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 Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. Decreased external home help use with improved clinical status in rheumatoid arthritis: an exploratory analysis of the Abatacept in Inadequate responders to Methotrexate (AIM) trial. 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. Development of a disease activity score based on judgment in clinical practice by rheumatologists. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. Treatment impact on estimated medical expenditure and job loss likelihood in rheumatoid arthritis: re-examining quality of life outcomes from a randomized placebo-controlled clinical trial with abatacept. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials
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 vali date the European League Against Rheumatism ( EULAR ) , the American College of Rheumatology ( ACR ) , and the World Health Organization (WHO)/International League Against Rheumatism ( ILAR ) response criteria for rheumatoid arthritis ( RA ) . METHODS EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up . In a trial comparing hydroxychloroquine and sulfasalazine , we studied construct ( radiographic progression ) , criterion ( functional capacity ) , and discriminant validity . RESULTS EULAR response criteria had good construct , criterion , and discriminant validity , ACR and WHO/ILAR criteria showed only good criterion validity . CONCLUSION EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig  per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo  ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate  , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis & NA ;  Pain intensity is frequently measured on an 11‐point pain intensity numerical rating scale ( PI‐NRS ) , where 0=no pain and 10=worst possible pain . However , it is difficult to interpret the clinical importance of changes from baseline on this scale ( such as a 1‐ or 2‐point change ) . To date , there are no data driven estimates for clinical ly important differences in pain intensity scales used for chronic pain studies . We have estimated a clinical ly important difference on this scale by relating it to global assessment s of change in multiple studies of chronic pain . Data on 2724 subjects from 10 recently completed placebo‐controlled clinical trials of pregabalin in diabetic neuropathy , postherpetic neuralgia , chronic low back pain , fibromyalgia , and osteoarthritis were used . The studies had similar design s and measurement instruments , including the PI‐NRS , collected in a daily diary , and the st and ard seven‐point patient global impression of change ( PGIC ) , collected at the endpoint . The changes in the PI‐NRS from baseline to the endpoint were compared to the PGIC for each subject . Categories of ‘ much improved ’ and ‘ very much improved ’ were used as determinants of a clinical ly important difference and the relationship to the PI‐NRS was explored using graphs , box plots , and sensitivity/specificity analyses . A consistent relationship between the change in PI‐NRS and the PGIC was demonstrated regardless of study , disease type , age , sex , study result , or treatment group . On average , a reduction of approximately two points or a reduction of approximately 30 % in the PI‐NRS represented a clinical ly important difference . The relationship between percent change and the PGIC was also consistent regardless of baseline pain , while higher baseline scores required larger raw changes to represent a clinical ly important difference . The application of these results to future studies may provide a st and ard definition of clinical ly important improvement in clinical trials of chronic pain therapies . Use of a st and ard outcome across chronic pain studies would greatly enhance the comparability , validity , and clinical applicability of these studies OBJECTIVE Rheumatoid arthritis ( RA ) patients who have inadequate response to anti-tumour necrosis factor ( TNF ) therapy  currently have treatment options that are limited and less than optimal in their risk-to-benefit ratio . Abatacept provides a new generation of RA medications that has previously been demonstrated to have positive clinical outcomes with this population . The current study sought to demonstrate the efficacy of abatacept on quality of life ( QoL ) for RA patients with inadequate response to anti-TNF therapy . METHODS Patients were entered into a double-blind , placebo-controlled , multicentre r and omized clinical trial , with 258 patients r and omized to abatacept + disease-modifying anti-rheumatic drugs ( DMARDs ) and 133 patients r and omized to placebo + DMARDS . The QoL was measured with the Short Form Health Survey ( SF-36 ) , Health Assessment Question naire ( HAQ ) and fatigue visual analogue scale , and was analysed with basic ( ANOVA , chi-square ) and multigroup growth curve techniques to assess differential change over time . RESULTS Treatment group QoL improved significantly more than placebo on the HAQ and fatigue indices , as well as seven of the eight SF-36 scales and SF-36 physical and mental summary scores . Improvement rate was faster for abatacept than for placebo on the QoL measures , and the improvements from abatacept related to normal levels of QoL on many domains . CONCLUSION Clinical ly relevant benefits of abatacept over placebo are discussed regarding improving QoL. Importantly , the larger rate of change for abatacept over placebo provides clinicians with a medication that can lead to meaningful changes in a patient 's life within a few weeks , even when the patient previously failed anti-TNF therapy OBJECTIVE T cells are involved in the pathogenesis of rheumatoid arthritis ( RA ) . In animal models of autoimmune diseases , blockade of costimulatory molecules on antigen-presenting cells has been demonstrated to be effective in preventing or treating this disease by preventing T cell activation . To date , the effect of costimulatory blockade in patients with RA is unknown . The goal of this multicenter , multinational study was to determine the safety and preliminary efficacy of costimulatory blockade using CTLA-4Ig and LEA29Y in RA patients who have been treated unsuccessfully with at least 1 disease-modifying agent . METHODS CTLA-4Ig , LEA29Y ( 0.5 , 2 , or 10 mg/kg ) , or placebo was administered intravenously to 214 patients with RA . Patients received 4 infusions of study medication , on days 1 , 15 , 29 , and 57 , and were evaluated on day 85 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( ACR20 ) . All patients were monitored for treatment safety and tolerability . RESULTS CTLA-4Ig and LEA29Y infusions were well tolerated at all dose levels . Peri-infusional adverse events were carefully monitored , and showed similar incidence across all dose groups with the exception of headaches , which were slightly more frequent in the 2 treatment groups . The incidence of discontinuations due to worsening of RA was 19 % , 12 % , and 9 % at 0.5 , 2 , and 10 mg/kg , respectively , in the CTLA-4Ig-treated patients and 3 % , 3 % , and 6 % at 0.5 , 2 , and 10 mg/kg , respectively , in the LEA29Y-treated patients ( versus 31 % in the placebo group ) . ACR20 responses on day 85 had increased in a dose-dependent manner ( 23 % , 44 % , and 53 % of CTLA-4Ig-treated patients and 34 % , 45 % , and 61 % of LEA29Y-treated patients at 0.5 , 2.0 , and 10 mg/kg , respectively , versus 31 % of placebo-treated patients ) . CONCLUSION Both of the costimulatory blocking molecules studied were generally safe and well tolerated . As compared with placebo , both CTLA-4Ig and LEA29Y demonstrated efficacy in the treatment of RA Objective : To evaluate the responsiveness of patient reported outcomes ( PROs ) , including fatigue , sleep , activity limitation , and quality of life , in patients with rheumatoid arthritis ( RA ) . Methods : Data were considered from a r and omised controlled trial comparing  abatacept ( n = 258 )  with placebo ( n = 133 ) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy ( ATTAIN study ) . PROs assessed included SF-36 , activity limitation , fatigue , and sleep . For each outcome the treatment difference , relative per cent improvement , st and ardised response mean ( SRM ) , and relative efficiency for assessing an outcome ’s ability to detect a treatment effect relative to tender joint count ( TJC ) were calculated . A relative efficiency > 1 suggests a measure that is more efficient than TJC in detecting treatment effect . Results : Moderate to large SRMs ( ⩾0.6 ) were observed for the PRO measures . In particular , SRMs ( 95 % confidence interval ) were : physician global , 0.72 ( 0.51 to 0.94 ) ; HAQ , 0.63 ( 0.42 to 0.85 ) ; SF-36 physical component score , 0.62 ( 0.40 to 0.83 ) ; SF-36 bodily pain , 0.68 ( 0.46 to 0.90 ) ; and fatigue , 0.59 ( 0.38 to 0.81 ) . Relative efficiencies for physician global ( 1.6 ) , SF-36 bodily pain domain ( 1.4 ) , pain intensity ( 1.4 ) , HAQ ( 1.2 ) , SF-36 physical component score ( 1.2 ) , fatigue ( 1.1 ) , and patient global assessment ( 1.04 ) were all more responsive than TJC . The SF-36 mental component score ( 0.3 ) , swollen joint count ( 0.6 ) , activity limitation ( 0.8 ) , sleep ( 0.7 ) , and C reactive protein ( 0.9 ) were less responsive . Conclusions : Using PROs for evaluating treatments for RA can detect improvements and will identify changes that are important to patients . In general , physical assessment s are more responsive to an effective treatment than mental assessment OBJECTIVE Abatacept , a soluble selective costimulation modulator , selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway . Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis ( RA ) and inadequate response to methotrexate when treated with abatacept ( 10 mg/kg or 2 mg/kg ) . To determine the mechanism of action of abatacept , we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial . RESULTS Following 12 months ' treatment , serum levels of interleukin 6 ( IL-6 ) , soluble IL-2 receptor , C-reactive protein , soluble E-selectin , and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo . Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group . Although there was no evidence for efficacy of the 2 mg/kg dose , small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy . CONCLUSION These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA , and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage . These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade OBJECTIVES The aims of this study were to examine the relationship between external home help ( EHH ) use ( ie , help provided by someone other than family or friends ) and clinical response and patient-reported outcomes in patients with rheumatoid arthritis ( RA ) , and to determine whether abatacept treatment in addition to methotrexate reduces the need for EHH . METHODS EHH use was recorded monthly in the Abatacept in Inadequate responders to Methotrexate ( AIM ) trial , a 12-month , r and omized , double-blind , placebo-controlled trial of abatacept in patients with active RA also receiving methotrexate .  Clinical response was defined using American College of Rheumatology ( ACR ) criteria , European League Against Rheumatism ( EULAR ) criteria , and Disease Activity Scale (DAS)-28 score . Patient-reported outcomes included the Health Assessment Question naire ( HAQ ) , 100-mm visual analog scales ( VASs ) for pain and fatigue , and the Medical Outcomes Study 36-item Short Form Health Survey ( SF-36 ) for health-related quality of life . Analysis of covariance and regression analysis were performed to investigate the relationship between change in EHH use and both clinical response and patient-reported outcomes . RESULTS Of 590 patients enrolled in the study , 232 ( 39.3 % ) were receiving EHH at baseline ( mean age , 50.2 years ; 88 % female ; 85 % white ; mean duration of RA , 8.8 years ; mean [ SD ] EHH use , 15.6 [ 11.3 ] days ) . The level of EHH use was consistently higher with poorer scores on the HAQ , pain and fatigue VASs , DAS28 , and SF-36 . At 12 months , the mean reduction from baseline in EHH use was significantly greater in patients with ACR-50 or ACR-70 clinical response , EULAR good or moderate response , DAS28 remission , and clinical ly meaningful improvements in patient-reported outcomes . On multiple regression analysis , change in SF-36 Physical Functioning subscale score was the most important contributor to change in EHH after adjustment for other variables . The mean reduction from baseline in EHH use was significantly greater with abatacept compared with placebo over the study period ( all , P<0.001 ) . CONCLUSIONS In this exploratory analysis of data from patients with active RA from the AIM trial , EHH use was decreased significantly with improvements in clinical response , disease activity , and patient-reported outcomes . Treatment with abatacept in addition to methotrexate was associated with significantly decreased EHH use , suggesting that abatacept may have been associated with improved function and increased physical independence in these patients with RA 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 In a prospect i ve study of up to 3 years ' duration of 113 patients with early rheumatoid arthritis a disease activity score ( DAS ) was developed based on the clinical judgment of 6 rheumatologists . The patients were divided in groups with high and low disease activity according to explicit rules . By various statistical methods , including discriminant analysis and multiple regression analysis , a DAS could be defined . This DAS is a continuous measure consisting of the variables Ritchie articular index , number of swollen joints , erythrocyte sedimentation rate and general health measured on a visual analog scale BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions OBJECTIVES Quality of life ( QoL ) improvement is important to demonstrate in RA clinical trials , but can be abstract . More meaningful measures of QoL include medical expenditure and job loss , aspects that have marked importance for RA patients , physicians and society . We re-examined previous positive QoL findings for abatacept over placebo by converting existing QoL measures into estimated medical expenditure and estimated likelihood of job loss . METHODS Two double-blind , placebo-controlled , multicentre r and omized clinical trials were undertaken : one for MTX failure ( n = 652 ) and one for more severe anti-TNF failure patients ( n = 391 ) . Based on derived scores using previously published formulae , measures of monthly medical expenditure , current inability to work and job loss at 6 months , 1 yr and 2 yrs were analysed . RESULTS Abatacept led to greater reduction in medical expenditure over time in MTX failure ( $ 152 lower ) and anti-TNF failure patients ( $ 122 lower ) compared with placebo at end-point . Likewise , significantly more reduction in likelihood for current and future job loss was achieved with abatacept compared with placebo , which has 25 - 64 % greater likelihood . CONCLUSIONS QoL changes provided greater reduction in medical expenditure and likelihood of an inability to work . The strong effect sizes obtained for all significant analyses suggest that the results are clinical ly meaningful . Moreover , given the nature of the variables , results should also be meaningful for patients , physicians , employers and health care insurance entities . Limitations are discussed regarding using estimated outcomes rather than analysis of actual outcomes BACKGROUND A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha ( TNF-alpha ) inhibitors . We conducted a r and omized , double-blind , phase 3 trial to evaluate the efficacy and safety of abatacept , a selective costimulation modulator , in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy .  METHODS Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy  were r and omly assigned in a 2:1 ratio to receive abatacept or placebo on days 1 , 15 , and 29 and every 28 days thereafter for 6 months , in addition to at least one disease-modifying antirheumatic drug . Patients discontinued anti-TNF-alpha therapy before r and omization . The rates of American College of Rheumatology ( ACR ) 20 responses ( indicating a clinical improvement of 20 percent or greater ) and improvement in functional disability , as reflected by scores for the Health Assessment Question naire ( HAQ ) disability index , were assessed . RESULTS After six months , the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group ( P<0.001 ) ; the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group ( 20.3 percent vs. 3.8 percent , P<0.001 ; and 10.2 percent vs. 1.5 percent , P=0.003 ) . At six months , significantly more patients in the abatacept group than in the placebo group had a clinical ly meaningful improvement in physical function , as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index ( 47.3 percent vs. 23.3 percent , P<0.001 ) . The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent , respectively , in the abatacept group and 71.4 percent and 3.0 percent , respectively , in the placebo group . The incidence of serious infections was 2.3 percent in each group . CONCLUSIONS Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy OBJECTIVE This study examined the effect of abatacept , a costimulation modulator , on the health-related quality of life ( HRQOL ) of patients with rheumatoid arthritis ( RA ) . METHODS Three hundred thirty-nine patients with RA on a background of methotrexate ( MTX ) , who participated in a multicenter , double-blind , placebo-controlled trial , were r and omized to abatacept 2 mg/kg , abatacept 10 mg/kg , or placebo .  HRQOL was assessed at pretreatment , and at 3 , 6 , and 12 months posttreatment using the SF-36 Health Survey ( SF-36 ) . Changes in SF-36 scores from baseline to 12 months were compared across treatment and placebo groups to examine HRQOL benefits of abatacept . A link between American College of Rheumatology improvement and changes in SF-36 scores was established to demonstrate the association between HRQOL outcomes and clinical response . RESULTS After 12 months of treatment , patients r and omized to abatacept 10 mg/kg showed significantly better HRQOL outcomes overall versus patients r and omized to placebo ( MANOVA F = 4.71 , p < 0.001 ) or to abatacept 2 mg/kg ( MANOVA F = 1.97 , p = 0.05 ) . Differences in SF-36 change scores between abatacept 10 mg/kg and placebo groups reached statistical significance on all 8 domain scales , the 2 summary measures , and the SF-36 utility index ( SF-6D ) . Differences in SF-36 change scores between abatacept 10 mg/kg and abatacept 2 mg/kg reached statistical significance on 5 of the 8 domain scales , the physical summary measure , and the SF-6D . Improvement in HRQOL was highly related to clinical response . CONCLUSION Abatacept 10 mg/kg plus MTX demonstrated a stronger HRQOL response than placebo plus MTX . The abatacept 2 mg/kg arm showed a very weak and transient response 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 OBJECTIVE To evaluate the efficacy , radiographic changes , and safety of abatacept and methotrexate therapy through 2 years in a long-term extension of a previously published 1-year study . METHODS Patients who received placebo during year 1 were switched to abatacept . Patients taking abatacept continued to take it . Efficacy and safety were assessed through 2 years . RESULTS Of 539 patients enrolled in the initial 1-year study , 488 completed 1 year of the long-term extension ( 2 % discontinued for lack of efficacy ) . At 2 years , patients taking abatacept had maintained their responses on the American College of Rheumatology ( ACR ) improvement criteria and the Disease Activity Score in 28 joints ( DAS28 ; using the C-reactive protein [ CRP ] level ) , as well as their physical function ( according to the Health Assessment Question naire [ HAQ ] disability index [ DI ] ) and health-related quality of life ( HRQOL ; assessed with the Short Form 36 [ SF-36 ] health survey ) , that were observed at the end of the double-blind period ( year 1 versus year 2 values were 81.9 % versus 80.3 % for ACR 20 % improvement , 25.4 % versus 30.9 % for a DAS28 [ CRP ] of < 2.6 , 71.8 % versus 66.8 % for the HAQ DI , and 9.7 versus 10.6 and 7.3 versus 7.2 , respectively , for the mean change in the physical and mental components summary scores of the SF-36 ) . In the abatacept group , post hoc analysis demonstrated further inhibition of radiographic progression during year 2 ( 57 % reduction in mean change of total score in year 2 versus year 1 ; P<0.0001 ) , and minimal radiographic progression was observed ( mean change in total score from baseline was 1.1 and 1.6 at year 1 and 2 , respectively ) . Rates of adverse events ( AEs ) and severe AEs were consistent throughout the cumulative period . CONCLUSION The improvements in signs and symptoms , physical function , and HRQOL observed after 1 year of abatacept treatment were maintained through 2 years of treatment . This durability was accompanied by a safety profile consistent with that in the double-blind portion of the study . Radiographic progression was further inhibited in year 2 compared with year 1 , suggesting an increasing effect of abatacept on the inhibition of structural damage in year 2 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 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 determine the clinical efficacy , safety , and immunogenicity of abatacept ( CTLA-4Ig ) , a selective costimulation modulator , in patients with rheumatoid arthritis ( RA ) that has remained active despite methotrexate ( MTX ) therapy .  METHODS This was a 12-month , multicenter , r and omized , double-blind , placebo-controlled study . A total of 339 patients with active RA despite MTX therapy were r and omly assigned to receive 10 mg/kg abatacept ( n = 115 ) , 2 mg/kg abatacept ( n = 105 ) , or placebo ( n = 119 ) . This report focuses on the results observed at month 12 of a phase IIb trial . RESULTS A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20 % improvement criteria ( achieved an ACR20 response ) at 1 year compared with patients who received placebo ( 62.6 % versus 36.1 % ; P < 0.001 ) . Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses ( 41.7 % versus 20.2 % ; P < 0.001 ) and ACR70 responses ( 20.9 % versus 7.6 % ; P = 0.003 ) compared with patients who received placebo . For patients treated with 10 mg/kg abatacept , there were also statistically significant and clinical ly important improvements in modified Health Assessment Question naire scores compared with patients who received placebo ( 49.6 % versus 27.7 % ; P < 0.001 ) . Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission ( Disease Activity Score in 28 joints of < 2.6 ) compared with placebo at 1 year ( 34.8 % versus 10.1 % ; P < 0.001 ) . The incidence of adverse events was comparable between the groups , and no significant formation of neutralizing antibodies was noted . CONCLUSION Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment . Abatacept was found to be well tolerated and safe over the course of 1 year . Abatacept in combination with MTX has the potential to play an important role in future RA therapy To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results
BACKGROUND Abatacept inhibits the co-stimulation of T cells and disrupts the inflammatory chain of events that leads to joint inflammation , pain , and damage in rheumatoid arthritis .
OBJECTIVES To assess the efficacy and safety of abatacept in reducing disease activity , pain , and improving function in people with rheumatoid arthritis .