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Cross-reactivity of anti-modified protein antibodies is also present in predisease and individuals without rheumatoid arthritis
  1. Sanne Reijm1,
  2. Astrid S Brehler1,
  3. Solbritt Rantapää-Dahlqvist2,
  4. Atsushi Kawakami3,
  5. Takahiro Maeda4,
  6. Shin-ya Kawashiri5,
  7. Mami Tamai5,
  8. Diane van der Woude1,
  9. René E M Toes1
  1. 1Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Public Health and Clinical Medicine/Rheumatology, Umeå Universitet, Umea, Sweden
  3. 3Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  4. 4Department of Community Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  5. 5Department of Immunology and Rheumatology Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
  1. Correspondence to Sanne Reijm, Department of Rheumatology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands; s.reijm{at}

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The presence of anti-citrullinated protein antibodies (ACPAs), anti-carbamylated protein antibodies (anti-CarPAs) and anti-acetylated protein antibodies (AAPAs) is a hallmark of rheumatoid arthritis (RA). ACPA and anti-CarPA can already be detected years before RA onset.1 Moreover, it has been shown that the citrullinated epitope recognition profile of ACPA expands before RA develops. Recently, it has become clear that ACPA can display cross-reactivity to other post-translational modifications (PTMs), more specifically homocitrulline and acetyllysine, as shown at both the monoclonal and polyclonal antibody level.2 3 B cell receptor analysis of ACPA-expressing B cells from patients with RA has shown that ACPAs have undergone extensive somatic hypermutation and that this can facilitate epitope spreading to multiple citrullinated epitopes.4 Given the association of ACPA epitope spreading with progression to disease, it is relevant to obtain more insights when cross-reactivity to other PTMs is introduced. Furthermore, insights in whether cross-reactivity is also present in ACPA-positive subjects without RA or confined to subjects that will—or have developed RA will also help to better understand the evolution of anti-modified protein antibody (AMPA) responses. Therefore, we analysed cross-reactivity of the ACPA response in pre-disease samples and ACPA-positive individuals without RA. To this end, ACPA, anti-CarPA and AAPA in different cohorts were measured using modified peptides as described …

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  • Handling editor Josef S Smolen

  • Contributors SR: concept design, acquisition, analysis and interpretation of data, drafting the manuscript. ASB: acquisition of data. SRD: providing samples and data analysis. MT, TM, S-yK and AK: providing samples. DvdW: interpretation of data. REMT: concept design and interpretation of data. All authors critically revised the manuscript and approved the final version to be published.

  • Funding The project leading to this application has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 884796), Target2B! (LSHM18055-SGF), Reuma Nederland (NR 17-1-402) and from the Swedish Research Council (Dnr:2018-02551).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • 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.

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