Are we making the most of the Stanford Health Assessment Questionnaire? Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised controlled trial. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial Aggressive therapy in patients with early arthritis results in similar outcome compared with conventional care: the STREAM randomized trial Contemporary patterns of care and disease activity outcome in early rheumatoid arthritis: the ERAN cohort. Strengthening clinical effectiveness trials: Equipoise-stratified randomization A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. Infliximab in active early rheumatoid arthritis Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. An open, randomized comparison study of cyclosporine A, cyclosporine A + methotrexate and cyclosporine A + hydroxychloroquine in the treatment of early severe rheumatoid arthritis Combination therapy with methotrexate and chloroquine in rheumatoid arthritis. A multicenter randomized placebo-controlled trial. Joint counts in routine practice. Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial) Subgroup analysis and other (mis)uses of baseline data in clinical trials Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis Adding low-dose cyclosporin A to parenteral gold therapy in rheumatoid arthritis: a double-blind placebo-controlled study. Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis Function and health-related quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. Assessing non-consent bias with parallel randomized and nonrandomized clinical trials. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. The uncertainty principle and industry-sponsored research 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. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): 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 When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Patient-reported outcomes better discriminate active treatment from placebo in randomized controlled trials in rheumatoid arthritis. Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low – results from RABBIT, the German biologics register Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-contro Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. The impact of escalating conventional therapy in rheumatoid arthritis patients referred for anti-tumour necrosis factor-alpha therapy. 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. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Combination of cyclosporine and leflunomide versus single therapy in severe rheumatoid arthritis. Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials. Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis. A forty-eight-week controlled clinical trial with radiologic outcome assessment. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial Radiological progression in rheumatoid arthritis: do D-penicillamine and hydroxychloroquine have different effects? Cost-Effectiveness of Combination Nonbiologic Disease-Modifying Antirheumatic Drug Strategies in Patients with Early Rheumatoid Arthritis Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Randomized, controlled trials, observational studies, and the hierarchy of research designs. Progression of radiological changes in rheumatoid arthritis. Combination therapy in rheumatoid arthritis--no benefit of addition of hydroxychloroquine to patients with a suboptimal response to intramuscular gold therapy. Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Intent-to-Randomize Corrections for Missing Data Resulting from Run-In Selection Bias in Clinical Trials for Chronic Conditions Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial Lymphoid irradiation in intractable rheumatoid arthritis. Long-term followup of patients treated with 750 rads or 2,000 rads. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot 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. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database. Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility. Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. A randomized, double-blind, multicenter, controlled clinical trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial
For many years , the Stanford Health Assessment Question naire ( HAQ ) has provided an effective measure of disability . Recently , some debate has emerged about whether or not the HAQ is an " ordinal ' or " interval ' scale . The opportunity to test its level of measurement arose when the scale was applied in a community survey which undertook a two-stage r and om sample using postal question naires to ascertain the health care needs of those with arthritis . The HAQ data are fitted to the Rasch model which tests for the presence of certain desirable characteristics of measurement , e.g. unidimensionality . The fit of the data to the model for those self-reporting rheumatoid arthritis ( RA ) was adequate . The transformed  HAQ score , derived from the Rasch analysis , is compared with the ordinary HAQ ( raw ) score . This shows that , for those with RA , incremental units of the raw score at the margins of the scale reflect an increasing level of (dis)ability compared to similar units in the centre of the scale . Thus , the traditional  HAQ score ( range 0 - 3 ) is an ordinal score . The findings also indicate that scoring all 20 items may lead to greater sensitivity . Questions are also raised about the construct validity for those with other types of arthritis . For osteoarthrosis , the grip item does not appear to belong to the same underlying construct as the other items Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response  versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function  versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : OBJECTIVE To 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 Objective : To compare the efficacy and toxicity of cyclosporin A ( CsA ) monotherapy with CsA plus methotrexate ( MTX ) combination therapy in patients with early rheumatoid arthritis ( RA ) . Patients and methods : 120 patients with active RA , rheumatoid factor positive and /or erosive , were r and omly allocated to receive CsA with MTX ( n=60 ) or CsA with placebo ( n=60 ) . Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks . MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16 . Primary outcomes were clinical remission ( Pinals criteria ) and radiological damage ( Larsen score ) , at week 48 . Results : Treatment was discontinued prematurely in 27 patients in the monotherapy group ( 21 because of inefficacy , and six because of toxicity ) and in 26 patients in the combination therapy group ( 14 and 12 , respectively ) . At week 48 , clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group ( p=0.5 ) . The median Larsen score increased to 10 ( 25th , 75th centiles : 3.5 ; 13.3 ) points in the monotherapy group and to 4 ( 1.0 ; 10.5 ) points in the combination therapy group ( p=0.004 ) . 28/60 ( 47 % ) of patients in the monotherapy group v 34/60 ( 57 % ) of patients in the combination therapy group had reached an American college of Rheumatology 20 % ( ACR20 ) response ( p=0.36 ) at week 48 ; 15/60 ( 25 % ) v 29/60 ( 48 % ) of patients had reached an ACR50 response ( p=0.013 ) ; and 7 ( 12 % ) v 12 ( 20 % ) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group . Conclusions : In patients with early RA , neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission . Combination therapy is probably better at improving clinical disease activity , and definitely better at slowing radiological progression . Combination therapy should still be compared with methotrexate monotherapy Objective . To compare the effects of aggressive tight control therapy and conventional care on radiographic progression and disease activity in patients with early mild inflammatory arthritis . Methods . Patients with two to five swollen joints , Sharp – van der Heijde radiographic score ( SHS ) < 5 and symptom duration ≤2 years were r and omized between two strategies . Patients with a definite non-RA diagnosis were excluded . The protocol of the aggressive group aim ed for remission ( DAS < 1.6 ) , with consecutive treatment steps : MTX , addition of adalimumab and combination therapy . The conventional care group followed a strategy with traditional DMARDs ( no prednisone or biologics ) without DAS-based guideline . Outcome measures after 2 years were SHS ( primary ) , remission rate and HAQ score ( secondary ) . Results . Eighty-two patients participated ( 60 % ACPA positive ) . In the aggressive group ( n = 42 ) , 19 patients were treated with adalimumab . In the conventional care group ( n = 40 ) , 24 patients started with hydroxychloroquin ( HCQ ) , 2 with sulfasalazine ( SSZ ) and 14 with MTX . After 2 years , the median SHS increase was 0 [ interquartile range ( IQR ) 0–1.1 ] and 0.5 ( IQR 0–2.5 ) , remission rates were 66 and 49 % and HAQ decreased with a mean of −0.09 ( 0.50 ) and −0.25 ( 0.59 ) in the aggressive and conventional care group , respectively . All comparisons were non-significant . Conclusion . In patients with early arthritis of two to five joints , both aggressive tight-control therapy including adalimumab and conventional therapy result ed in remission rates around 50 % , low radiographic damage and excellent functional status after 2 years . However , full disease control including radiographic arrest in all patients remains an elusive target even in moderately active early arthritis . Trial registration . Dutch Trial Register , http://www.trialregister.nl/ , NTR 144 OBJECTIVES To report from the Early Rheumatoid Arthritis Network ( ERAN ) , time from symptom onset to start of therapy , treatment choices and disease outcome in early RA . METHODS Patients with newly diagnosed RA were prospect ively enrolled from 19 centres in the UK and Eire . St and ardized information was collected on case report forms at first presentation , 3 - 6 months , 1 yr and annually thereafter . The choice and intensity of drug treatment was left to the discretion of individual centres . RESULTS A total of 808 patients were recruited between 2002 and 2007 , with a mean follow-up of 16 ( 0 - 60 ) months . Of them , 62 % fulfilled four or more ACR criteria for RA at first visit . The median time from onset of symptoms to referral to secondary care was 4 months [ interquartile range ( IQR ) 2 - 9 , n = 655 ] and to start of first DMARD 8 months ( IQR 4 - 13 , n = 638 ) . DMARDs were prescribed in 97 % of the patients , initially as monotherapy in 91 % , and as combination therapy in 9 % . The second DMARD ( n = 220 ) was a switch to another as monotherapy in 52 % and step-up to combination therapy in 48 % . The proportions with a 28-joint disease activity score > 5.1 at baseline and 3 yrs were 46 and 19 % , > 3.2 were 84 and 54 % and < 2.6 were 6 and 33 % , respectively . CONCLUSIONS Patients presenting with RA in ERAN do not receive DMARDs promptly , largely due to delays in referral to secondary care . Contemporary treatment practice is to start with DMARD monotherapy , and to use combination DMARDs as second-line therapy in approximately half of them . Over 3 yrs the proportion of patients continuing to have active disease remains high As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy , research studies with broader aims will become increasingly important . R and omized trials may need to accommo date multiple treatment options . In completely r and omized design s , patients are assigned at r and om to one of the options , requiring that patients and clinicians find each of the options acceptable . In " clinician 's choice " design s , patients are r and omized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician . The clinician 's choice design permits some scope to patient and clinician preferences , but sacrifices the ability to make r and omization-based comparisons of specific options . We describe a new approach , which we call the " equipoise stratified " design , that merges the advantages and avoids the disadvantages of the other two design s for clinical trials . The three design s are contrasted , using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate .  METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone Objective : To examine the impact of the combination of infliximab plus methotrexate ( MTX ) on the progression of structural damage in patients with early rheumatoid arthritis ( RA ) . Methods : Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy ( ATTRACT ) study , in which 428 patients with active RA despite MTX therapy received placebo with MTX ( MTX-only ) or infliximab 3 mg/kg or 10 mg/kg every ( q ) 4 or 8 weeks with MTX ( infliximab plus MTX ) for 102 weeks . Early RA was defined as disease duration of 3 years or less ; 82 of the 428 patients ( 19 % ) met this definition . Structural damage was assessed with the modified van der Heijde-Sharp score . The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group . Results : The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen . Consistent benefit was seen in the joints of both h and s and feet . Conclusions : Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment . Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA Purpose To determine whether a regimen of cyclosporine ( CSA ) and methotrexate ( MTX ) , or CSA and hydroxychloroquine ( HCQ ) introduced in early rheumatoid arthritis ( RA ) can produce a significant improvement in clinical outcome and /or retard radiographic damage in comparison with st and ard monotherapy with CSA alone . Methods One hundred five patients with active RA of less than 36 months duration , who had never previously been treated with immunosuppressive agents , were included in a 12-month , multi-center , open , r and omized trial . Patients who fulfilled the criteria for early severe RA were r and omized to receive either combination therapy ( CSA+MTX n=34 , CSA+HCQ n=35 ) or CSA alone ( n=36 ) . Results CSA+MTX was more effective than the other two treatment groups in controlling RA symptoms . CSA+MTX did not show a significant radiographic progression according to Larsen – Dale ( 0.90±3.89 compared to baseline values , P>0.05 ) ; moreover , patients treated with CSA alone or CSA+HCQ showed a significant worsening of Larsen – Dale score ( 2.91±5.99 and 2.97±4.28 respectively vs baseline values , P<0.05 ) , although not significant when compared with the CSA+HCQ group ( P=0.56 and 0.39 , respectively ) . Conclusions This trial indicated that CSA+MTX was more effective than the other two treatments in improving clinical data and inhibiting radiographic progression , although the differences were not significant in this relatively small study . However , the difference was significant in favor of CSA+MTX regarding ACR 50 % response To compare the efficacy of the combination therapy Methotrexate ( MTX ) and Chloroquine ( CHLO ) with MTX and Placebo ( PLA ) in the treatment of Rheumatoid Arthritis . A total of 82 patients with Rheumatoid Arthritis ( RA ) , diagnosed according to the American College of Rheumatology criteria , received orally either MTX 7.5 mg/week and CHLO 250 mg/day or MTX 7.5 mg/week and PLA 1 tablet/day . Adverse effects ( AE ) were monitored monthly and disease activity was assessed at 0 , 2 , 4 and 6 months . Sixty-eight patients completed the study . All outcome measures improved significantly in both treatment groups . Patients receiving MTX/CHLO ended the study with a significantly lower joint count , greater grip strength and better functional ability the patients in the MTX/PLA group , respectively ; 4.5 vs 7.5 ( P < 0.05 ) , 113.3 vs 89.1 ( P < 0.05 ) and 0.636 vs 0.811 ( P < 0.05 ) . Mild AE were more frequently observed in the MTX/CHLO , 17 events in 15 patients , compared to 9 events in 8 patients in the MTX/PLA group ( NS ) . These data indicate that MTX/CHLO is slightly more efficacious and toxic than is MTX/PLA in the treatment of RA Swollen and tender joints are the most characteristic features of rheumatoid arthritis ( RA ) and disease severity is directly related to the numbers of swollen and tender joints . Consequently , clinical trials of diseasemodifying anti-rheumatic drugs and biologicals use reductions in swollen and tender joint counts as key outcome measures . Despite their central place in RA , we believe that joint counts are not always recorded in specialist clinical care . Our purpose in this editorial is to make the case for their invariable adoption in routine practice . Counting the number of swollen joints is a clinical method of quantifying the amount of inflamed synovial tissue . Joint tenderness , by contrast , is more closely associated with the amount of pain . As the relationship between joint swelling and tenderness varies from case to case and time to time in the same patient , it is traditional to assess them both . There is no existing consensus on a single st and ardized method of counting the number of joints involved . The methods available vary in the number of joints assessed , whether these joints are weighted according to size , and whether the joint abnormality is scored on a grade d scale or simply as being normal or abnormal w1x . The favoured methods include the extended 66u68-joint count , the Ritchie articular index w2x and the reduced 28-joint count w3x . As there is no advantage in examining large numbers of joints , the 28-joint count is becoming the international st and ard w4 , 5x . Several studies provide the rationale for using the simple 28-joint count . A longitudinal study by Prevoo et al. w6x compared a number of different joint counts and indices . They found that their validity and reliability did not differ substantially , though weighted indices performed less well . Subsequently , Smolen et al. w7x compared the  28-joint count  with the 66u68-joint count in 735 prospect ively studied RA patients . The joints in the 28-joint count were more commonly involved than others , and findings from the 28-joint count correlated highly with the 66u68-joint count . These studies show that the 28-joint count is the preferred measure as it is not only a reliable and valid measure but is also easier to perform than the 66u68-joint count , and it evaluates the joints that are critically involved . This does not mean that joint counts are ideal measures . Several studies w8–12x reported considerable variation in joint counts between both individual observers and centres in clinical trials and in routine clinical practice . Despite this , determining the numbers of swollen joints and tender joints is the most stable method of clinical assessment . Furthermore , training to st and ardize methods w13x increases the sensitivity of counting swollen and tender joints and reduces the variability of measurement , though it does not entirely abolish it . As the assessment of RA should integrate several clinical and laboratory measures , there has been a growing belief in indices that combine the various assessment s to give an overall clinical score . There are many examples of such combined indices . These include the  Stoke index  w14x , the  Mallya and Mace index  w15x , the  Overall Status in RA ( OSRA ) measure of  Symmons  w16x and the  Disease Assessment Score ( DAS )  w17x . Both the Stoke index and the Mallya and Mace index require more clinical data and are more complicated and less able to discriminate between patients than the DAS , and the OSRA has never been widely used . Consequently , the DAS has become the preferred combined index . The development of the DAS date s back to 1983 , when a modification of an existing disease activity index was used in a small clinical trial w18x . Subsequently all patients with early RA were assessed and classified into cases with high or low disease activity . This classification was based on a joint decision by the rheumatologist and the patient . Using this classification , it was possible to identify a combination of variables that discriminated best between these two disease states , which led in turn to the development of the DAS w19x . The original DAS used the Ritchie articular index , a 44-swollen joint count , the erythrocyte sedimentation rate ( ESR ) and a general health assessment on a visual analogue scale ( VAS ) However , the DAS was subsequently modified to include 28-joint counts for swelling and tenderness w20x . Serial measurements of DAS28 are strong predictors of physical disability and radiological progression w21 , 22x and provide a sensitive discriminator between patients with high and low disease activity w23x . Unlike the American College of Rheumatology ( ACR ) response criteria w24 , 25x , the DAS score was derived for use in clinical practice as well as clinical trials . We believe that it is sensible to combine the use of joint counts with the calculation of DAS scores in routine specialist practice . We have considered carefully whether or not there is room for further simplification of joint scores or DAS . The 28-joint count includes the shoulders , and it is likely that assessment of shoulder involvement is relatively insensitive and inaccurate . There is thus a case for removing the shoulder joints from routine counts . The use of reduced joint counts in the clinic has been considered by Wolfe et al. w26x , and this group of experts believe an 18-tender and uor swollen joint count , which Rheumatology 2003;42:919–923 doi:10.1093/rheumatology/keg235 , available online at www.rheumatology.oupjournals.org Advance Access publication 31 March The concept of ' equipoise ' , or the ' uncertainty principle ' , has been represented as a central ethical principle , and holds that a subject may be enrolled in a r and omized controlled trial ( RCT ) only if there is true uncertainty about which of the trial arms is most likely to benefit the patient . We sought to estimate the frequency with which equipoise conditions were met in industry-sponsored RCTs in rheumatology , to explore the reasons for any deviations from equipoise , to examine the concept of ' design bias ' , and to consider alternative ethical formulations that might improve subject safety and autonomy . We studied abstract s accepted for the 2001 American College of Rheumatology meetings that reported RCTs , acknowledged industry sponsorship , and had clinical end-points ( n = 45 ) , and examined the proportion of studies that favored the registration or marketing of the sponsor 's drug . In every trial ( 45/45 ) results were favorable to the sponsor , indicating that results could have been predicted in advance solely by knowledge of sponsorship ( P < 0.0001 ) . Equipoise clearly was being systematic ally violated . Publication bias appeared to be an incomplete explanation for this dramatic result ; this bias occurs after a study is completed . Rather , we hypothesize that ' design bias ' , in which extensive preliminary data are used to design studies with a high likelihood of being positive , is the major cause of the asymmetric results . Design ' bias ' occurs before the trial is begun and is inconsistent with the equipoise principle . However , design bias increases scientific efficiency , decreases drug development costs , and limits the number of subjects required , probably reducing aggregate risks to participants . Conceptual and ethical issues were found with the equipoise principle , which encourages performance of negative studies ; ignores patient values , patient autonomy , and social benefits ; is applied at a conceptually inappropriate decision point ( after r and omization rather than before ) ; and is in conflict with the Belmont , Nuremberg , and other sets of ethical principles , as well as with US Food and Drug Administration procedures . We propose a principle of ' positive expected outcomes ' , which informs the assessment that a trial is ethical , together with a restatement of the priority of personal autonomy 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 BACKGROUND Baseline data collected on each patient at r and omisation in controlled clinical trials can be used to describe the population of patients , to assess comparability of treatment groups , to achieve balanced r and omisation , to adjust treatment comparisons for prognostic factors , and to undertake subgroup analyses . We assessed the extent and quality of such practice s in major clinical trial reports . METHODS A sample of 50 consecutive clinical -trial reports was obtained from four major medical journals during July to September , 1997 . We tabulated the detailed information on uses of baseline data by use of a st and ard form . FINDINGS Most trials presented baseline comparability in a table . These tables were often unduly large , and about half the trials inappropriately used significance tests for baseline comparison . Methods of r and omisation , including possible stratification , were often poorly described . There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear . Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference . Two-thirds of the reports presented subgroup findings , but mostly without appropriate statistical tests for interaction . Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power . INTERPRETATION Clinical trials need a predefined statistical analysis plan for uses of baseline data , especially covariate-adjusted analyses and subgroup analyses . Investigators and journals need to adopt improved st and ards of statistical reporting , and exercise caution when drawing conclusions from subgroup findings OBJECTIVE To investigate whether disease control can be achieved in early active rheumatoid arthritis ( RA ) by treatment with methotrexate and intraarticular betamethasone , and whether the addition of cyclosporine to the regimen has any additional effect . METHODS Patients ( n = 160 ) were r and omized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day ( combination therapy ) or methotrexate plus placebo-cyclosporine ( monotherapy ) . At weeks 0 , 2 , 4 , 6 , and 8 and every 4 weeks thereafter , betamethasone was injected into swollen joints ( maximum 4 joints or 4 ml per visit ) . Beginning at week 8 , if synovitis was present , the methotrexate dosage was increased stepwise up to 20 mg/week , with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg . RESULTS At 52 weeks , 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) was achieved in 85 % of the combination therapy group versus 68 % of the monotherapy group ( P = 0.02 ) . The median individual overall ACR response ( ACR-N ) in the 2 groups was 80.0 % ( interquartile range 40.1 - 91.8 % ) and 54.5 % ( interquartile range 2.4 - 87.8 % ) , respectively ( P = 0.025 ) . At 48 and 52 weeks , ACR remission criteria were met in 35 % of the combination therapy group and 28 % of the monotherapy group . Progression in the Larsen score at 52 weeks was -0.2 + /- 6.5 and 0.4 + /- 6.9 ( mean + /- SD ) in the combination therapy and monotherapy groups , respectively . Serum creatinine levels increased by 7 % , and hypertrichosis was more prevalent , in the combination therapy group . CONCLUSION Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA , who had a poor prognosis . Addition of cyclosporine improved the ACR20 and ACR-N responses , whereas the ACR50 and ACR70 responses , remission rates , and radiographic changes did not differ between the 2 study groups 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 A double-blind , r and omized comparison between parenteral gold therapy ( PGT ) and cyclosporin A ( CyA ) vs PGT and placebo during 6 months was performed in 40 RA patients experiencing a decreasing effect of ongoing PGT .  Patients ' overall assessment of health was the only efficacy variable significantly better in the CyA- and PGT-treated vs the placebo- and PGT-treated group . Higher blood pressure and more signs of renal impairment were found during the 6 months treatment in the former compared with the latter group . Six months after the end of the combination therapy , a higher potassium value in the CyA-treated group was the only difference . In conclusion , no effects additional to those expected with single-drug therapy or additional risks of side-effects of either drug were found when combining low-dose CyA with ongoing PGT in RA patients with long disease duration OBJECTIVE To investigate whether there is interaction between chloroquine and cyclosporine ( CyA ) at the level of efficacy and toxicity in patients with recent onset rheumatoid arthritis ( RA ) . METHODS Eighty-eight patients with recent onset RA , who had shown a suboptimal clinical response on low dose chloroquine monotherapy  , were r and omly assigned to additional treatment with placebo , CyA 1.25 mg/kg/day , or CyA 2.50 mg/kg/day ( fixed doses ) for another 24 weeks . The tender joint count was the primary outcome assessment of efficacy and the serum creatinine of toxicity . The 1995 preliminary ACR response criteria for improvement were applied to evaluate individual clinical responses . RESULTS Two patients in the placebo group ( n = 29 ) , 7 patients in the CyA 1.25 mg group ( n = 29 ) , and 8 patients in the CyA 2.50 mg group ( n = 30 ) ( p = 0.06 ) discontinued study medication prematurely for inefficacy or adverse events . The intention-to-treat analysis revealed that the tender joint count decreased 2.2 + /- 6.1 ( mean + /- SD ) joints in the placebo group , 2.2 + /- 6.6 joints in the CyA 1.25 mg group , and 5.0 + /- 5.8 joints in the CyA 2.50 mg group ( p = 0.04 ) . The 1995 preliminary ACR response criteria for clinical improvement were met by 8 ( 28 % ) patients in the placebo group , 10 ( 34 % ) patients in the CyA 1.25 mg group , and 15 ( 50 % ) patients in the CyA 2.50 mg group ( p = 0.07 ) . The serum creatinine increased 2 + /- 7 micromol/l in the placebo group , decreased 1 + /- 8 micromol/l in the CyA 1.25 mg group , and increased 10 + /- 15 micromol/l in the CyA 2.50 mg group ( p < 0.001 ) . CONCLUSION The addition of low dose CyA is moderately effective in patients with early RA already treated with low dose chloroquine , but results in statistically significant renal function loss Objective : Treating early active rheumatoid arthritis ( RA ) with disease modifying antirheumatic drug ( DMARD ) monotherapy achieves incomplete outcomes and intensive treatment seems preferable . As the relative benefits of combining two DMARDs , one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial . Methods : A 2-year r and omised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate  studied the benefits of added ciclosporin , 9 months intensive prednisolone or both ( triple therapy ) . The primary outcome was the number of patients with new erosions . Secondary outcomes included Larsen ’s x-ray scores , disability , quality of life and adverse events . Findings : 1391 patients were screened and 467 r and omised . Over 2 years 132 ( 28 % ) changed therapy and 88 ( 19 % ) were lost to follow-up . The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone ( p = 0.01 and 0.03 ) ; both treatments reduced increases in Larsen ’s x-ray scores by over 2 units ( p = 0.008 and 0.003 ) . A further reduction in erosive damage was seen with combined use of both treatments . Their effects on erosive damage appeared independent . Triple therapy reduced disability and improved quality of life compared with methotrexate ; ciclosporin and prednisolone acted synergistically . More patients withdrew because of adverse events with triple therapy , without an increase in serious adverse effects . Conclusions : This study confirms the existence of a “ window of opportunity ” in early RA , when intensive combination therapy produces sustained benefits on damage and disability . Although methotrexate – prednisolone combinations reduce erosive damage , the synergistic effect of two DMARDs is needed to improve quality of life OBJECTIVE To assess the efficacy of leflunomide or methotrexate compared with placebo in improving function and health-related quality of life in patients with active rheumatoid arthritis ( RA ) , and to examine correlations between response status ( as defined by the American College of Rheumatology [ ACR ] response criteria ) and improvement in these measures . METHODS This 52-week , multicenter , doubleblind , controlled trial compared responses to the Health Assessment Question naire ( HAQ ) , modified Health Assessment Question naire ( MHAQ ) , Problem Elicitation Technique ( PET ) , Medical Outcomes Study Short Form 36 ( SF-36 ) , and questions regarding work productivity among 3 treatment groups ( leflunomide , methotrexate , and placebo ) . Improvement in the PET top 5 and SF-36 scales and component scores were compared with ACR response rates . RESULTS Clinical ly meaningful and statistically significant ( P<0.0001 ) improvement in measures of function and heath-related quality of life ( MHAQ scores , all scales and disability index of the HAQ , weighted top 5 score of the PET , 5 of 8 scales and physical component score of the SF-36 , and work productivity ) was seen during treatment with leflunomide in comparison with placebo . Methotrexate administration result ed in significant improvements ( P<0.05 ) in comparison with placebo in the MHAQ scores , HAQ disability index , weighted top 5 score of the PET , physical component score of the SF-36 , and bodily pain scale . Compared with methotrexate , leflunomide administration result ed in significantly ( P<0.01 ) more improvement in the MHAQ scores , 5 of 8 scales and disability index of the HAQ , weighted top 5 score of the PET , and 2 of 8 scales and physical component score of the SF-36 . Improvements in the PET score , SF-36 physical component score , and work productivity correlated with the ACR responder rates of > or = 20 % and > or = 50 % improvement . CONCLUSION Significant improvements in function and health-related quality of life occurred in patients with RA during treatment with leflunomide or methotrexate . These findings were clinical ly meaningful and correlated with the ACR response status In some r and omized clinical trials , a large proportion of patients eligible for r and omization may withhold consent to be r and omized . When the subjects in the r and omized trial differ from the eligible population with respect to characteristics that are associated with the magnitude of the treatment effect , there may be non-consent bias , i.e. , the treatment effect for those in the r and omized trial may not reflect the treatment effect for the eligible population . In response to this problem , some investigators have conducted , in addition to the r and omized trial , a separate nonr and omized but otherwise identical trial consisting of those patients who are eligible for r and omization  , but instead choose their own treatment . Observed baseline covariate data can be used to adjust for differences between the r and omized population and the eligible population when estimating the treatment effect for the eligible population . After adjusting , different outcomes for the r and omized versus nonr and omized treated groups and /or the r and omized versus nonr and omized control groups reflect the presence of hidden non-consent bias result ing from differences between the trial population and the eligible population with respect to unobserved covariates . A sensitivity analysis can display how hidden non-consent bias can account for an imbalance in the treatment groups with respect to an unobserved covariate . A parallel r and omized and nonr and omized trial which compares adenoidectomy versus medical treatment  for children with recurrent otitis media [ Paradise et al. Efficacy of adenoidectomy for recurrent otitis media in children previously treated with tympanostomy-tube placement . J Am Med Assoc 1990 ; 263 : 2066 - 2073 ] is used as an illustration OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX .  METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy  in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo BACKGROUND Reporting of pharmaceutical-industry-sponsored r and omised clinical trials often result in biased findings , either due to selective reporting of studies with non-equivalent arms or publication of low- quality papers , wherein unfavourable results are incompletely described . A r and omised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another . Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle . METHODS We examined the quality of 136 published r and omised trials that focused on one disease category ( multiple myeloma ) and adherence to the uncertainty principle . To evaluate whether the uncertainty principle was upheld , we compared the number of studies favouring experimental treatments over st and ard ones . We analysed data according to the source of funding . FINDINGS Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores ( mean 2.94 [ SD 1.3 ] ; median 3 ) than r and omised trials supported by 95 governmental or other non-profit organisations ( 2.4 [ 0.8 ] ; 2 ; p=0.06 ) . Overall , the uncertainty principle was upheld , with 44 % of r and omised trials favouring st and ard treatments and 56 % innovative treatments ( p=0.17 ) ; mean and median preference evaluation scores were 3.7 ( 1.0 ) and 4 . However , when the analysis was done according to the source of funding , studies funded by non-profit organisations maintained equipoise favouring new therapies over st and ard ones ( 47 % vs 53 % ; p=0.608 ) to a greater extent than r and omised trials supported solely or in part by profit-making organisations ( 74 % vs 26 % ; p=0.004 ) . INTERPRETATION The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle . Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls 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 Objective To assess the efficacy and safety of adalimumab plus methotrexate ( ADA+MTX ) compared with methotrexate monotherapy in achieving stable low disease activity ( LDA ; disease activity score ( DAS28(CRP ) ) < 3.2 at weeks 22 and 26 ) and clinical , radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis ( RA ) . Methods 1032 patients with active RA were r and omly assigned 1:1 to ADA+MTX or placebo plus methotrexate ( PBO+MTX ) for 26 weeks . Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP ) < 3.2 at weeks 22 and 26 . Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission . Results Among patients completing 6 months , 44 % ( 207/466 ) ADA+MTX versus 24 % ( 112/460 ) PBO+MTX patients achieved stable LDA at weeks 22 and 26 ( p<0.001 ) . Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses , more clinical remissions , greater mean reductions in DAS28(CRP ) , no radiographic progression , and normal functional status at week 26 ( p<0.001 for all ) . The only factor predicting stable LDA was disease activity at week 12 . Patients achieving ACR/EULAR remission , particularly in the PBO+MTX group , had some advantage in radiographic outcomes compared with patients who only achieved LDA ( but not remission ) . The overall frequency of adverse events was comparable between groups . There were more serious infections and deaths in the ADA+MTX group , with a possible age effect . Conclusions Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical , radiographic and functional outcomes in patients with early active RA . Before initiating treatment with adalimumab , individual patient evaluation of the benefit/risk ratio should be carefully considered OBJECTIVES To investigate the potential clinical benefit of a combination therapy . METHODS 205 patients fulfilling the ACR criteria for rheumatoid arthritis ( RA ) , not treated with disease modifying anti-rheumatoid drugs previously , with an early ( ⩽1 year duration ) , active ( Disease Activity Score ( DAS ) > 3.0 ) , rheumatoid factor and /or HLA DR 1/4 positive disease were r and omised between sulphasalazine ( SASP ) 2000 ( maximum 3000 ) mg daily ( n = 68 ) , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly ( n = 69 ) or the combination ( SASP + MTX ) of both ( n = 68 ) . RESULTS The mean changes in the DAS during the one year follow up of the study was −1.15 , −0.87 , −1.26 in the SASP , MTX , and SASP + MTX group respectively ( p = 0.019 ) . However , there was no statistically significant difference in terms of either EULAR good responders 34 % , 38 % , 38 % or ACR criteria responders 59 % , 59 % , 65 % in the SASP , MTX , and SASP + MTX  group respectively . Radiological progression evaluated by the modified Sharp score was very modest in the three groups : mean changes in erosion score : + 2.4 , + 2.4 , + 1.9 , in narrowing score : + 2.3 , + 2.1 , + 1.6 and in total damage score : + 4.6 , + 4.5 , + 3.5 , in the SASP , MTX , and SASP +  MTX groups respectively . Adverse events occurred more frequently in the SASP + MTX group 91 % versus 75 % in the SASP and MTX group ( p = 0.025 ) . Nausea was the most frequent side effect : 32 % , 23 % , 49 % in the SASP , MTX , and SASP + MTX groups respectively ( p = 0.007 ) . CONCLUSION This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit . However , this study was unable to demonstrate a clinical ly relevant superiority of the combination therapy although several outcomes were in favour of this observation . The tolerability of the three treatment modalities seems acceptable OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy 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 OBJECTIVE To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy .  METHODS Patients with active RA ( ( DAS28 ) > 3.2 ) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks . Inadequate responders then entered the double blind phase and received a further 24 weeks ' treatment with leflunomide ( 20 mg once daily ) plus sulfasalazine ( final dose 2 g once daily ) , or placebo plus sulfasalazine ( dose as above ) . The primary efficacy variable was the DAS28 response rate , and secondary efficacy outcomes were ACR 20 % , 50 % , and 70 % response rates . Adverse events , including st and ard laboratory tests , were recorded . RESULTS 106 inadequate responders entered the double blind phase ; 56 received leflunomide plus sulfasalazine , and 50 placebo plus sulfasalazine . In the intention to treat population , more patients receiving leflunomide plus sulfasalazine ( 25/56 ( 45 % ) ) achieved a DAS28 response than those receiving placebo plus sulfasalazine ( 17/50 ( 34 % ) ) ( p = 0.179 ) . In week 24 completers , more patients receiving leflunomide plus sulfasalazine ( 17/56 ( 30 % ) ) were DAS28 responders than those receiving placebo plus sulfasalazine ( 10/50 ( 20 % ) ) ( p = 0.081 ) . Comparable numbers in each group were ACR 20 % responders ; the ACR 50 % response rate was significantly higher in the leflunomide plus sulfasalazine group ( 8.9 % ) than in the placebo plus sulfasalazine group ( 0 % ) ( p = 0.038 ) . The safety profiles of both groups were comparable . CONCLUSION Patient numbers are small and firm conclusions can not be reached , but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide OBJECTIVE To determine whether patients with early rheumatoid arthritis ( RA ) treated with cyclosporin A ( CsA ) and methotrexate ( MTX ) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone . METHODS In this controlled and r and omized single-blind trial , 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy ( n = 30 ) or MTX alone ( n = 31 ) . The primary end-point was radiographic progression after 12 months , measured using the damage score ( DS ) of the Sharp and van der Heijde method . RESULTS Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups ( MTX/CsA , 1.93 + /- 0.90 ; MTX , 7.47 + /- 2.03 ) , it was significantly less in the combination arm ( P = 0.018 ) . Of the 30 evaluable CsA + MTX patients , 16 ( 53 % ) were ACR20 responders , 15 ( 50 % ) ACR50 and 14 ( 47 % ) ACR70 ; the corresponding figures in the MTX arm were 19 ( 61 % ) , 13 ( 44 % ) and 6 ( 19 % ) . Toxicity was acceptable in both groups . CONCLUSIONS In patients with early RA , CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression , was effective on inflammatory articular symptoms , and was well tolerated BACKGROUND Recent r and omized controlled trials ( RCTs ) in rheumatoid arthritis ( RA ) have used patient- and physician-reported outcomes , ESR and /or CRP as components of ACR response criteria to assess efficacy . OBJECTIVES Mean changes from baseline in patient- and physician-reported outcome measures , ESR and CRP were compared in two RCTs in patients with active RA . Comparisons between active and placebo treatment used mean percentage improvements and st and ard effect sizes ( SESs ) . RESULTS In both protocol s , patient-reported assessment s of disease activity , pain and physical function reflected little or no improvement with placebo , best discriminating between active and placebo therapy , as did ESR and CRP . CONCLUSION Improvements in signs and symptoms of active RA in placebo RCTs appear to be best reflected by patient-reported measures of physical function , as long as reported changes in global assessment s of disease activity and /or pain reflect similar benefit . Patient-reported outcome measures should be considered objective ; treatment-associated changes are congruent with measures of inflammation , and appear less susceptible to the placebo response BACKGROUND Evidence for disease modifying activity of low dose corticosteroid treatment in rheumatoid arthritis is contradictory . Studies showing radiological benefit suggest that continued treatment is required to sustain the effect . OBJECTIVE To evaluate the effect of low dose oral prednisolone in early rheumatoid arthritis on disease activity over two years . DESIGN Double blind placebo controlled trial . METHODS Patients with rheumatoid arthritis , duration <3 years ( n = 167 ) , were started on a disease modifying antirheumatic drug ( DMARD ; sulphasalazine )  and allocated by stratified r and omisation to prednisolone 7 mg/day or placebo . Primary outcome measure was radiological damage , assessed by the modified Sharp method . Clinical benefit was a secondary outcome . A proactive approach to identifying and treating corticosteroid adverse events was adopted . Patients who discontinued sulphasalazine were offered an alternative DMARD . RESULTS 90 of 257 patients eligible for the study refused to participate ( more women than men ) . Of those enrolled , 84 % were seropositive for rheumatoid factor , median age 56 years , median disease duration 12 months , female to male ratio 1.8:1 .  Prednisolone was given to 84 patients ; of these 73 % continued prednisolone and 70 % sulphasalazine at 2 years . Of the 83 patients on placebo , 80 % continued placebo and 64 % sulphasalazine at 2 years . There were no significant differences in radiological score or clinical and laboratory measures at 0 and 2 years . CONCLUSIONS Low dose prednisolone conferred no radiological or clinical benefit on patients maintained on a DMARD over two years . Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs We investigated the frequency of remission according to the disease activity score ( DAS28 ) definition , modified American Rheumatology Association ( ARA ) criteria , and the frequency of an achievement of a functional status above defined thresholds ( ' functional remission ' , ' physical independence ' ) in rheumatoid arthritis ( RA ) patients treated with either biologics or conventional DMARDs .  We used the data of a prospect i ve cohort study , the German biologics register RABBIT ( German acronym for Rheumatoid Arthritis – Observation of Biologic Therapy ) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics ( BIOL ; n = 818 ) or a conventional DMARD ( n = 265 ) .  Logistic regression analysis was applied to adjust for differences in baseline risks . Taking risk indicators such as previous DMARD failures or baseline clinical status into account , we found that biologics doubled the chance of remission compared to conventional DMARD therapies ( DAS28 remission , adjusted odds ratio ( OR ) 1.95 ( 95 % confidenece interval ( CI ) 1.2–3.2 ) ) ; ARA remission , OR 2.05 ( 95 % CI 1.2–3.5 ) ) . High remission rates ( DAS28 remission , 30.6 % ; ARA remission , 16.9 % ) were observed in BIOL patients with a moderate disease activity ( DAS28 , 3.2 to 5.1 ) at the start of treatment . These rates decreased to 8.5 % in patients with DAS28 > 6 . Sustained remission at 6 and 12 months was achieved in < 10 % of the patients . Severely disabled patients ( ≤50 % of full function ) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence ( ≥67 % of full function ) than controls ( OR 3.88 ( 95 % CI 1.7–8.8 ) ) . ' Functional remission ' ( ≥83 % of full function ) was more often achieved in BIOL than in controls ( OR 2.18 ( 95 % CI 1.04–4.6 ) ) . In conclusion , our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence . However , temporary or even sustained remission remain ambitious aims , which are achieved in a minority of patients only OBJECTIVES In early and active RA despite MTX , continuous treatment with TNF blockers in combination with MTX is recommended . To compare this strategy with an initial combination of MTX and adalimumab ( ADA ) given for 3 months and then adjusted based on the disease activity status . METHODS Prospect i ve unblinded r and omized multicentre controlled 1-year trial in which 65 patients with early ( < 6 months ) and active [ disease activity score ( DAS28(ESR ) ) > 5.1 ] RA were assigned to Group 1 ( 32 patients ):  MTX ( 0.3 mg/kg/week , maximum of 20 mg/week , without escalating dose regimen ) or to Group 2 ( 33 patients ): initial combination therapy with MTX ( as in Group 1 ) and ADA ( 40 mg eow ) . In both groups , treatment was adjusted every 3 months . The aim was to achieve a low DAS ( DAS28(ESR ) < 3.2 ) . RESULTS From Week 12 until Week 52 , seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy ( P = 0.28 ) . The 1-year area under the curve ( AUC ) of DAS28 was lower in Group 2 owing to an initial better response . The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups . CONCLUSIONS Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX OBJECTIVE Anti-tumor necrosis factor alpha agents are among the most effective therapies for rheumatoid arthritis ( RA ) . However , their optimal use is yet to be determined . This 12-month double-blind study attempted remission induction using st and ard therapy with or without infliximab in patients with early , poor-prognosis RA . The primary end point was synovitis ( measured by magnetic resonance imaging [ MRI ] ) . Clinical observations continued to 24 months . METHODS All patients had fewer than 12 months of symptoms . Assessment s included full metrologic evaluation , laboratory tests , radiographs , functional evaluation using the Health Assessment Question naire ( HAQ ) , and quality of life measurement using the RA Quality of Life ( RAQoL ) question naire . MRI was performed at 0 , 4 , 14 , and 54 weeks ; MR images were scored blindly . Patients received methotrexate ( MTX ) and were r and omized to receive either infliximab or placebo for 12 months . RESULTS Twenty patients were recruited ( mean age 52 years , mean symptom duration 6 months , mean C-reactive protein level 42 mg/liter , and 65 % rheumatoid factor positive ) . At 1 year , all MRI scores were significantly better , with no new erosions in the infliximab plus MTX group ; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology ( ACR ) 50 % and 70 % improvement criteria ( 78 % versus 40 % in the placebo plus MTX group and 67 % versus 30 % , respectively ) and had a greater functional benefit ( P < 0.05 for all comparisons ) . Importantly , at 1 year after stopping induction therapy , response was sustained in 70 % of the patients in the infliximab plus MTX group , with a median Disease Activity Score in 28 joints ( DAS28 ) of 2.05 ( remission range ) . At 2 years , there were no significant between-group differences in the DAS28 , ACR response , or radiographic scores , but differences in the HAQ and RAQoL scores were maintained ( P < 0.05 ) . CONCLUSION Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year . At 2 years , functional and quality of life benefits were sustained , despite withdrawal of infliximab therapy . These data may have significant implication s for the optimal use of expensive biologic therapies BACKGROUND Tumour necrosis factor alpha ( TNFalpha ) inhibitors are frequently used to treat rheumatoid arthritis , but whether use of a different TNFalpha inhibitor can improve patient response is unknown . We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors . METHODS 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were r and omly allocated by interactive voice response system , stratified by study site and methotrexate use , to receive subcutaneous injections of placebo ( n=155 ) , 50 mg golimumab ( n=153 ) , or 100 mg golimumab ( n=153 ) every 4 weeks between Feb 21 , 2006 , and Sept 26 , 2007 . Allocation was double-blind . Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously . Patients continued stable doses of methotrexate , sulfasalazine , hydroxychloroquine , oral corticosteroids , and non-steroidal anti-inflammatory drugs . The primary endpoint was achievement at week 14 of 20 % or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis ( ACR20 ) . At week 16 , patients who had less than 20 % improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab , or from 50 mg to 100 mg golimumab .  Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given . This study is registered with Clinical Trials.gov , number NCT00299546 . FINDINGS Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness ( 269 [ 58 % ] patients ) or reasons unrelated to effectiveness ( 246 [ 53 % ] patients ) , such as intolerance and accessibility issues . Patients had active disease , which was indicated by a median of 14.0 ( IQR 9.0 - 22.0 ) swollen and 26.0 ( 16.0 - 41.0 ) tender joints for the whole group . 28 ( 18 % ) patients on placebo , 54 ( 35 % ) patients on 50 mg golimumab ( odds ratio 2.5 [ 95 % CI 1.5 - 4.2 ] , p=0.0006 ) , and 58 ( 38 % ) patients on 100 mg golimumab ( 2.8 [ 1.6 - 4.7 ] , p=0.0001 ) achieved ACR20 at week 14 . Two patients were never treated , and 57 patients did not complete the study because of adverse events , unsatisfactory treatment effect , loss to follow-up , death , or other reasons .  155 patients on placebo , 153 on 50 mg golimumab , and 153 on 100 mg golimumab  were assessed for drug efficacy . For weeks 1 - 16 , serious adverse events were recorded in 11 ( 7 % ) patients on placebo , 8 ( 5 % ) on 50 mg golimumab , and 4 ( 3 % ) on 100 mg golimumab . For weeks 1 - 24 , after some patients were given rescue therapy , serious adverse events were recorded in 15 ( 10 % ) patients on placebo , 14 ( 5 % ) on 50 mg golimumab , and 8 ( 4 % ) on 100 mg golimumab . INTERPRETATION Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors . FUNDING Centocor Research and Development and Schering-Plough Research Institute OBJECTIVE To define clinical ly meaningful changes in 2 widely used health-related quality of life ( HQL ) instruments in studies of patients with rheumatoid arthritis ( RA ) . METHODS Patients with RA ( n = 693 ) who were enrolled in 2 double-blind , placebo-controlled clinical trials completed the Short Form 36 ( SF-36 ) modified health survey and the Health Assessment Question naire ( HAQ ) disability index at baseline and 6-week followup assessment s. Data on 5 RA severity measures were also collected at baseline and at 6 weeks ( patient and physician global assessment s , joint swelling and tenderness counts , and global pain assessment ) . Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure . RESULTS With few exceptions , changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure . Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessment s and patient pain assessment than to changes in the joint swelling and tenderness counts . CONCLUSION Based on these results , minimally important changes in the SF-36 scales and HAQ disability scores were determined , which will be useful in interpreting HQL results in clinical trials OBJECTIVE To compare the relative safety and efficacy of azathioprine ( AZA ) , methotrexate ( MTX ) , and the combination of both in the treatment of active rheumatoid arthritis ( RA ) . METHODS Two hundred twelve patients with active RA were entered into a 24-week prospect i ve , controlled , double-blind , multicenter trial and were r and omly assigned to 1 of 3 treatment groups . RESULTS One hundred fifty-eight patients finished 24 weeks of the study . There were no remissions seen but response rates were greater than 30 % for all outcome measures . Combination therapy was not statistically superior to MTX therapy alone , but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures . If only patients who continued taking the therapy were analyzed , the mean improvement was greater for AZA therapy than for MTX , while the combination remained the most active . Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations . CONCLUSION Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment OBJECTIVE To assess the impact of escalating conventional therapy in patients with RA who satisfy BSR/NICE criteria for biologics . METHODS A total of 308 consecutive patients referred to a tertiary centre for biological therapy between January 1999 and February 2001 were studied prospect ively . They were considered by their own consultant to have failed st and ard therapy . Prior to biologics , conventional therapy was escalated to include combination and parenteral methotrexate treatment . Patients were assessed at 12-weekly intervals for 1 yr and therapy was changed if response was not satisfactory . The subsequently released BSR/NICE biologic eligibility criteria were applied retrospectively . Response ( disease activity , disability and quality of life ) to escalated therapy in those patients who did or did not satisfy current eligibility criteria were compared . RESULTS In total , 159 satisfied BSR/NICE criteria and would have been eligible for immediate treatment with biologics [ DAS28 > 5.1 , failed methotrexate ( 20 mg/week or lower dose owing to toxicity ) and one other DMARD ] ; however , 93 of these responded to escalated conventional therapy and did not require biologics [ significant improvement ( P < 0.01 ) in disease activity , disability and quality of life ] . However , mild disease activity ( DAS28 < 3.2 ) was only achieved in 7 % of these patients at 12 months . CONCLUSIONS Although over half the patients who satisfied st and ard criteria for biologics responded satisfactorily to escalated therapy , only a minority achieved mild disease activity . The savings achieved by treating with conventional therapies need to be weighed against the risk of persistent disease activity OBJECTIVES To examine the effectiveness and cost-effectiveness of symptomatic versus aggressive treatment in patients with established , stable rheumatoid arthritis ( RA ) . DESIGN A r and omised observer-blinded controlled trial and economic evaluation with an initial assessment at r and omisation and follow-ups at 12 , 24 and 36 months . SETTING Five rheumatology centres in Engl and . The ' symptomatic care ' patients were managed predominantly in primary care with regular visits by a rheumatology specialist nurse . The ' aggressive care ' patients were managed predominantly in the hospital setting . PARTICIPANTS Patients with RA for more than 5 years were screened in rheumatology clinics . INTERVENTIONS The symptomatic care patients were seen at home every 4 months by a rheumatology specialist nurse and annually by the rheumatologist . The aim of treatment was symptom control . The aggressive care patients were seen at least every 4 months in hospital . Their treatment was altered ( following predefined algorithms ) with the aim of suppressing both clinical and laboratory evidence of joint inflammation . MAIN OUTCOME MEASURES The main outcome measure was the Health Assessment Question naire ( HAQ ) . Others included the patient and physician global assessment , pain , tender and swollen joint counts , the erythrocyte sedimentation rate and the OSRA ( Overall Status in Rheumatoid Arthritis ) score . X-rays of the h and s and feet were performed at the beginning and end of the study . The EQ-5D was used in the health economic evaluation . Comprehensive costs were also estimated and were combined with measures of outcome to examine between-group differences . RESULTS A total of 466 patients were recruited ; 399 patients completed the 3 years of follow-up . There was a significant deterioration in physical function ( HAQ ) in both arms . There was no significant difference between the groups for any of the clinical outcome measures except the physician global assessment [ adjusted mean difference 3.76 ( 95 % CI 0.03 to 7.52 ) ] and the OSRA disease activity component [ adjusted mean difference 0.41 ( 95 % CI 0.01 to 0.71 ) ] , both in favour of the aggressive arm . During the trial , second-line drug treatment was changed in 77.1 % of the aggressive arm and 59.0 % of the symptomatic arm . There were instances when the rheumatologist should have changed treatment but did not do so , usually because of mild disease activity . The symptomatic arm was associated with higher costs and higher quality -adjusted life-years ( QALYs ) . There was a net cost of 1517 Pounds Sterling per QALY gained for the symptomatic arm . Overall , the primary economic analysis and sensitivity analyses of the cost and QALY data indicate that symptomatic treatment is likely to be more cost-effective than aggressive treatment in 58 - 90 % of cases . CONCLUSIONS This trial showed no benefit of aggressive treatment in patients with stable established RA . However , it was difficult to persuade the rheumatologist and /or the patient to change treatment if the evidence of disease activity was minimal . Patients in the symptomatic arm were able to initiate changes of therapy when their symptoms deteriorated , without frequent hospital assessment . Approximately one-third of current clinic attenders with stable RA could be managed in a shared care setting with annual review by a rheumatologist and regular contact with a rheumatologist nurse . Further research is needed into disease progression and the use of biological agents , minimum disease activity level below which disease progression does not occur , cost-effectiveness through shared care modelling , the development of a robust and fail-safe system of primary -care based disease-modifying anti-rheumatic drug ( DMARD ) monitoring , and predicting response to DMARDs OBJECTIVE To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol ( a novel PEGylated anti-tumor necrosis factor agent ) as adjunctive therapy to methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) with an inadequate response to MTX therapy alone . METHODS In this 52-week , phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial , 982 patients were r and omized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0 , 2 , and 4 , with a subsequent dosage of 200 mg or 400 mg given every 2 weeks , plus MTX , or placebo plus MTX . Co- primary end points were the response rate at week 24 according to the American College of Rheumatology 20 % criteria for improvement ( ACR20 ) and the mean change from baseline in the modified total Sharp score at week 52 . RESULTS At week 24 , ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8 % and 60.8 % , respectively , as compared with 13.6 % for the placebo group . Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 ( P < 0.001 ) . At week 52 , mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg ( 0.4 Sharp units ) or 400 mg ( 0.2 Sharp units ) as compared with that in placebo-treated patients ( 2.8 Sharp units ) ( P < 0.001 by rank analysis ) . Improvements in all ACR core set of disease activity measures , including physical function , were observed by week 1 with both certolizumab pegol dosage regimens . Most adverse events were mild or moderate . CONCLUSION Treatment with certolizumab pegol 200 or 400 mg plus MTX result ed in a rapid and sustained reduction in RA signs and symptoms , inhibited the progression of structural joint damage , and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX OBJECTIVE This study assessed the efficacy and safety of combination ( COMB ) of cyclosporine ( CSA ) and leflunomide ( LEF ) versus each drug alone , in the treatment of severe rheumatoid arthritis ( RA ) . METHODS One hundred six patients with active RA refractory to at least one disease modifying antirheumatic drug ( methotrexate obligatorily ) were entered into a 12-month open , prospect i ve trial and were r and omly allocated to receive either CSA 2.5 to 5 mg/kg/day , or LEF 20 mg/day , or the combination of both at the same initiating dose . RESULTS The American College of Rheumatology 50 % ( ACR50 ) response rates for the 3 groups were COMB 80 % , CSA 40 % , and LEF 42 % ( p = 0.001 ) . Combination therapy was also significantly better than CSA and  LEF at the more stringent 70 % response rate ( 69 % vs 34 % vs 30 % , respectively ; p = 0.001 ) . Comparable Disease Activity Score 28 reduction rates were noted at trial termination for all 3 treatment arms : COMB -2.74 vs CSA -2.53 vs LEF -2.28 ( p nonsignificant ) . Discontinuation rates were more common in LEF vs CSA arm ( p = 0.046 ) . No unexpected or serious adverse drug effects were identified in the combination group during the 12-month period . CONCLUSION The combination of CSA and LEF in patients with refractory RA provided statistically significant benefit in ACR50 and ACR70 . Adverse events were not substantially increased OBJECTIVE R and omized clinical trials ( RCTs ) evaluate the efficacy of treatments in selected groups of patients defined by strict inclusion criteria . The value of these trials in predicting therapeutic effectiveness in " real world " patients is limited . This observational cohort study was design ed to complement the knowledge obtained in RCTs by evaluating the effectiveness of tumor necrosis factor ( TNF ) inhibitors in patients with rheumatoid arthritis ( RA ) according to their eligibility for the major trials . METHODS Using the data from the German biologics register Rheumatoid Arthritis Observation of Biologic Therapy ( RABBIT [ in German ] ) , we investigated how many of the RA patients who were treated with a TNF inhibitor ( infliximab , etanercept , or adalimumab )  would have been eligible for the major clinical trials that led to approval of the drugs . In addition , therapeutic effectiveness was compared in the eligible and ineligible patients using the American College of Rheumatology 20 % ( ACR20 ) and 50 % ( ACR50 ) improvement response criteria . RESULTS Only 21 - 33 % of the patients in the RABBIT register would have been eligible for the major trials . In these patients , the ACR20 and ACR50 improvement responses , indicating therapeutic effectiveness , were comparable with the response rates in the published trials . ACR response rates were lower in those patients considered ineligible for the trials ; however , absolute improvement was similar to that in eligible patients . Ineligible patients had lower baseline disease activity , more comorbidity , and lower functional status . CONCLUSION RCT cohorts reflect only a minor proportion of the patients treated with biologic agents in routine care . In the clinic setting , the indications for treatment with biologic agents are not identical to the inclusion criteria for trials . Despite the smaller relative improvement achieved in these patients with longst and ing , severe RA who would not fulfill the inclusion criteria of a major trial , the majority of such patients would nevertheless benefit from biologic therapy OBJECTIVE To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) in a double-blind , prospect i ve , multicenter , controlled trial . METHODS Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5 mg MTX/week plus 50 mg AZA/day-7.5 mg MTX/week plus 100 mg AZA/day ) , with opportunity to increase the dosage at 6-week intervals . The patients were evaluated for significant clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . RESULTS One hundred ten patients remained on the initial , r and omly assigned therapeutic regimen . The percentage of patients who were responders , defined as those who had 30 % or greater improvement in at least 3 of 4 variables , was 38 % for the combination treatment , 26 % for AZA , and 45 % for MTX ( P = 0.06 ) . A trend toward decreased radiologic progression was seen in the MTX-treated patients . Termination of treatment due to adverse experience occurred more frequently with combination and AZA treatments than with MTX treatment . Lack of effectiveness , adverse gastrointestinal effects , and liver enzyme elevation were the most frequent causes of treatment discontinuation . CONCLUSION This study establishes that the combination of MTX and AZA in the dosages utilized is not associated with more toxicity than treatment with single agents ; however , enhanced efficacy is also not seen . There is a trend toward decreased radiologic progression in patients treated with MTX OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone Tumour necrosis factor alpha ( TNF alpha ) is a critical inflammatory mediator in rheumatoid arthritis , and may therefore be a useful target for specific immunotherapy . In support of this hypothesis , we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a  chimeric monoclonal antibody to TNF alpha ( cA2 ) . We now report the results of a four-centre , r and omised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis . The primary endpoint of the study was the achievement at week 4 of a Paulus 20 % response , an amalgam of six clinical , observational , and laboratory variables . Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time , compared with 11 of 25 patients treated with low-dose cA2 ( p = 0.0083 ) and 19 of 24 patients treated with high-dose cA2 ( p < 0.0001 ) . Over half of the high-dose cA2 patients responded by the more stringent 50 % Paulus criteria at this time ( p = 0.0005 ) . The magnitude of these responses was impressive , with maximum mean improvements in individual disease-activity assessment s , such as tender or swollen-joint counts and in serum C-reactive protein , exceeding 60 % for patients on high-dose treatment . There were two severe adverse events . 1 patient on 1 mg/kg cA2 developed pneumonia ( " possibly " treatment-related ) and 1 on 10 mg/kg had a fracture ( " probably not " treatment-related ) . The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis OBJECTIVE To 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 assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis ( RA ) receiving st and ardized disease-modifying antirheumatic drug ( DMARD ) therapy .  METHODS Patients with active RA of < 2 years ' duration were r and omly assigned in a double-blinded manner to receive prednisolone or placebo while starting concomitant DMARD therapy ( gold sodium thiomalate or methotrexate ) . H and and foot radiographs were taken at baseline and at 6 , 12 , and 24 months and were evaluated according to the Ratingen score and the total modified Sharp/van der Heijde score ( SHS ) . RESULTS Of 192 included patients , 166 were available for the intent-to-treat analysis ( ITT ) . Seventy-six patients completed the study per protocol ( PP ) . Radiographic progression ( increase in the Ratingen score ) was significantly less with prednisolone than with placebo . The difference in the progression rate between the groups was greatest in the first 6 months . At 24 months in the ITT population , the least squares ( LS ) mean difference was 3.14 ( 95 % confidence interval [ 95 % CI ] 0.94 , 5.34 ) , P = 0.006 . The results were confirmed by the total SHS in the ITT population ( LS mean difference 7.20 [ 95 % CI 0.93 , 13.47 ] , P = 0.022 ) and with the PP population . Clinical and functional outcomes tended to be better and the rate of remissions was higher in the prednisolone group . Side effects were observed more frequently in the prednisolone group than in the control group : weight gain ( 4 versus 0 patients ) , hypertension ( 6 versus 2 patients ) , glaucoma ( 3 versus 0 patients ) , Cushing 's syndrome ( 5 versus 0 patients ) , gastric distress ( 9 versus 4 patients ) , and gastric ulcers ( only with concomitant nonsteroidal antiinflammatory drug therapy ; 3 versus 0 patients ) . No new lumbar fractures were found in either group . CONCLUSION The very low daily dose of 5 mg prednisolone given over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied .  ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268  methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research We studied 43 patients with active rheumatoid disease of less than 4 years ' duration : 23 were given hydroxychloroquine and 20 penicillamine .  Efficacy was assessed using clinical and laboratory variables . Radiological progression was measured using Larsen 's method for scoring plain radiographs of the h and s and feet . Twenty-four patients received 2 years ' continuous therapy . Clinical ly both drugs were effective with falls in articular index and C-reactive protein . Initial radiological damage was less with penicillamine ( P less than 0.05 by Wilcoxon rank sum test ) . By 2 years there were no significant differences between the two drugs ; mean increases in Larsen score were 20.3 with penicillamine and 27.5 with hydroxychloroquine . Both groups progressed at a rate likely to give severe joint destruction over 10 - 20 years Objective . To compare the costs and benefits of alternative combination strategies of disease-modifying antirheumatic drugs ( DMARD ) and DMARD monotherapy in patients with early , active rheumatoid arthritis ( RA ) . Methods . Data were drawn from r and omized controlled trials that compared  DMARD monotherapy or any DMARD combination strategy , with or without combined steroid therapy . Mixed treatment comparison methods were used to estimate the relative effectiveness of the different strategies . A mathematical model was developed to compare the longterm costs and benefits of the alternative strategies , combining data from a variety of sources . Costs were considered from a health sector viewpoint and benefits were expressed in terms of quality -adjusted life-years ( QALY ) . Results . If decision makers use a threshold of £ 20,000 ( US$ 29,000 ) per QALY , then the strategies most likely to be cost-effective are either DMARD combination therapy with downward titration ( probability of being optimal = 0.50 ) or intensive , triple DMARD combination therapy ( probability of being optimal = 0.43 ) . The intensive DMARD strategy generated an additional cost of £ 27,392 per additional QALY gained compared to the downward titration strategy . Other combination strategies were unlikely to be considered cost-effective compared to DMARD monotherapy . Results were robust to a range of scenario sensitivity analyses . Conclusion . Combination DMARD therapy is likely to be cost-effective compared to DMARD monotherapy where treatment entails rapid downward dose titration or intensive , triple DMARD therapy 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 Recently , new treatment options for rheumatoid arthritis ( RA ) patients with an inadequate response to methotrexate ( MTX )  have become available . Given the wide variability in efficacy and costs among these different treatment options , we sought to determine their cost-effectiveness ( CE ) in order to guide policy in different cost-constrained setting s. METHODS We performed a CE analysis comparing 6 treatment options for patients with MTX-resistant RA : 1 )  etanercept + MTX , 2 ) etanercept monotherapy , 3 ) cyclosporine + MTX , 4 ) triple therapy ( hydroxychloroquine , sulfasalazine , and MTX ) , 5 ) continuation of MTX monotherapy , and 6 ) no second-line agent . A decision model was used with a time horizon of 6 months . We used 2 measures of effectiveness based on published clinical trial data : the American College of Rheumatology 20 % response criteria ( ACR 20 ) ; and a weighted average of proportions of patients achieving responses of ACR 70 , ACR 50 , and ACR 20 ( ACR 70 weighted response [ ACR 70WR ] ) . Incremental CE ratios were calculated as the additional cost per patient achieving either outcome , compared with the next least expensive option . To help interpret CE relative to these RA-specific outcomes , we conducted a separate , " reference " CE analysis of MTX use in  MTX-naive RA patients , using the same outcomes . RESULTS In our reference analysis , MTX therapy for MTX-naive RA cost $ 1,100 per ACR 20 outcome and $ 1,500 per ACR 70WR , compared with no second-line agent . In our base-case analysis with either outcome , MTX continuation , cyclosporine + MTX , and etanercept monotherapy cost more , but either were not more efficacious or had a higher incremental CE ratio than the next most expensive option ( i.e. , they were dominated ) . Therefore , these options were not cost-effective . The least expensive option , triple therapy , cost 1.3 times more per patient with ACR 20 outcome ( $ 1,500/ACR 20 ) and 2.1 times more per ACR 70WR ( $ 3,100/ACR 70WR ) than MTX therapy for MTX-naive RA . The most efficacious option , the combination of etanercept and MTX , cost 38 times more per patient with ACR 20 outcome ( $ 4,600/ACR 20 ) and 23 times more per ACR 70WR ( $ 34,800/ACR 70WR ) than MTX therapy for MTX-naive RA . Overall , the results of extensive sensitivity analyses did not substantially affect these results . CONCLUSION Our analysis indicates that if 15 mg/week MTX is cost-effective for achieving ACR 20 or ACR 70WR in MTX-naive RA over a 6-month period , then most likely so is triple therapy in MTX-resistant RA . Whether etanercept + MTX is cost-effective depends on whether $ 34,800/ACR 70WR ( or $ 42,600/ACR 20 ) over a 6-month period is considered acceptable OBJECTIVE To compare the effects of methotrexate ( MTX ) , alone or in combination with intravenous ( IV ) methylprednisolone ( MP ) or infliximab , on magnetic resonance imaging (MRI)-detected synovitis , bone edema , and erosive changes in patients with early rheumatoid arthritis ( RA ) . METHODS Forty-four patients with early RA were r and omized to receive MTX alone ( MTX group ) , MTX plus IV MP ( IV MP group ) , or MTX plus infliximab ( infliximab group ) , infused on day 0 and weeks 2 , 6 , 14 , 22 , 30 , 38 , and 46 . Gadolinium-enhanced MRI scans of the metacarpophalangeal joints , wrists , and metatarsophalangeal joints were performed at baseline , week 18 , and week 52 . RESULTS Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups , with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups . Scores for MRI-detected erosion significantly increased over time in all groups . There were no differences in erosion scores between the MTX group and the other groups . It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab . At week 22 , response rates according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the ACR50 , and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group . At week 52 , remission was achieved in 40 % of patients in the MTX group and in 70 % of patients in the IV MP and infliximab groups . Health Assessment Question naire scores improved significantly over time in all groups , with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone . No severe side effects were observed , except 1 case of MTX-related pneumonitis . CONCLUSION The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA . Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab BACKGROUND In the hierarchy of research design s , the results of r and omized , controlled trials are considered to be evidence of the highest grade , whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects . We used published meta-analyses to identify  r and omized clinical trials and observational studies that examined the same clinical topics . We then compared the results of the original reports according to the type of research design . METHODS A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of r and omized , controlled trials and meta-analyses  of either cohort or case-control studies that assessed the same intervention . For each of five topics , summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual r and omized , controlled trials and the individual observational studies . RESULTS For the five clinical topics and 99 reports evaluated , the average results of the observational studies were remarkably similar to those of the r and omized , controlled trials . For example , analysis of 13 r and omized , controlled trials of the effectiveness of bacille  Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 ( 95 percent confidence interval , 0.34 to 0.70 ) among vaccinated patients , as compared with an odds ratio of 0.50 ( 95 percent confidence interval , 0.39 to 0.65 ) from 10 case-control studies . In addition , the range of the point estimates for the effect of vaccination was wider for the r and omized , controlled trials ( 0.20 to 1.56 ) than for the observational studies ( 0.17 to 0.84 ) . CONCLUSIONS The results of well- design ed observational studies ( with either a cohort or a case-control design ) do not systematic ally overestimate the magnitude of the effects of treatment as compared with those in r and omized , controlled trials on the same topic A prospect i ve study over one year of patients who had active rheumatoid arthritis discovered 64 who had received treatment for an adequate time with second-line drugs .  In these patients there was evidence of continuing joint destruction as shown by radiological progression . During the year there were highly significant correlations between improvements in clinical and laboratory measurements , but neither group of tests was related to the degree of radiological change . However , in the second 6 months of treatment there was evidence that radiological progression was reduced . In a second prospect i ve study of 88 patients with rheumatoid arthritis given prolonged , intensive therapy with second-line drugs and followed up for 10 years two-thirds showed radiological progression . However , the number of joints damaged per year fell significantly during the study period . There was a divergence between deterioration in radiological features and improvements in the ESR and functional capacity , though patients with a persistently low ESR had less radiological progression . These studies provide evidence that treatment may be associated with a reduced rate of radiological progression but suggest that changes in radiological progression and clinical and laboratory measurements may result from different mechanisms OBJECTIVE To determine if there is any advantage in adding hydroxychloroquine to intramuscular gold therapy in patients with rheumatoid arthritis ( RA ) with a suboptimal response to gold after 6 months of treatment . METHODS Prospect i ve double blind placebo controlled study at the Centre for Rheumatic Diseases , Glasgow Royal Infirmary and Gartnavel General Hospital , Glasgow . Patients --440 patients with RA began intramuscular gold therapy . One hundred forty-two patients with a suboptimal response at 6 months were r and omized to receive additional treatment with hydroxychloroquine ( 400 mg/day ) or placebo , and followed for a further 6 months . Outcome measures were erythrocyte sedimentation rate , C-reactive protein , Ritchie articular index , grip strength , visual analog pain score , duration of morning stiffness , health assessment question naire , and rate of side effects . RESULTS There was no difference in outcome in terms of efficacy or toxicity . CONCLUSION There is no justification for using a combination of intramuscular gold and hydroxychloroquine in patients with RA with a partial response to gold OBJECTIVE To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis ( RA ) receiving infliximab + methotrexate ( MTX ) versus placebo + MTX over 18 weeks , and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the h and s and feet at 54 weeks . METHODS Patients with early RA ( duration <3 years ) receiving stable dosages of MTX  were r and omly assigned to receive blinded infusions of 5 mg/kg infliximab ( n = 12 ) or placebo ( n = 12 ) at weeks 0 , 2 , 6 , and then every 8 weeks until week 46 . At baseline and week 18 , clinical assessment s were performed , and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements . Radiographs of the h and s and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method ( vdH-Sharp score ) . RESULTS Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks , we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX . Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54 . Infliximab + MTX treatment abolished these relationships . CONCLUSION The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks In many clinical trials for chronic conditions a run-in period is used prior to r and omization . Often , only those participants who meet certain criteria during the run-in phase go on to get r and omized . The others , along with the information that they might have provided , are excluded from the study . This exclusion of the relevant response data from any subsequent study analysis can be considered as result ing in missing data ; although quite common in practice , this approach has expectedly been shown to create a bias in favor of the active treatment when this active treatment is used during the run-in . Hence , many r and omized clinical trials report overly optimistic results , with the extent of the bias depending in large part on how many otherwise eligible subjects were excluded due to the use of the run-in . If these biased trials are to contribute valid information to medical decision making , then the biases need to be corrected , and this involves accounting for all participants who were intended to be r and omized . We propose specific imputation methods for doing so BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly . We aim ed to compare addition of conventional disease-modifying antirheumatic drugs ( sulfasalazine and hydroxychloroquine ) with addition of a tumour necrosis factor antagonist ( infliximab ) to methotrexate in patients with early rheumatoid arthritis . METHODS We undertook a r and omised trial in 15 rheumatology units in Sweden . We enrolled patients with early rheumatoid arthritis ( symptom duration < 1 year ) and administered methotrexate ( up to 20 mg per week ) . After 3 - 4 months , those who had not achieved low disease activity but who could tolerate methotrexate were r and omly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab . Primary outcome was achievement of a good response according to European League Against Rheumatism ( EULAR ) criteria at 12 months . Patients were followed up to 24 months ; here , we present findings at 12 months . Analysis was by intention to treat and we used non-responder imputation . The Swefot ( Swedish Pharmacotherapy ) study is registered in the WHO data base at the Karolinska University Hospital , number CT20080004 . FINDINGS 487 patients were initially enrolled . Of 258 who had not achieved low disease activity with methotrexate  , 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab . 32 of 130 ( 25 % ) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 ( 39 % ) assigned infliximab ( risk ratio 1.59 [ 95 % CI 1.10 - 2.30 ] , p=0.0160 ) . Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used . No deaths occurred in either group . INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed , addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinical ly superior to addition of conventional disease-modifying antirheumatic drugs . FUNDING Swedish Rheumatism Association , Schering-Plough Twenty patients with intractable rheumatoid arthritis were r and omized to receive 750 or 2,000 rads of lymphoid irradiation ( LI ) in a double-blind comparative study , and were followed for a maximum of 48 months ( mean 40 months ) after treatment . During followup , sustained immunomodulation ( including lymphopenia , particularly of the T helper cell subset ; reduced ratio of helper cells to suppressor cells ; and impaired in vitro lymphocyte proliferation in response to phytohemagglutinin and pokeweed mitogen ) was observed . Significant improvements in early morning stiffness , Ritchie articular index , pain score , grip strength , and 15-meter walk time were observed in both treatment groups , but these were not sustained through the followup period . Progressive joint damage was observed radiologically in both groups during followup . Thus , LI induced sustained immunosuppression , but result ed in only short-lived clinical improvement and was associated with progressive joint erosion in these patients OBJECTIVE To compare the efficacy of doxycycline plus methotrexate ( MTX ) versus MTX alone in the treatment of early seropositive rheumatoid arthritis ( RA ) , and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline . METHODS Sixty-six patients with seropositive RA of < 1 year 's duration who had not been previously treated with disease-modifying antirheumatic drugs were r and omized to receive 100 mg of doxycycline twice daily with MTX ( high-dose doxycycline group ) , 20 mg of doxycycline twice daily with MTX ( low-dose doxycycline group ) , or placebo with MTX ( placebo group ) , in a 2-year double-blind study . Treatment was started with an MTX dosage of 7.5 mg/week , which was titrated every 3 months until remission was reached ( maximum dosage of 17.5 mg/week ) . The primary end point was an American College of Rheumatology 50 % improvement ( ACR50 ) response at 2 years . RESULTS ACR50 responses were observed in 41.6 % of patients in the high-dose doxycycline group , 38.9 % of those in the low-dose doxycycline group , and 12.5 % of patients in the placebo group . Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different ( P = 0.02 ) . Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups ( P = 0.04 and P = 0.03 , respectively ) . MTX doses at 2 years were not different among groups . Four patients in the high-dose doxycycline group , 2 patients in the low-dose doxycycline group , and 2 patients in the placebo group were withdrawn because of toxic reactions . CONCLUSION In patients with early seropositive RA , initial therapy with MTX plus doxycycline was superior ( based on an ACR50 response ) to treatment with MTX alone . The therapeutic responses to low-dose and high-dose doxycycline were similar , suggesting that the antimetalloproteinase effects were more important than the antibacterial effects . Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated BACKGROUND Neutralization of tumor necrosis factor a ( TNF-alpha ) for three to six months reduces the symptoms and signs of rheumatoid arthritis . However , the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known . METHODS We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab , a chimeric monoclonal antibody against TNF-alpha  , in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks . We assessed clinical responses with use of the criteria of the American College of Rheumatology , the quality of life with a health-status question naire , and the effect on joint damage radiographically . RESULTS The combination of infliximab and methotrexate was well tolerated and result ed in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone ( clinical response , 51.8 percent vs. 17.0 percent ; P<0.001 ) . The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone . Radiographic evidence of joint damage increased in the group given methotrexate , but not in the groups given infliximab and methotrexate ( mean change in radiographic score , 7.0 vs. 0.6 , P<0.001 ) . Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response . CONCLUSIONS In patients with persistently active rheumatoid arthritis despite methotrexate therapy , repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage BACKGROUND Analysis of the Swedish Farmacotherapy ( Swefot ) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis . Here we report the 2 year follow-up assessment . METHODS In this r and omised , non-blinded , parallel-group trial , we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December , 2002 and December , 2006 . All patients were started on methotrexate .  After 3 - 4 months , those who failed treatment were r and omly assigned ( 1:1 ) to group A ( conventional treatment ; additional sulfasalazine and hydroxychloroquine ) or group B ( biological treatment ; additional infliximab ) . R and omisation was done with a computer-generated sequence . We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism , and radiographs of patients ' h and s and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score . Analysis was by intention to treat . This trial is registered with www . Clinical Trials.gov , number NCT00764725 . FINDINGS Of 493 screened individuals , we enrolled 487 , of whom 258 were r and omly allocated to treatment . The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months ( 49 of 128 [ 38 % ] vs 38 of 130 [ 29 % ] ) and at 24 months ( 49 of 128 [ 38 % ] vs 40 of 130 [ 31 % ] ; p=0·204 ) . After 24 months , radiological disease progression was greater in patients in group A than it was in those in group B ( mean 7·23 [ SD 12·72 ] vs 4·00 [ 10·0 ] ; p=0·009 ) . We recorded three serious adverse events : an extended generalised illness in group A , an extended febrile episode in group B , and a generalised illness in group B. INTERPRETATION Additional biological treatment is a valid option for patients who fail initial methotrexate treatment . However , improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs . Therefore , for many patients who fail initial methotrexate treatment , add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option . FUNDING Swedish Rheumatism Association , Stockholm County , and Schering-Plough/Merck Sharp and Dohme 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 BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone  ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine OBJECTIVE A primary therapeutic goal in rheumatoid arthritis ( RA ) is to reduce functional disability . The recent introduction of several new drugs for RA creates a need for readily assessing the effectiveness of therapy . Because the consistent use of disease-modifying anti-rheumatic drugs ( DMARDs ) reduces long-term disability , we analysed the large data base of 1817 RA patients from leflunomide trials to assess if changes in the Health Assessment Question naire ( HAQ ) can measure the effectiveness of RA therapy . METHODS Data from three r and omized double-blind RA trials were evaluated . The patients had received 100 mg leflunomide ( then 20 mg/day in 807 cases ) , methotrexate ( 15 - 20 mg/day in 669 cases ) , sulphasalazine ( 2 g/day in 132 cases ) and placebo ( in 209 cases ) . HAQ scores and outcomes were assessed using the American College of Rheumatology core data set . Detailed statistical analyses were made of changes in outcome variables at 1 and 6 months , changes in HAQ scores at 1 - 12 months , and effect sizes for outcome variables at 6 and 12 months . Multiple regression models of changes in HAQ scores were evaluated using backwards stepwise linear regression . RESULTS Mean HAQ scores declined progressively with treatment with all three DMARDs . Changes occurred rapidly , and at month 1 were most pronounced with leflunomide . HAQ scores correlated closely with clinical response , as seen in changes in non-responders and ACR 20 % and 50 % responders . Regression analysis indicated that pain intensity and global assessment s were significant determinants of HAQ . CONCLUSION HAQ scores are sensitive measures of effective DMARD therapy . HAQ may be especially useful early in the treatment process to assess patients ' responses to DMARDs that show rapid onset of action , such as leflunomide Context Several disease-modifying antirheumatic drugs ( DMARDs ) slow disease progression in patients with rheumatoid arthritis . Many experts prefer methotrexate , although trials do not uniformly show that it is superior to other DMARDs . It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone . Contribution This 24-week , r and omized , double-blind , placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone . Caution s Some adverse effects , such as diarrhea , were more common with combination therapy . All patients receiving DMARD therapy  need close monitoring for toxicities . The Editors Rheumatoid arthritis has considerable societal costs ( 1 - 5 ) . Many patients with rheumatoid arthritis become disabled within a few years of disease onset ( 4 , 5 ) . Methotrexate is the st and ard treatment for rheumatoid arthritis . During the past several years , investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy ( 6 - 9 ) . Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism ( 10 ) . The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate ( 11 ) , but methotrexate is thought to act primarily on purine pathways of cellular metabolism ( 10 ) . Leflunomide ( Arava , Aventis Pharmaceuticals , Bridgewater , New Jersey ) also has antimetabolic effects , inhibiting pyrimidine intracellular pathways ( 12 ) . Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind , placebo-controlled trials ( 13 , 14 ) . Given the diverse intracellular pathways affected by both drugs , the combination of leflunomide and methotrexate has the potential for biochemical synergy . The possibility of increased benefits should be weighed against the possible toxicities of this combination . Abnormal aminotransferase levels have been seen with both methotrexate ( 15 ) and leflunomide ( 14 ) monotherapy in patients with rheumatoid arthritis . In a small open study , we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels ( 16 ) . We therefore sought to determine whether similar results could be achieved in a large , double-blind investigation of the combination of these two antimetabolic agents . Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology ( ACR ) criteria ( 17 ) . Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate ( 15 to 20 mg/wk , or 10 to 15 mg/wk if this was the maximum tolerated dose ) . Patients were recruited from active outpatient practice centers , and study participants were approached without a particular schema . Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy , including stable dosage for at least 8 weeks . Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations , 7 to 21 days apart : at least nine tender joints , at least six swollen joints , at least 45 minutes of morning stiffness , and an erythrocyte sedimentation rate of at least 28 mm/h . Previous disease-modifying antirheumatic drugs , not including ongoing methotrexate , had failed in 11 patients . Patients receiving corticosteroids  were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration , and the corticosteroid dose was required to remain constant throughout the study . Complete exclusion criteria are listed in Appendix Table 1 . Study Design The 24-week , r and omized , double-blind , placebo-controlled study , with evaluations occurring at 4-week intervals ( Figure 1 ) , was conducted in 20 centers in the United States and Canada between September 1998 and June 2000 . The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis . All participants provided written consent , and the institutional review board at each center approved the protocol . Figure 1 . Patient eligibility , r and omization , assignment , and discontinuation . Include no wish to continue in study , poor adherence to treatment , protocol violation , and moving away from the study area . A r and omization schedule , generated by and stored with Quintiles , Inc. , Kansas City , Missouri , was used to assign sequential numbers to r and omly allocated treatment codes . R and omization was done by using the Aventis st and ard r and om-code generator . Investigators allocated numbers to patients , beginning with the lowest available number . Quintiles , Inc. , packaged and labeled the study medication . The r and omization code used was concealed from investigators and patients throughout the study . R and omization was stratified by center . A set of 500 r and om numbers was generated , with treatment groups r and omly assigned in a balanced manner ( 1:1 ratio ) within each block of four consecutive r and om numbers ( block size , 4 ) . A set of these blocks was then sent to each investigative center . This method is identical to stratification by center because centers are balanced with respect to treatment assignment . Patients were r and omly assigned to receive leflunomide , 100 mg/d , for 2 days followed by 10 mg/d or matching placebo . If substantial adverse events occurred , this dose could be reduced to 10 mg every other day . If 10 mg/d was tolerated but active disease , as defined earlier , was still present at week 8 or thereafter , an increase to 20 mg of leflunomide or matching placebo per day was required . If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day , a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator . At least 1 mg of folate supplementation per day was m and ated by the protocol . Adherence to study medication , assessed at each visit by tablet counts ( actual number of tablets returned compared with number expected to be returned ) , was similar in the two groups . The mean adherence for all patients in the intention-to-treat sample was 98.0 % ( 98.5 % for those receiving placebo and 97.4 % for those receiving leflunomide ) . In the placebo group and leflunomide group , respectively , 90.2 % ( 120 of 133 patients ) and 87.7 % ( 114 of 130 patients ) had adherence rates of 80 % to 120 % . Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20 % improvement in ACR criteria ( ACR20 ) at the end of the study . To be classified as having achieved ACR20 , patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study ( 13 ) . The ACR20 criteria were developed to define improvement in rheumatoid arthritis ( 18 ) . Clinical improvement is indicated by 20 % improvement in tender and swollen joint counts and 20 % improvement in three of the following five criteria : patient global assessment , physician global assessment , pain intensity , physical function or disability measure , and level of acute-phase reactant ( 19 ) . All ACR assessment s were performed by the investigators , and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment . Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis . Count of tender joints was based on 68 joint assessment s , and count of swollen joints was based on 66 joint assessment s. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit . Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable . Secondary outcomes included ACR50 and ACR70 responder rates at week 24 ( analyses of responders at study end for the non primary efficacy measures ) . The ACR50 and ACR70 were defined as at least 50 % and 70 % improvement , respectively , in the same criteria used to calculate ACR20 response . Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor . Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2 . Measurement of Safety Safety was evaluated by adverse event reports ; laboratory assays for changes in hematologic characteristics , blood chemistry , urinalysis , and liver function ; and physical examination . Potential adverse events were assessed by using open-ended questions at each study visit . The assessor was blinded to reported toxicities and to any additional information obtained at the visit . The study protocol provided recommendations for dosage change and discontinuation of drug therapy , without unblinding , when patients were found to have alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) values greater than two times the upper limit of normal . Investigators decreased the dose of the study medication if , on repeated analysis at 72 hours , test values remained greater than two times but less than or equal to five times the upper limit of normal ; only one dose adjustment was allowed before discontinuation of therapy with the study drug . Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated 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 OBJECTIVE To evaluate the efficacy and safety of adding intramuscular ( IM ) gold to the treatment regimen of patients with rheumatoid arthritis ( RA ) who have a suboptimal response to methotrexate ( MTX ) .  METHODS A r and omized , double-blind , double-observer , placebo-controlled multicenter trial of 48 weeks was conducted . Sixty-five RA patients who had a suboptimal response to > /=12 weeks of MTX therapy were r and omly assigned to receive weekly IM gold or placebo in addition to MTX . Gold was administered according to a st and ard protocol developed for the study . The primary outcome measure was the percentage of patients who met the  American College of Rheumatology ( ACR ) 20 % improvement criteria ( achieved an ACR20 response ) at week 48 . Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses , the individual criteria that make up the primary outcome , quality of life , direct and indirect health care costs , intraarticular steroid use , and adverse events , among other measures . Statistical analyses were based on an intent-to-treat strategy . RESULTS Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30 % of patients receiving placebo ( chi(2 ) = 6.04 , P = 0.014 ; logistic regression odds ratio 3.64 [ 95 % confidence interval 1.3 , 10.4 ] , P = 0.016 ) . Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4 % of patients receiving placebo ( P = 0.017 ) , and 21 % of patients receiving gold achieved an ACR70 response compared with 0 % of patients receiving placebo ( P = 0.011 ) . From both clinical and cost-effectiveness perspectives , gold was the preferred and dominant strategy . Study treatment was discontinued in 23 patients ( 14 in the placebo group compared with 9 in the gold group ; P = 0.022 ) due to loss to followup , adverse events , or lack of efficacy . CONCLUSION In RA patients with a suboptimal response to MTX , adding weekly IM gold causes significant clinical improvement . Adverse events were minor , and IM gold-related adverse events led to discontinuation in only 11 % of the gold group over 48 weeks In trial-based cost-effectiveness analysis baseline mean utility values are invariably imbalanced between treatment arms . A patient 's baseline utility is likely to be highly correlated with their quality -adjusted life-years ( QALYs ) over the follow-up period , not least because it typically contributes to the QALY calculation . Therefore , imbalance in baseline utility needs to be accounted for in the estimation of mean differential QALYs , and failure to control for this imbalance can result in a misleading incremental cost-effectiveness ratio . This paper discusses the approaches that have been used in the cost-effectiveness literature to estimate absolute and differential mean QALYs alongside r and omised trials , and illustrates the implication s of baseline mean utility imbalance for QALY calculation . Using data from a recently conducted trial-based cost-effectiveness study and a micro-simulation exercise , the relative performance of alternative estimators is compared , showing that widely used methods to calculate differential QALYs provide incorrect results in the presence of baseline mean utility imbalance regardless of whether these differences are formally statistically significant . It is demonstrated that multiple regression methods can be usefully applied to generate appropriate estimates of differential mean QALYs and an associated measure of sampling variability , while controlling for differences in baseline mean utility between treatment arms in the trial OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) .  METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate  frequently have only partial improvement . METHODS In a six-month r and omized , double-blind trial , we compared combination therapy with cyclosporine ( 2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals ) and methotrexate ( at the maximal tolerated dose ) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment . The primary outcome measure was the change in the number of tender joints . RESULTS The mean ( + /- SD ) dose of cyclosporine at the final treatment was 2.97 + /- 1.02 mg per kilogram per day . As compared with the placebo group , the patients in the treatment group had a net improvement in the tender-joint count of 25 percent , or 4.8 joints ( 95 percent confidence interval , 0.7 to 8.9 ; P = 0.02 ) , and in the swollen-joint count of 25 percent , or 3.8 joints ( 95 percent confidence interval , 1.3 to 6.3 ; P = 0.005 ) ; improvement in overall disease activity as assessed by the physician ( 19 percent , P < 0.001 ) and the patient ( 21 percent , P < 0.001 ) ; and improvement in joint pain ( 23 percent , P = 0.04 ) and in the degree of disability ( 26 percent , P < 0.001 ) . The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group ( P = 0.006 ) . Thirty-six patients ( 48 percent ) in the cyclosporine group and 12 patients ( 16 percent ) in the placebo group ( P < 0.001 ) met the 1993 criteria for improvement of the American College of Rheumatology ( more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables ) . Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study ; 2 patients in the cyclosporine group died , 1 from viral pneumonia and the other in a motor vehicle accident . Serum creatinine concentrations increased by a mean of 0.14 + /- 0.27 mg per deciliter ( 12 + /- 24 mmol per liter ) in the cyclosporine group and by 0.05 + /- 0.19 mg per deciliter ( 4 + /- 17 mmol per liter ) in the placebo group ( P = 0.02 ) . CONCLUSIONS In a six-month study , patients with severe rheumatoid arthritis and only partial responses to methotrexate  had clinical ly important improvement after combination therapy with cyclosporine and methotrexate .  Side effects were not substantially increased . Long-term follow-up of patients treated with this combination is needed BACKGROUND Our objective was to assess the efficacy and safety of cyclosporine-A ( CsA ) plus chloroquine ( Clq ) in early-onset rheumatoid arthritis ( RA ) compared to CsA plus placebo . METHODS We conducted a prospect i ve , 12-month follow-up , multicenter , double-blind , placebo-controlled study of CsA ( 2.5 - 5 mg/kg/day[d ] ) plus Clq ( 150 mg/d ) vs. CsA plus placebo in active RA of < 2 years of evolution . RESULTS A total of 149 patients were included ; 111 patients ( 74.4 % ) completed the 12-month follow-up period . Evaluation at 6 and 12 months showed improvement for all clinical disease parameters . In both groups there was a decrease in tender joint count , swollen joint count , pain , assessment of efficacy by both investigator and patient , functional assessment , and morning stiffness , all differences statistically significant . With an intention-to-treat analysis , there was 64 % in the CsA plus Clq group ( CsA/Clq ) and 63 % in the CsA plus placebo group ( CsA/Plac ) at 12 months in the American College of Rheumatology (ACR)-20 criteria of improvement . Response rate for ACR-50 was 48 and 47 % , and for ACR-70 it was 29 % in both groups ; the difference was not statistically significant between study groups . Gastrointestinal complaints were common in both groups . Four patients in CsA/Clq group and five patients in CsA/placebo group increased creatinine levels ; two patients in each group discontinued treatment due to this reason . CONCLUSIONS There was no advantage to adding chloroquine to cyclosporine in patients with RA To compare the efficacy of sulphasalazine , methotrexate , and the combination of both in patients with early rheumatoid arthritis ( RA ) , not treated with disease-modifying anti-rheumatic drugs previously , we conducted a double-blind , double-dummy , controlled , clinical trial . One hundred and five patients with active , early RA , rheumatoid factor and /or HLA DR1/4 positive were r and omized between sulphasalazine ( SSZ ) 2000 ( maximum 3000 ) mg daily , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly , or the combination ( COMBI ) of both , and were followed up by a single observer for 52 weeks . The mean change over time per patient , including all visits , in Disease Activity Score ( DAS ) was : SSZ : -1.6 ( 95 % CI -2.0 to -1.2 ) ; MTX : -1.7 ( -2.0 to -1.4 ) ; COMBI : -1.9 ( -2.2 to -1.6 ) ; the difference week 0-week 52 ( SSZ , MTX , COMBI respectively ) ; DAS : -1.8 , -2.0 , -2.3 , Ritchie articular index : -9.2 , -9.5 , -10.6 , swollen joints : -9.2 , -12.4 , -14.3 , erythrocyte sedimentation rate : -17 , -21 , -28 . Nausea occurred significantly more in the COMBI group . The numbers of drop-outs due to toxicity were SSZ 9 , MTX 2 , COMBI 5 . In conclusion , there were no significant differences in efficacy between combination and single therapy , only a modest trend favouring COMBI . The results of MTX and SSZ were very comparable . Nausea occurred more often in the COMBI group : the number of withdrawals due to adverse events did not differ significantly OBJECTIVE To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis ( RA ) . METHODS Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate ( MTX ) at a dosage of 15 - 25 mg/week for > or = 4 weeks were r and omized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg , with or without MTX , every 12 weeks through week 48 . Patients with < 20 % improvement in the swollen and tender joint counts  could enter early escape and receive additional active treatment ( week 16 ) or could have their dose regimen adjusted ( week 24 ) . The primary end point was the proportion of patients achieving a 50 % response according to the American College of Rheumatology improvement criteria ( ACR50 ) at week 14 . RESULTS The primary study end point was not met ( at week 14 , an ACR50 response was observed in 21 % of the patients treated with golimumab plus MTX compared with 13 % of the patients treated with placebo plus MTX [ P = 0.051 ] ) . By week 24 , significantly more patients treated with golimumab plus MTX had achieved an ACR50 response . Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 ( 16 % versus 13 % ) or week 24 ( 10 % versus 9 % ) . At week 48 , the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX ( 70 % and 48 % , respectively ) . Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab . The most commonly reported adverse events through week 48 were infections ( 48 % of patients treated with golimumab with or without MTX and 41 % of patients receiving placebo plus MTX ) . CONCLUSION The primary end point was not met . However , intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients , with no unexpected safety concerns 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 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 .