Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis

Arthritis Res Ther. 2006;8(4):R128. doi: 10.1186/ar2017.


Several recent publications have established a strong association between anti-cyclic citrullinated peptide antibody (anti-CCP)-positive rheumatoid arthritis (RA) and carriage of shared epitope (SE) alleles. Although anti-CCP have also been associated with more severe RA, the issue of whether this is independent of rheumatoid factor (RF) has not been addressed. To identify associations between RF, anti-CCP, SE status and radiological damage, we studied a large cross-sectional cohort with longstanding RA. Individuals (n = 872) enrolled in the study all fulfilled the American College of Rheumatology criteria for RA, had a minimum disease duration of 3 years, and at least one definite radiographic erosion was present in hands or feet. Radiographs were scored blind at study entry by a single musculoskeletal radiologist using a modified Larsen's score. Anti-CCP and RF levels were determined using enzyme-linked immunosorbent assay, and DRB1 typing was performed using polymerase chain reaction based methodology. Both anti-CCP and RF levels were strongly associated with radiographic severity (P < 0.0001). In subgroups stratified for both anti-CCP and RF status, evidence of independent associations of both antibodies with radiographic outcome was found (P < 0.0001). An association of SE alleles with radiographic severity was present only in RF-negative individuals. Anti-CCP positivity was associated with SE status with evidence of a gene-dose effect, most markedly in RF-negative individuals (P < 0.01). Anti-CCP and RF status are independent severity factors for RA, with SE alleles playing at most a secondary role. Our data support the view that previously described associations between SE and radiological severity, especially in RF-negative patients, may be indirect and due to an association with anti-CCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antibodies / blood*
  • Arthritis, Rheumatoid / blood*
  • Arthritis, Rheumatoid / diagnostic imaging*
  • Arthritis, Rheumatoid / immunology
  • Arthrography*
  • Cohort Studies
  • Cross-Sectional Studies
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / genetics
  • Female
  • Gene Dosage
  • Humans
  • Male
  • Middle Aged
  • Peptides, Cyclic / immunology*
  • Rheumatoid Factor / blood*
  • Severity of Illness Index


  • Antibodies
  • Epitopes
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Rheumatoid Factor