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

Abstract

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.

The likelihood of persistent arthritis increases with the level of anti-citrullinated peptide antibody and immunoglobulin M rheumatoid factor: a longitudinal study of 376 patients with very early undifferentiated arthritis

“…The overlap between RF and anti-CCP positivity may be greater in established RA (93% in a study of 784 RA patients, mean disease duration 18 years) [30], than in early arthritis (50 to 80% in different studies) [5,7,31]. In the present study only 58% (37/64) of antibody positive patients with persistent arthritis were positive for both RF and anti-CCP.…”

High serum cholesterol predicts rheumatoid arthritis in women, but not in men: a prospective study

“…Another limitation is the lack of data on anti-citrullinated antibody (ACPA) status after diagnosis, which is due to the fact that for the majority of patients the diagnosis was before routine ACPA analysis was available. However, we did have data on RF, and RF positivity and ACPA positivity are known to have a major overlap in patients with RA [ 47 ]. Previous studies have indicated that predictors differ for RF/ACPA-positive versus RF/ACPA-negative RA [ 48 ].…”

Genetic influences modulating the radiological severity of rheumatoid arthritis

“…The variance of radiological hand and foot damage that could be explained by these measurements was 44% at 5 years and only 32% at 10 years 16. In established disease the presence of RFs and anti-citrullinated protein antigens (ACPA) are both independently associated with increased radiological damage,17 but the variance in radiological damage related to these markers is modest at 3% and 2%, respectively 17. These results highlight the need to identify additional biomarkers predictive of severe RA that could be used to target treatments more effectively.…”