Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors

Arthritis Rheum. 2004 Feb;50(2):380-6. doi: 10.1002/art.20018.


Objective: Autoantibodies have been demonstrated in single serum samples from healthy subjects up to 10 years before they developed rheumatoid arthritis (RA). However, the time course for the development of antibodies before onset of clinical RA is unknown, nor is it known which antibody, or combinations of antibodies, might be most sensitive or specific for predicting future development of the disease. The present study was undertaken to investigate this.

Methods: Patients with RA who had been blood donors before the onset of disease symptoms were enrolled. Frozen serum samples from each donor were retrieved, together with 2 serum samples from controls matched for age, sex, and date of donation. All samples were tested for IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies.

Results: Seventy-nine patients with RA (62% female; mean age at onset of symptoms 51 years) were included. A median of 13 samples (range 1-51) per patient were available; the earliest samples had been collected a median of 7.5 years (range 0.1-14.5) before the onset of symptoms. Thirty-nine patients (49%) were positive for IgM-RF and/or anti-CCP on at least one occasion before the development of RA symptoms, a median of 4.5 years (range 0.1-13.8) before symptom onset. Of the 2,138 control samples, 1.1% were positive for IgM-RF, and 0.6% were positive for anti-CCP.

Conclusion: Approximately half of patients with RA have specific serologic abnormalities several years before the onset of symptoms. A finding of an elevated serum level of IgM-RF or anti-CCP in a healthy individual implies a high risk for the development of RA. We conclude that IgM-RF and anti-CCP testing with appropriately high specificity may assist in the early detection of RA in high-risk populations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / diagnosis*
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / blood*
  • Citrulline / immunology*
  • Female
  • Humans
  • Immunoglobulin M / blood
  • Male
  • Middle Aged
  • Netherlands / epidemiology
  • Rheumatoid Factor / blood
  • Risk Factors
  • Sensitivity and Specificity
  • Seroepidemiologic Studies


  • Autoantibodies
  • Immunoglobulin M
  • Citrulline
  • Rheumatoid Factor