Skip to main content

Does ACPA-negative RA consist of subgroups related to sustained DMARD-free remission and serological markers at disease presentation? Comment on article by Boeters DM et al.

A Letter to this article was published on 20 March 2020

The Original Article was published on 14 May 2019

Letter to the Editor

We read with interest the article by Boeters DM et al. [1]. We would like to clarify the significant findings and suggest further research needed to validate the novel conclusion. In ACPA-negative patients, 1 sustained DMARD-free remission (SDFR) occurred over 5 years follow-up in 17 (6%) with baseline low (< 30) MBDA score vs approximately 50% remissions in both moderate (30–44) and high (> 44) MBDA score patients ([1], Fig. 1). All ACPA-positive RA patients had low percentages of SDFR and no difference was found by baseline MBDA score category [1]. Percentages of 3 MBDA categories did not differ (p = 0.470) between the ACPA-positive and ACPA-negative groups [1].

SDFR was recently reported by ACPA-negative vs ACPA-positive patients in the total Leiden early arthritis cohort (1993–2016; n = 1296) [2], from which the Boeters et al. study [1] was the most recent inclusion subgroup (2011–2016). In the total inclusion period (1993–2011), SDFR occurred between 5 and 15% in ACPA-positive RA vs 40 to 50% in the ACPA-negative RA [2], as in Boeters et al. [1].

Unexpectedly, in multivariate analyses ([1], Table 2), the 95 ACPA-negative RA patients with high (> 44) baseline scores had greater DMARD-free remission than the 17 reference patients with low (< 30) MBDA scores (p = 0.041). If MBDA were truly a marker of disease activity, one might expect low rather than high MBDA to predict SDFR. Alternatively, if ACPA-negative RA does consist of subgroups [1], its documentation will require further serological study in separate cohorts [2, 3] or search for genetic markers [3]. Confounding variables should be excluded, possibly clinical features related to age at onset, which was found to be a significant (p = 0.036) predictor of SDFR ([1], Table 2) and other disease variables not studied. Is it conceivable that this anomaly [1] is due to chance occurrence in a small sample size study leading to an incorrect conclusion, especially when borderline (p = 0.041) statistical correlation is found [1]?

A critical review of the value of multibiomarker disease activity score to predict remission in RA was recently published [4]. The challenging question is whether or not baseline MBDA (or serological markers) are being overinterpreted or overstated with respect to outcomes (or disease subgroups) was critically analyzed [4].

Availability of data and materials

Data are in published article and reference citations.


  1. 1.

    Boeters DM, Burgers LE, Sasso EH, Huizinga TWJ, van der Helm-van Mil AHM. 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. Arthritis Res Ther. 2019;21:1–9.

    Article  Google Scholar 

  2. 2.

    Matthijssen XM, Niemantsverdriet E, Huizinga TW, van der Helm-van Mil AHM. ACPA-positive patients benefited more than ACPA-negative patients; 25 year results of a longitudinal cohort study. Presentation 2871 at the 2019 American College of Rheumatology Meeting, Atlanta GA (pps 5098–5100 in <>).

  3. 3.

    Hedström AK, Rönnelid J, Klareskog L, Alfredsson L. Complex relationships of smoking, HLA-DRB1 genes, and serologic profiles in patients with early rheumatoid arthritis: update from a Swedish population-based case-control study. Arthritis Rheumatol. 2019;71:1504–11.

    Article  Google Scholar 

  4. 4.

    Fleischmann R. Value of the multibiomarker of disease activity score to predict remission in RA: what does the evidence show? J Rheumatol. 2019;46:443–6.

    Article  Google Scholar 

Download references


No acknowledgements or conflict of interest.


No funding contributed to the statements in the letter.

Author information




Both authors contributed to interpretation of published and comments in Letter. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to Alfonse T. Masi.

Ethics declarations

Ethics approval and consent to participate

Letter refers to published article without new subjects.

Consent for publication

Both authors agree to publication.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Masi, A.T., Fleischmann, R. Does ACPA-negative RA consist of subgroups related to sustained DMARD-free remission and serological markers at disease presentation? Comment on article by Boeters DM et al.. Arthritis Res Ther 22, 17 (2020).

Download citation


  • Rheumatoid arthritis
  • Anti-citrullinated protein antibody (ACPA)
  • Multi-biomarker disease activity (MBDA) score
  • Remission