Conversion to seronegative status after abatacept treatment in patients with early and poor prognostic rheumatoid arthritis is associated with better radiographic outcomes and sustained remission: post hoc analysis of the AGREE study

Diahann T S L Jansen, Paul Emery, Josef S Smolen, Rene Westhovens, Manuela Le Bars, Sean E Connolly, June Ye, René E M Toes, Tom W J Huizinga, Diahann T S L Jansen, Paul Emery, Josef S Smolen, Rene Westhovens, Manuela Le Bars, Sean E Connolly, June Ye, René E M Toes, Tom W J Huizinga

Abstract

Objective: To evaluate the effects of the T-cell costimulation blocker abatacept on anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) in early rheumatoid arthritis (RA), and associations between changes in serological status and clinical response.

Methods: Post hoc analysis of the phase III AGREE study in methotrexate (MTX)-naïve patients with early RA and poor prognostic factors. Patients were randomised to abatacept (~10 mg/kg intravenously according to weight range) or placebo, plus MTX over 12 months followed by open-label abatacept plus MTX for 12 months. Autoantibody titres were determined by ELISA at baseline and months 6 and 12 (double-blind phase). Conversion to seronegative status and its association with clinical response were assessed at months 6 and 12.

Results: Abatacept plus MTX was associated with a greater decrease in ACPA (but not RF) titres and higher rates of both ACPA and RF conversion to seronegative status versus MTX alone. More patients converting to ACPA seronegative status receiving abatacept plus MTX achieved remission according to Disease Activity Score in 28 joints (C-reactive protein) or Clinical Disease Activity Index than patients who remained ACPA seropositive. Patients who converted to ACPA seronegative status treated with abatacept plus MTX had a greater probability of achieving sustained remission and less radiographic progression than MTX alone or patients who remained ACPA seropositive (either treatment).

Conclusions: Treatment with abatacept plus MTX was more likely to induce conversion to ACPA/RF seronegative status in patients with early, erosive RA. Conversion to ACPA seronegative status was associated with better clinical and radiographic outcomes.

Trial registration number: NCT00122382.

Keywords: DMARD (biologic); ant-CCP; early rheumatoid arthritis; rheumatoid factor.

Conflict of interest statement

Competing interests: PE: clinical trials and expert advice: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Samsung, Sandoz and Lilly. JSS: expert advice and speakers’ bureau: Bristol-Myers Squibb; institutional grants: Phadia. RW: advisory board: Janssen; principal investigator: Galapagos; research grants: Roche; speakers’ bureau: Bristol-Myers Squibb. MLB: employee and shareholder: Bristol-Myers Squibb. SEC: employee and shareholder: Bristol-Myers Squibb. JY: employee and shareholder: Bristol-Myers Squibb. TWJH: the Department of Rheumatology at LUMC has received lecture fees/consultancy fees from Merck, UCB, Bristol-Myers Squibb, Biotest, Pfizer, GlaxoSmithKline, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boehringer, Takeda, Zydus, Epirus and Eli Lilly. DTSLJ and REMT: nothing to disclose.

Figures

Figure 1
Figure 1
ACPA and RF titres in patients with early RA treated with abatacept+MTX compared with MTX alone. Antibody titres were determined by ELISA at baseline and months 6 and 12. Baseline to month 6 and baseline to month 12 were carried out as separate analyses. Baseline means (SD) for: *abatacept+MTX versus MTX alone were 305 (469) vs 273 (342); **abatacept+MTX versus MTX alone were 305 (534) vs 272 (514); †abatacept+MTX versus MTX alone were 297 (426) vs 272 (344); ‡abatacept+MTX versus MTX alone were 300 (537) vs 270 (524). ACPA titres were determined by assessment of second-generation anti-cyclic citrullinated peptide-2 antibodies. ACPA, anti-citrullinated protein antibody; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor.
Figure 2
Figure 2
Conversion to ACPA and RF seronegative status in patients with early RA treated with abatacept+MTX compared with MTX alone. The proportion of patients with conversion to ACPA and RF seronegative status at months 6 and 12 and estimates of difference (95% CIs) between treatment groups are shown. Baseline to month 6 and baseline to month 12 were carried out as separate analyses. ACPA, anti-citrullinated protein antibody; MTX, methotrexate; N, total number of patients in respective analysis; n, number of patients that showed seroconversion; RA, rheumatoid arthritis; RF, rheumatoid factor.
Figure 3
Figure 3
Percentage of patients achieving remission by conversion to ACPA seronegative status. Antibody titres were determined by ELISA at baseline and months 6 and 12. Baseline to month 6 and baseline to month 12 were carried out as separate analyses. ACPA, anti-citrullinated protein antibody; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; diff, difference; MTX, methotrexate.
Figure 4
Figure 4
Cumulative probability of time to achieve first sustained DAS28 (CRP) remission by conversion to ACPA seronegative status. The cumulative probability of the time to achieve sustained first DAS28 (CRP) remission over 12 months in all patients treated with abatacept+MTX or MTX alone who underwent conversion to ACPA seronegative status compared with those who remained ACPA seropositive was evaluated based on estimated Kaplan-Meier curves. DAS28 (CRP) values were measured at all study visits (screening, days 1, 15 and 29, and then every 28 days) over 12 months. Antibody titres were determined by ELISA at baseline and months 6 and 12. Baseline to month 6 and baseline to month 12 were carried out as separate analyses. ACPA, anti-citrullinated protein antibody; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 joints; MTX, methotrexate.
Figure 5
Figure 5
Radiographic outcomes in patients with early RA treated with (A) abatacept+MTX or (B) MTX alone by conversion to ACPA seronegative status. Antibody titres were determined by ELISA at baseline and months 6 and 12. Baseline to month 6 and baseline to month 12 were carried out as separate analyses. Error bars represent 95% CIs. ACPA, anti-citrullinated protein antibody; diff, difference; JSN, joint space narrowing; MTX, methotrexate; RA, rheumatoid arthritis; TSS, total Sharp score.

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