ACPA-negative RA consists of subgroups: patients with high likelihood of achieving sustained DMARD-free remission can be identified by serological markers at disease presentation

Eric H. Sasso,Leonie E. Burgers,Annette H. M. van der Helm – van Mil,Debbie M. Boeters,Tom W. J. Huizinga

doi:10.1186/s13075-019-1902-2

Abstract

BackgroundDisease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA). However, underlying mechanisms are unknown and patient subgroups that achieve this outcome are insufficiently characterized. We evaluated whether serological biomarkers at disease onset, as measured within the multi-biomarker disease activity (MBDA) score, are differently expressed in RA patients who achieve sustained DMARD-free remission.MethodsTwo hundred ninety-nine RA patients were evaluated for achievement of sustained DMARD-free remission during a median follow-up of 4.3 years. Twelve biomarkers, as included in the MBDA score, were determined from the serum obtained at disease onset. Patients were categorized as having a low (< 30), moderate (30–44) or high (> 44) score. Analyses were stratified for anti-citrullinated protein antibodies (ACPA) based under the assumption that ACPA-positive and ACPA-negative RA are different disease entities.ResultsTwenty percent achieved sustained DMARD-free remission. Overall, high MBDA scores were associated with achieving DMARD-free remission (high vs. low HR 3.8, 95% CI 1.2–12.2). Among ACPA-negative RA patients, moderate or high scores associated strongly with DMARD-free remission (moderate vs. low HR 9.4, 95% CI 1.2–72.9; high vs. low HR 9.7, 95% CI 1.3–71.1). This association was independent of age and other clinical factors (high vs. low HR 8.2, 95% CI 1.1–61.8). For ACPA-negative RA patients, the biomarkers C-reactive protein, serum amyloid A and matrix metalloproteinase-3 were individually associated with sustained DMARD-free remission. Among ACPA-positive RA patients, scores were not associated with DMARD-free remission.ConclusionsACPA-negative RA patients who achieved sustained DMARD-free remission after treatment withdrawal were characterized by moderate to high MBDA scores at diagnosis. This is the first evidence that ACPA-negative RA can be subdivided in clinically relevant subsets at disease onset using a protein profile.

Highlights

Disease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA)
Sustained DMARD-free remission was achieved in 20% (59/299) of RA patients after a median follow-up of 2.9 years (IQR 2.2–4.0)
A combination of serological markers associated with sustained DMARD-free remission, independent of clinical factors we investigated whether the association between baseline multibiomarker disease activity (MBDA) score and sustained DMARD-free remission within anti-citrullinated protein antibodies (ACPA)-negative patients was independent of clinical characteristics

Summary

Introduction

Disease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA). We investigated if we could identify patients in the ACPA-negative subgroup that have the best clinical outcome, which currently is the achievement of sustained disease-modifying antirheumatic drug (DMARD)-free remission. The biological mechanisms underlying the achievement of sustained DMARD-free remission are unknown It is undefined whether this outcome is potentially achievable by all RA patients or whether the ability to permanently stop DMARDs is restricted to a set of RA patients with certain biological characteristics. The absence of autoantibodies only explains part of the variability in outcome, since a proportion of ACPA-positive patients can achieve sustained DMARD-free remission and the majority of ACPA-negative patients do not achieve it [7]. Other inflammatory proteins have not been studied in relation to sustained DMARD-free remission

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