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Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis
  1. Diane van der Woude1,
  2. Solbritt Rantapää-Dahlqvist2,
  3. Andreea Ioan-Facsinay1,
  4. Carla Onnekink3,
  5. Carla M Schwarte3,
  6. Kirsten N Verpoort1,
  7. Jan W Drijfhout4,
  8. Tom W J Huizinga1,
  9. Rene E M Toes1,
  10. Ger J M Pruijn3
  1. 1Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Department of Rheumatology, Umeå University Hospital, Umeå, Sweden
  3. 3Department of Biomolecular Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands
  4. 4Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
  1. Correspondence to Dr Diane van der Woude, Department of Rheumatology, Leiden University Medical Centre, PO Box 9600, Leiden RC 2300, The Netherlands; dvanderwoude{at}


Background Anti-citrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA).

Objective To investigate whether the recognition of citrullinated epitopes changes during disease onset or progression, by studying the fine specificity of ACPA in serum samples collected throughout the disease course, from before the onset of arthritis to longstanding RA.

Methods Antibodies recognising five distinct citrullinated antigens were determined by enzyme-linked immunosorbent assay. Serum samples from 36 individuals who had donated blood before and after disease manifestation were used to investigate the development of citrullinated antigen recognition before disease onset. The association of ACPA reactivities with disease outcome was studied using sera from anti-cyclic citrullinated peptide-2 (CCP2)-positive patients with undifferentiated arthritis (UA) who did or did not progress to RA (UA–RA n=81, or UA–UA n=35). To investigate the ACPA recognition profile in patients with RA over a prolonged period of time, baseline serum samples from 68 patients were compared with samples obtained 7 years later.

Results The number of recognised citrullinated peptides increased in the period preceding disease onset. At the time of disease manifestation, patients with UA who later developed RA recognised significantly more peptides than UA–UA patients. At later stages of the disease course, the ACPA fine specificity did not change.

Conclusion Epitope spreading with an increase in the recognition of citrullinated antigens occurs before the onset of RA. Immunological differences in ACPA fine specificity between UA–UA patients and UA–RA patients are present at baseline and are associated with the future disease course.

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  • Funding DvdW was supported by the Dutch Organisation for Scientific Research (AGIKO grant). REMT was supported by the Dutch Organisation for Scientific Research (VIDI and VICI grant). Supported in part by research funding from the European Community FP6 funding project Autocure and the FP7 funding project Masterswitch.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the medical ethical committee university of Umea, and Leiden University Medical Centre.

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