The presence of citrullinated proteins is not specific for rheumatoid synovial tissue

Arthritis Rheum. 2004 Nov;50(11):3485-94. doi: 10.1002/art.20584.


Objective: Antibodies directed toward citrullinated proteins (e.g., anti-cyclic citrullinated peptide antibodies) are highly specific for rheumatoid arthritis (RA) and are produced locally at the site of inflammation. Although the presence of citrullinated proteins in rheumatoid synovium has been described in the literature, it is uncertain whether their presence is specific for RA. The present study was undertaken to investigate this.

Methods: The local production of the anti-citrullinated protein antibodies was investigated by comparing the concentration of the antibodies (corrected for the total amount of IgG present) in paired samples of serum and synovial fluid from RA patients. The presence of citrullinated proteins in the synovial tissue was investigated by immunohistochemical analysis of synovial tissue from RA patients and from patients with other arthropathies, using a variety of specific antibodies to citrullinated proteins.

Results: In RA patients, anti-citrullinated protein antibodies constituted a 1.4-fold higher proportion of IgG in synovial fluid compared with serum, which is indicative of a local production of the antibodies. Immunohistochemical staining of citrullinated proteins was observed in the lining layer, the sublining layer, and in extravascular fibrin deposits in inflamed synovial tissue from RA as well as non-RA patients.

Conclusion: The presence of citrullinated proteins in the inflamed synovium is not specific for RA, but rather, it may be an inflammation-associated phenomenon. The high specificity of the anti-citrullinated protein antibodies is, therefore, most likely the result of an abnormal humoral response to these proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies / blood
  • Antibodies / metabolism
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Case-Control Studies
  • Citrulline / immunology
  • Citrulline / metabolism
  • Female
  • Humans
  • Immunoglobulins / metabolism
  • Immunohistochemistry / methods
  • Joint Diseases / blood
  • Joint Diseases / metabolism
  • Male
  • Middle Aged
  • Peptides, Cyclic / blood
  • Peptides, Cyclic / immunology
  • Peptides, Cyclic / metabolism*
  • Staining and Labeling
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism*


  • Antibodies
  • Immunoglobulins
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Citrulline