Article Text

Download PDFPDF
Do autoantibody-responses mature between presentation with arthralgia suspicious for progression to rheumatoid arthritis and development of clinically apparent inflammatory arthritis? A longitudinal serological study
  1. Fenne Wouters1,
  2. Ellis Niemantsverdriet1,
  3. Nazike Salioska1,
  4. Annemarie L Dorjée1,
  5. René E M Toes1,
  6. Annette H M van der Helm-van Mil1,2
  1. 1 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2 Department of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Fenne Wouters, Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands; f.wouters{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Several nested case-control studies have shown that autoantibody-response maturation in rheumatoid arthritis (RA) precedes clinical arthritis development.1–3 This suggests a role in disease triggering. However, nested case-control studies have, similar to case-control studies, the disadvantage that controls are selected and that prospective data from non-progressing patients in a similar predisease stage are absent. The phase preceding clinically apparent inflammatory arthritis (IA) can be distinguished into an asymptomatic and symptomatic (ie, clinically suspect arthralgia, CSA) subphase. It is unknown whether autoantibody-response maturation occurs in the symptomatic phase. Likewise, its role in progression to clinical arthritis is undetermined; if autoantibody-response maturation relates to disease development, maturation is expected to be more pronounced in patients with CSA that progress compared with patients with CSA that do not. To better understand the relation between autoantibody-response maturation in time and development of clinical arthritis (RA/IA), we performed a longitudinal study on autoantibody-response maturation in patients with CSA that did and did not progress.

In serum from 147 patients with CSA, we determined with in-house ELISAs the presence and levels of IgM, IgG, IgA anti-citrullinated, anti-carbamylated and anti-acetylated protein antibodies (ACPA, anti-CarP, AAPA), resulting in nine autoantibody measurements per patient per timepoint. Autoantibody-response maturation was defined as increase in number of autoantibody reactivities or isotypes, and/or increase in autoantibody levels. Patients with CSA with paired samples at first presentation at the outpatient clinic and at IA development (n=55) or else after 2 years (n=92) were selected. Analyses were repeated with the outcome RA (the subgroup of patients with IA that fulfilled …

View Full Text


  • Handling editor Josef S Smolen

  • Contributors FW, EN and AHMvdH-vM were involved in study conception and design. FW, EN, NS and ALD contributed to collection of the data. FW performed the data analyses. FW, EN, REMT and AHMvdH-vM evaluated and interpreted the results. FW, EN and AHMvdH-vM wrote the first version of the manuscript and REMT critically revised it. All authors read and approved the final manuscript.

  • Funding This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No. 714312), and the Dutch Arthritis Society.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Local Medical Ethics Committee, named ‘Commissie Medische Ethiek’.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.