Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis

Arthritis Rheum. 2003 Oct;48(10):2741-9. doi: 10.1002/art.11223.


Objective: To evaluate the prevalence and predictive value of anti-cyclic citrullinated peptide (anti-CCP) antibodies in individuals who subsequently developed rheumatoid arthritis (RA) and to determine the relationship to rheumatoid factor (RF) of any isotype.

Methods: A case-control study was nested within the Northern Sweden Health and Disease Study and the Maternity cohorts of Northern Sweden. Patients with RA were identified among blood donors whose samples had been taken years before the onset of symptoms. Control subjects matched for age, sex, date of sampling, and residential area were selected randomly from the same cohorts. Anti-CCP antibody and RFs were determined using enzyme immunoassays.

Results: Eighty-three individuals with RA were identified as having donated blood before presenting with any symptoms of joint disease (median 2.5 years [interquartile range 1.1-4.7] before RA). In samples obtained before the onset of RA, the prevalence of autoantibodies was 33.7% for anti-CCP, 16.9% for IgG-RF, 19.3% for IgM-RF, and 33.7% for IgA-RF (all highly significant compared with controls). The sensitivities for detecting these autoantibodies >1.5 years and </=1.5 years before the appearance of any RA symptoms were 25% and 52% for anti-CCP, 15% and 30% for IgM-RF, 12% and 27% for IgG-RF, and 29% and 39% for IgA-RF. In conditional logistic regression models, anti-CCP antibody and IgA-RF were found to be significant predictors of RA.

Conclusion: Anti-CCP antibody and RFs of all isotypes predated the onset of RA by several years. The presence of anti-CCP and IgA-RF predicted the development of RA, with anti-CCP antibody having the highest predictive value. This indicates that citrullination and the production of anti-CCP and RF autoantibodies are early processes in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / diagnosis*
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / blood*
  • Case-Control Studies
  • Citrulline / immunology*
  • Cohort Studies
  • Female
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Rheumatoid Factor / metabolism
  • Seroepidemiologic Studies


  • Autoantibodies
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M
  • Citrulline
  • Rheumatoid Factor