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Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years

Xanthe M. E. Matthijssen , Ellis Niemantsverdriet, Tom W. J. Huizinga, Annette H. M. van der Helm–van Mil



Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients.


Careful clinical observations over time have led to the description of diseases. In addition, the subdividing of diseases has also been based on clinical observations, with differences in pathogenetic etiology identified subsequently. For instance, the subdividing of diabetes into type 1 and type 2 was based on differences in clinical presentation (young patients versus older and obese patients); this distinction was confirmed by treatment response to insulin, and subsequently fueled targeted etiological studies [1].


Longitudinal cohort

The Leiden Early Arthritis Clinic (EAC) cohort is a population-based inception cohort including all consecutive patients newly presenting with recent-onset arthritis, that was started in 1993 and has been described in [14]. Inclusion criteria were presence of synovitis determined at physical examination by a rheumatologist and symptom duration of <2 years. The department of rheumatology in the Leiden University Medical Center is the only center for rheumatic diseases in a semi-rural area with >400,000 inhabitants. Since the start of the cohort, general practitioners (GPs) were informed on the relevance of early referral, and patients referred with suspicion of early arthritis were seen with priority, generally within 2 weeks. Of note, in line with Dutch GP guidelines, autoantibodies were rarely determined in primary care [15]. Written informed consent was obtained from all participants. The study was approved by the local medical ethics committee (Commissie Medische Ethiek of the Leiden University Medical Center; B19.008).


Summary of findings

During the last 25 years, the treatment of RA has changed in several aspects. We studied outcomes of RA and observed that improved treatment strategies were paralleled by reduced disease activity in autoantibody-positive and autoantibody-negative RA, but resulting significant improvements in long-term outcomes—SDFR, mortality, and functional disability—were only present in autoantibody-positive RA and not in autoantibody-negative RA. In line with these findings, DAS28-ESR, SDFR, and functionality showed greater improvements over the last 25 years within autoantibody-positive than within autoantibody-negative RA. Especially the introduction of treat-to-target treatment adjustments was associated with significantly greater improvements in autoantibody-positive RA than in autoantibody-negative RA. The disconnection between improvements in disease activity and in several long-term outcomes suggests that the underlying pathogenesis of autoantibody-positive and autoantibody-negative RA is different. We therefore propose that the time has come to subdivide RA into type 1 and type 2.

Citation: Matthijssen XME, Niemantsverdriet E, Huizinga TWJ, van der Helm–van Mil AHM (2020) Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years: A longitudinal cohort study in the Netherlands. PLoS Med 17(9): e1003296.

Academic Editor: Carlomaurizio Montecucco, Dept. Rheumatology - I.R.C.C.S S.Matteo Hospital PAVIA, UNITED STATES

Received: January 31, 2020; Accepted: August 18, 2020; Published: September 22, 2020

Copyright: © 2020 Matthijssen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Our dataset, used for the analyses, contains potentially identifying and sensitive patient information. Therefore our data cannot be made publicly available because it is prohibited by Dutch law in the regulation “Algemene verordening gegevensbescherming” and does not comply with the study protocol as it was submitted to the local ethics committee. Inquiries can be directed to

Funding: The research leading to these results has received funding from the from the Dutch Arthritis Foundation and European Research Council (ERC, under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312, AHMvdHvM). The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TH is a member of the Editorial Board of PLOS Medicine.

Abbreviations: ACPA, anti-citrullinated protein antibody; DAS, Disease Activity Score; DAS28-ESR, Disease Activity Score–28 with erythrocyte sedimentation rate; DMARD, disease-modifying antirheumatic drug; EAC, Early Arthritis Clinic; GP, general practitioner; HAQ, Health Assessment Questionnaire; HR, hazard ratio; RA, rheumatoid arthritis; RF, rheumatoid factor; SDFR, sustained DMARD-free remission

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