Jean-Claude Becker

Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors

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 randomly 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.

Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial

Objective: To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year, randomised, placebo-controlled, double-blind phase, followed by an open-label, long-term extension (LTE). Methods: Patients continued etanercept (25 mg twice weekly) and were randomised 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 randomised; 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.

Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial

OBJECTIVE To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA). METHODS In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) ≥2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1:1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigators global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score. RESULTS Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P = 0.006) and 30/10 mg/kg (P = 0.022) groups, but not for 3 mg/kg group (P = 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigators global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms. CONCLUSION The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.

Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate.

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 Questionnaire [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.

Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial)

Background Several agents provide treatment for established rheumatoid arthritis (RA), but a crucial therapeutic goal is to delay/prevent progression of undifferentiated arthritis (UA) or very early RA. Objective To determine the impact of T-cell costimulation modulation in patients with UA or very early RA. Methods In this double-blind, phase II, placebocontrolled, 2-year study, anti-cyclic citrullinated peptide (CCP)2-positive patients with UA (not fulfilling the ACR criteria for RA) and clinical synovitis of two or more joints were randomised to abatacept (∼10 mg/kg) or placebo for 6 months; the study drug was then terminated. The primary end point was development of RA (by ACR criteria) at year 1. Patients were monitored by radiography, MRI, CCP2, rheumatoid factor and 28 joint count Disease Activity Score (DAS28) over 2 years. Results At year 1, 12/26 (46%) abatacept-treated versus 16/24 (67%) placebo-treated patients developed RA (difference (95% CI) −20.5% (−47.4% to 7.8%)). Adjusted mean changes from baseline to year 1 in Genant-modified Sharp radiographic scores for abatacepttreated versus placebo-treated patients, respectively, were 0 versus 1.1 for total score, and 0 versus 0.9 for erosion score. Mean changes from baseline to year 1 in MRI erosion, osteitis and synovitis scores were 0, 0.2 and 0.2, respectively, versus 5.0, 6.7 and 2.3 in the abatacept versus placebo groups. Safety was comparable between groups; serious adverse events occurred in one patient (3.6%) in each group. Conclusion Abatacept delayed progression of UA/very early RA in some patients. An impact on radiographic and MRI inhibition was seen, which was maintained for 6 months after treatment stopped. This suggests that it is possible to alter the progression of RA by modulating T-cell responses at a very early stage of disease. Trial registration number NCT00124449.

Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial

Objective: Assess the effect of abatacept on progression of structural damage over 2 years in patients with rheumatoid arthritis who had an inadequate response to methotrexate. Methods: 539 patients entered an open-label extension of the AIM (Abatacept in Inadequate responders to Methotrexate) trial and received abatacept. Radiographic assessment of the hands and feet was performed at baseline, year 1 and year 2. At year 2, each patient’s radiographs were scored for progression blinded to sequence and treatment allocation. Results: In patients treated with abatacept for 2 years, greater reduction in progression of structural damage was observed in year 2 than in year 1. The mean change in total Genant-modified Sharp scores was reduced from 1.07 units in year 1 to 0.46 units in year 2. Similar reductions were observed in erosion and joint space narrowing scores. Following 2 years of treatment with abatacept, 50% of patients had no progression of structural damage as defined by a change in the total score of ⩽0 compared with baseline. 56% of patients treated with abatacept had no progression during the first year compared with 45% of patients treated with placebo. In their second year of treatment with abatacept, more patients had no progression than in the first year (66% vs 56%). Conclusions: Abatacept has a sustained effect that inhibits progression of structural damage. Furthermore, the mean change in radiographic progression in patients treated with abatacept for 2 years was significantly lower in year 2 versus year 1, suggesting that abatacept may have an increasing disease-modifying effect on structural damage over time.

Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial

Objective To evaluate abatacept treatment over 3 years in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX). Methods Patients randomised to abatacept or placebo (+MTX) during the 1-year double-blind period of the Abatacept in Inadequate responders to Methotrexate (AIM) trial received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed for patients who received ≥1 dose of abatacept, regardless of randomisation group. Efficacy was assessed for patients randomised to abatacept who entered the LTE. Results 433 and 219 patients were randomised and treated with abatacept or placebo, respectively; 378 and 161 entered the LTE. At year 3, 440/539 patients were ongoing. No unexpected safety events were observed in the LTE. By year 3, incidence rates of adverse event and serious adverse events were 249.8/100 and 15.1/100 patient-years, respectively. Incidence rates were generally stable over time. At year 3, 84.8%, 63.4% and 37.5% of patients achieved American College of Rheumatology (ACR) criteria of 20, 50 and 70, respectively, compared with 82.3%, 54.3% and 32.4% of patients at year 1. Mean changes in Genant-modified Sharp scores were reduced progressively over 3 years, with significantly greater inhibition during year 3 compared with year 2 (p=0.022 for total score). Conclusion In MTX-inadequate responders with RA, abatacept provided consistent safety and sustained efficacy over 3 years. The data suggest an increasing inhibitory disease-modifying effect on radiographic progression.

Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study.

Objective. To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis. Methods. Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years. Results. Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respectively. Using exploratory analyses, improvements observed at Year 1 in the 10 mg/kg group were maintained at Year 5, as assessed by ACR responses (ACR20 = 77.1% vs 82.7%; ACR50 = 53.0% vs 65.4%; ACR70 = 28.9% vs 40.4% at Years 1 and 5, respectively) and disease activity (Low Disease Activity State = 48.2% vs 58.5%; Disease Activity Score-28-defined remission = 25.3% vs 45.3% at Years 1 and 5, respectively). Conclusion. Abatacept maintained the efficacy observed at Year 1 over 5 years of treatment, and demonstrated consistent safety and tolerability. These data, along with relatively high retention rates, support the longterm clinical benefit provided by selective T cell costimulation modulation. Clinical trial registry: ClinicalTrials.gov; clinical trial registration number: NCT00254293.

Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment

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, randomised 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.

Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept: open-label extension of the ATTEST Study

Objective To assess the efficacy and safety of abatacept in biological-naive patients with rheumatoid arthritis and an inadequate response to methotrexate treated in the long-term extension (LTE) of the ATTEST trial. Methods Patients randomly assigned to abatacept, placebo or infliximab completing the 1-year double-blind period were eligible to receive abatacept ∼10 mg/kg in the open-label LTE. Efficacy to year 2 is presented for patients randomly assigned to abatacept or infliximab who switched to open-label abatacept. Safety data are presented for all patients entering LTE regardless of double-blind treatment. Results Of 431 patients randomly assigned, 79.8% remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept patients achieved disease activity score 28-defined remission (<2.6). Safety with abatacept during the cumulative study period was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept. Conclusion In methotrexate-inadequate responders, abatacept efficacy was maintained over 2 years. For infliximab-to-abatacept patients, efficacy improvements were seen in year 2 after patients switched to abatacept. Switching directly from infliximab to abatacept was well tolerated. These data demonstrate that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept is a viable treatment option.