15 ( 23 % ) who had received placebo were in remission ( P=0.10 for combination therapy vs. methotrexate alone ; P=0.02 for combination therapy vs. placebo ; P=0.55 for methotrexate alone vs. placebo ) . No significant between-group differences were observed in radiographic progression of disease . Serious adverse events were reported in 3 patients ( 5 % ) in the combination-therapy group , 2 ( 3 % ) in the methotrexate-alone group , and 2 ( 3 % ) in the placebo group . CONCLUSIONS In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy , continuing combination therapy at a reduced dose result ed in better disease control than switching to methotrexate alone or placebo , but no significant difference was observed in radiographic progression . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00913458 . )
OBJECTIVE To determine whether an induction-maintenance strategy of combined therapy ( methotrexate (MTX)+tumour necrosis factor ( TNF ) inhibitor ( TNFi ) ) followed by withdrawal of TNFi could yield better long-term results than a strategy with MTX monotherapy , since it is unclear if the benefits from an induction phase with combined therapy are sustained if TNFi is withdrawn .