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The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia
  1. Lotte A van de Stadt1,2,
  2. Ann R van der Horst3,
  3. Margret H M T de Koning2,
  4. Wouter H Bos1,2,
  5. Gerrit Jan Wolbink1,2,
  6. Rob J van de Stadt2,
  7. Ger J M Pruijn4,
  8. Ben A C Dijkmans2,5,
  9. Dirkjan van Schaardenburg2,5,
  10. Dörte Hamann3
  1. 1Sanquin Research and Landsteiner Laboratorium, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Jan van Breemen Institute, Amsterdam, The Netherlands
  3. 3Sanquin Diagnostic Services, Amsterdam, The Netherlands
  4. 4Department of Biomolecular Chemistry, Nijmegen Center for Molecular Life Sciences, Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands
  5. 5Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr L A van de Stadt, Department of Immunopathology, Sanquin Research, PO Box 9190, 1006 AD Amsterdam, The Netherlands; l.vandestadt{at}


Objectives To determine the fine specificity of anti-citrullinated protein antibodies (ACPA) in the early phase of arthritis development, the ACPA repertoire in arthralgia patients and the association with arthritis development were studied.

Methods A total of 244 patients with arthralgia positive for anti-cyclic citrullinated peptide antibodies (aCCPs) and/or IgM rheumatoid factor (IgM-RF), without arthritis were included. Development of arthritis was defined as presence of one or more swollen joints at clinical examination during follow-up. Sera were tested at baseline for reactivity to five citrullinated peptides derived from fibrinogen (three), vimentin (one) and α-enolase (one) and five corresponding arginine peptides in an ELISA.

Results In all, 69 patients (28%) developed arthritis in a median of 3 joints after a median follow-up of 11 (IQR 5–20) months. Reactivity to each peptide was significantly associated with arthritis development (p<0.001). The ACPA repertoire did not differ between patients who did or did not develop arthritis. Among aCCP-positive patients, patients recognising two or more additional citrullinated peptides developed arthritis more often (p=0.04). The number of recognised peptides was positively associated with the aCCP level (p<0.001). Crossreactivity between different peptides was minimal.

Conclusions Arthritis development is not associated with recognition of a specific citrullinated peptide once joint complaints are present. The ACPA repertoire in some patients with arthralgia is expanded. High aCCP levels are associated with a qualitatively broad ACPA repertoire. Patients with an extended ACPA repertoire have a higher risk of developing arthritis.

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  • Funding The Netherlands Organisation for Health Research and Development (ZonMw), grant number 6100.0010 and the Dutch Arthritis Association, grant number 0801034, funded this work.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Ethics Committee of the Slotervaart Hospital and the Jan van Breemen Institute, Amsterdam, The Netherlands.

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

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