ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for combination DMARDs and corticosteroids: secondary analysis of a randomized controlled trial

Abstract

Introduction: UK guidelines recommend that all early active rheumatoid arthritis (RA) patients are offered combination disease-modifying antirheumatic drugs (DMARDs) and short-term corticosteroids. Anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA may differ in their treatment responses. We used data from a randomized controlled trial - the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trial - to examine whether responses to intensive combination treatments in early RA differ by ACPA status.

Methods: The CARDERA trial randomized 467 early active RA patients to receive: (1) methotrexate, (2) methotrexate/ciclosporin, (3) methotrexate/prednisolone or (4) methotrexate/ciclosporin/prednisolone in a factorial-design. Patients were assessed every six months for two years. In this analysis we evaluated 431 patients with available ACPA status. To minimize 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 for each outcome (Larsen, disease activity scores on a 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), EuroQol, SF-36 physical component summary (PCS) and mental component summary (MCS) scores). When a significant interaction was present, mean changes in outcomes were compared by treatment group 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.

Results: ACPA status influenced the need for combination treatments to reduce radiological progression. ACPA-positive patients had significant reductions in Larsen score progression with all treatments. ACPA-positive patients receiving triple therapy had the greatest benefits: two-year mean Larsen score increases comprised 3.66 (95% confidence interval (CI) 2.27 to 5.05) with triple therapy and 9.58 (95% CI 6.76 to 12.39) with monotherapy; OR for new erosions with triple therapy versus monotherapy was 0.32 (95% CI 0.14 to 0.72; P = 0.003). ACPA-negative patients had minimal radiological progression irrespective of treatment. Corticosteroid's impact on improving DAS28/PCS scores was confined to ACPA-positive RA.

Conclusions: ACPA status influences the need for combination DMARDs and high-dose tapering corticosteroids in early RA. In CARDERA, combination therapy was only required to prevent radiological progression in ACPA-positive patients; corticosteroids only provided significant disease activity and physical health improvements in ACPA-positive disease. This suggests ACPA is an important biomarker for guiding treatment decisions in early RA.

Trial registration: Current Controlled Trials ISRCTN32484878.

Figure 1

Number of individuals in each treatment group stratified by ACPA status. ACPA, anti-citrullinated protein antibody.

Figure 2

Treatment effect on mean changes in Larsen scores in ACPA-positive and ACPA-negative patients. Standard error bars are shown for each time point; *denotes significance at P <0.05; **denotes significance at P ≤0.01; ***denotes significance at P ≤0.001; no asterisk denotes P ≥0.05. ACPA, anti-citrullinated protein antibody.

Figure 3

Treatment effect on mean changes in DAS28 scores in ACPA-positive and ACPA-negative patients. Standard error bars are shown for each time point; *denotes significance at P <0.05; **denotes significance at P ≤0.01; ***denotes significance at P ≤0.001; no asterisk denotes P ≥0.05. ACPA, anti-citrullinated protein antibody; DAS28, disease activity scores on a 28 joint count.

Figure 4

Treatment effect on mean changes in EuroQol scores in ACPA-positive and ACPA-negative patients. Standard error bars are shown for each time-point; *denotes significance at P <0.05; **denotes significance at P ≤0.01; ***denotes significance at P ≤0.001; no asterisk denotes P ≥0.05. ACPA, anti-citrullinated protein antibody.

Figure 5

Treatment effect on mean changes in PCS scores in ACPA-positive and ACPA-negative patients. Standard error bars are shown for each time point; *denotes significance at P <0.05; **denotes significance at P ≤0.01; ***denotes significance at P ≤0.001; no asterisk denotes P ≥0.05. ACPA, anti-citrullinated protein antibody; PCS, physical component summary.