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A non-inferiority trial of an attenuated combination strategy (‘COBRA-light’) compared to the original COBRA strategy: clinical results after 26 weeks Combination therapy with cyclosporine and methotrexate in patients with early rheumatoid arthritis soon inhibits TNFalpha production without decreasing TNFalpha mRNA levels. An in vivo and in vitro study. Comparison of intra-articular glucocorticoid injections with DMARDs versus DMARDs alone in rheumatoid arthritis. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Impact of a magnetic resonance imaging-guided treat-to-target strategy on disease activity and progression in patients with rheumatoid arthritis (the IMAGINE-RA trial): study protocol for a randomized controlled trial Early combination disease-modifying antirheumatic drug therapy and tight disease control improve long-term radiologic outcome in patients with early rheumatoid arthritis: the 11-year results of the Finnish Rheumatoid Arthritis Combination Therapy trial Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study) Response to glucocorticoids at 2 weeks predicts the effectiveness of DMARD induction therapy at 3 months: post hoc analyses from the tREACH study Longterm Effect of Delaying Combination Therapy with Tumor Necrosis Factor Inhibitor in Patients with Aggressive Early Rheumatoid Arthritis: 10-year Efficacy and Safety of Adalimumab from the Randomized Controlled PREMIER Trial with Open-label Extension The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis. 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Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. 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Impact of physicians’ adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis in the NEO-RACo trial Less Radiographic Progression with Adalimumab Plus Methotrexate Versus Methotrexate Monotherapy Across the Spectrum of Clinical Response in Early Rheumatoid Arthritis Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two‐Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial Health-related Quality of Life Outcomes of Adalimumab for Patients with Early Rheumatoid Arthritis: Results from a Randomized Multicenter Study Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. 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Intention-to-treat approach to data from randomized controlled trials: a sensitivity analysis. Step-down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis. Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis. The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. Early disease control by low-dose prednisone comedication may affect the quality of remission in patients with early rheumatoid arthritis. Implementation of treat-to-target in rheumatoid arthritis through a Learning Collaborative: Rationale and design of the TRACTION trial. Cost-utility analysis of treatment strategies in patients with recent-onset rheumatoid arthritis. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial
Background Preliminary , mostly uncontrolled studies suggest that dose reduction or discontinuation of tumour necrosis factor blockers can be achieved in a relevant proportion of patients with RA without loss of disease control . However , long term safety , cost effectiveness and feasibility in clinical practice remain uncertain . Methods / Design This study is a 18-months pragmatic , non-inferiority , cost minimalisation , r and omized controlled trial on dose reduction and discontinuation of the subcutaneous tumour necrosis factor ( TNF ) blockers adalimumab and etanercept in RA patients with low disease activity . 180 RA patients with low disease activity ( DAS28 < 3.2 or clinical judgment of the rheumatologist ) are r and omized 2:1 to either increased spacing and eventually discontinuation after 6 months of the TNF blocker , and usual care . Implementation is done in routine daily care , using treat to target and feedback implementation in both treatment arms . The primary outcome is non-inferiority ( NI margin 20 % ) in cumulative incidence of persistent ( > 3 months ) RA flare , according to a recently vali date d DAS28 based flare criterion ( DAS28 change > 1.2 , or DAS28 increase of 0.6 and current DAS28 ≥ 3.2 ) . Secondary outcomes include mean disease activity , function , radiographic progression , safety and cost effectiveness . Cost per quality adjusted life year ( QALY ) differences between groups are expressed as a decremental cost effectiveness ratio ( DCER ) , i.e. saved costs divided by ( possible ) loss in QALY . Discussion The design of this study targeted several clinical and method ological issues on TNF blocker dose de-escalation , including how to taper the TNF blockers , the satisfactory control condition , how to define flare , implementation in clinical practice , and the choice of the non-inferiority margin . Pragmatic cost minimalisation studies using non-inferiority design s and DCERs will become more mainstream as cost effectiveness in healthcare gains importance .Trial registration Dutch Trial Register NTR3216 , The study has received ethical review board approval ( number NL37704.091.11 OBJECTIVE To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis ( RA ) combined with monitoring both disease activity and cartilage degradation . METHODS In a pilot trial , 21 patients with active early RA ( mean DAS28 5.3 ; mean disease duration 3 months ) were treated with COBRA treatment comprising sulfasalazine , methotrexate and high-dose step-down prednisolone , intensified by adding hydroxychloroquine and continued low-dose prednisolone . In addition , based on measurements of disease activity or a marker of cartilage degradation ( CTX-II ) , treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks ; and with infliximab after 21 weeks . RESULTS Nineteen of 21 patients ( 90 % ) were in remission ( DAS28 < 2.6 ) after 40 weeks ( 8 weeks , 57 % ; 21 weeks , 76 % ) . American College of Rheumatology ( ACR ) criteria , ACR20 , 50 , 70 and 90 improvements rates were 100 % , 95 % , 71 % and 43 % respectively . CTX-II excretion decreased by mean ( SD ) 347(292 ) ng/mmol creatinine , but only 50 % of patients reduced their CTX-II excretion below the cut-off point . The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion , despite a trend towards more intensive treatment in the CTX-II group . Treatment intensification was feasible according to protocol . CONCLUSIONS This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA . TRIAL REGISTRATION NUMBER IS RCT N96372677 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 OBJECTIVE To test the efficacy of st and ardised monitoring using the disease activity index DAS28 versus usual care on disease modifying antirheumatic drug ( DMARD ) prescription and disease activity in rheumatoid arthritis . METHODS A 24 week cluster r and omised trial . Rheumatology outpatient centres were r and omised to systematic monitoring of disease activity  using the  DAS28  ( 12 centres , 205 patients ) or usual care ( 12 centres , 179 patients ) . The aim for the DAS group was to reach a DAS28 score of < or = 3.2 by changes in DMARD treatment , at the discretion of the rheumatologist and the patient . RESULTS At baseline ,  disease activity  was the same in both groups , with an overall mean ( SD ) DAS28  of 4.5 ( 1.2 ) ; 13 % of the patients had a  DAS28 of < or = 3.2 . At 24 weeks , 31 % of patients in the DAS group had a DAS28 < or = 3.2 , while in the usual care centres this was 16 % ( p = 0.028 ) .  DMARDs  were changed on average in 18 % of visits in the DAS centres ; in the 12 usual care centres they were changed on 8 % of the visits ( p = 0.013 ) . The doses of methotrexate , sulfasalazine , and corticosteroids  appeared to be higher in the DAS centres than in the usual care centres , but the differences were not significant . CONCLUSIONS In daily practice , systematic monitoring of disease activity in rheumatoid arthritis may lead to more changes in DMARD treatment , result ing in a larger number of patients with low disease activity Objectives To compare the efficacy and safety of intensive combination strategies with glucocorticoids ( GCs ) in the first 16 weeks ( W ) of early rheumatoid arthritis ( eRA ) treatment , focusing on high-risk patients , in the Care in early RA trial . Methods 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers . High-risk patients ( n=290 ) were r and omised to 1/3 treatment strategies : combination therapy for early rheumatoid arthritis ( COBRA ) Classic ( methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7 ) , COBRA Slim ( MTX+30 mg prednisone tapered to 5 mg from W6 ) and COBRA Avant-Garde ( MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6 ) . Treatment modifications to target low-disease activity were m and atory from W8 , if desirable and feasible according to the rheumatologist . The primary outcome was remission ( 28 joint disease activity score calculated with C-reactive protein < 2.6 ) at W16 ( intention-to-treat analysis ) . Secondary endpoints were good European League Against Rheumatism response , clinical ly meaningful health assessment question naire ( HAQ ) response and HAQ equal to zero . Adverse events ( AEs ) were registered . Results Data from 98 Classic , 98 Slim and 94 Avant-Garde patients were analysed . At W16 , remission was reached in 70.4 % Classic , 73.6 % Slim and 68.1 % Avant-Garde patients ( p=0.713 ) . Likewise , no significant differences were shown in other secondary endpoints . However , therapy-related AEs were reported in 61.2 % of Classic , in 46.9 % of Slim and in 69.1 % of Avant-Garde patients ( p=0.006 ) . Conclusions For high-risk eRA , MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile . EudraCT number : 2008 - 007225 - 39 Objectives : To determine whether prolonged intensive disease-modifying antirheumatic drug ( DMARD ) treatment ( PRINT ) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis ( RA ) . Methods : In this multicenter , r and omized and parallel treatment trial , 346 patients with active RA ( disease activity score ( 28 joints ) [ DAS28 ] ( erythrocyte sedimentation rate [ ESR ] ) > 5.1 ) were enrolled from 9 centers . In phase 1 , patients received intensive treatment with methotrexate , leflunomide , and hydroxychloroquine , up to 36 weeks , until remission ( DAS28 ⩽ 2.6 ) or a low disease activity ( 2.6 < DAS28 ⩽ 3.2 ) was achieved . In phase 2 , patients achieving remission or low disease activity were followed up with r and omization to 1 of 2 step-down protocol s : leflunomide plus hydroxychloroquine combination or leflunomide monotherapy . The primary endpoints were good European League Against Rheumatism ( EULAR ) response ( DAS28 ( ESR ) < 3.2 and a decrease of DAS28 by at least 1.2 ) during the intensive treatment and the disease state retention rate during step-down maintenance treatment . Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought . Results : A good EULAR response was achieved in 18.7 % , 36.9 % , and 54.1 % of patients at 12 , 24 , and 36 weeks , respectively . By 36 weeks , 75.4 % of patients achieved good and moderate EULAR responses . Compared with those achieving low disease activity and a high health assessment question naire ( HAQ > 0.5 ) , patients achieving remission ( DAS28 ⩽ 2.6 ) and low HAQ ( ⩽ 0.5 ) had a significantly higher retention rate when tapering the DMARDs treatment ( P = 0.046 and P = 0.01 , respectively ) . There was no advantage on tapering to combination rather than monotherapy . Conclusions : Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy .  Low disease activity at the start of disease taper leads to less subsequent flares . Leflunomide is a good maintenance treatment as single treatment Objectives To compare 1-year clinical efficacy of ( 1 ) initial triple disease-modifying antirheumatic drug therapy ( iTDT ) with initial methotrexate ( MTX ) monotherapy ( iMM ) and ( 2 ) different glucocorticoid ( GC ) bridging therapies : oral versus a single intramuscular injection in early rheumatoid arthritis . Methods In a single-blinded r and omised clinical trial patients were r and omised into three arms : ( A ) iTDT ( methotrexate+sulfasalazine+hydroxychloroquine ) with GCs intramuscularly ; ( B ) iTDT with an oral GC tapering scheme and ( C ) MTX with oral GCs similar to B. Primary outcomes were ( 1 ) area under the curve ( AUC ) of Health Assessment Question naire ( HAQ ) and Disease Activity Score ( DAS ) and ( 2 ) the proportion of patients with radiographic progression . Results 281 patients were r and omly assigned to arms A ( n=91 ) , B ( n=93 ) or C ( n=97 ) . The AUC DAS and HAQ were respectively −2.39 ( 95 % CI −4.77 to −0.00 ) and −1.67 ( 95 % CI −3.35 to 0.02 ) lower in patients receiving iTDT than in those receiving iMM . After 3 months , treatment failure occurred less often in the iTDT group , result ing in 40 % fewer treatment intensifications . The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time . No differences were seen between the two GC bridging therapies . Respectively 21 % , 24 % and 23 % of patients in arms A , B and C had radiographic progression after 1 year . Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM . Conclusions Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM . However , no difference in radiographic progression is seen . Both GC bridging therapies are equally effective and , therefore , both can be used . Trial registration number IS RCT N26791028 Objective . To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA . Methods . Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches : ( i ) treatment to target ( TT ) : patients assessed 24 weeks after each course and retreated if not in remission [ DAS in 28 joints based on ESR ( DAS-28-ESR ) ≥ 2.6 ] ; ( ii ) treatment as needed ( PRN ) : patients retreated at the physician ’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses , if both swollen and tender joint counts were ≥8 . All courses consisted of i.v . rituximab 2 × 1000 mg 2 weeks apart plus MTX . Observed data were analysed according to treatment strategy . Results . Multiple courses of rituximab maintained or improved responses irrespective of regimen . TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN . TT result ed in significantly more patients achieving major clinical response . PRN result ed in recurrence of disease symptoms between courses , with TT significantly reducing the incidence of RA flares . Despite more frequent retreatment with TT compared with PRN , the rates of serious adverse events and serious infections were comparable between regimens . Conclusions . Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile . TT may be the preferable rituximab treatment regimen for patients with RA Biologics have mainly been assessed in patients with severe rheumatoid arthritis ( RA ) globally . Less attention has been paid to moderately active disease , especially in Central and Eastern Europe ( CEE ) . Access to biologics and the disease features of RA patients may differ in CEE , relative to other regions . We assessed the clinical and patient-reported outcomes ( PROs ) of treatment from CEE patients in the multinational PRESERVE study ( NCT00565409 ) . Patients with moderate RA 28-joint disease activity score ( ( DAS28 ) erythrocyte sedimentation rate ( ESR ) > 3.2 and ≤5.1 ) despite methotrexate ( MTX ) treatment received open-label etanercept ( ETN ) 50 mg QW + MTX for 36 weeks . Low disease activity ( DAS28 low disease activity ( LDA ) ≤3.2 ) and remission ( DAS28 ESR < 2.6 ) were assessed . PROs included Health Assessment Question naire Disability Index ( HAQ-DI ) , patient global assessment ( PGA ) , EuroQol-5 Dimension ( EQ-5D ) , pain visual analogue scale ( VAS ) , Medical Outcomes Study sleep question naire ( MOS Sleep ) , Functional Assessment of Chronic Illness Therapy ( FACIT ) , and Work Productivity and Activity Impairment for RA ( WPAI-RA ) . Descriptive summary statistics were employed . Of the 834 enrolled patients , 302 were from CEE . At baseline , CEE patients had similar disease states versus the overall population . By week 36 , LDA was achieved by 87 % , remission by 67 % , and normal HAQ-DI ( ≤0.5 ) by 53 % of patients . Mean scores ( SDs ) for PROs significantly improved by week 36 as follows : HAQ-DI total by −0.6 ( 0.5 ) ; PGA by −2.4 ( 2.1 ) ; EQ-5D total index by 0.2 ( 0.2 ) . Pain VAS , MOS Sleep , FACIT , and WPAI-RA also showed significant improvements . In conclusion , induction therapy with ETN + MTX led to DAS28 LDA , remission , and improvements in PROs in most CEE patients with moderately active RA despite treatment with MTX . These results are similar to the overall study population in the PRESERVE trial The aim of this study was to assess safety and efficacy of ultrasonography (US)-guided intra-articular injections using tumor necrosis factor ( TNF ) blockers compared to corticosteroids in rheumatoid arthritis ( RA ) or psoriatic arthritis ( PsA ) patients , experiencing refractory monoarthritis despite the current systemic therapy . Eighty-two patients were r and omized to receive three intra-articular injections monthly of either corticosteroid or TNF blockers . Primary endpoints were the safety and an improvement greater than 20 % for visual analogic scales of involved joint pain in patients injected with anti-TNFα . Further clinical , US , and magnetic resonance imaging ( MRI ) evaluations were considered secondary endpoints . Intra-articular TNF blockers are a safe strategy , determining a significant reduction of patient and physician reported clinical outcomes and US/MRI scores , in RA and PsA patients , when compared to intra-articular injections of corticosteroids . US guidance excluded the possibility to inject the drug in the wrong site , maximizing local effects , reducing systemic effects , and increasing the safety of the procedure . Patients with inflammatory monoarthritis could be successfully treated with US-guided intra-articular TNF blockers that are a safe and well tolerated procedure , to achieve a longst and ing clinical and radiological good clinical response and /or disease remission Background Where health economic studies are frequently performed using modelling , with input from r and omized controlled trials and best guesses , we used real-life data to analyse the cost-effectiveness and cost-utility of a treatment strategy aim ing to the target of remission compared to usual care in early rheumatoid arthritis ( RA ) . Methods We used real-life data from comparable cohorts in the Dutch Rheumatoid Arthritis Monitoring ( DREAM ) registry : the DREAM remission induction cohort ( treat-to-target , T2 T ) and the Nijmegen early RA inception cohort ( usual care , UC ) . Both cohorts were followed prospect ively using the DREAM registry methodology . All patients fulfilled the American College of Rheumatology criteria for RA and were included in the cohort at the time of diagnosis . The T2 T cohort was treated according to a protocol ised strategy aim ing at remission ( Disease Activity Score in 28 joints ( DAS28 ) < 2.6 ) . The UC cohort was treated without DAS28-guided treatment decisions .  EuroQol-5D utility scores were estimated from the Health Assessment Question naire . A health care perspective was adopted and direct medical costs were collected . The incremental cost effectiveness ratio ( ICER ) per patient in remission and incremental cost utility ratio ( ICUR ) per quality -adjusted life year ( QALY ) gained were calculated over two and three years of follow-up . Results Two year data were available for 261 T2 T patients and 213 UC patients ; an extended follow-up of three years was available for 127 and 180 patients , respectively . T2 T produced higher remission percentages and a larger gain in QALYs than UC . The ICER was € 3,591 per patient in remission after two years and T2 T was dominant after three years . The ICUR was € 19,410 per QALY after two years and T2 T was dominant after three years . Conclusions We can conclude that treating to the target of remission in early RA is cost-effective compared with UC . The data suggest that in the third year , T2 T becomes cost-saving OBJECTIVES Treatment of early rheumatoid arthritis ( RA ) include aim ing at disease control with early use of methotrexate ( MTX ) in monotherapy or in combination with glucocorticoids or other disease-modifying drugs ( DMARDs ) . The CIMESTRA study applied an aggressive treatment with DMARD and intra-articular injections of glucocorticoids ( i.a . GC ) to control disease activity . This paper review s the results of the five years ' study . METHODS 160 patients with early RA ( < 6 months duration ) were r and omized to receive MTX 7.5 - 20 mg/week+cyclosporine ( CYA ) 2.5 - 4 mg/kg ( combination ) or MTX+placebo-CYA ( monotherapy ) . At each visit ( week 0 , 2 , 4 , 6 , 8 , thereafter monthly up to 24 months ) patients had steroid injections in all swollen joints . During year 2 , CYA/placebo was withdrawn , and hydroxychlorochine added . Clinical responses were assessed by ACR20 , 50 and 70 , ACR and DAS remission . Radiographic progression by x-rays of h and s and feet . RESULTS At year 1 ( year 5 ) treatment responses in mono/combination groups were : ACR20 : 68 % ( 85 % ) / 85 % ( 94 % ) , ACR50 : 53 % ( 74 % ) / 68 % ( 88 % ) , ACR70 : 44 % ( 63 % ) / 59 % ( 72 % ) . After year 1 , no significant differences between groups were found . Remission rates were : ACR-remission : 28 % ( 52 % ) / 35 % ( 60 % ) , DAS28-remission : 34 % ( 76 % ) / 43 % ( 80 % ) . Radiographic progression in both groups was < 1TSS unit/year . After 1 and 2 years , 62 % and 56 % of the injected joints had not relapsed ( both groups ) . Cumulated i.a . GC dose < 1 mg prednisolone/day . 19 % received biologics by 5 years , 16 % no treatment ( sustained ACR-remission ) . Baseline magnetic resonance imaging ( MRI ) bone oedema best predicted radiographic progression after 2 years . Treatments were well tolerated . CONCLUSIONS MTX and i.a . GC in a treat-to-target strategy over 5 years halted radiographic progression and induced remission in the majority of patients . I.a . GC had in long-lasting effect and cumulated dosages were low OBJECTIVE The Tight Control of Rheumatoid Arthritis study previously demonstrated that an intensive step-up disease-modifying antirheumatic drug ( DMARD ) treatment strategy targeting persistent disease activity was superior to routine care in the management of early rheumatoid arthritis ( RA ) . We undertook this study to test the hypothesis that early parallel triple therapy achieves better outcomes than step-up therapy within an intensive disease management regimen . METHODS Ninety-six patients with early RA ( mean disease duration 11.5 months ) were r and omized to receive step-up therapy ( sulfasalazine [ SSZ ] monotherapy , then after 3 months , methotrexate [ MTX ] was added , and when the maximum tolerated dosage of MTX was reached , hydroxychloroquine [ HCQ ] was added ) or parallel triple therapy ( SSZ/MTX/HCQ ) . All patients were assessed monthly for 12 months . If their disease activity score in 28 joints ( DAS28 ) was > or = 3.2 , the dosage of DMARDs was increased according to protocol , and swollen joints were injected with triamcinolone acetonide ( maximum dosage 80 mg per month ) . A metrologist who was blinded to the treatment allocation performed assessment s every 3 months . The primary outcome measure was the mean decrease in the DAS28 score at 12 months . RESULTS Both groups showed substantial improvements in disease activity and functional outcome . At 12 months , the mean decrease in the DAS28 score was -4.0 ( step-up therapy group ) versus -3.3 ( parallel therapy group ) ( P = 0.163 ) . No significant differences in the percentages of patients with DAS28 remission ( step-up therapy group 45 % versus parallel triple therapy group 33 % ) , DAS28 good response ( 60 % versus 41 % , respectively ) , or American College of Rheumatology criteria for 20 % improvement ( ACR20 ) ( 77 % versus 76 % , respectively ) , ACR50 ( 60 % versus 51 % , respectively ) , or ACR70 ( 30 % versus 20 % , respectively ) responses were seen . Radiologic progression was similar in both groups . CONCLUSION This study confirms that highly effective control of disease activity can be achieved using conventional DMARDs as part of an intensive disease management strategy . Within this setting , step-up therapy is at least as effective as parallel triple therapy Objective : To assess the relative cost effectiveness of clinical nurse specialist care , inpatient team care , and day patient team care . Methods : Incremental cost effectiveness analysis and cost utility analysis , alongside a prospect i ve r and omised controlled trial with two year follow up . Included were patients with rheumatoid arthritis ( RA ) with increasing difficulty in performing activities of daily living over the previous six weeks .  Quality of life and utility were assessed by the Rheumatoid Arthritis Quality of Life question naire , the Short Form-6D , a transformed rating scale , and the time tradeoff . A cost-price analysis was conducted to estimate the costs of inpatient and day patient hospitalisations . Other healthcare and non-healthcare costs were estimated from cost question naires . Results : 210 patients with RA ( 75 % female , median age 59 years ) were included . Aggregated over the two year follow up period , no significant differences were found on the quality of life and utility instruments . The costs of the initial treatment were estimated at € 200 for clinical nurse specialist care , € 5000 for inpatient team care , and € 4100 for day patient team care . Other healthcare costs and non-healthcare costs were not significantly different . The total societal costs did not differ significantly between in patients and day patients , but were significantly lower for the clinical nurse specialist patients by at least € 5400 . Conclusions : Compared with inpatient and day patient team care , clinical nurse specialist care was shown to provide equivalent quality of life and utility , at lower costs . Therefore , for patients with health conditions that allow for any of the three types of care , the preferred treatment from a health-economic perspective is the care provided by the clinical nurse specialist OBJECTIVE Joint damage is related to disease activity in rheumatoid arthritis ( RA ) , but the degree of its progression and the temporal associations between disease activity and joint damage are unclear . The aim of this study was to evaluate whether there is a latency in the effect of disease activity on radiographic progression in patients with RA . METHODS Data were obtained from the PREMIER trial , a 2-year r and omized , controlled clinical trial of adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in early RA .  Radiographic progression of joint damage was calculated using the modified total Sharp score in a subset of patients whose disease was in remission ( Simplified Disease Activity Index < or=3.3 ) in the second year of the trial . The progression of damage in the second year was compared between groups of patients whose disease was already in remission for an additional period of 3 , 6 , or 9 months during the first year . Analysis of variance was used to test for a linear trend . RESULTS Among 794 patients with early RA , 119 ( 15 % ) achieved sustained remission during the second year , with no difference in radiographic progression across the 3 treatment groups . Radiographic progression in the second year was significantly different between patients with 3 , 6 , or 9 additional months of remission during year 1 ( mean change in the modified Sharp score 1.19 in those with 3 additional months of remission versus 0.20 in those with 6 additional months of remission and -0.32 in those with 9 additional months of remission ; P<0.05 ) . The results were supported by similar findings in a series of sensitivity analyses . CONCLUSION These data indicate that the level of disease activity as well as the duration of remission affect subsequent progression of radiographic damage in RA . This latency between disease activity and its effects on radiographic progression should be considered when evaluating radiographic outcomes in trials of RA Background CT-P13 ( Remsima ® , Inflectra ® ) is a biosimilar of the infliximab reference product ( RP ; Remicade ® ) . The aim of this study was to compare the 54-week efficacy , immunogenicity , safety , pharmacokinetics ( PK ) and pharmacodynamics ( PD ) of CT-P13 and RP in patients with active rheumatoid arthritis ( RA ) . Methods In this multinational phase III double-blind study , patients with active RA and an inadequate response to methotrexate ( MTX ) were r and omized ( 1:1 ) to receive CT-P13 ( 3 mg/kg ) or RP ( 3 mg/kg ) at weeks 0 , 2 , 6 and then every 8 weeks to week 54 in combination with MTX ( 12.5–25 mg/week ) . Efficacy endpoints included American College of Rheumatology (ACR)20 , ACR50 and ACR70 response rates , Disease Activity Score in 28 joints ( DAS28 ) , Simplified Disease Activity Index ( SDAI ) , Clinical Disease Activity Index ( CDAI ) , European League Against Rheumatism ( EULAR ) response rates , patient-reported outcomes and joint damage progression . Immunogenicity , safety and PK/PD outcomes were also assessed . Results Of 606 r and omized patients , 455 ( CT-P13 233 , RP 222 ) were treated up to week 54 . At week 54 , ACR20 response rate was highly similar between groups ( CT-P13 74.7 % , RP 71.3 % ) . ACR50 and ACR70 response rates were also comparable between groups ( CT-P13 43.6 % and 21.3 % , respectively ; RP 43.1 % and 19.9 % , respectively ) . DAS28 , SDAI and CDAI decreased from baseline to week 54 to a similar extent with CT-P13  and RP . Radiographic progression measured by Sharp scores as modified by van der Heijde was also comparable . With both treatments , patient assessment s of pain , disease activity and physical ability , as well as mean scores on the Medical Outcomes Study Short Form Health Survey ( SF-36 ) , improved markedly at week 14 and remained stable thereafter up to week 54 . The proportion of patients positive for antidrug antibodies at week 54 was similar between the two groups : 41.1 % and 36.0 % with CT-P13 and RP , respectively . CT-P13 was well tolerated and had a similar safety profile to RP . PK/PD results were also comparable between CT-P13 and RP . Conclusions CT-P13 and RP were comparable in terms of efficacy ( including radiographic progression ) , immunogenicity and PK/PD up to week 54 . The safety profile of CT-P13 was also similar to that of RP.Trial registration Clinical Trials.gov identifier : NCT01217086 . Registered 4 Oct 2010 Background Rheumatoid arthritis ( RA ) is a chronic inflammatory arthritis , with significant impact on quality of life and functional status . Whilst biologic disease modifying anti-rheumatic drugs ( bDMARD ) such as tumour necrosis factor-inhibitor ( TNFi ) agents have revolutionised outcomes in RA , early diagnosis with immediate conventional therapy , titrated in a treat to target approach is also associated with high remission rates . The main aim of the VEDERA study ( Very Early versus Delayed Etanercept in Rheumatoid Arthritis ) is to assess the depth of remission , sustainability of remission and immunological normalisation induced by very early TNFi with etanercept ( ETN ) or st and ard of care + /- delayed ETN . Methods / Design VEDERA is a pragmatic , phase IV single-centre open-label r and omised superiority trial of 120 patients with early , treatment-naive RA . Patients will be r and omised 1:1 to first-line ETN and methotrexate ( MTX ) or MTX with additional synthetic disease modifying anti-rheumatic drugs ( sDMARDs ) according to a treat to target ( TT ) protocol with further step up to ETN and MTX after 24 weeks if remission is not achieved . Participants will have regular disease activity assessment s and imaging evaluation including musculoskeletal ultrasound and MRI . The main objective of this study is to assess the proportion of patients with early RA that achieve clinical remission at 48 weeks , following either treatment strategy . In addition , the participants are invited to take part in a cardio-vascular sub- study ( Coronary Artery Disease in RA , CADERA ) , which aims to identify the incidence of cardiovascular abnormalities in early RA . Discussion The hypothesis underlining this study is that very early treatment with first-line ETN increases the proportion of patients with rheumatoid arthritis achieving clinical remission , in comparison to conventional therapy . Trial registration NCT02433184 , Background : To investigate whether intensive treatment with methotrexate ( MTX ) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis . Methods : In a two-year multicentre open label strategy trial , 299 patients with early rheumatoid arthritis were r and omly assigned to the intensive strategy group or the conventional strategy group . Patients in both groups received MTX , the aim of treatment being remission . Patients in the intensive treatment group came to the outpatient clinic once every month ; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria , using a computerised decision program . Patients of the conventional strategy group came to the outpatient clinic once every three months ; they were treated according to common practice . Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses . Results : Seventy six ( 50 % ) patients in the intensive strategy group achieved at least one period of remission during the two year trial , versus 55 patients ( 37 % ) in the conventional strategy group ( p = 0.03 ) . Areas under the curve for nearly all clinical variables were significantly lower — that is , there was a better clinical effect for the intensive treatment group compared with the conventional treatment group . Conclusion : The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX , aim ing for remission , tailored to the individual patient . Furthermore , participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice Objective To assess the efficacy and safety of tocilizumab ( TCZ ) plus methotrexate/placebo ( MTX/PBO ) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission . Methods ACT-RAY was a double-blind 3-year trial . Patients with active rheumatoid arthritis despite MTX were r and omised to add  TCZ  to ongoing MTX  ( add-on strategy ) or switch to  TCZ plus PBO  ( switch strategy ) . Using a treat-to-target approach , open-label conventional synthetic disease-modifying antirheumatic drugs ( csDMARDs ) , other than MTX , were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate ( DAS28-ESR ) > 3.2 . Between weeks 52 and 104 , patients in sustained clinical remission ( DAS28-ESR < 2.6 at two consecutive visits 12 weeks apart ) discontinued TCZ and were assessed every 4 weeks for 1 year . If sustained remission was maintained , added csDMARDs , then MTX/PBO , were discontinued . Results Of the 556 r and omised patients , 76 % completed year 2 . Of patients entering year 2 , 50.4 % discontinued TCZ after achieving sustained remission and 5.9 % achieved drug-free remission . Most patients who discontinued TCZ ( 84.0 % ) had a subsequent flare , but responded well to TCZ re introduction . Despite many patients temporarily stopping TCZ  , radiographic progression was minimal , with differences favouring add-on treatment . Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients . In patients with normal baseline values , alanine aminotransferase elevations > 3 × upper limit of normal were more frequent in add-on ( 14.3 % ) versus switch patients ( 5.4 % ) . Conclusions Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission , after which TCZ was stopped . Biologic-free remission was maintained for about 3 months , but most patients eventually flared . TCZ restart led to rapid improvement . Trial registration number NCT00810199 Background Recently , we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy ( methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day ) compared with the original COBRA therapy ( methotrexate 7.5 mg/week , sulfasalazine 2 g/day , with initial prednisolone 60 mg/day ) after 26 weeks in patients with early active rheumatoid arthritis ( RA ) . Objective To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity ( DAS44 ) , functional outcome ( Health Assessment Question naire ( HAQ ) ) and radiographic progression ( Sharp/van der Heijde score ( SHS ) ) , and to assess the effect of adding etanercept . Methods An open-label , r and omised controlled , non-inferiority trial of 162 patients with active early RA , following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39 . Results Both groups showed major improvements in DAS44 after 52 weeks : mean ( SD ) −2.41 ( 1.2 ) in the COBRA and −2.02 ( 1.0 ) in the COBRA-light group ( p = ns ) . In both groups , functional ability improved and radiological progression of joints was minimal . At least one adverse event was reported in 96 % of the patients in both groups . In total , 25 serious adverse events occurred : 9 vs 16 in COBRA and COBRA-light , respectively . Treatment actually instituted was often less intensive than required by the protocol : of the total population , 108 patients ( 67 % ) required etanercept ( more in the COBRA-light group ) , but only 67 of these ( 62 % ) actually received it . Conclusions Intensive COBRA or COBRA-light therapy has major , comparably favourable effects on disease activity , functional ability and radiological outcome after 1 year in patients with early RA . Protocol ised addition of etanercept was often not implemented by treating rheumatologists , and patients receiving it appeared to have limited added benefit , probably because of low disease activity levels at its initiation . Trial registration number : IS RCT N55552928 BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis ( RA ) are highly effective but can be improved . OBJECTIVE To investigate whether adding prednisone , 10 mg/d , at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness . DESIGN A 2-year , prospect i ve , r and omized , placebo-controlled , double-blind , multicenter trial ( CAMERA-II [ Computer Assisted Management in Early Rheumatoid Arthritis trial-II ] ) . ( International St and ard R and omised Controlled Trial Number : IS RCT N 70365169 ) SETTING 7 hospitals in the Netherl and s. PATIENTS 236 patients with early RA ( duration < 1 year ) . INTERVENTION Patients were r and omly assigned to an MTX-based , tight control strategy starting with either MTX and prednisone or MTX and placebo . Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aim ing for remission . MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years . Secondary outcomes included response criteria , remission , and the need to add cyclosporine or a biologic agent to the treatment . RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone ( n = 117 ) than in the group receiving MTX and placebo ( n = 119 ) . The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability , achieving sustained remission , and avoiding the addition of cyclosporine or biologic treatment . Adverse events were similar in both groups , but some occurred less in the MTX and prednisone group . LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic , which is not always feasible . CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes . PRIMARY FUNDING SOURCE Catharijne Foundation BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis Background Early and intensive treatment is important to inducing remission and preventing joint damage in patients with rheumatoid arthritis . While intensive combination therapy ( Disease Modifying Anti-rheumatic Drugs and /or biologicals ) is the most effective , rheumatologists in daily clinical practice prefer to start with monotherapy methotrexate and bridging corticosteroids . Intensive treatment should be started as soon as the first symptoms manifest , but at this early stage , ACR criteria may not be fulfilled , and there is a danger of over-treatment . We will therefore determine which induction therapy is most effective in the very early stage of persistent arthritis . To overcome over-treatment and under-treatment , the intensity of induction therapy will be based on a prediction model that predicts patients ' propensity for persistent arthritis . Methods A multicenter stratified r and omized single-blind controlled trial is currently being performed in patients 18 years or older with recent-onset arthritis . Eight hundred ten patients are being stratified according to the likelihood of their developing persistent arthritis . In patients with a high probability of persistent arthritis , we will study combination Disease Modifying Antirheumatic Drug therapy compared to monotherapy methotrexate . In patients with an intermediate probability of persistent arthritis , we will study Disease Modifying Antirheumatic Drug of various intensities . In patients with a low probability , we will study non-steroidal anti-inflammatory drugs , hydroxychloroquine and a single dose of corticosteroids . If disease activity is not sufficiently reduced , treatment will be adjusted according to a step-up protocol . If remission is achieved for at least six months , medication will be tapered off . Patients will be followed up every three months over two years . Discussion This is the first rheumatological study to base treatment in early arthritis on a prediction rule . Treatment will be stratified according to the probability of persistent arthritis , and different combinations of treatment per stratum will be evaluated . Treatment will be started early , and patients will not need to meet the ACR- criteria for rheumatoid arthritis . Trial registration This trial has been registered in Current Controlled Trials with the IS RCT N26791028 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 Background Early , intensive treatment of rheumatoid arthritis ( RA ) with the combination of ( initially high dose ) prednisolone , methotrexate and sulfasalazine ( COBRA therapy ) considerably lowers disease activity and suppresses radiological progression , but is infrequently prescribed in daily practice . Attenuating the COBRA regimen might lessen concerns about side effects , but the efficacy of such strategies is unknown . Objective To compare the ‘ COBRA-light ’ strategy with only two drugs , comprising a lower dose of prednisolone ( starting at 30 mg/day , tapered to 7.5 mg/day in 9 weeks ) and methotrexate ( escalated to 25 mg/week in 9 weeks ) to COBRA therapy ( prednisolone 60 mg/day , tapered to 7.5 mg/day in 6 weeks , methotrexate 7.5 mg/week and sulfasalazine 2 g/day ) . Method An open , r and omised controlled , non-inferiority trial in 164 patients with early active RA , all treated according to a treat to target strategy . Results At baseline patients had moderately active disease : mean ( SD ) 44-joint disease activity score ( DAS44 ) 4.13 ( 0.81 ) for COBRA and 3.95 ( 0.9 ) for COBRA-light . After 6 months , DAS44 significantly decreased in both groups ( –2.50 ( 1.21 ) for COBRA and –2.18 ( 1.10 ) for COBRA-light ) . The adjusted difference in DAS44 improvement between the groups , 0.21 ( 95 % CI –0.11 to 0.53 ) , was smaller than the predefined clinical ly relevant difference of 0.5 . Minimal disease activity ( DAS44 < 1.6 ) was reached in almost half of patients in both groups ( 49 % and 41 % in COBRA and COBRA-light , respectively ) . Conclusions At 6 months COBRA-light therapy is most likely non-inferior to COBRA therapy . Clinical Trial Registration Number 55552928 OBJECTIVE To evaluate the ability of two different combination therapies with prednisone ( PDN ) , methotrexate ( MTX ) and cyclosporine ( CSA ) to modulate both TNFalpha transcription and production in early rheumatoid arthritis ( RA ) . METHODS 24 patients with early RA received a step-down bridge therapy with MTX and PDN ( group A ) . Twelve patients out of the 24 r and omly received also CSA ( group B ) . Blood sample s and peripheral blood mononuclear cells ( P BMC ) were collected at different times . TNFalpha levels were measured both in sera and in P BMC supernatants . TNFalpha mRNA was assessed by use of RT-PCR . RESULTS 10 patients in group A and 9 in group B improved . At baseline , RA patients  serum TNFalpha levels were increased compared to controls ( p < 0.001 ) and did not correlate with clinical and serological parameters . These levels decreased within the first month of therapy in both groups , the lower levels being observed in the sera of CSA treated patients . After 30 days of therapy , TNFalpha levels in group B supernatants were significantly lower than those observed in group A , both after 24 and 48 hours of PHA stimulation ( p < 0.03 and p < 0.05 respectively ) . TNFalpha mRNA levels never differed between patients and controls , independently of both the clinical picture and the assigned therapy . CONCLUSION The addition of CSA to a treatment regimen of PDN + MTX lowers TNFalpha production in vitro without decreasing TNFalpha mRNA expression . This effect could help to induce early immunosoppressive and therapeutic effects during RA BACKGROUND Intra-articular triamcinolone in combination with DMARDs may be able to achieve faster and tighter control of disease activity in early rheumatoid arthritis that may be the key to preventing or minimizing later deformities . OBJECTIVE To compare the efficacy of a combination of Disease Modifying Anti-Rheumatoid Drugs ( DMARDs ) with Intra-articular Glucocorticoids versus only DMARDs in a group of patients with early Rheumatoid Arthritis ( RA ) . METHODS Fifty patients diagnosed as Rheumatoid Arthritis ( RA ) by American Rheumatology Association ( ARA ) criteria ( 1987 ) with disease duration less than two years were r and omized into two groups . The Control group received a combination of Methotrexate 15 mg daily with Sulfasalazine 2 gm daily for 3 months and the Study group received the above combination along with Intra-articular injections of Triamcinolone acetate ( 40 mg per ml ) in each of the swollen joints at the start of the study . Outcome was assessed in terms of Disease Activity Score ( DAS-28 ) , American College of Rheumatology ( ACR ) 20/50/70 criteria and number of rescue medications used at the end of 3 months . RESULTS The study group had significant reductions in DAS 28 scores ( 3.39 versus 4.99 in control group ) and significantly more subjects achieved the ACR 20/50/70 criteria at the end of 3 months ( 100/60/36 % versus 84/20/0 % ) Secondary end-points like tender and swollen joint count , ESR , early morning stiffness , health assessment question naire ( HAQ ) scores and general health status were significantly reduced in the study group . Also , significantly lesser rescue medications were needed in the study group . CONCLUSION Combination of DMARDs with Intra-articular corticosteroids is significantly better than DMARDs alone in early RA Objective To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo , which was augmented by a treat-to-target strategy from week 24 . Methods ACT-RAY was a double-blind , 3-year trial . Adults with active rheumatoid arthritis despite methotrexate were r and omised to add tocilizumab to ongoing methotrexate ( add-on strategy ) or to switch to tocilizumab plus placebo  ( switch strategy ) . Tocilizumab 8 mg/kg was administered every 4 weeks . Conventional open-label disease-modifying antirheumatic drugs ( DMARDs ) other than methotrexate were added at week 24 or later in patients with DAS28>3.2 . Results 556 patients were r and omised ; 85 % completed 52 weeks . The proportion of patients receiving open-label DMARDs was comparable in the add-on ( 29 % ) and switch ( 33 % ) arms . Overall , week 24 results were maintained or further improved at week 52 in both arms . Some endpoints favoured the add-on strategy . Mean changes in Genant-modified Sharp scores were small ; more add-on ( 92.8 % ) than switch patients ( 86.1 % ) had no radiographic progression . At week 52 , comparable numbers of patients had antidrug antibodies ( ADAs ; 1.5 % and 2.2 % of add-on and switch patients , respectively ) and neutralising ADAs ( 0.7 % and 1.8 % ) . Rates of serious adverse events and serious infections per 100 patient-year ( PY ) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients . In patients with normal baseline values , alanine aminotransferase elevations > 3 × upper limit of normal were observed in 11 % of add-on and 3 % of switch patients . Conclusions Despite a trend favouring the add-on strategy , these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses OBJECTIVE To evaluate two monotherapies followed by step-up combination therapy with two or three complementary drugs in active rheumatoid arthritis ( RA ) in comparison with sulphasalazine ( SSZ ) alone . METHODS One hundred and twenty-six consecutive patients with early active RA were enrolled in this open controlled clinical trial . The primary end-point was 50 % improvement according to the ACR criteria ( ACR50 ) at 6 , 12 or 18 months . The secondary end-points were a full response ( Magnusson criteria ) and /or remission ( ACR criteria ) at 3 yr . Methotrexate ( MTX ) ( group 1 ) , cyclosporin A ( CsA ) ( group 2 ) or SSZ ( group 3 ) was used first . After 6 months , a combination of two drugs ( CsA and MTX ) was employed in groups 1 and 2 . SSZ was added after 12 months if improvement was less than ACR50 with the combination . Group 3 continued with SSZ alone . RESULTS After 6 months , 57 % of patients in group 1 , 31 % of group 2 ( MTX vs CsA , P=0.002 ) and 33 % of group 3 ( MTX vs SSZ , P=0.01 ) had reached ACR50 improvement according to intention-to-treat analysis . At month 12 after starting a drug combination , 67 % of group 1 and 76 % of group 2 had reached ACR50 compared with 24 % of group 3 . At the 18-month follow-up , 90 % of group 1 and 88 % of group 2 but only 24 % of group 3 had reached ACR50 . After 18 months , 62 % of group 1 , 60 % of group 2 and 48 % of group 3 showed side-effects and three , five and eight patients in the three groups respectively had dropped out of the study . At the 3-yr follow-up , 9 % of the patients in groups 1 and 2 and 7 % of group 3 were in remission according to the ACR criteria ; according to the Magnusson criteria , 40 % showed a full response in groups 1 and 2 but only 21 % did so in group 3 . CONCLUSION MTX appears to be the fastest-acting agent . A step-up approach with MTX plus CsA plus SSZ led to a 50 % improvement according to the ACR criteria in most patients . After 3 yr , 40 % of patients receiving combination therapy and 21 % of patients receiving monotherapy showed a full response , while 9 and 7 % respectively attained remission Background Rheumatoid arthritis ( RA ) is a chronic , progressive joint disease , which frequently leads to irreversible joint deformity and severe functional impairment . Although patients are treated according to existing guidelines and reach clinical remission , erosive progression still occurs . This demonstrates that additional methods for prognostication and monitoring of the disease activity are needed . Bone marrow edema ( BME ) detected by magnetic resonance imaging ( MRI ) has proved to be an independent predictor of subsequent radiographic progression . Guiding the treatment based on the presence/absence of BME may therefore be clinical ly beneficial . We present the design of a r and omized controlled trial ( RCT ) aim ing to evaluate whether an MRI-guided treatment strategy compared to a conventional treatment strategy in anti-CCP-positive erosive RA is better to prevent progression of erosive joint damage and increase the remission rate in patients with low disease activity or clinical remission . Methods / design The study is a non-blinded , multicenter , 2-year RCT with a parallel group design . Two hundred anti-CCP-positive , erosive RA patients characterized by low disease activity or remission , no clinical ly swollen joints and treatment with synthetic disease-modifying antirheumatic drugs ( DMARDs ) will be included . Patients will be r and omized to either a treatment strategy based on conventional laboratory and clinical examinations ( control group ) or a treatment strategy based on conventional laboratory and clinical examinations as well as MRI ( intervention group ) . Treatment is intensified according to a predefined treatment algorithm in case of inflammation defined as a disease activity score ( DAS28 ) > 3.2 and at least one clinical ly swollen joint ( control and intervention groups ) and /or MRI-detected BME ( intervention group only ) . The primary outcome measures are DAS28 remission ( DAS28 < 2.6 ) and radiographic progression ( Sharp/vdHeijde score ) . Discussion The perspectives , strengths and weaknesses of this study are discussed . This study has been approved by The Regional Scientific Ethical Committees for Southern Denmark , S-20110109 . Dissemination will occur through presentations and publication in international peer- review ed journals . Trial registration The study is registered in http://www . Clinical Trials.gov identifier : NCT01656278 ( 5 July 2012 Introduction Early treatment of rheumatoid arthritis ( RA ) has been shown to retard the development of joint damage for a period of up to 5 years . The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs ( DMARDs ) or a single DMARD .  Methods A cohort of 199 patients with early active RA were initially r and omized to receive treatment with a combination of methotrexate , sulfasalazine , and hydroxychloroquine with prednisolone ( FIN-RACo ) , or treatment with a single DMARD ( initially , sulfasalazine ) with or without prednisolone ( SINGLE ) . After 2 years , the drug-treatment strategy became unrestricted , but still targeted remission . The radiographs of h and s and feet were analyzed by using the Larsen score at baseline , 2 , 5 , and 11 years , and the radiographs of large joints , at 11 years . Results Sixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of h and s and feet available at baseline and at 11 years . The mean change from baseline to 11 years in Larsen score was 17 ( 95 % CI , 12 to 26 ) in the FIN-RACo group and 27 ( 95 % CI , 22 to 33 ) in the SINGLE group ( P = 0.037 ) . In total , 87 % ( 95 % CI , 74 to 94 ) and 72 % ( 95 % CI , 58 to 84 ) of the patients in the FIN-RACo and the SINGLE treatment arms , respectively , had no erosive changes in large joints at 11 years . Conclusions Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients . Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy . Trial registration Current Controlled Trials IS RCT N18445519 Introduction Considering a lack of efficacy data in patients with early rheumatoid arthritis ( eRA ) presenting without classical markers of poor prognosis , we compared methotrexate ( MTX ) with or without step-down glucocorticoids in the CareRA trial . Methods Disease-modifying antirheumatic drug – naïve patients with eRA were stratified into a low-risk group based on prognostic markers that included non-erosiveness , anti – citrullinated protein antibodies and rheumatoid factor negativity and low disease activity ( Disease Activity Score in 28 joints based on C-reactive protein ( DAS28(CRP ) ) ≤3.2 ) . Patients were r and omized to  15 mg of MTX weekly ( MTX with tight step-up ( MTX-TSU ) ) or 15 mg of MTX weekly with prednisone bridging , starting at 30 mg and tapered to 5 mg daily from week 6 ( COmbinatie therapie bij Reumatoïde Artritis ( COBRA Slim ) ) . A TSU approach was applied . Outcomes assessed were DAS28(CRP)-determined remission , cumulative disease activity , Health Assessment Question naire ( HAQ ) scores and adverse events ( AEs ) after 16 treatment weeks . Results We analyzed 43 COBRA Slim and 47 MTX-TSU patients and found that 65.1 % in the COBRA Slim group and 46.8 % in the MTX-TSU group reached remission ( P = 0.081 ) . Mean ± st and ard deviation area under the curve values of DAS28(CRP ) were 13.84 ± 4.58 and 11.18 ± 4.25 for the MTX-TSU and COBRA Slim patients , respectively ( P = 0.006 ) . More COBRA Slim patients had an HAQ score of 0 ( 51.2 % versus 23.4 % , P = 0.006 ) at week 16 . Therapy-related AEs between groups did not differ . Conclusion In patients with low-risk eRA  , MTX with step-down glucocorticoid bridging seems more efficacious than MTX step-up monotherapy , with a comparable number of AEs observed over the first 16 treatment weeks . Trial registration EU Clinical Trials Register Identifier : EudraCT number 2008 - 007225 - 39 . Registered 5 November 2008 Objective To determine the most effective induction disease-modifying antirheumatic drug ( DMARD ) strategy in early rheumatoid arthritis ( RA ) , second to compare one single dose of intramuscular glucocorticoids ( GCs ) with daily oral GCs during the induction phase . Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis ( tREACH ) were used . Patients were included who had a high probability ( > 70 % ) of progressing to persistent arthritis , based on the prediction model of Visser . Patients were r and omised into three induction therapy strategies : ( A ) combination therapy ( methotrexate ( MTX ) + sulfasalazine + hydroxychloroquine ) with GCs intramuscularly ; ( B ) combination therapy with an oral GC tapering scheme and ( C ) MTX with oral GCs similar to B. A total of 281 patients were r and omly assigned to strategy ( A ) ( n=91 ) , ( B ) ( n=93 ) or ( C ) ( n=97 ) . Results The Disease Activity Score ( DAS ) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy ( 0.39 ( 0.67 to 0.11 , 95 % CI ) ) . DAS did not differ between the different GC bridging treatments . After 3 months 50 % fewer biological agents were prescribed in the combination therapy groups . Although the proportion of patients with medication adjustments differed significantly between the treatment arms , no differences were seen in these adjustments due to adverse events after stratification for drug . Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA . Furthermore , no differences were seen in medication adjustments due to adverse events after stratification for drug . Intramuscular and oral GCs are equally effective as bridging treatments and both can be used Objectives In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis ( RA ) , to compare the efficacy of methotrexate ( MTX ) and infliximab ( IFX ) with MTX and intravenous corticosteroid for remission induction . Methods In a 78-week multicentre r and omised controlled trial , double-blinded to week 26 , 112 treatment-naive RA patients ( 1987 American College of Rheumatology classification criteria ) with disease activity score 44 (DAS44)>2.4 were r and omised to  MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg . A treat-to-target approach was used with treatment escalation if DAS44>2.4 . In the IFX group , IFX was discontinued for sustained remission ( DAS44<1.6 for 6 months ) . The primary outcome was change in modified total Sharp-van der Heijde score ( mTSS ) at week 50 . Results The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units , respectively ( adjusted difference ( 95 % CI ) −1.45 ( −3.35 to 0.45 ) ; p=0.132 ) . Radiographic non-progression ( mTSS<2.0 ) occurred in 81 % vs 71 % ( OR 1.77 ( 0.56 to 5.61 ) ; p=0.328 ) . DAS44 remission was achieved at week 50 in 49 % and 36 % ( OR 2.13 ( 0.91 to 5.00 ) ; p=0.082 ) , and at week 78 in 48 % and 50 % ( OR 1.12 ( 0.47 to 2.68 ) ; p=0.792 ) . Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group . Of the IFX group , 25 % ( 14/55 ) achieved sustained remission and stopped IFX . No substantive differences in adverse events were seen . Conclusions In DMARD-naive early RA patients , initial therapy with MTX+high-dose intravenous steroid result ed in good disease control with little structural damage . MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach Objective To investigate if a glucocorticoid ( GC ) response at 2 weeks , defined by EULAR response criteria , can predict active disease ( Disease Activity Score (DAS)>2.4 ) at 3 months . Methods For this study , data of the Treatment in the Rotterdam Early Arthritis Cohort study ( tREACH ) , an ongoing clinical trial that evaluates different induction therapies in early rheumatoid arthritis , were used . We selected patients who had a high probability of progressing to persistent arthritis ( > 70 % based on the prediction model of Visser ) . All patients within the high-probability stratum , who had a baseline DAS>2.2 and a DAS assessment at 2 weeks after r and omisation , were included ( n=120 ) . Besides GC response at 2 weeks , we investigated which other factors were associated with active disease ( DAS>2.4 ) after 3 months of disease-modifying antirheumatic drug ( DMARD ) treatment . All variables with a p≤0.25 were assessed in our logistic regression model with backward selection . Variables were eliminated until all remaining variables had a significant association ( p<0.05 ) . Results Patients who did not respond to GC bridging therapy at 2 weeks had an overall OR of having active disease at 3 months of 10.29 ( 95 % CI 3.34 to 31.64 ; p<0.001 ) in comparison with responders . The corrected OR was 14.00 ( 95 % CI 3.31 to 59.21 ; p<0.001 ) . Our final model predicting response at 3 months included the following variables : gender , GC response , induction therapy arms and baseline DAS , which had an explained variance of 39 % . Conclusions GC response at 2 weeks is a useful tool for recognising those patients who will probably have active disease ( DAS>2.4 ) after 3 months of DMARD treatment Objective . To evaluate the longterm safety of adalimumab administered with or without methotrexate ( MTX ) and compare the efficacy of combination therapy initialization to adalimumab or MTX monotherapy initialization during the open-label extension ( OLE ) of the PREMIER trial ( Clinical Trials.gov Identifier : NCT00195663 ) . Methods . Patients with early rheumatoid arthritis ( RA ) were r and omized to receive blinded adalimumab + MTX , adalimumab alone , or MTX alone for 2 years . Following the double-blinded period , patients enrolling in the OLE were given adalimumab for up to 8 additional years , beginning as monotherapy ; investigators could add MTX at their discretion . Results for clinical , functional , and radiographic progression were collected for up to 10 years of treatment . Results . During the PREMIER OLE , 250/497 patients ( 50.3 % ) completed the trial without new safety signals arising . Similar proportions of patients discontinued the trial early , although lack of efficacy was reported less often for patients initially r and omized to the adalimumab + MTX arm ( 9.3 % ; 21.2 % , and 23.7 % for adalimumab and MTX monotherapies , respectively ) . Clinical and functional disease control was maintained throughout the trial . Patients initially r and omized to adalimumab + MTX displayed better outcomes , particularly in prevention of radiographic progression ( modified total Sharp score change = 4.0 , 8.8 , 11.0 at Year 10 for the initial adalimumab + MTX , adalimumab , and MTX arms , respectively ) . Conclusion . Intensive therapy with adalimumab + MTX combination in patients with early RA has longterm benefits compared to patients initiating with 2-year adalimumab or MTX monotherapy that persists up to 10 years following adalimumab OLE . No new safety findings were observed following longterm adalimumab treatment 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 AIM To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis ( RA ) . METHODS In the BeSt study , 508 patients with newly diagnosed ( < 2 years ) active RA were r and omised to be treated according to four treatment strategies : 1 . sequential monotherapy , 2 . step up to combination therapy ( both starting with methotrexate ) , 3 . initial combination therapy with methotrexate , sulphasalazine , and a tapered high dose of prednisone , and 4 . initial combination therapy with methotrexate and infliximab . Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score ( DAS ) , with the goal to achieve and maintain a DAS < or= 2.4 . Functional ability was measured every 3 months with the Health Assessment Question naire . Radiographs of h and s and feet were assessed yearly , blinded for patient identity and treatment , and in r and om order , to measure joint damage progression ( Sharp/van der Heijde score ) . RESULTS After 2 years of treatment , 80 % of all patients achieved the goal of DAS < or= 2.4 , and 42 % reached clinical remission ( DAS < 1.6 ) . Initial combination therapy , either with prednisone ( group 3 ) or with infliximab ( group 4 ) , result ed in earlier improvement in functional ability , more continuous clinical remission ( DAS < 1.6 ) , and less joint damage progression than initial monotherapy ( groups 1 and 2 ) . Patients in groups 1 and 2 needed more therapy adjustments , including introduction of combination therapy with prednisone or infliximab , to achieve a DAS < or= 2.4 , whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate , respectively , monotherapy . The adverse events profile was comparable in all groups . The presence or absence of rheumatoid factor , HLA DR4 , or anti-CCP was not associated with radiologic damage progression . CONCLUSION In patients with early , active RA , remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent , objective ly steered treatment adjustments . The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate , sulphasalazine and prednisone or with methotrexate and infliximab , which can be tapered to DMARD monotherapy once low disease activity is achieved In a step-up approach of DMARD treatment of RA a fast response and an early DMARD switch in the case of non-response is important . Therefore , we performed an open trial in which we compared an 8-week and a 16-week observation period during treatment of RA with MTX or LEF , both given in intensified starting doses and accompanied by moderate dose prednisone .  MTX and LEF naïve patients with RA ( mean time since diagnosis : 2.3 years ) were r and omised to receive either LEF in a 3-day-loading dose of 100 mg/day followed by 20 mg/day ( n = 19 ) or MTX intramuscularly in a dose of 25 mg once weekly ( n = 21 ) . All patients received concomitant treatment with oral prednisone in an initial dose of 20 mg/day with weekly dose reductions of 5 mg/day . The disease activity was re-evaluated 8 and 16 weeks after the start of the treatment . Mean DAS28 before the start of treatment was 5.36 ± 0.8 for the MTX-group and 5.46 ± 0.8 for the LEF-group . After 8 weeks of treatment the DAS28 in the MTX-group was 2.59 ± 1.0 and 3.16 ± 0.8 in the LEF group ( difference not significant ) . The mean DAS28 at re-evaluation 16 weeks after the starting of treatment ( 2.58 ± 1.5 for the MTX-group and 3.25 ± 1.16 for the LEF-group ) was significantly different neither in between the both treatment groups nor in comparison to the week 8 evaluation . Efficiency of RA treatment with MTX or LEF in intensified doses and in combination with moderate dose prednisone can be sufficiently judged 8 weeks after its initiation Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity OBJECTIVE To determine whether a regimen of methotrexate , cyclosporin A , and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis ( RA ) can produce a significant improvement in outcome compared with st and ard monotherapy with sulfasalazine ( SSZ ) . METHODS Eighty-two consecutive patients presenting with new , untreated RA of less than 12 months ' duration who fulfilled criteria for poor long-term outcome were r and omized to receive either combination therapy ( n = 40 ) or SSZ alone ( n = 42 ) . The primary outcome measures were remission and American College of Rheumatology ( ACR ) criteria for 20 % improvement at 48 weeks . RESULTS After 48 weeks , the numbers of patients who met the ACR criteria for 20 % improvement were not significantly different between the two groups ( combination 58 % versus SSZ 45 % ) , and similar numbers of patients had persisting clinical remission ( approximately 10 % both groups ) . During the first 3 months , there were significantly greater reductions in parameters of disease activity in the combination group . By 24 weeks , the swollen and tender joint counts , C-reactive protein levels , and erythrocyte sedimentation rates had fallen significantly in both groups , with a greater improvement in the swollen and tender joint count in the combination group . At 48 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 42.5 ) in the combination group and 1.25 ( range 0 - 72.5 ) in the SSZ group ( P = 0.28 ; although there were significant differences in the scores for the right h and ) . There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group ( 1 of 40 versus 10 of 42 ; P = 0.007 ) . In the combination group , dose reduction was needed in 22.5 % because of hypertension and in 22.5 % because of elevated creatinine levels . Over 48 weeks , serum creatinine increased in both groups , but particularly in the combination arm . CONCLUSION In poor-prognosis RA patients , " aggressive " combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates . This suggests that in poor-prognosis disease , an approach based on identifying patients with poor treatment responses before extra therapy is added ( " step-up " approach ) may be more appropriate than the use of combination therapy in all patients from the outset BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the  single-therapy  group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis 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 OBJECTIVES To determine whether DAS28 measurements by a specialized nurse , before the rheumatologist visit , in combination with the advice to rheumatologists to reach a DAS28 < or = 3.2 , had beneficial effects on disease activity and medication prescription in patients with RA and to explore possible predictors for variation in medication changes and reasons for non-adherence to the advice to reach a DAS28 < or = 3.2 . METHODS In this pilot study , rheumatologists were r and omized to ' usual care ' ( n = 3 ) or  DAS28 measurement by a nurse prior the rheumatologist visit ( n = 4 ) . In the usual care group , the  DAS28 was measured but not provided to rheumatologists . Mixed model analyses were used for analysing between-group differences and for the prediction model . Rheumatologists in the intervention group were asked to provide reasons in cases of non-adherence to the advice . RESULTS After 18 months , DAS28 was reduced by - 0.69 and - 0.66 ( P = 0.70 ) in , respectively , the intervention ( 144 patients ) and the usual care ( 104 patients ) groups . In the intervention group , medication was changed by rheumatologists in 35 % of the visits with a DAS28 > 3.2 ; in the usual care group this was 33 % ( P = 0.99 ) . Baseline DAS28 ( OR 1.6 ; P < or = 0.0001 ) and HAQ ( OR 1.3 ; P = 0.03 ) were positively related to a medication change . The most frequently mentioned reason not to change medication was patient refusal ( 26 % ) . CONCLUSIONS  DAS28 measurement by a nurse was as effective as usual care ; however , this intervention without protocol ized treatment adjustments is not sufficient to lead to a considerable reduction in disease activity compared with trials with protocol ized treatment adjustments OBJECTIVE To describe the effect of indirect costs for patients with early rheumatoid arthritis ( RA ) within the COBRA trial ( Combinatietherapie Bij Reumatoide Artritis ) on the cost-effectiveness of both therapies . Analyses of the efficacy and direct costs of the treatments have already been reported . METHODS Patients with early RA selected for the 56-week trial were r and omly assigned to prednisolone , methotrexate , and sulfasalazine ( the COBRA combination ) ( n = 76 , tapered after 28 weeks ) or to sulfasalazine ( SSZ ; n = 79 , of which 78 patients were evaluable ) alone . The main efficacy outcomes were a pooled index and radiographic damage score in h and s and feet , and utilities . Direct and indirect costs were measured ( from a societal perspective ) by means of cost diaries and interviews completed by patients during the intervention phase and the followup phase , each lasting 28 weeks . Differences in mean costs between groups and cost-utility ratios were evaluated by applying nonparametric bootstrapping techniques . RESULTS In the first 28 weeks , indirect costs per patient totaled US $ 2,578 and US $ 3,638 for COBRA and SSZ therapy , respectively ( p = 0.09 ) . The total costs were $ 5,931 and $ 7,853 , respectively ( p < 0.05 ) . These differences were lost in the second 28 weeks . For the total period the mean total costs per patient were $ 10,262 and $ 12,788 , respectively ( p = 0.11 ) . Sensitivity analyses showed robustness of the data . The point estimate of the cost per quality -adjusted life-year based on the rating scale was negative at $ -385 , suggesting dominance of COBRA ( more effect at lower cost ) . CONCLUSION COBRA therapy adds additional disease control ( improvements in disease activity , physical function , and rate of damage progression ) at lower or equal cost compared to SSZ in early RA OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline factors could predict outcome . METHODS All patients had participated in the 56-week COBRA trial . During followup , they were seen by their own rheumatologists and were also assessed regularly by study nurses ; no treatment protocol was specified . Disease activity , radiologic damage , and functional ability were the primary outcome domains . Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method . Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat , starting with data obtained at the last visit of the COBRA trial ( 56 weeks after baseline ) . RESULTS At the beginning of followup , patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score ( DAS28 ) and a significantly lower median radiologic damage ( Sharp ) score compared with those in the SSZ monotherapy group . The functional ability score ( Health Assessment Question naire [ HAQ ] ) was similar in both groups . During the 4 - 5 year followup period , the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group . The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group . After adjustment for differences in treatment and disease activity during followup , the between-group difference in the rate of radiologic progression was 3.7 points per year . The HAQ score did not change significantly over time . Independent baseline predictors of radiologic progression over time ( apart from treatment allocation ) were rheumatoid factor positivity , Sharp score , and DAS28 . CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA , independent of subsequent antirheumatic therapy Objective To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis ( RA ) . Methods Ninety-nine patients with early , DMARD-naïve RA were treated with a triple combination of DMARDs , starting with methotrexate ( max 25 mg/week ) , sulfasalazine ( max 2 g/day ) , hydroxychloroquine ( 35 mg/kg/week ) , and with prednisolone ( 7.5 mg/day ) , and r and omised to double blindly receive either infliximab ( 3 mg/kg ; FIN-RACo+INFL ) or placebo ( FIN-RACo+PLA ) infusions during the first 6 months . After 2 years the treatment strategies became unrestricted , but the treatment goal was strict ACR remission . At 5 years the clinical and radiographic outcomes were assessed . Results Ninety-one patients ( 92 % ) were followed up to 5 years , 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups . At 5 years , the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60 % ( 95 % CI 44 % to 74 % ) and 61 % ( 95 % CI 45 % to 75 % ) ( p=0.87 ) , and 84 % ( 95 % CI 71 % to 94 % ) and 89 % ( 95 % CI 76 % to 96 % ) ( p=0.51 ) . The corresponding mean ( SD ) total Sharp/van der Heijde scores at 5 years were 4.3 ( 7.6 ) , and 5.3 ( 7.3 ) , while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 ( 95 % CI 0.0 to 3.4 ) and 3.7 ( 95 % CI 2.2 to 5.8 ) ( p=0.13 ) . Conclusions In early RA , targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years ; adding initial infliximab for 6 months does not improve these outcomes Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis ( ERA ) , and whether adalimumab provides an additional effect . Methods In a double-blind , placebo-controlled trial , 85 disease-modifying antirheumatic drug-naïve patients with ERA were r and omised to receive methotrexate , intra-articular glucocorticosteroid injections and placebo/adalimumab ( 43/42 ) .  Contrast-enhanced MRI of the right h and was performed at months 0 , 6 and 12 . Synovitis , osteitis , tenosynovitis , MRI bone erosion and joint space narrowing ( JSN ) were scored with vali date d methods . Dynamic contrast-enhanced MRI ( DCE-MRI ) was carried out in 14 patients .  Results Synovitis , osteitis and tenosynovitis scores decreased highly significantly ( p<0.0001 ) during the 12-months ’ follow-up , with mean change scores of −3.7 ( median −3.0 ) , −2.2 ( −1 ) and −5.3 ( −4.0 ) , respectively . No overall change in MRI bone erosion and JSN scores was seen , with change scores of 0.1 ( 0 ) and 0.2 ( 0 ) . The tenosynovitis score at month 6 was significantly lower in the adalimumab group , 1.3 ( 0 ) , than in the placebo group , 3.9 ( 2 ) , Mann – Whitney : p<0.035 . Furthermore , the osteitis score decreased significantly during the 12-months ’ follow-up in the adalimumab group , but not in the placebo group , Wilcoxon : p=0.001–0.002 and p=0.062–0.146 . DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters . Clinical measures decreased highly significantly during follow-up . Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis , osteitis and tenosynovitis and halted structural damage progression as judged by MRI . The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis 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 Objectives : It is well recognized that medication adherence of rheumatoid arthritis ( RA ) patients is often poor . As less attention has been paid to physicians ’ adherence to targeted treatment , we aim ed to investigate how it affects outcomes in aggressively treated early RA patients . Method : In the new Finnish RA Combination Therapy ( NEO-RACo ) trial , 99 patients with early active RA were treated , targeting remission , with a combination of methotrexate , sulfasalazine , hydroxychloroquine , and low-dose prednisolone for 2 years , and r and omized to receive infliximab or placebo for the initial 6 months . After 2 years , therapy was unrestricted while remission was still targeted . Patients were divided into tertiles by physicians ’ adherence to treat-to-target , which was evaluated with a scoring system during the initial 2 years . After 5 years of follow-up , the between-tertile differences in remission rates , 28-joint Disease Activity Score ( DAS28 ) levels , radiological changes , cumulative days off work , and the use of anti-rheumatic medication were assessed . Results : Follow-up data were available for 93 patients . Physicians ’ good adherence was associated with improved remission rates at 2–4 years and lower DAS28 levels throughout the follow-up . In a multivariable model , physicians ’ adherence was the most important predictor of remission at 3 months and 2 years ( p < 0.001 for both ) . Between 2 and 5 years , biologics were used more often in the tertile of low adherence compared with the other two groups ( p = 0.024 ) . No significant differences were observed in radiological progression and cumulative days off work . Conclusions : Physicians ’ good adherence is associated with improved remission rates and lesser use of biologics in early RA 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 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 Objective : To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early , active rheumatoid arthritis ( RA ) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs ( DMARDs ) and intra-articular corticosteroid . This paper presents the results of the second year of the r and omised , controlled double-blind CIMESTRA ( Ciclosporine , Methotrexate , Steroid in RA ) study . Methods : 160 patients with early RA ( duration < 6 months ) were r and omised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine ( monotherapy ) or methotrexate plus ciclosporine ( combination therapy ) during the first 76 weeks . At week 68 hydroxychlorochine 200 mg daily was added . From week 76–104 ciclosporine/placebo-ciclosporine was tapered to zero . Results : American College of Rheumatology 20 % improvement ( ACR20 ) , ACR50 and ACR70 levels were achieved in 88 % , 79 % and 59 % of patients in the combination vs 72 % , 62 % and 54 % in the monotherapy group ( p = 0.03 , 0.02 and 0.6 between groups ) . The patients globally declined from 50 to 12 vs 52 to 9 , with 51 % and 50 % in Disease Activity Score ( DAS ) remission , respectively . Mean ( SD ) progressions in total Sharp – van der Heijde scores were 1.42 ( 3.52 ) and 2.03 ( 5.86 ) in combination and monotherapy groups , respectively ( not significant ) . Serum creatinine levels increased by 7 % in the combination group ( 4 % in monotherapy ) , but hypertension was not more prevalent . Conclusion : Continuous methotrexate and intra-articular corticosteroid treatment result ed in excellent clinical response and disease control at 2 years , and the radiographic erosive progression was minimal . Addition of ciclosporine during the first 76 weeks result ed in significantly better ACR20 and ACR50 responses , but did not have any additional effect on remission rate and radiographic outcome To evaluate long‐term changes in cholesterol levels in patients with early rheumatoid arthritis ( RA ) who were r and omized to begin treatment with methotrexate ( MTX ) monotherapy , MTX plus etanercept , or triple therapy ( MTX plus sulfasalazine plus hydroxychloroquine ) in the Treatment of Early Aggressive Rheumatoid Arthritis ( TEAR ) trial 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 ) Objectives Combining disease-modifying antirheumatic drugs ( DMARDs ) with glucocorticoids ( GCs ) is an effective treatment strategy for early rheumatoid arthritis ( ERA ) , yet the ideal schedule and feasibility in daily practice are debated . We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients ;  and methotrexate ( MTX ) with or without GC remission induction in good prognosis patients , during the first treatment year . Methods The Care in ERA ( CareRA ) trial is a 2-year investigator-initiated r and omised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach . DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions , disease activity , rheumatoid factor and anticitrullinated protein antibodies . High-risk patients were r and omised to a COBRA Classic ( MTX + sulfasalazine + prednisone step-down from 60 mg ) , COBRA Slim ( MTX + prednisone step-down from 30 mg ) or COBRA Avant Garde ( MTX + leflunomide + prednisone step-down from 30 mg ) scheme . Low-risk patients were r and omised to MTX tight step-up ( MTX-TSU ) or COBRA Slim . Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis . Secondary outcomes were safety and effectiveness ( Clinical Trial.gov identifier NCT01172639 ) . Results 98 COBRA Classic , 98 COBRA Slim ( high risk ) , 93 COBRA Avant Garde , 47 MTX-TSU and 43 COBRA Slim ( low risk ) patients were evaluated . Remission was achieved in 64.3 % ( 63/98 ) COBRA Classic , 60.2 % ( 59/98 ) COBRA Slim ( high risk ) and 62.4 % ( 58/93 ) COBRA Avant Garde patients at W52 ( p=0.840 ) ; and in 57.4 % ( 27/47 ) MTX-TSU and 67.4 % ( 29/43 ) COBRA Slim ( low risk ) patients ( p=0.329 ) . Less adverse events occurred per patient with COBRA Slim ( high risk ) compared with COBRA Classic or COBRA Avant Garde ( p=0.038 ) . Adverse events were similar in MTX-TSU and COBRA Slim ( low risk ) patients ( p=0.871 ) . At W52 , 76.0 % patients were on DMARD monotherapy , 5.2 % used GCs and 7.5 % biologicals . Conclusions MTX with a moderate-dose GC remission induction scheme ( COBRA Slim ) seems an effective , safe , low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile , provided a treat-to-target approach is followed . Trial registration numbers EudraCT-number 2008 - 007225 - 39 and NCT01172639 ; Results OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis ( RA ) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response ( as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ DAS28-ESR ] of ≥ 3.2 at week 24 )  to methotrexate ( MTX ) monotherapy , and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine . METHODS The Treatment of Early Aggressive Rheumatoid Arthritis ( TEAR ) study is a 2-year , r and omized , double-blind trial . A 2 × 2 factorial design was used to r and omly assign subjects to 1 of 4 treatment arms : immediate treatment with MTX plus etanercept , immediate oral triple therapy ( MTX plus sulfasalazine plus hydroxychloroquine ) , or step-up from MTX monotherapy to one of the combination therapies ( MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine ) at week 24 if the DAS28-ESR was ≥ 3.2 . All treatment arms included matching placebos . The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102 . RESULTS At week 24 ( beginning of the step-up period ) , subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups ( 3.6 versus 4.2 ; P < 0.0001 ) ; no differences between the combination-therapy regimens were observed . Between week 48 and week 102 , subjects r and omized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy , regardless of the treatment arm . There was no significant difference in the DAS28-ESR between subjects r and omized to oral triple therapy and those r and omized to receive MTX plus etanercept . By week 102 , there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy ( 0.64 versus 1.69 ; P = 0.047 ) . CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48 - 102 between subjects r and omized to receive MTX plus etanercept and those r and omized to triple therapy , regardless of whether they received immediate combination treatment or step-up from MTX monotherapy . At 102 weeks , immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy . Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine ( or etanercept , if necessary , after 6 months ) is a reasonable therapeutic strategy for patients with early RA . Treatment with the combination of MTX plus etanercept result ed in a statistically significant radiographic benefit compared with oral triple therapy Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis ( RA ) in remission . Objective The trial aims to compare the effect of progressive spacing of TNF-blocker injections ( S-arm ) to their maintenance ( M-arm ) for established patients with RA in remission . Methods The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year , patients in remission on 28-joint Disease Activity Score ( DAS28 ) for ≥6 months and patients with stable joint damage . Patients were r and omised into two arms : maintenance or injections spacing by 50 % every 3 months up to complete stop . Spacing was reversed to the previous interval in case of relapse , and eventually reattempted after remission was reachieved . The primary outcome was the st and ardised difference of DAS28 slopes , based on a linear mixed-effects model ( equivalence interval set at ±30 % ) . Results 64 and 73 patients were included in the S-arm and M-arm , respectively , which was less than planned . In the S-arm , TNF blockers were stopped for 39.1 % , only tapered for 35.9 % and maintained full dose for 20.3 % . The equivalence was not demonstrated with a st and ardised difference of 19 % ( 95 % CI −5 % to 46 % ) . Relapse was more common in the S-arm ( 76.6 % vs 46.5 % , p=0.0004 ) . However , there was no difference in structural damage progression . Conclusions Tapering was not equivalent to maintenance strategy , result ing in more relapses without impacting structural damage progression . Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings . Trial registration number : Clinical Trials.gov : NCT00780793 ; EudraCT identifier : 2007 - 004483 - 41 BACKGROUND For patients with newly diagnosed rheumatoid arthritis , treatment aim is early , rapid , and sustained remission . We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate ( a conventional synthetic disease-modifying antirheumatic drug [ DMARD ] ) , versus initiation of methotrexate monotherapy in line with international guidelines . METHODS We did a 2-year , multicentre , r and omised , double-blind , double-dummy , strategy study at 21 rheumatology outpatient departments in the Netherl and s. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion , were DMARD-naive , aged 18 years or older , met current rheumatoid arthritis classification criteria , and had a disease activity score assessing 28 joints ( DAS28 ) of at least 2·6 . We r and omly assigned patients ( 1:1:1 ) to start tocilizumab plus methotrexate ( the tocilizumab plus methotrexate arm ) , or tocilizumab plus placebo-methotrexate ( the tocilizumab arm ) , or methotrexate plus placebo-tocilizumab ( the methotrexate arm ) . Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose . Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week , until remission or dose-limiting toxicity . We did the r and omisation using an interactive web response system . Masking was achieved with placebos that were similar in appearance to the active drug ; the study physicians , pharmacists , monitors , and patients remained masked during the study , and all assessment s were done by masked assessors . Patients not achieving remission on their initial regimen switched from placebo to active treatments ; patients in the tocilizumab plus methotrexate arm switched to st and ard of care therapy ( typically methotrexate combined with a tumour necrosis factor inhibitor ) . When sustained remission was achieved , methotrexate ( and placebo-methotrexate ) was tapered and stopped , then tocilizumab ( and placebo-tocilizumab ) was also tapered and stopped . The primary endpoint was the proportion of patients achieving sustained remission ( defined as DAS28 < 2·6 with a swollen joint count ≤four , persisting for at least 24 weeks ) on the initial regimen and during the entire study duration , compared between groups with a two-sided Cochran-Mantel-Haenszel test . Analysis was based on an intention-to-treat method . This trial was registered at Clinical Trials.gov , number NCT01034137 . FINDINGS Between Jan 13 , 2010 , and July 30 , 2012 , we recruited and assigned 317 eligible patients to treatment ( 106 to the tocilizumab plus methotrexate arm , 103 to the tocilizumab arm , and 108 to the methotrexate arm )  . The study was completed by a similar proportion of patients in the three groups ( range 72 - 78 % ) . The most frequent reasons for dropout were adverse events or intercurrent illness : 27 ( 34 % ) of dropouts , and insufficient response : 26 ( 33 % ) of dropouts . 91 ( 86 % ) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen , compared with 86 ( 84 % ) of 103 in the tocilizumab arm , and 48 ( 44 % ) of 108 in the methotrexate arm ( relative risk [ RR ] 2·00 , 95 % CI 1·59 - 2·51 for tocilizumab plus methotrexate vs methotrexate , and 1·86 , 1·48 - 2·32 for tocilizumab vs methotrexate , p<0·0001 for both comparisons ) . For the entire study , 91 ( 86 % ) of 106 patients in the tocilizumab plus methotrexate arm , 91 ( 88 % ) of 103 in the tocilizumab arm , and 83 ( 77 % ) of 108 in the methotrexate arm achieved sustained remission ( RR 1·13 , 95 % CI 1·00 - 1·29 , p=0·06 for tocilizumab plus methotrexate vs methotrexate , 1·14 , 1·01 - 1·29 , p=0·0356 for tocilizumab vs methotrexate , and p=0·59 for tocilizumab plus methotrexate vs  tocilizumab ) . Nasopharyngitis was the most common adverse event in all three treatment groups , occurring in 38 ( 36 % ) of 106 patients in the tocilizumab plus methotrexate arm , 40 ( 39 % ) of 103 in the tocilizumab arm , and 37 ( 34 % ) of 108 in the methotrexate arm . The occurrence of serious adverse events did not differ between the treatment groups ( 17 [ 16 % ] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [ 18 % ] of 103 in the tocilizumab arm and 13 [ 12 % ] of 108 in the methotrexate arm ) , and no deaths occurred during the study . INTERPRETATION For patients with newly diagnosed rheumatoid arthritis , strategies aim ed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective , and with a similar safety profile , compared with initiation of methotrexate in line with current st and ards . FUNDING Roche Nederl and BV Background : Optimal use of disease-modifying antirheumatic drugs ( DMARDs ) in rheumatoid arthritis is vital if progression of disease is to be reduced . Methotrexate ( MTX ) and sulfasalazine ( SASP ) are widely used inexpensive DMARDs , recently often combined despite no firm evidence of benefit from previous studies . Aim : To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP . Methods : A r and omised controlled study of step-up DMARD treatment in early rheumatoid arthritis . In phase I , 687 patients received SASP for 6 months . Those with a disease activity score ( DAS ) ⩾2.4 were offered additional treatment in phase II ( SASP alone , MTX alone or a combination of the two ) . The primary outcome measure was change in DAS . Results : At 6 months , 191 ( 28 % ) patients had a DAS < 2.4 , 123 ( 18 % ) were eligible but did not wish to enter phase II , 130 ( 19 % ) stopped SASP because of reversible adverse events and 165 ( 24 % ) entered phase II . DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX : monotherapy arms did not differ . Improvement in European League Against Rheumatism and American College of Rheumatology 20 , 50 and 70 scores favoured combination therapy . Conclusions : In this “ true-to-life ” study , an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP . There was no increase in toxicity . These results provide an evidence base for the use of this combination as a component of tight control strategies Context A treat-to-target strategy , or treatment to achieve low disease activity , has been associated with improved outcomes among patients with early active rheumatoid arthritis ( RA ) . Long-term data on this approach are lacking . Contribution This r and omized , controlled trial compared 4 treat-to-target strategies for early active RA over 10 years . Most patients had persistently reduced disease activity scores , improved functional status , and limited joint damage during follow-up . They had survival similar to that of the general Dutch population . Caution The trial lacked a nontargeted treatment strategy . Implication Potential outcomes of a treat-to-target approach for early RA include sustained clinical improvement , drug-free remission , and normalized survival . Suppression of inflammation in patients with rheumatoid arthritis ( RA ) is associated with clinical improvement and prevention of radiographic joint damage . Rapid suppression can be achieved with initial combination therapy , including synthetic disease-modifying antirheumatic drugs and corticosteroids or a tumor necrosis factor- inhibitor ( 17 ) . In addition , tightly controlled targeted treatment ( that is , frequent measurements of disease activity with treatment adjustments aim ing to achieve a predefined target ) results in better outcomes than routine care ( 8 , 9 ) . The BeSt ( Beh and elStrategien in reumatode artritis ) study integrated a treat-to-target concept to achieve low disease activity ( defined as a disease activity score [ DAS ] 2.4 ) with a comparison of 4 dynamic treatment strategies . Patients with early active RA were r and omly assigned to sequential monotherapy , step-up combination therapy , or initial combination therapy with either prednisone or an antitumor necrosis factor- agent ( infliximab ) . Based on measurements of disease activity every 3 months , the medication dosage was increased when the DAS was higher than 2.4 and tapered if DAS was persistently 2.4 or less . The study compared the clinical , radiographic , and toxicity outcomes of these strategies over time . We report on these outcomes among participants during 10-year follow-up and compare their survival with that of the general population . Methods Design Overview The r and omized , multicenter , assessor-blinded BeSt study ( 2 ) was design ed by Dutch rheumatologists to determine in which order available antirheumatic medication could best be used to treat patients with newly diagnosed RA , aim ing at low disease activity over 10 years . The original study protocol and amendments for study extension after 2 and 5 years ( Supplements 1 through 3 ) were approved by the medical ethics committees of all participating hospitals . All patients gave written informed consent . Supplement . Data Supplement Setting and Participants The study enrolled 508 patients aged 18 years or older with early active RA according to the revised 1987 American College of Rheumatology criteria for RA ( 10 ) , with symptom duration of fewer than 2 years . They were recruited in 18 nonuniversity and 2 university hospitals in the Netherl and s between 2000 and 2002 . Exclusion criteria encompassed contraindications to the antirheumatic medications used in the study protocol ( Appendix 1 ) ( 2 , 11 ) . R and omization and Interventions Patients were allocated to 1 of 4 dynamic treatment strategies by variable block r and omization , stratified by center : strategy 1 , sequential monotherapy ; strategy 2 , step-up combination therapy ( both starting with methotrexate monotherapy ) ; strategy 3 ; initial combination therapy with methotrexate , sulfasalazine , and prednisone ; and strategy 4 , initial combination therapy with methotrexate and infliximab . For all strategies , subsequent treatment adjustments were specified in the study protocol for patients with an inadequate response ( Appendix Figure 1 ) . Over 10 years , treatment response was measured every 3 months using the DAS ( 12 ) based on a swollen joint count in 44 joints , a tender joint count in 53 joints ( Ritchie articular index ) ( 13 ) , erythrocyte sedimentation rate , and patient 's assessment of global health on a visual analogue scale ( 0 to 100 mm ) ( 12 ) . A DAS of 2.4 or less , indicating low disease activity ( 14 ) , was set as the treatment goal . Treatment was intensified ( medication changed or dosage increased , according to the treatment strategy ) at each study visit that the DAS was greater than 2.4 ( Appendix Figure 1 ) . In case of a continued good response ( DAS 2.4 for 6 months ) , dosage was tapered to a maintenance dose ( if DAS remained < 1.6 for 6 months ; defined as remission ) ( 15 ) and eventually discontinued ( defined as drug-free remission [ DFR ] ) ( Appendix 2 ) . Appendix Figure 1 . Flow diagram of treatment steps per strategy . The figure shows the required treatment intensification steps for each strategy as long as the DAS remained > 2.4 when measured every 3 mo . In all 4 strategies , patients may progress from one treatment step to the next at different times , depending on individual DAS results determined at observation every 3 mo . Patients receiving infliximab ( who receive their dose every 8 wk ) had additional DAS measurements 1 wk before each infusion . These measurements dictated if the next dose needed to be increased . Doses started at 3 mg/kg of body weight . If the DAS was greater than 2.4 , the dose was increased in a stepwise manner to 6 mg/kg , then 7.5 mg/kg , and finally 10 mg/kg ( always rounded to the nearest hundredth ) . The dosage could be tapered if DAS calculations determined every 3 mo were 2.4 or less for at least 6 mo consecutively . Medication dosages were as follows : azathioprine , 2 mg/kg to 3 mg/kg per day ; cyclosporine A , 2.5 mg/kg per day ; methylprednisolone , 3 doses of 120 mg in weeks 1 , 4 , and 8 ; gold , 50 mg/wk ; hydroxychloroquine , 200 mg/d ; infliximab , dose as indicated every 8 wk ; leflunomide , 20 mg/d ; methotrexate , dose as indicated every week ; prednisone , 7.5 mg/d unless indicated otherwise ; sulfasalazine , 2000 mg/d .  DAS= disease activity score . Outcomes and Follow-up The patients were clinical ly assessed every 3 months at study visits during the 10-year follow-up . Functional status , laboratory tests , and adverse events ( AEs ) were assessed . Functional ability was measured using the Health Assessment Question naire ( HAQ ) ( range , 0 [ best ] to 3 [ worst ] ) ( 16 ) . Conventional radiography of h and s and feet were performed annually to assess joint damage progression . All radiographs from baseline to year 10 were scored by 2 independent blinded readers using the modified Sharpvan der Heijde score ( SHS ) ( range 0 [ best ] to 448 [ worst ] ) ( 17 ) in 1 session in r and om order . The intraclass correlation coefficient between the 2 readers was 0.96 ( 95 % CI , 0.95 to 0.97 ) . The mean score of the 2 readers was used for the analysis . The AEs , either reported during visits or apparent in continued laboratory assessment s every 3 months , and serious AEs ( SAEs ) , which also included death during follow-up , were recorded during the trial . For patients who dropped out of the study , life and death status from inclusion to year 10 was obtained from the hospital ( where they enrolled ) , general practitioner , or municipality of the patient 's residence . Those who emigrated and could not be traced thereafter were censored from the date of emigration ( n= 6 ) . One patient could not be located after loss to follow-up and was also censored from the last moment of contact . Survival data of the general Dutch population were acquired from Statistics Netherl and s. Statistical Analysis For each analysis , patients were analyzed in their allocated treatment strategy at baseline , regardless of the number of treatment steps during follow-up . Time to dropout was compared among the treatment strategies with the log-rank test . The HAQ score , low disease activity , remission rate , DFR , SHS , and initial treatment step at year 10 ( intention-to-treat and completer analyses ) were reported separately for each strategy . After multiple imputation of the DAS , the percentages of low disease activity ( DAS 2.4 ) and remission ( DAS < 1.6 ) at year 10 were estimated and compared among the strategies . The imputation model included terms for observed DAS , HAQ score , r and omization strategy , age , sex , anticitrullinated peptide antibody , rheumatoid factor , SHS , and treatment step ; 10 data sets were imputed ( Supplement 4 ) . The imputation method assumed the missing values to be missing at r and om . Sensitivity analyses using controlled imputation methods ( 18 ) tested the robustness of this assumption against violations ( Supplement 4 ) . The HAQ score was analyzed over time using a linear mixed model , taking into account repeated measurements , with a Toeplitz covariance type under the assumption of equally spaced visits ( scheduled every 3 months ) . This model included time as a continuous variable , treatment , and a time-by-treatment interaction term . Sensitivity analyses were also performed for this outcome ( Supplement 4 ) . Radiographic progression at 10 years ( defined as an increase in SHS from baseline to year 10 ) was observed in patients who completed the study using a cumulative probability plot . Radiographic progression over time was analyzed by using a weighted generalized estimating equation ( GEE ) with a negative binomial working distribution , AR1 ( that is , autoregressive ) working correlation , and robust estimation of SEs . This analysis is valid under the missing-at-r and om assumption and was chosen because of the skewed nature of the SHS ( 18 ) . Weights per patient per year were found by using a logistic regression that modeled the inverse probability of a patient having radiographic data available at that measurement time ( Supplement 5 ) . Survival in the study population was compared with the general population ( matched by sex , age , and calendar year ) using the st and ardized mortality ratio : ( observed deathsexpected deaths ) ( 19 ) . KaplanMeier curves and the log-rank test were used to compare survival among the treatment strategies . Cox regression analysis was used to identify OBJECTIVE The aim of this study was to explore the clinical utility of the clinical disease activity index ( CDAI ) . We compared the disease control with protocol ized treatment adjustment following a tight control strategy utilizing either the simplified disease activity index ( SDAI ) or the CDAI . METHODS In a prospect i ve 12 month study , DMARD-naive RA patients were r and omized to either a CDAI or SDAI arm and were treated with traditional DMARDs , increased on a monthly basis according to a predefined protocol to achieve low disease activity . RESULTS Of 102 patients ( 84 females , 96 Black Africans ) , the mean symptom duration was 3.0 years ( s.d . 3.8 ) and the mean 28-joint DAS ( DAS28 ) at baseline was 6.2 ( s.d . 1.2 ) . By 12 months , the proportion of patients in the CDAI and SDAI groups achieving low disease activity ( 30 % and 32 % ) and remission ( 33 and 34 % ) were similar . There were no significant differences in the mean DAS28 or its components or in HAQ Disability Index or health-related quality of life scores . Baseline predictors of low disease activity at 12 months were shorter symptom duration ( P = 0.03 ) and lower HAQ-DI score ( P = 0.04 ) . CONCLUSION Given that the CDAI performed as well as the SDAI , and considering the cost savings and convenience because no acute phase reactant test is necessary , we suggest the CDAI may be an appropriate tool for monthly disease activity monitoring as part of a tight control strategy in developing countries The intention-to-treat ( ITT ) approach to r and omized controlled trials analyzes data on the basis of treatment assignment , not treatment receipt . Alternative approaches make comparisons according to the treatment received at the end of the trial ( as-treated analysis ) or using only subjects who did not deviate from the assigned treatment ( adherers-only analysis ) . Using a sensitivity analysis on data for a hypothetical trial , we compare these different analytical approaches in the context of two common protocol deviations : loss to follow-up and switching across treatments . In each case , two rates of deviation are considered : 10 % and 30 % . The analysis shows that biased estimates of effect may occur when deviation is nonr and om , when a large percentage of participants switch treatments or are lost to follow-up , and when the method of estimating missing values accounts inadequately for the process causing loss to follow-up . In general , ITT analysis attenuates between-group effects . Trialists should use sensitivity analyses on their data and should compare the characteristics of participants who do and those who do not deviate from the trial protocol . The ITT approach is not a remedy for unsound design , and imputation of missing values is not a substitute for complete , good quality data OBJECTIVE To evaluate the feasibility and outcome of the step-down approach using either cyclosporin A ( CSA ) or methotrexate ( MTX ) as maintenance therapy following 6 months treatment with these 2 agents in combination in early , nonerosive rheumatoid arthritis ( RA ) . METHODS Fifty-seven patients younger than 65 years with early , nonerosive RA were first treated with CSA and MTX in combination for 6 months . They were then r and omly stepped down to single-agent maintenance treatment for another 18 months . Safety , clinical efficacy , survival on treatment , and radiographic progression were evaluated . RESULTS When being treated with combination therapy , 7 of the 57 patients ( 12.3 % ) withdrew because of adverse events . Of the remaining 50 patients , 42 ( 84.0 % ) were American College of Rheumatology ( ACR ) 20 % responders , 30 ( 60.0 % ) were ACR 50 % responders , and 23 ( 46.0 % ) were ACR 70 % responders . At month 6 , 22 patients were r and omized to CSA and 27 to MTX . During this trial period , the treatment was discontinued by 16 patients taking CSA ( mainly because of loss of efficacy ) and by 4 taking MTX . At month 24 , the probability ( + /- SEM ) of survival on treatment was 0.273 + /- 0.09 for CSA and 0.852 + /- 0.07 for MTX . Of the 6 CSA patients who completed the trial , 4 ( 66.7 % ) were ACR 20 % responders , and 3 ( 50 % ) were both ACR 50 % and ACR 70 % responders . Of the 23 completers in the MTX arm , 21 ( 91.3 % ) were ACR 20 % responders , 18 ( 78.3 % ) were ACR 50 % , and 10 ( 43.5 % ) were ACR 70 % responders . The treatment was not responsible for severe adverse events . Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups . CONCLUSION Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX . Because this treatment did not prevent some radiographic progression , other approaches ( e.g. , step-up approach ) may be more appropriate in early RA OBJECTIVE To study prospect ively the daily practice effectiveness of a step-down early rheumatoid arthritis ( RA ) treatment strategy . METHODS Patients with severe RA and no contra-indications were proposed step-down therapy , the others step-up . Step-down patients received a modified combination therapy in early RA ( COBRA ) regimen : sulphasalazine ( SPS ) , 2 g daily , and methotrexate ( MTX ) , 15 mg weekly , combined with step-down oral prednisolone ( start 60 mg daily , fast tapering to 7.5 mg over 6 weeks , discontinuation from week 28 ) . At week 40 , patients were r and omized to maintenance therapy with either SPS or MTX if disease activity score-28 ( DAS28 ) was acceptably low . The step-up group started disease-modifying anti-rheumatic drug ( DMARD ) monotherapy . In both groups , treatment was adjusted at follow-up , based on DAS28 . DAS28 , functionality Health Assessment Question naire ( HAQ ) , adverse events , DMARD changes and steroid use were registered 4-monthly for 2 yrs . RESULTS Nineteen patients received step-down and 52 step-up treatment . More patients completed the first year without unplanned DMARD changes and without dosage adjustment and fewer had DMARD changes due to side effects or inefficacy in the step-down group compared with step-up , whereas the number of adverse events was comparable . MTX proved to be the most effective maintenance therapy after step-down . The DAS response , proportion of patients in remission , HAQ response and proportion of patients without disability at 4 months was higher in the step-down group . CONCLUSIONS In daily practice , a step-down treatment strategy for early RA is more effective than a step-up approach OBJECTIVE To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis ( RA ) initially treated with a combination of 3 disease-modifying antirheumatic drugs ( DMARDs ) or with a single DMARD .  METHODS A cohort of 199 patients with early active RA were initially r and omized to receive treatment with a combination of methotrexate , sulfasalazine , and hydroxychloroquine with prednisolone or treatment with a single DMARD ( initially , sulfasalazine ) with or without prednisolone . After 2 years , the drug treatment strategy became unrestricted , but still targeted remission . At 11 years , function was assessed with the Health Assessment Question naire ( HAQ ) , and clinical outcomes were assessed with the modified Minimal Disease Activity ( MDA ) measure and the American College of Rheumatology ( ACR ) criteria for remission . RESULTS At 11 years , 138 patients were assessed ( 68 in the combination-DMARD group and 70 in the single-DMARD group ) . The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group ( P=0.88 ) . Modified MDA was achieved by 63 % ( 95 % confidence interval [ 95 % CI ] 51 , 77 ) and by 43 % ( 95 % CI 32 , 55 ) ( P=0.016 ) of the combination-DMARD group and the single-DMARD group , respectively , and ACR remission by 37 % ( 95 % CI 26 , 49 ) and by 19 % ( 95 % CI 11 , 29 ) ( P=0.017 ) , respectively . CONCLUSION Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy . Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients OBJECTIVE Methotrexate ( MTX ) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis ( RA ) . The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early , poor-prognosis RA . METHODS In the Treatment of Early Rheumatoid Arthritis ( TEAR ) trial , 755 participants with early , poor-prognosis RA were r and omized to receive MTX monotherapy or combination therapy ( MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine ) .  Participants r and omized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ( DAS28-ESR ) was ≥3.2 . RESULTS Attrition at 24 weeks was similar in the MTX monotherapy and combination groups . Of the 370 evaluable participants in the initial MTX group , 28 % achieved low levels of disease activity and did not step-up to combination therapy ( MTX monotherapy group ) . The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2 , which is similar to that in participants who were r and omized to immediate combination therapy ( 2.9 ± 1.2 ) . Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy ( mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4 ) . Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks ( 72 % ) demonstrated similar DAS28-ESR values ( 3.5 ± 1.3 versus 3.2 ± 1.3 at week 48 ) and radiographic progression ( change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102 ) as those assigned to immediate combination therapy . The results for either of the immediate combination approaches , whether triple therapy or MTX plus etanercept , were similar . CONCLUSION These results in patients with early , poor prognosis RA vali date the strategy of starting with MTX monotherapy . This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy . Approximately 30 % of patients will not need combination therapy , and the 70 % who will need it are clinical ly and radiographically indistinguishable from those who were r and omized to receive immediate combination therapy In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis ( RA ) , we evaluated patients with early RA ( < 1 year ) who were r and omized to receive ( P ) or not ( non-P ) low-dose prednisone in association with step-up disease-modifying antirheumatic drug therapy over 2 years .  Prevalence and duration of clinical remission were evaluated in the first and second year . Each treatment group included 105 patients ; no significant differences were found at baseline . During the first year , P patients achieved higher rates of clinical remission with a time-averaged odds ratio ( OR ) of 1.965 ( CI 95 % 1.214 - 3.182 , P= 0.006 ) . Moreover , they showed a higher probability of sustained remission during the second year ( OR 4.480 , CI 95 % 1.354 - 14.817 , P= 0.014 ) . In conclusion , we found as in early RA low-dose prednisone comedication is associated with higher rate of clinical remission , earlier disease activity control and more stable remission over time BACKGROUND / PURPOSE Treat-to-target ( TTT ) is a recommended strategy in the management of rheumatoid arthritis ( RA ) , but various data sources suggest that its uptake in routine care in the US is suboptimal . Herein , we describe the design of a r and omized controlled trial of a Learning Collaborative to facilitate implementation of TTT . METHODS We recruited 11 rheumatology sites from across the US and r and omized them into the following two groups : one received the Learning Collaborative intervention in Phase 1 ( month 1 - 9 ) and the second formed a wait-list control group to receive the intervention in Phase 2 ( months 10 - 18 ) . The Learning Collaborative intervention was design ed using the Model for Improvement , consisting of a Change Package with corresponding principles and action phases . Phase 1 intervention practice s had nine learning sessions , collaborated using a web-based tool , and shared results of plan-do- study -act cycles and monthly improvement metrics collected at each practice . The wait-list control group sites had no intervention during Phase 1 . The primary trial outcome is the implementation of TTT as measured by chart review , comparing the differences from baseline to end of Phase 1 , between intervention and control sites . RESULTS All intervention sites remained engaged in the Learning Collaborative throughout Phase 1 , with a total of 38 providers participating . The primary trial outcome measures are currently being collected by the study team through medical record review . CONCLUSIONS If the Learning Collaborative is an effective means for improving implementation of TTT , this strategy could serve as a way of implementing disseminating TTT more widely 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
BACKGROUND Treat to target ( TTT ) is a broad concept for treating patients with rheumatoid arthritis ( RA ) .
It involves setting a treatment target , usually remission or low disease activity ( LDA ) .
This is often combined with frequent patient assessment and intensive and rapidly adjusted drug treatment , sometimes based on a formal protocol .
OBJECTIVE To investigate the clinical effectiveness and cost-effectiveness of TTT compared with routine care .