Impact of intravenous abatacept on synovitis, osteitis and structural damage in patients with rheumatoid arthritis and an inadequate response to methotrexate: the ASSET randomised controlled trial

Abstract

Objectives: This randomised, double-blind, placebo-controlled phase IIIb study evaluated the impact of abatacept on MRI pathology as a primary outcome in methotrexate (MTX)-refractory patients with rheumatoid arthritis.

Methods: Patients received intravenous abatacept (∼10 mg/kg) or placebo, on background MTX, for 4 months, followed by an 8-month open-label extension (OLE; all patients received abatacept plus MTX). Patients had 1.5T MRI with intravenous contrast at baseline, Months 4 and 12; wrist synovitis (three locations assessed), and wrist and hand (15 and eight locations assessed, respectively) osteitis and erosion were scored using OMERACT-RAMRIS.

Results: 26/27 abatacept- and 23/23 placebo-randomised patients completed Month 4 and entered the OLE; 26 and 21 completed Month 12. The primary endpoint was not achieved; mean change (SD) from baseline in synovitis was -0.44 (1.47) for abatacept versus 0.52 (1.38) for placebo (p=0.103) at Month 4. For mean change in synovitis adjusted for baseline score (sensitivity analysis), the difference between groups was -0.69, p=0.078. Adjusted mean changes (SE) in osteitis and erosion were -1.94 (0.86) and 0.45 (0.43) for abatacept, and 1.54 (0.90) and 0.95 (0.45) for placebo. Further MRI improvements were observed up to Month 12 for abatacept and from Months 4 to 12 for placebo-treated patients switched to abatacept at Month 4. Clinical efficacy was shown with abatacept and sustained to Month 12.

Conclusions: Despite small patient numbers, MRI detected structural and synovial benefit, sustained to Month 12 in abatacept+MTX-treated patients, and improvements in structural and inflammatory outcomes for placebo+MTX-treated patients following addition of abatacept.

Clinical trial registration: Clinicaltrials.gov NCT00420199.

Keywords: Disease Activity; Magnetic Resonance Imaging; Rheumatoid Arthritis; Synovitis; T Cells.

Figure 1

(A) Mean baseline and Month 4 MRI scores based on the first MRI reading and adjusted mean changes from baseline in (B) synovitis, (C) osteitis and (D) erosion scores based on the second MRI reading. Treatment groups represent treatment received in the DB period. Data are presented for all patients who had MRIs available at the visits of interest (as-observed analysis); for the analyses presented in A, data are based on MRIs read at Month 4, and for the analyses presented in (B–D), data are based on MRIs read at Month 12 (baseline and Month 4 MRIs were reread at this timepoint); patients with MRI outside of Days 92–134 were excluded from the Day 113 (Month 4) analysis, and with MRI >4 weeks prior to or after Day 337 were excluded from the Month 12 MRI analysis. Adjustment (B–D) is based on ANCOVA model with treatment as factor and baseline value as covariate. (B–D) Error bars represent 95% CI of the adjusted mean change. Synovitis was assessed only in the wrist (three regions), whereas osteitis and erosion were assessed in the wrist and MCP joints (23 sites: 15 sites in wrist, plus eight in the hand). ANCOVA, analysis of covariance; DB, double-blind; MCP, metacarpophalangeal; MTX, methotrexate.

Figure 2

MRI non-progressors at Month 4 and Month 12 in (A) synovitis score, (B) osteitis score and (C) erosion score. Treatment groups represent treatment received in the DB period. Data are presented for all patients who had MRIs available at the visits of interest (as-observed analysis); patients with MRI outside of Days 92–134 were excluded from the Day 113 (Month 4) analysis, and with MRI >4 weeks prior to or after Day 337 were excluded from the Month 12 MRI analysis. Non-progressors defined by mean change from baseline in MRI score <1 RAMRIS unit. Error bars represent 95% CI. Synovitis was assessed only in the wrist, whereas osteitis and erosion were assessed in the wrist and MCP joints. DB, double-blind; MCP, metacarpophalangeal; MTX, methotrexate; RAMRIS, rheumatoid arthritis MRI score.

Figure 3

Patients achieving improvements in disease activity according to (A) DAS28-derived criteria and (B) SDAI-derived criteria. Treatment groups represent treatment received in the DB period. DB data (Month 4) are based on the mITT population including all randomised and treated patients with data available at the visits of interest (as-observed analysis); OLE data (Month 12) are based on patients treated in the OLE, with data available at the visit of interest. Error bars represent 95% CI. CRP, C reactive protein; DAS28, Disease Activity Score 28; DB, double-blind; LDAS, low disease activity state (DAS28 (CRP) ≤3.2; SDAI≤11); mITT, modified intent to treat; MTX, methotrexate; OLE, open-label extension; Remission (DAS28 (CRP) <2.6; SDAI≤3.3); SDAI, Simplified Disease Activity Index.