Assessment of combination therapy responses in early rheumatoid arthritis defined by presence or absence of anti-citrullinated protein antibodies

Abstract

BackgroundUK guidelines recommend that all patients with early active rheumatoid arthritis are offered combination disease-modifying anti-rheumatic drugs (DMARDs) and short-term corticosteroids. This heterogeneous disease has several subsets; one crucial subdivision is defined by the presence or absence of anti-citrullinated protein antibodies (ACPA). These subsets may differ in their treatment responses. We used data from a published randomised controlled trial to assess whether responses to intensive combination treatments in early rheumatoid arthritis differ by ACPA status. MethodsThe Combination Anti-Rheumatic Drugs in Early Rheumatoid Arthritis trial randomised 467 patients with early active disease to receive: methotrexate, methotrexate plus ciclosporin, methotrexate plus prednisolone, or methotrexate plus ciclosporin plus prednisolone in a factorial-design. Patients were assessed 6-monthly for 2 years. In this secondary analysis we assessed 431 patients with available ACPA status. To minimise multiple testing we used a mixed-effects repeated measures ANOVA model to test for an interaction between ACPA and treatment on mean changes from baseline to 2 years for each outcome (Larsen score, disease activity score in 28 joints [DAS28], health assessment questionnaire, EuroQol, and physical component and mental component summary scores). When a significant interaction was present, mean changes in outcomes were compared between treatment groups at each time-point using t tests stratified by ACPA status. Odds ratios (ORs) for the onset of new erosions with treatment were calculated stratified by ACPA. FindingsOf the 431 rheumatoid arthritis cases, 310 (72%) were ACPA-positive and 121 (28%) were ACPA-negative. Effect of treatment on radiological progression differed according to ACPA status, with a significant interactive effect between ACPA and treatment on Larsen score changes observed (p<0·001, ANOVA). ACPA-positive patients had significant reductions in Larsen score progression with all treatments; no effect was seen in ACPA-negative disease. ACPA-positive patients receiving triple therapy had the greatest benefits compared with those on monotherapy (2-year mean Larsen score increase 3·66 [95% CI 2·27–5·05] vs 9·58 [6·76—12·39]; OR for new erosions 0·32 [0·14–0·72], p=0·003). ACPA-negative patients had negligible radiological progression irrespective of treatment (2-year mean Larsen score increase 1·70 [0·29–3·10] with triple therapy vs 2·72 [1·15–4·29] with monotherapy; 7% developed new erosions). The beneficial effects of high-dose corticosteroids on reducing disease activity and improving physical health were confined to ACPA-positive disease. InterpretationIn our study, combination DMARDs and corticosteroids provided radiological, disease activity, and physical health benefits only to patients with ACPA-positive early rheumatoid arthritis. These findings suggest that ACPA is an important biomarker for guiding treatment decisions in rheumatoid arthritis. They indicate that current guidelines advocating combination DMARDs and corticosteroids in all patients with early active disease might require reconsideration. FundingArthritis Research UK, National Institute for Health Research, NIHR Biomedical Research Centre.