The risk of hospitalized infection in patients with rheumatoid arthritis. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab bef Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis. Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. 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. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors Efficacy and safety of the new DMARD leflunomide: comparison to placebo and sulfasalazine in active rheumatoid arthritis. Comparison of different definitions to classify remission and sustained remission: 1 year TEMPO results Treatment continuation in patients receiving biological agents or conventional DMARD therapy. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate Antirheumatic drug use and the risk of acute myocardial infarction. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low – results from RABBIT, the German biologics register 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 Aiming at low disease activity in rheumatoid arthritis with initial combination therapy or initial monotherapy strategies: the BeSt study. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Long term safety of infliximab. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Etanercept in combination with sulfasalazine, hydroxychloroquine, or gold in the treatment of rheumatoid arthritis. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised 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 Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-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 Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: the ADORE study Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. The LUNDEX, a new index of drug efficacy in clinical practice: results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern Sweden. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. 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 Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions. Predictors of infection in rheumatoid arthritis. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Effectiveness, predictive response factors, and safety of anti-tumor necrosis factor (TNF) therapies in anti-TNF-naive rheumatoid arthritis. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study. Infliximab treatment maintains employability in patients with early rheumatoid arthritis. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). Impact of concomitant DMARD therapy on adherence to treatment with etanercept and infliximab in rheumatoid arthritis. Results from a six-year observational study in southern Sweden
OBJECTIVE To determine whether patients with rheumatoid arthritis ( RA ) are at increased risk of hospitalized infection and whether the risk varies by RA treatment . METHODS A retrospective cohort study was conducted using data from a medical and pharmacy cl aims managed-care data base from 1999 to 2006 . A total of 24,530 patients were included in the RA cohort ; a r and om sample of non-RA patients served as a comparison cohort ( n = 500,000 ) .  Rates of hospitalized infection were compared between the cohorts . A nested case-control analysis was performed within the RA cohort to assess the effect of current RA medication use on hospitalized infection risk . RESULTS A total of 1,993 patients with RA and 11,977 non-RA patients experienced a hospitalized infection . The rate of first hospitalized infection was higher in the RA cohort [ adjusted hazard ratio = 2.03 ; 95 % confidence interval ( CI ) 1.93 - 2.13 ] . In the case-control analysis , the current use of biological disease modifying antirheumatic drugs ( DMARD ) was associated with slightly increased risk of hospitalized infection [ rate ratio ( RR ) = 1.21 ; 95 % CI 1.02 - 1.43 ] . Methotrexate and hydroxychloroquine were associated with decreased risk .  Oral corticosteroid use increased risk ( RR = 1.92 ; 95 % CI 1.67 - 2.21 ) , and there was a dose-related effect [ < or = 5 mg/day : RR = 1.32 ( 95 % CI 1.06 - 1.63 ) , 6 - 10 mg/day : RR = 1.94 ( 95 % CI 1.53 - 2.46 ) , > 10 mg/day : RR = 2.98 ( 95 % CI 2.41 - 3.69 ) ] . CONCLUSION These data confirm that individuals with RA are at increased risk of hospitalized infection compared to those without RA . Oral corticosteroid use was associated with a dose-related increase . Biological DMARD use was associated with slightly elevated risk ; however , this may reflect confounding and channeling bias OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns OBJECTIVE To evaluate the safety of anakinra ( a recombinant human interleukin-1 receptor antagonist ) in a large population of patients with rheumatoid arthritis ( RA ) , typical of those seen in clinical practice . METHODS A total of 1,414 patients were r and omly assigned to treatment with 100 mg of anakinra or placebo , administered daily by subcutaneous injection . Background medications included disease-modifying antirheumatic drugs , corticosteroids , and nonsteroidal antiinflammatory drugs , alone or in combination . The primary end point was safety , which was evaluated by adverse events ( including infections ) , discontinuation from study due to adverse events , and death . RESULTS Safety was evaluated in 1,399 patients ( 1,116 in the anakinra group and 283 in the placebo group ; 15 patients were r and omized but did not receive any study drug ) during the initial 6-month , double-blind , placebo-controlled phase of this long-term safety study . Baseline demographics , disease characteristics , and concomitant medications were similar between the 2 groups . The study group included patients with numerous comorbid conditions and a wide range of RA disease activity .  Serious adverse events occurred at a similar rate in the anakinra group and the placebo group ( 7.7 % and 7.8 % , respectively ) . Serious infectious episodes were observed more frequently in the anakinra group ( 2.1 % versus 0.4 % in the placebo group ) . The rate of withdrawal due to adverse events was 13.4 % in the anakinra group and 9.2 % in the placebo group . CONCLUSION Results from this large , placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA , including those with comorbid conditions and those using multiple combinations of concomitant therapies . Although the frequency of serious infection was slightly higher in the anakinra group , no infection was attributed to opportunistic microorganisms or result ed in death 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 : OBJECTIVES To compare budesonide , a locally acting glucocorticoid with minimal systemic exposure , with conventional glucocorticoid treatment and placebo in rheumatoid arthritis . METHODS A double blind , r and omised , controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis , comparing budesonide 3 mg daily , budesonide 9 mg daily , prednisolone 7.5 mg daily , and placebo . Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment . RESULTS There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo ( 28 % for tender and 34 % for swollen joint counts , p<0.05 ) . Prednisolone 7.5 mg gave similar results , while budesonide 3 mg was less effective . ACR20 response criteria were met by 25 % of patients on placebo , 22 % on budesonide 3 mg , 42 % on budesonide 9 mg , and 56 % on prednisolone 7.5 mg . A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks . There was no evidence that budesonide provided a different pattern of symptom control from prednisolone , or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment . Adverse effects attributable to glucocorticoids were equally common in all groups . CONCLUSIONS The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment , are maintained for three months , and are not associated with any rebound in symptoms after stopping treatment Objective : To compare patient reported measures of function , health related quality of life ( QoL ) , and satisfaction with medication among patients with rheumatoid arthritis ( RA ) treated with methotrexate ( MTX ) , etanercept , or both for up to 1 year . Methods : In a 52 week , double blind , clinical trial , patients with active RA were r and omised to receive etanercept 25 mg twice weekly , methotrexate up to 20 mg weekly , or combination therapy .  The Health Assessment Question naire ( HAQ ) disability index , EuroQoL health status visual analogue scale ( EQ-5D VAS ) , patient global assessment , and patient general health VAS were administered at baseline and weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 32 , 40 , 48 , and 52 . Satisfaction with the medication was compared at 52 weeks . Results : Of 682 enrolled patients , 522 completed 52 weeks of treatment . Mean improvement from baseline in HAQ score was 0.65 , 0.70 , and 1.0 for MTX , etanercept , and the combination , respectively . The mean percentage and absolute improvement in the HAQ was significantly higher ( p<0.01 ) for combination therapy than for either of the monotherapies . Combination therapy produced significantly more rapid achievement of HAQ ⩽0.5 sustained for 6 months than either of the monotherapies ( p<0.01 ) . Compared with patients receiving monotherapy , those receiving combination therapy achieved a significantly better ( p<0.05 ) health state as measured by the EQ-5D VAS ( mean ( SD ) 63.7 ( 3.2 ) , 66.8 ( 3.2 ) , 72.7 ( 3.1 ) for MTX , etanercept , and the combination , respectively ) . Results were similar for other assessment s ( p<0.01 ) . Patients in combination and etanercept groups were significantly more likely ( p<0.0001 , p = 0.0009 , respectively ) to report satisfaction with the medication . Conclusions : Combination therapy with etanercept and methotrexate improved function , QoL , and satisfaction with the medication significantly more than monotherapy BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical BACKGROUND An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis . To confirm these observations , we conducted a r and omized , double-blind , controlled study . METHODS We r and omly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate  to receive one of four treatments : oral methotrexate ( > or = 10 mg per week ) ( control ) ; rituximab ( 1000 mg on days 1 and 15 ) ; rituximab plus cyclophosphamide ( 750 mg on days 3 and 17 ) ; or rituximab plus methotrexate . Responses defined according to the criteria of the American College of Rheumatology ( ACR ) and the European League against Rheumatism ( EULAR ) were assessed at week 24 ( primary analyses ) and week 48 ( exploratory analyses ) . RESULTS At week 24 , the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria , the primary end point , was significantly greater with the rituximab-methotrexate combination ( 43 percent , P=0.005 ) and the rituximab-cyclophosphamide combination ( 41 percent , P=0.005 ) than with methotrexate alone ( 13 percent ) . In all groups treated with rituximab , a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria ( 65 to 76 percent vs. 38 percent , P < or = 0.025 ) or had EULAR responses ( 83 to 85 percent vs. 50 percent , P < or = 0.004 ) . All ACR responses were maintained at week 48 in the rituximab-methotrexate group . The majority of adverse events occurred with the first rituximab infusion : at 24 weeks , serious infections occurred in one patient ( 2.5 percent ) in the control group and in four patients ( 3.3 percent ) in the rituximab groups . Peripheral-blood immunoglobulin concentrations remained within normal ranges . CONCLUSIONS In patients with active rheumatoid arthritis despite methotrexate treatment , a single course of two infusions of rituximab , alone or in combination with either cyclophosphamide or continued methotrexate , provided significant improvement in disease symptoms at both weeks 24 and 48 CONTEXT The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor alpha ( TNF-alpha ) . Little is known about the reactivation of latent viral infections during treatment with TNF-alpha inhibitors . OBJECTIVE To investigate whether TNF-alpha inhibitors together as a class , or separately as either monoclonal anti-TNF-alpha antibodies ( adalimumab , infliximab ) or a fusion protein ( etanercept ) , are related to higher rates of herpes zoster in patients with rheumatoid arthritis . DESIGN , SETTING , AND PATIENTS Patients were enrolled in the German biologics register RABBIT , a prospect i ve cohort , between May 2001 and December 2006 at the initiation of treatment with infliximab , etanercept , adalimumab , or anakinra , or when they changed conventional disease-modifying antirheumatic drug ( DMARD ) .  Treatment , clinical status , and adverse events were assessed by rheumatologists at fixed points during follow-up . MAIN OUTCOME MEASURES Hazard ratio ( HR ) of herpes zoster episodes following anti-TNF-alpha treatment . Study aims were to detect a clinical ly significant difference ( HR , 2.0 ) between TNF-alpha inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-alpha inhibitors , the monoclonal antibodies or the fusion protein , compared with conventional DMARDs . RESULTS Among 5040 patients receiving TNF-alpha inhibitors or conventional DMARDs  , 86 episodes of herpes zoster occurred in 82 patients . Thirty-nine occurrences could be attributed to treatment with anti-TNF-alpha antibodies , 23 to etanercept , and 24 to conventional DMARDs . The crude incidence rate per 1000 patient-years was 11.1 ( 95 % confidence interval [ CI ] , 7.9 - 15.1 ) for the monoclonal antibodies , 8.9 ( 95 % CI , 5.6 - 13.3 ) for etanercept , and 5.6 ( 95 % CI , 3.6 - 8.3 ) for conventional DMARDs . Adjusted for age , rheumatoid arthritis severity , and glucocorticoid use , a significantly increased risk was observed for treatment with the monoclonal antibodies ( HR , 1.82 [ 95 % CI , 1.05 - 3.15 ] ) , although this risk was lower than the threshold for clinical significance . No significant associations were found for etanercept use ( HR , 1.36 [ 95 % CI , 0.73 - 2.55 ] ) or for anti-TNF-alpha treatment ( HR , 1.63 [ 95 % CI , 0.97 - 2.74 ] ) as a class . CONCLUSION Treatment with monoclonal anti-TNF-alpha antibodies may be associated with increased risk of herpes zoster , but this requires further study 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 Objectives : To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis ( RA ) and poor prognostic factors . Methods : In this double-blind , phase IIIb study , patients with RA for 2 years or less were r and omly assigned 1 : 1 to receive abatacept ( ∼10 mg/kg ) plus methotrexate , or placebo plus methotrexate .  Patients were methotrexate-naive and seropositive for rheumatoid factor ( RF ) , anti-cyclic citrullinated protein ( CCP ) type 2 or both and had radiographic evidence of joint erosions . The co- primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission ( C-reactive protein ) and joint damage progression ( Genant-modified Sharp total score ; TS ) at year 1 . Safety was monitored throughout . Results : At baseline , patients had a mean DAS28 of 6.3 , a mean TS of 7.1 and mean disease duration of 6.5 months ; 96.5 % and 89.0 % of patients were RF or anti-CCP2 seropositive , respectively . At year 1 , a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission ( 41.4 % vs 23.3 % ; p<0.001 ) and there was significantly less radiographic progression ( mean change in TS 0.63 vs 1.06 ; p = 0.040 ) versus methotrexate alone . Over 1 year , the frequency of adverse events ( 84.8 % vs 83.4 % ) , serious adverse events ( 7.8 % vs 7.9 % ) , serious infections ( 2.0 % vs 2.0 % ) , autoimmune disorders ( 2.3 % vs 2.0 % ) and malignancies ( 0.4 % vs 0 % ) was comparable for abatacept plus methotrexate versus methotrexate alone . Conclusions : In a methotrexate-naive population with early RA and poor prognostic factors , the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable , favourable safety profile The efficacy and safety of the novel DMARD leflunomide was compared to placebo and sulfasalazine in a r and omized , double-blind study . At Week 24 , leflunomide significantly reduced tender and swollen joint counts and physician and patient assessment scores compared to placebo ( P < 0.001 ) . Response rates with leflunomide were significantly greater than placebo : ACR 20 % ( 55 % vs 29 % , P = 0.0001 ) . Comparable response rates were observed with sulfasalazine ( ACR 20 % : 56 % ) . Leflunomide  significantly improved HAQ scores compared to placebo or sulfasalazine ( P < 0.009 ) . The onset of action with leflunomide was rapid and was seen as early as Week 2 . Radiographic disease progression was significantly slower with leflunomide than placebo ( P < 0.01 ) . Leflunomide was well tolerated . No long-term safety issues were reported with leflunomide in patients who opted to continue treatment for up to 2 years . Efficacy of leflunomide in the treatment of RA was maintained at 2 years Objective : To assess methods to calculate achieving and sustaining remission in a double blind r and omised trial in patients with RA who received etanercept , methotrexate , or an etanercept/methotrexate combination .  Methods : Remission was defined as DAS < 1.6 , DAS28 < 2.6 , and ACR70 response . Sustaining remission was analysed in three ways : ( a ) analysis of sustained DAS remission , DAS28 remission , or ACR70 response continuously for 6 months ; ( b ) analysis of sustained remission appraised through a continuity rewarded scoring system , which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission ; or ( c ) longitudinal modelling of remission odds using generalised estimating equations . Results : Significantly more patients treated with the  etanercept/methotrexate combination reached DAS remission ( 37 % ) than those treated with either methotrexate ( 14 % ) or etanercept ( 18 % ) alone ( p<0.01 ) . Results for DAS28 and for the ACR70 response were similar . Agreement between DAS remission and DAS28 remission was good , but agreement between either of these and the ACR70 response was less . Patients in DAS or DAS28 remission had a lower level of disease activity ( fewer active joints , lower ESR ) than those achieving ACR70 response ; the converse was seen using pain VAS . The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy , which increased the number and durability of remission periods . Conclusions : DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA , frequently differing from patients classified as ACR70 responders . The three methods of examining duration of remission produced comparable results OBJECTIVE To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug ( DMARD ) treatment after previous DMARD failure . METHODS Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study . Data were available for 511 patients treated with etanercept , 343 with infliximab , 70 with anakinra , and 599 controls .  Propensity scores were used to select a sub sample of patients from the control group who were likely to be treated with biological agents because of their disease severity , as well as comparable infliximab and etanercept cases . RESULTS Treatment continuation after 12 months was similar for etanercept ( 68.6 % ( 95 % confidence interval , 62 % to 75 % ) ) and infliximab ( 65.4 % ( 58 % to 73 % ) ) but lower for anakinra ( 59 % ( 41 % to 77 % ) ) . Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone . Patients treated with  biological agents were more severely ill than those in the control group and had more previous DMARD failures . After adjustment for baseline differences , the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate . CONCLUSIONS Treatment continuation of biological agents in clinical practice is less likely than in r and omised clinical trials but more likely than in comparable controls treated with conventional DMARDs Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX )  were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX .  Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 OBJECTIVE To assess the risk of  acute myocardial infa rct ion ( AMI ) associated with the use of disease-modifying antirheumatic drugs ( DMARDs ) and other medications commonly used in rheumatoid arthritis ( RA ) . METHODS We conducted a nested case-control analysis within a cohort of subjects with RA , observed between 1999 and 2003 , identified from the PharMetrics cl aims data base . For each first AMI hospitalization identified during followup , 10 controls matched on sex , age , and time of study entry were r and omly selected from the cohort . Conditional logistic regression was used to estimate the rate ratio ( RR ) of AMI associated with the current use of anti-RA therapy , as measured from dispensed prescriptions , after adjustment for AMI risk factors . RESULTS The cohort included 107,908 subjects ( average age 54 years at cohort entry ) . During followup , 558 AMI cases occurred ( 3.4 per 1,000 per year ) . AMI rate was significantly decreased with the current use of any DMARD ( adjusted RR 0.80 , 95 % confidence interval [ 95 % CI ] 0.65 - 0.98 ) . This effect was consistent across all DMARDs , including methotrexate ( RR 0.81 , 95 % CI 0.60 - 1.08 ) , leflunomide ( RR 0.28 , 95 % CI 0.12 - 0.65 ) , and other traditional DMARDs ( RR 0.67 , 95 % CI 0.46 - 0.97 ) , but not biologic agents ( RR 1.30 , 95 % CI 0.92 - 1.83 ) . AMI rate increased with the use of glucocorticoids ( RR 1.32 , 95 % CI 1.02 - 1.72 ) but not with nonselective nonsteroidal antiinflammatory drugs ( RR 1.05 , 95 % CI 0.81 - 1.36 ) or cyclooxygenase 2 ( COX-2 ) inhibitors ( RR 1.11 , 95 % CI 0.87 - 1.43 ) . CONCLUSION DMARD use is associated with a reduction in AMI risk in patients with RA . No risk increase was found with the COX-2 inhibitors in this population Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA  , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy OBJECTIVE To determine whether the incidence of herpes zoster is elevated in patients with rheumatoid arthritis ( RA ) and whether herpes zoster is associated with use of disease-modifying antirheumatic drugs ( DMARDs ) in patients with RA . METHODS Two retrospective cohort studies were conducted using data from a US integrated managed care data base ( PharMetrics cl aims data base ) from 1998 - 2002 and the UK General Practice Research Data base ( GPRD ) between 1990 - 2001 . Rates of herpes zoster among patients with RA and r and omly sample d non-RA patients were compared . A nested case-control analysis was performed within each RA cohort to examine the effect of current treatment on herpes zoster risk . RESULTS A total of 122,272 patients with RA from the PharMetrics data base and 38,621 from the GPRD were included . The adjusted hazard ratios of herpes zoster for patients with RA compared with non-RA patients were 1.91 ( 95 % confidence interval [ 95 % CI ] 1.80 - 2.03 ) in the PharMetrics data base and 1.65 ( 95 % CI 1.57 - 1.75 ) in the GPRD . In the PharMetrics data base , current use of biologic DMARDs alone was associated with herpes zoster ( odds ratio [ OR ] 1.54 , 95 % CI 1.04 - 2.29 ) , as was current use of traditional DMARDs alone ( OR 1.37 , 95 % CI 1.18 - 1.59 ) . In the GPRD , current use of traditional DMARDs was associated with herpes zoster ( OR 1.27 , 95 % CI 1.10 - 1.48 ) . In both data sources , use of oral corticosteroids was associated with herpes zoster regardless of concomitant therapies . CONCLUSION Data from 2 large data bases suggested that patients with RA are at increased risk of herpes zoster . Among patients with RA , DMARDs and /or use of oral corticosteroids appeared to be associated with herpes zoster Objectives : This study assessed the relative efficacy of etanercept ( ETN ) or etanercept and methotrexate ( ETN+MTX ) for patients with rheumatoid arthritis ( RA ) who had an unsatisfactory response to MTX  , using patient-reported outcomes ( PROs ) of function , pain , general health , disease activity and morning stiffness . Methods : The PROs were secondary assessment s in a 16-week , prospect i ve , r and omised , parallel-group study conducted at 60 European centres . Patients with RA were r and omly assigned either to monotherapy with ETN or combination therapy with ETN+MTX . PRO instruments administered included the Stanford Health Assessment Question naire , the pain visual analogue scale , the EuroQoL assessment of current health state ( EQ-5D ) , the EQ-5D visual analogue scale , a patient global assessment of disease activity and an assessment of morning stiffness . Treatment groups were compared by percentage of patients within clinical ly meaningful categories . The primary endpoint for all PROs was comparison of mean improvement from baseline to week 16 between ETN and ETN+MTX groups . Results : Three hundred and fifteen patients were r and omised to ETN or ETN+MTX . Both treatment arms had similar Health Assessment Question naire Disability Index DI , EQ-5D , patient global assessment of disease activity , pain or morning stiffness scores and improvement from baseline to week 16 . Conclusions : For patients with active RA and intolerance or unsatisfactory response to MTX  , substituting ETN for MTX and adding ETN to MTX are both effective ways of reducing disability , pain , disease activity , morning stiffness , and improving general health OBJECTIVE To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate ( MTX ) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early , active rheumatoid arthritis . METHODS Subjects were r and omized at baseline for the entire 2-year period ; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2 . The original combination group either continued combination therapy ( the EM/EM group ; n = 111 ) or received etanercept monotherapy ( the EM/E group ; n = 111 ) in year 2 ; the original MTX monotherapy group either received combination therapy ( the M/EM group ; n = 90 ) or continued monotherapy ( the M/M group ; n = 99 ) in year 2 . Efficacy end points included remission ( a Disease Activity Score in 28 joints [ DAS28 ] < 2.6 ) and radiographic nonprogression ( change in the modified Sharp/van der Heijde score < or = 0.5 ) at year 2 . A last observation carried forward analysis from the modified intention-to-treat population ( n = 398 ) and a post hoc nonresponder imputation ( NRI ) analysis ( n = 528 ) were performed for remission . RESULTS At year 2 , DAS28 remission was achieved by 62/108 , 54/108 , 51/88 , and 33/94 subjects in the EM/EM , EM/E , M/EM , and M/M groups , respectively ( P < 0.01 for the EM/EM and M/EM groups versus the M/M group ) . This effect was corroborated by a more conservative post hoc 2-year NRI analysis , with remission observed in 59/131 , 50/134 , 48/133 , and 29/130 of the same respective groups ( P < 0.05 for each of the EM/EM , EM/E , and M/EM groups versus the M/M group ) . The proportions of subjects achieving radiographic nonprogression ( n = 360 ) were 89/99 , 74/99 , 59/79 , and 56/83 in the EM/EM ( P < 0.01 versus each of the other groups ) , EM/E , M/EM , and M/M groups , respectively . No new safety signals or between-group differences in serious adverse events were seen . CONCLUSION Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy . Combination therapy result ed in important clinical and radiographic benefits over 2 study years , without significant additional safety risk 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 CONTEXT Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis ( RA ) . OBJECTIVE To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA . DESIGN R and omized , double-blind , placebo , and active-controlled 12-month study . SETTING Forty-seven university and private rheumatology practice s in the United States and Canada . PATIENTS Diagnosis of RA by the American College of Rheumatology ( ACR ) criteria for duration of 6 months or longer and no previous methotrexate treatment . INTERVENTION Leflunomide treatment ( 20 mg/d ) , placebo , or methotrexate treatment ( 7.5 - 15 mg/wk ) . MAIN OUTCOME MEASURES American College of Rheumatology success rate ( completed 52 weeks of treatment and met the ACR > or = 20 % response criteria ) , disease progression as assessed by x-ray films , and improvement in function and health-related quality of life using the intent-to-treat population . RESULTS The 482 patients studied were predominantly women ( mean age , 54 years ; mean disease duration , 6.7 years ) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed . The ACR response and success rates for patients receiving leflunomide treatment ( 52 % and 41 % , respectively ) and methotrexate treatment ( 46 % and 35 % , respectively ) were significantly higher than those for patients receiving placebo ( 26 % and 19 % , respectively ) ( P<.001 ) , and they were statistically equivalent , with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy . X-ray analyses demonstrated less disease progression with leflunomide ( P=.001 ) and methotrexate ( P = .02 ) therapy than with placebo . Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo ( P<.001 and P<.05 , respectively ) . Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints , skin rash , and reversible alopecia . Asymptomatic transaminase elevations result ed in treatment discontinuations for 7.1 % of patients receiving leflunomide therapy , 1.7 % of patients receiving placebo , and 3.3 % of patients receiving methotrexate therapy . CONCLUSIONS Clinical responses following administration of leflunomide , a new therapeutic agent for the treatment of RA , were statistically superior to those with placebo and equivalent to those with methotrexate treatment . Both active treatments improved signs and symptoms of active RA , delayed disease progression as demonstrated by x-ray films , and improved function and health-related quality of life 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 Objectives : The phase III RADIATE study examined the efficacy and safety of tocilizumab , an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis ( RA ) refractory to tumour necrosis factor ( TNF ) antagonist therapy . Methods : 499 patients with inadequate response to one or more TNF antagonists were r and omly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo ( control ) intravenously every 4 weeks with stable methotrexate for 24 weeks . ACR20 responses , secondary efficacy and safety endpoints were assessed . Results : ACR20 was achieved at 24 weeks by 50.0 % , 30.4 % and 10.1 % of patients in the 8 mg/kg , 4 mg/kg and control groups , respectively ( less than p<0.001 both tocilizumab groups versus control ) . At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls ( less than p = 0.001 ) . Patients responded regardless of most recently failed anti-TNF or the number of failed treatments . DAS28 remission ( DAS28 < 2.6 ) rates at week 24 were clearly dose related , being achieved by 30.1 % , 7.6 % and 1.6 % of 8 mg/kg , 4 mg/kg and control groups ( less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control ) . Most adverse events were mild or moderate with overall incidences of 84.0 % , 87.1 % and 80.6 % , respectively . The most common adverse events with higher incidence in tocilizumab groups were infections , gastrointestinal symptoms , rash and headache . The incidence of serious adverse events was higher in controls ( 11.3 % ) than in the 8 mg/kg ( 6.3 % ) and 4 mg/kg ( 7.4 % ) groups . Conclusion : Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile . Trial registration number : NCT00106522 Objective : To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis ( RA ) . Methods : Safety data for  adalimumab treated patients from r and omised controlled trials , open label extensions , and two phase IIIb open label trials were analysed . In addition , postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002 . Results : As of 15 April 2005 , the RA clinical trial safety data base analysed covered 10 050 patients , representing 12 506 patient-years ( PYs ) of adalimumab exposure . The rate of serious infections , 5.1/100 PYs , was comparable to that reported on 31 August 2002 ( 4.9/100 PYs ) , and to published reports of RA population s naive to anti-tumour necrosis factor ( TNF ) therapy . Following implementation of tuberculosis ( TB ) screening in clinical trials , the rate of TB decreased . There were 34 cases of TB as of this analysis ( 0.27/100 PYs ) . The st and ardised incidence ratio for lymphoma was 3.19 ( 95 % CI 1.78 to 5.26 ) , consistent with the observed increased incidence in the general RA population . As of 30 June 2005 , there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period . Seventeen TB cases were spontaneously reported ( 0.02/100 PYs ) from the US . Rates of other postmarketing events of interest , such as congestive heart failure , systemic lupus erythematosus , opportunistic infections , blood dyscrasias , lymphomas , and demyelinating disease , support observations from clinical trials . Conclusion : Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ;  etanercept  , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated OBJECTIVE 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 We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) .  In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX 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 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 AIM To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis ( RA ) . METHODS In the BeSt study , 508 patients with newly diagnosed ( < 2 years ) active RA were r and omised to be treated according to four treatment strategies : 1 . sequential monotherapy , 2 . step up to combination therapy ( both starting with methotrexate ) , 3 . initial combination therapy with methotrexate , sulphasalazine , and a tapered high dose of prednisone , and 4 . initial combination therapy with methotrexate and infliximab . Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score ( DAS ) , with the goal to achieve and maintain a DAS < or= 2.4 . Functional ability was measured every 3 months with the Health Assessment Question naire . Radiographs of h and s and feet were assessed yearly , blinded for patient identity and treatment , and in r and om order , to measure joint damage progression ( Sharp/van der Heijde score ) . RESULTS After 2 years of treatment , 80 % of all patients achieved the goal of DAS < or= 2.4 , and 42 % reached clinical remission ( DAS < 1.6 ) . Initial combination therapy , either with prednisone ( group 3 ) or with infliximab ( group 4 ) , result ed in earlier improvement in functional ability , more continuous clinical remission ( DAS < 1.6 ) , and less joint damage progression than initial monotherapy ( groups 1 and 2 ) . Patients in groups 1 and 2 needed more therapy adjustments , including introduction of combination therapy with prednisone or infliximab , to achieve a DAS < or= 2.4 , whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate , respectively , monotherapy . The adverse events profile was comparable in all groups . The presence or absence of rheumatoid factor , HLA DR4 , or anti-CCP was not associated with radiologic damage progression . CONCLUSION In patients with early , active RA , remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent , objective ly steered treatment adjustments . The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate , sulphasalazine and prednisone or with methotrexate and infliximab , which can be tapered to DMARD monotherapy once low disease activity is achieved 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 Infliximab is a chimeric anti-tumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn 's disease and rheumatoid arthritis . In several placebo controlled , r and omized clinical trials and open trials , 771 patients have been given infliximab ( a further 192 received placebo ) . Follow-up for safety has included the time of study ( 12 weeks after the last infusion ) , plus three additional years . Acute infusion reactions ( headache , fever , chills , urticaria , chest pain ) were seen in 17 % of patients receiving infliximab compared with 7 % of those receiving placebo . While infections were reported more frequently overall in the patients given infliximab ( 26 % over 27 weeks of follow-up versus 16 % of placebo-treated patients over 20 weeks of follow-up ) , there was no increased risk of serious infections . There was no difference in the overall mortality rate between the groups . While low titres of autoantibodies developed in less than 10 % of patients , drug-induced lupus was seen in less than 1 % , with these cases resolving upon discontinuation of the drug . Overall , infliximab showed an acceptable safety profile OBJECTIVE To assess the safety of abatacept , a selective costimulation modulator , in patients with active rheumatoid arthritis ( RA ) who had been receiving > or = 1 traditional nonbiologic and /or biologic disease-modifying antirheumatic drugs ( DMARDs ) approved for the treatment of RA for at least 3 months prior to entry into the study . METHODS This was a 1-year , multicenter , r and omized , double-blind , placebo-controlled trial . Patients were r and omized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range  , or placebo . RESULTS The abatacept and placebo groups exhibited similar frequencies of adverse events ( 90 % and 87 % , respectively ) , serious adverse events ( 13 % and 12 % , respectively ) , and discontinuations due to adverse events ( 5 % and 4 % , respectively ) . Five patients ( 0.5 % ) in the abatacept group and 4 patients ( 0.8 % ) in the placebo group died during the study . Serious infections were more frequent in the abatacept group than in the placebo group ( 2.9 % versus 1.9 % ) . Fewer than 4 % of patients in either group experienced a severe or very severe infection . The incidence of neoplasms was 3.5 % in both groups . When evaluated according to background therapy , serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent ( 22.3 % ) than in the other subgroups ( 11.7 - 12.5 % ) . CONCLUSION Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes . However , abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events . Therefore , abatacept is not recommended for use in combination with biologic therapy OBJECTIVE To prospect ively determine the efficacy and safety of etanercept in combination with sulfasalazine ( SSZ ) , hydroxychloroquine ( HCQ ) , and gold in the treatment of rheumatoid arthritis ( RA ) . METHODS A prospect i ve open-label study enrolled 119 patients with RA who had active disease despite stable therapy with SSZ ( n = 50 ) , HCQ ( n = 50 ) , or intramuscular gold ( n = 19 ) . Primary efficacy endpoints consisted of American College of Rheumatology responses at 24 and 48 weeks . Safety was established at regularly scheduled visits . RESULTS Patients in each etanercept combination showed significant improvement at both 24 and 48 weeks . Toxicity withdrawals by 48 weeks included gold ( n = 1 ) : proteinuria ; HCQ  ( n = 5 ) : septic wrist and bilateral pneumonia , rash , optic neuritis , breast cancer , squamous cancer of the tongue ; and  SSZ  ( n = 5 ) : otitis media , elevated liver function indicators , pericarditis , rash , and gastroenteritis . The most common adverse events not requiring discontinuation from the study were injection site reactions ( 43 % of patients ) and upper respiratory type infections ( 34 % ) . CONCLUSION This study is the first to prospect ively evaluate the safety of etanercept in combination with SSZ , HCQ , and gold in patients with RA .  Etanercept in combination with SSZ , HCQ , or gold was efficacious and well tolerated , with a discontinuation rate of 9 % ( 11/119 ) for adverse events at 48 weeks 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 BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied .  ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis OBJECTIVE To determine whether the rate of serious infection is higher in  anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis ( RA ) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs ( DMARDs ) .  METHODS This was a national prospect i ve observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register . All serious infections , stratified by site and organism , were included in the analysis . RESULTS Between December 2001 and September 2005 , there were 525 serious infections  in the  anti-TNF-treated cohort and 56 in the comparison cohort ( 9,868 and 1,352 person-years of followup , respectively ) . The incidence rate ratio ( IRR ) , adjusted for baseline risk , for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 ( 95 % confidence interval 0.68 - 1.57 ) . However , the frequency of serious skin and soft tissue infections was increased in  anti-TNF-treated patients , with an adjusted IRR of 4.28 ( 95 % confidence interval 1.06 - 17.17 ) . There was no difference in infection risk between the 3 main anti-TNF drugs . Nineteen serious bacterial intracellular infections occurred , exclusively in patients in the anti-TNF-treated cohort . CONCLUSION In patients with active RA , anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment , after adjustment for baseline risk . In contrast , the rate of serious skin and soft tissue infections was increased , suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX )  were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab  dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268  methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX  group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX  result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis Objective : To explore the feasibility of prospect ively monitoring treatment efficacy and tolerability of infliximab , etanercept , and leflunomide over a two year period in patients with established rheumatoid arthritis ( RA ) in clinical practice using a structured protocol . Methods : All patients with RA at seven centres in southern Sweden , for whom at least two disease modifying antirheumatic drugs , including methotrexate , had failed or not been tolerated , who started treatment with either infliximab , etanercept , or leflunomide were included . They were evaluated at predefined times using a st and ardised protocol including items required for evaluating response to the American College of Rheumatology ( ACR ) or EULAR criteria . All adverse events were recorded using World Health Organisation terminology . Concomitant treatment and survival while receiving a drug were recorded . Results : During the study 166 patients were treated with etanercept , 135 with infliximab , and 103 with leflunomide .  Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor ( TNF ) blockers . The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis . Thus 79 % and 75 % continued to receive etanercept or infliximab compared with 22 % of patients who started leflunomide after 20 months . The spectrum of side effects did not differ from those previously reported in the clinical trials . The initial two year experience of a protocol for postmarketing surveillance of etanercept , infliximab , and leflunomide shows that a structured protocol with central data h and ling can be used in clinical practice for documenting the performance of newly introduced drugs . Conclusions : Efficacy data for the TNF blockers comply with results in clinical trials , whereas leflunomide appeared to perform worse than in clinical trials . Prolonged monitoring is required to identify possible rare side effects OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline factors could predict outcome . METHODS All patients had participated in the 56-week COBRA trial . During followup , they were seen by their own rheumatologists and were also assessed regularly by study nurses ; no treatment protocol was specified . Disease activity , radiologic damage , and functional ability were the primary outcome domains . Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method . Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat , starting with data obtained at the last visit of the COBRA trial ( 56 weeks after baseline ) . RESULTS At the beginning of followup , patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score ( DAS28 ) and a significantly lower median radiologic damage ( Sharp ) score compared with those in the SSZ monotherapy group . The functional ability score ( Health Assessment Question naire [ HAQ ] ) was similar in both groups . During the 4 - 5 year followup period , the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group . The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group . After adjustment for differences in treatment and disease activity during followup , the between-group difference in the rate of radiologic progression was 3.7 points per year . The HAQ score did not change significantly over time . Independent baseline predictors of radiologic progression over time ( apart from treatment allocation ) were rheumatoid factor positivity , Sharp score , and DAS28 . CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA , independent of subsequent antirheumatic therapy OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA OBJECTIVE Patients with rheumatoid arthritis ( RA ) in whom the response to anti-tumor necrosis factor ( anti-TNF ) therapy is inadequate have several therapeutic options , such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab ( RTX ) . Although both therapeutic options have been proven effective in trials , no head-to-head comparisons are available . The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy .  METHODS This prospect i ve cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent .  The primary outcome was the evolution of RA disease activity ( as measured on the Disease Activity Score in 28 joints [ DAS28 ] ) , which was analyzed using multivariate regression models for longitudinal data . RESULTS One hundred sixteen patients with RA were included ; 50 patients received 1 cycle of RTX , and 66 patients were treated with a second or a third alternative anti-TNF agent . At baseline , there were no significant differences between the 2 groups in age , sex , disease duration , and disease activity . Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent ( P = 0.01 ) . At 6 months , the mean decrease in the DAS28 was -1.61 ( 95 % confidence interval [ 95 % CI ] -1.97 , -1.25 ) among patients receiving RTX and -0.98 ( 95 % CI -1.33 , -0.62 ) among those receiving subsequent anti-TNF therapy . CONCLUSION The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy ABSTRACT Objective : To evaluate the effectiveness of select biologics , methotrexate ( MTX ) , and other disease-modifying anti-rheumatic drugs ( DMARDs ) in the management of adult rheumatoid arthritis ( RA ) in routine clinical practice . Research design and methods : RADIUS ( Rheumatoid Arthritis DMARD Intervention and Utilization Study ) comprises two prospect i ve , 5‐year , observational registries of over 10 000 patients . Over 4600 patients who initiated MTX or a biologic regimen ( etanercept [ ETN ] , infliximab [ INF ] , ETN + MTX , and INF + MTX ) and who had at least one on-regimen , follow-up evaluation , were included in this analysis . Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation . Other common DMARD regimens ( N = 762 ) were also compared with MTX . Patients who initiated less commonly used regimens , such as anakinra or cyclosporine , and those who did not have at least one on-regimen , follow-up evaluation , were not eligible for this analysis . Because ESR/CRP measurements were often not available , a modified ACR20 response ( mACR20 ) , defined as three out of four response criteria excluding ESR/CRP , was used to assess response at 12 months . Logistic regression analysis was performed to control for baseline covariates that may affect outcomes . Main outcome measures : The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry . Results : After adjusting for baseline covariates , patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone ( odds ratio [ OR ] 1.29 , 95 % confidence interval [ CI ] 1.09–1.52 ; p < 0.01 and OR 1.23 , 95 % CI 1.02–1.47 ; p < 0.05 , respectively ) . Conversely , patients treated with MTX + leflunomide ( LEF ) were less likely to achieve a mACR20 response than those receiving MTX alone ( OR 0.68 , 95 % CI 0.48–0.96 ; p < 0.05 ) . Significant differences were not observed between patients receiving MTX alone and either INF + MTX , MTX + hydroxychloroquine , MTX + hydroxychloroquine + sulfasalazine , INF monotherapy , or LEF monotherapy . Conclusion : These data from routine rheumatology clinical practice setting s highlight the effectiveness of common biologic and DMARD therapies , and provide additional data beyond those of r and omized , controlled trials OBJECTIVE Patients with rheumatoid arthritis ( RA ) who experience treatment failure with one anti-tumor necrosis factor ( anti-TNF ) agent  , due to either inefficacy or toxicity , are frequently switched to a second anti-TNF agent , although the benefits of switching are unknown . The present study was undertaken to compare drug continuation rates between the first course and second course of anti-TNF therapy . METHODS The study involved a prospect i ve cohort of RA patients from a UK national register of new anti-TNF treatment starts ( n = 6,739 ; 876 starting adalimumab , 2,826 starting etanercept , and starting 3,037 infliximab ) . Over a mean 15 months of followup , 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity , of whom 503 and 353 , respectively , were switched to a second anti-TNF agent .  Kaplan-Meier survival curves were plotted to determine continuation rates for each course , and Cox regression was used to compare each course for the risk of stopping and the reason for stopping ( inefficacy or toxicity ) . RESULTS Overall , 73 % of patients who switched to a second anti-TNF agent remained on the new therapy by the end of followup . First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy ( hazard ratio [ HR ] 2.7 , 95 % confidence interval [ 95 % CI ] 2.1 - 3.4 ) but not toxicity ( HR 1.1 , 95 % CI 0.9 - 1.5 ) . Similarly , first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity ( HR 2.3 , 95 % CI 1.9 - 2.9 ) but not inefficacy ( HR 1.2 , 95 % CI 0.8 - 1.6 ) . CONCLUSION RA patients who are switched to a  second anti-TNF drug have high rates of continuation , although among those who must discontinue treatment , the reasons for stopping a second drug are related to the reasons for stopping the first drug . This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long-st and ing severe RA OBJECTIVE To assess the efficacy and safety of tocilizumab plus methotrexate ( MTX ) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX .  METHODS A total of 1,196 patients were enrolled in a 2-year , r and omized , double-blind , placebo-controlled trial . Patients received tocilizumab ( 8 mg/kg or 4 mg/kg ) or placebo every 4 weeks plus MTX . Rescue treatment was available from week 16 . Results from year 1 are presented . RESULTS Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX , respectively , versus 1.13 with placebo plus MTX ( P < 0.0001 for both comparisons ) . Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Question naire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg ( -144.1 and -128.4 units , respectively ) than with placebo ( -58.1 units ; P < 0.0001 for both comparisons ) . Proportions of patients with American College of Rheumatology 20 % , 50 % , and 70 % improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo ( P < 0.0001 for all comparisons ) . The safety profile of tocilizumab was consistent with the profiles in previous studies . Infections were the most common adverse and serious adverse events . CONCLUSION The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone . Tocilizumab has a well-characterized safety profile OBJECTIVE To describe the use of the LUNDEX , a new index for comparing the long-term efficacy and tolerability of biologic therapies in rheumatoid arthritis ( RA ) patients treated in clinical practice . METHODS Patients ( n = 949 ) with active RA that had not responded to at least 2 disease-modifying antirheumatic drugs ( DMARDs ) including methotrexate , in whom biologic therapy was being initiated , were included in a structured clinical followup protocol . The protocol included collection of data on diagnosis , disease duration , previous and ongoing DMARD treatment , and date s on which biologic treatment was started and terminated . In addition , data on efficacy measures used for calculating vali date d response criteria , i.e. , the European League Against Rheumatism and American College of Rheumatology response criteria , were collected at fixed time points . Data were prospect ively registered from March 1999 through January 2004 . The LUNDEX , a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy , was design ed to compare the efficacy of the different therapies . RESULTS Etanercept had higher overall LUNDEX values compared with infliximab , mostly because of a lower rate of adherence to therapy with infliximab . The relationship between the drugs was consistent irrespective of the response criteria used . CONCLUSION The LUNDEX is a valuable tool for evaluating drug efficacy in observational studies . It has the advantage of integrating clinical response as well as adherence to therapy in a composite value . Moreover , the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo :  ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated .  Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly . We aim ed to compare addition of conventional disease-modifying antirheumatic drugs ( sulfasalazine and hydroxychloroquine ) with addition of a tumour necrosis factor antagonist ( infliximab ) to methotrexate in patients with early rheumatoid arthritis . METHODS We undertook a r and omised trial in 15 rheumatology units in Sweden . We enrolled patients with early rheumatoid arthritis ( symptom duration < 1 year ) and administered methotrexate ( up to 20 mg per week ) . After 3 - 4 months , those who had not achieved low disease activity but who could tolerate methotrexate were r and omly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab . Primary outcome was achievement of a good response according to European League Against Rheumatism ( EULAR ) criteria at 12 months . Patients were followed up to 24 months ; here , we present findings at 12 months . Analysis was by intention to treat and we used non-responder imputation . The Swefot ( Swedish Pharmacotherapy ) study is registered in the WHO data base at the Karolinska University Hospital , number CT20080004 . FINDINGS 487 patients were initially enrolled . Of 258 who had not achieved low disease activity with methotrexate  , 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab . 32 of 130 ( 25 % ) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 ( 39 % ) assigned infliximab ( risk ratio 1.59 [ 95 % CI 1.10 - 2.30 ] , p=0.0160 ) . Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used . No deaths occurred in either group . INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed , addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinical ly superior to addition of conventional disease-modifying antirheumatic drugs . FUNDING Swedish Rheumatism Association , Schering-Plough Objective : To examine the impact of added abatacept treatment on health related quality of life ( HRQoL ) in patients with rheumatoid arthritis ( RA ) who have inadequate response to methotrexate ( MTX ) .  Methods : The impact of abatacept treatment on HRQoL was examined in a longitudinal , r and omised double blind , placebo controlled clinical trial . Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups . The relationship between American College of Rheumatology ( ACR ) clinical markers and disease duration with changes in HRQoL indicators was also examined . Finally , a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population . Results : Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures , including physical function , fatigue , all eight domains of the SF-36 , and the physical and mental component summaries ( PCS and MCS ) . Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains . By day 169 , all HRQoL measures were significantly better with abatacept than with placebo .  HRQoL gains were associated with greater ACR clinical improvement , and the effects were consistent for patients with different disease duration . A significantly greater percentage of patients treated with abatacept reached normative levels of PCS , MCS , physical functioning , and fatigue compared with patients treated with MTX alone . Conclusion : Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept  ( 10 or 25 mg ) or weekly  oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis Objective : To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year , r and omised , placebo-controlled , double-blind phase , followed by an open-label , long-term extension ( LTE ) . Methods : Patients continued etanercept ( 25 mg twice weekly ) and were r and omised to receive abatacept 2 mg/kg ( n = 85 ) or placebo ( n = 36 ) . As the effective dose of abatacept was established as 10 mg/kg in a separate trial , all patients received abatacept 10 mg/kg and etanercept during the LTE . Results : A total of 121 patients were r and omised ; 80 completed double-blind treatment and entered the LTE . During double-blind treatment , the difference in the percentage of patients achieving the primary end point ( modified American College of Rheumatology ( ACR ) 20 response at 6 months ) was not significant between groups ( 48.2 % v 30.6 % ; p = 0.072 ) . At 1 year , no notable changes in modified ACR responses were observed . Subsequent to the dosing change , similar modified ACR responses were seen during the LTE . Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year . More abatacept and etanercept-treated patients experienced serious adverse events ( SAEs ) at 1 year than patients receiving placebo and etanercept ( 16.5 % v 2.8 % ) , with 3.5 % v 0 % experiencing serious infections . Conclusion : The combination of abatacept ( at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE ) and etanercept was associated with an increase in SAEs , including serious infections , with limited clinical effect . On the basis of the limited efficacy findings and safety concerns , abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment OBJECTIVE To determine in a placebo-controlled , double-blind trial the safety profile of daily anakinra ( Kineret ) use in patients with active rheumatoid arthritis ( RA ) and concurrent comorbid conditions . METHODS In 169 centers in 9 countries , 1,414 patients with active RA were r and omly assigned to receive either anakinra ( 100 mg ) or placebo treatment ( 4:1 anakinra-to-placebo allocation ratio ) , with study drug administered by daily subcutaneous injection for 6 months . The current post hoc analysis assessed baseline comorbid conditions , and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following : cardiovascular event , pulmonary event , central nervous system-related event , infection , diabetes , malignancy , or renal impairment . Within each treatment group ( anakinra or placebo ) , incidence rates were summarized for serious adverse events , infectious events , and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions . RESULTS The majority of patients in the trial had one or more comorbid conditions . In these high-risk patients , there were no differences in the incidence of serious adverse events or infectious events between treatment groups . The incidence of serious infectious events with anakinra use was similar between high-risk patients ( 2.5 % ) and the entire study population ( 2.1 % ) and was not attributable to any single comorbidity . CONCLUSION Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population OBJECTIVE Patients with rheumatoid arthritis ( RA ) have been shown to have an increased susceptibility to the development of infections . The exact causes of this increased risk are unknown , but may relate to immunologic disturbances associated with the disease or to the immunosuppressive effects of agents used in its treatment . This study was undertaken to identify predictors of serious infections among patients with RA . Identification of such factors is the necessary first step in reducing the excess risk of infection in RA . METHODS Members of a population -based incidence cohort of Rochester , Minnesota residents ages > or=18 years , who had been diagnosed with RA between 1955 and 1994 , were followed up longitudinally through their complete medical records until January 1 , 2000 . We examined potential risk factors for the development of all objective ly confirmed ( by microbiology or radiology ) infections and for infections requiring hospitalization . Potential risk factors included RA severity measures ( rheumatoid factor positivity , elevated erythrocyte sedimentation rate , extraarticular manifestations of RA , and functional status ) , comorbidities ( diabetes mellitus , alcoholism , and chronic lung disease ) , and other risk factors for infection ( presence of leukopenia , smoking ) . Predictors were identified using multivariate time-dependent Cox proportional hazards modeling . RESULTS The 609 RA patients in the cohort had a total followup time of 7,729.7 person-years ( mean 12.7 years per patient ) . A total of 389 patients ( 64 % ) had at least 1 infection with objective confirmation , and 290 ( 48 % ) had at least 1 infection requiring hospitalization . Increasing age , presence of extraarticular manifestations of RA , leukopenia , and comorbidities ( chronic lung disease , alcoholism , organic brain disease , and diabetes mellitus ) , as well as use of corticosteroids , were strong predictors of infection ( P < 0.004 ) in both univariate and multivariate analyses . Notably , use of disease-modifying antirheumatic drugs was not associated with increased risk of infection in multivariate analyses , after adjustment for demographic characteristics , comorbidities , and disease-related variables . CONCLUSION We identified a number of strong predictors of infections in a population -based cohort of patients with RA . These results can be used to prospect ively identify high-risk patients , who may benefit from closer followup and implementation of preventive strategies OBJECTIVE Tumor necrosis factor ( TNF ) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis ( RA ) . We investigated the ability of adalimumab , a human anti-TNF monoclonal antibody , to inhibit the progression of structural joint damage , reduce the signs and symptoms , and improve physical function in patients with active RA receiving concomitant treatment with methotrexate ( MTX ) .  METHODS In this multicenter , 52-week , double-blind , placebo-controlled study , 619 patients with active RA who had an inadequate response to MTX were r and omized to receive adalimumab 40 mg subcutaneously every other week ( n = 207 ) , adalimumab 20 mg subcutaneously every week ( n = 212 ) , or placebo ( n = 200 ) plus concomitant MTX . The primary efficacy end points were radiographic progression at week 52 ( total Sharp score by a modified method [ TSS ] ) , clinical response at week 24 ( improvements of at least 20 % in the American College of Rheumatology core criteria [ ACR20 ] ) , and physical function at week 52 ( disability index of the Health Assessment Question naire [ HAQ ] ) . RESULTS At week 52 , there was statistically significantly less radiographic progression , as measured by the change in TSS , in the patients receiving adalimumab either 40 mg every other week ( mean + /- SD change 0.1 + /- 4.8 ) or 20 mg weekly ( 0.8 + /- 4.9 ) as compared with that in the placebo group ( 2.7 + /- 6.8 ) ( P < or = 0.001 for each comparison ) . In addition , there were statistically significant changes in the components of the TSS . At week 24 , ACR20 responses were achieved by 63 % and 61 % of patients in the adalimumab 40 mg every other week and 20 mg weekly groups , respectively , versus 30 % of patients in the placebo group ( P < or = 0.001 for each comparison ) . At week 52 , ACR20 responses were achieved by 59 % and 55 % of patients taking adalimumab 40 mg every other week and 20 mg weekly , respectively , versus 24 % of patients taking placebo ( P < or = 0.001 for each comparison ) . At week 52 , physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo ( mean change in HAQ score -0.59 and -0.61 , respectively , versus -0.25 ; P < or = 0.001 for each comparison ) . A total of 467 patients ( 75.4 % ) completed 52 weeks of treatment . Adalimumab was generally well tolerated . Discontinuations occurred in 22.0 % of adalimumab-treated patients and in 30.0 % of placebo-treated patients . The rate of adverse events ( both serious and nonserious ) was comparable in the adalimumab and placebo groups , although the proportion of patients reporting serious infections was higher in patients receiving adalimumab ( 3.8 % ) than in those receiving placebo ( 0.5 % ) ( P < or = 0.02 ) , and was highest in the patients receiving 40 mg every other week . CONCLUSION In this 52-week trial , adalimumab was more effective than placebo at inhibiting the progression of structural joint damage , reducing the signs and symptoms , and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX OBJECTIVE To evaluate the effectiveness and safety of anti-tumor necrosis factor ( anti-TNF ) therapies in rheumatoid arthritis ( RA ) , and to identify the factors involved in this response . METHODS Dynamic prospect i ve cohort study of patients with RA treated with anti-TNF under clinical practice conditions .  Effectiveness was evaluated using Disease Activity Score ( DAS ) 28 , European League Against Rheumatism ( EULAR ) response , Health Assessment Question naire ( HAQ ) , and time to treatment failure . Prior adherence was evaluated retrospectively and safety was evaluated by adverse events ( AE ) . The analysis was restricted to anti-TNF-naive patients . RESULTS The study included 161 patients treated for RA during 6 years ( 60 infliximab , 79 etanercept , and 22 adalimumab ) . At 6 months , 15 % reached a good EULAR response and 38 % a moderate response . A mean decrease of -1.5 ( p < 0.0001 ) was observed in the DAS28 and of -0.34 in the HAQ ( p < 0.0001 ) ; however , women showed poorer progress in terms of DAS and HAQ . In the first year , 64.3 % did not experience treatment failure and this figure was 50.5 % after 2 years . In one-third , glucocorticoids were withdrawn and in the remainder the dose was reduced by 50 % . Adherence to treatment , selection of etanercept , and intensification of infliximab were associated with a lower probability of premature failure in the multivariate model . AE were similar to other those in studies and no outst and ing differences in safety were found between the 3 anti-TNF therapies . CONCLUSIONS Anti-TNF treatments are effective and safe , reducing the activity of the disease , disability , and the need for corticosteroids . Patients who displayed good adherence prior to the anti-TNF treatment and were treated with etanercept or with increasing doses of infliximab had the best chance of displaying a response 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 Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate  , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo .  Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for  adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities  , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) .  METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX OBJECTIVE To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis ( RA ) . METHODS  Methotrexate (MTX)-naive patients with active early RA were r and omly allocated to receive MTX plus placebo or MTX plus infliximab ( 3 mg/kg or 6 mg/kg ) at weeks 0 , 2 , and 6 and then every 8 weeks through week 46 . Data for patients younger than age 65 years were included in the analyses . A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available . RESULTS The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo ( 0.5 % versus 1.3 % ; P > 0.5 ) . However , the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone ( 8 % versus 14 % ; P = 0.05 ) . Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability ( odds ratio 2.4 ; P < 0.001 ) ; this likelihood was not significantly greater in patients receiving MTX alone . The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group ( P = 0.010 ) . CONCLUSION The actual employment rates among patients in the 2 treatment groups were not different . However , patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone OBJECTIVE This study , known as STAR ( Safety Trial of Adalimumab in Rheumatoid Arthritis ) , evaluated the safety and efficacy of adalimumab ( Humira ) , a fully human monoclonal tumor necrosis factor-alpha ( TNF-a ) antibody , when given with st and ard antirheumatic therapy in patients with active rheumatoid arthritis ( RA ) not adequately responding to such therapies .  St and ard antirheumatic therapy included traditional disease modifying antirheumatic drugs ( DMARD ) , low dose corticosteroids , nonsteroidal antiinflammatory drugs ( NSAID ) , and /or analgesics . METHODS In this 24-week , double-blind , placebo-controlled study , 636 patients with RA were r and omly assigned to receive adalimumab 40 mg subcutaneously ( sc ) every other week ( n = 318 ) or placebo ( n = 318 ) while continuing st and ard antirheumatic therapy . The frequencies of adverse events , serious adverse events , severe or life-threatening adverse events , adverse events leading to withdrawal , infection , or serious infection were the primary endpoints . Secondary endpoints were determined by American College of Rheumatology ( ACR ) response criteria . RESULTS During the study , the majority of patients received concomitant traditional DMARD ( 83.5 % ) and /or corticosteroids , NSAID , and /or analgesics ( 97.3 % ) . Overall , 56.0 % of patients continued treatment with one , 23.6 % with 2 , and 3.9 % with > or = 3 traditional DMARD . At 24 weeks , there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events ( 86.5 % vs 82.7 % ) , serious adverse events ( 5.3 % vs 6.9 % ) , severe or life-threatening adverse events ( 11.9 % vs 15.4 % ) , or those leading to withdrawal ( 2.8 % vs 2.2 % ) . There were also no statistically significant differences in the rates of infections ( 52.2 % vs 49.4 % ) or serious infections ( 1.3 % vs 1.9 % ) between the groups . The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD ( 0 , 1 , or 2 ) . Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 ( 52.8 % vs 34.9 % ) , ACR50 ( 28.9 % vs 11.3 % ) , and ACR70 ( 14.8 % vs 3.5 % ) response rates at Week 24 ( p < or = 0.001 ) . CONCLUSION This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant st and ard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA . The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to st and ard antirheumatic therapy , including one or more traditional DMARD  , corticosteroids , NSAID , and analgesics The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis . Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate ( MTX ) or other disease-modifying antirheumatic drugs ( DMARDs ) .  Patients ( n = 1,161 ) with active rheumatoid arthritis , not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time , were included in a structured clinical follow-up protocol . Information on diagnosis , disease duration , previous and ongoing DMARDs , treatment start and termination , as well as cause of withdrawal was prospect ively collected during the period of March 1999 through December 2004 . Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs . Five-year level ( one-year ) of adherence to therapy was 36 % ( 69 % ) for patients receiving infliximab in combination with MTX compared with 65 % ( 89 % ) for patients treated with etanercept and MTX ( p < 0.001 ) . Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept ( p < 0.001 ) . Also , the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers ( p < 0.001 ) . Moreover , patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs ( p < 0.010 ) . The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events . In addition , the study identifies low C-reactive protein level , high age , elevated health assessment question naire score , and higher previous number of DMARDs as predictors of premature treatment termination . In summary , treatment with etanercept has higher adherence to therapy than treatment with infliximab . Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs
BACKGROUND In 2011 , the Agency for Health Care Research and Quality ( AHRQ ) published a systematic review on the comparative effectiveness of disease-modifying anti-rheumatic drugs ( DMARDs ) used to treat adults with rheumatoid arthritis ( RA ) .
The publication was an up date to a 2007 report .
AHRQ compiled this report in an attempt to summarize and integrate the available data for clinicians to make evidence based practice decisions for their patients since there is limited consensus among the medical community regarding the comparative effectiveness of drugs used to treat RA .
The report reveals there is still much research to be done concerning the side effects of these agents and their influence in different patient subgroups .
OBJECTIVES To : ( a ) utilize review findings to make diagnostic and treatment management decisions in clinical practice , ( b ) inform clinicians on the findings from the up date d AHRQ 's 2011 comparative effectiveness review on drug therapy for RA in adults , and ( c ) identify shortcomings in the current research and future directions revealed by the report .
SUMMARY Rheumatoid arthritis is a major public health burden .
The 2011 up date d AHRQ report includes several new medications approved by the FDA since 2007 .