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Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study
  1. W H Bos1,
  2. G J Wolbink1,2,
  3. M Boers1,3,4,
  4. G J Tijhuis1,
  5. N de Vries5,
  6. I E van der Horst-Bruinsma3,
  7. P P Tak5,
  8. R J van de Stadt1,
  9. C J van der Laken1,3,
  10. B A C Dijkmans1,3,
  11. D van Schaardenburg1,3
  1. 1Jan van Breemen Instituut, Amsterdam, The Netherlands
  2. 2Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands
  3. 3Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands
  4. 4Department of Epidemiology and Biostatistics, VU University Medical Centre, Amsterdam, The Netherlands
  5. 5AMC/University of Amsterdam, Department of Clinical Immunology and Rheumatology; Amsterdam, The Netherlands
  1. Correspondence to Dr D van Schaardenburg, Jan van Breemen Instituut, Jan van Breemenstraat 2, 1056 AB Amsterdam, The Netherlands; d.v.schaardenburg{at}


Background Anti-citrullinated protein antibodies (ACPA) are associated with increased risk for rheumatoid arthritis.

Objective To investigate the effect of the presence and levels of ACPA on arthritis development in patients with arthralgia.

Methods Patients with arthralgia positive for ACPA or IgM rheumatoid factor (IgM-RF) were tested for the shared epitope (SE) and were prospectively followed up for at least 12 months. Absence of clinical arthritis at inclusion and arthritis development during follow-up were independently confirmed by two investigators. Cox regression hazard analyses were used to calculate hazard ratios (HRs) for arthritis development.

Results 147 patients with arthralgia were included (50 ACPA positive, 52 IgM-RF positive and 45 positive for both antibodies). After a median follow-up of 28 months (interquartile range (IQR) 19–39), 29 patients developed arthritis in a median of 4 (IQR 3–6) joints and 26 (90%) of these were ACPA positive. The presence of ACPA (HR = 6.0; 95% confidence interval (95% CI) 1.8 to 19.8; p = 0.004), but not of IgM-RF (HR = 1.4, 95% CI 0.6 to 3.1) nor the SE (HR = 1.5, 95% CI 0.7 to 3.0), was associated with arthritis development. Within the group of ACPA-positive patients, the risk for arthritis was enhanced by the presence of IgM-RF (HR = 3.0; 95% CI 1.4 to 6.9; p = 0.01) and high ACPA levels (HR = 1.7; 95% CI 1.1 to 2.5; p = 0.008), but not the SE (HR = 1.0; 95% CI 0.5 to 2.1; p = 1.0).

Conclusion In patients with arthralgia the presence of ACPA (but not of IgM-RF or SE) predicts arthritis development. The risk in ACPA-positive patients may be further increased by the concomitant presence of IgM-RF or high levels of ACPA.

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  • Competing interests None.

  • Ethics approval Approval from the ethics committee, Jan van Breemen Instituut/ Slotervaart Hospital, Amsterdam, The Netherlands.

    The funding source did not have any involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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