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

Antibodies to cyclic citrullinated peptides (anti-CCP) exhibit high specificity for rheumatoid arthritis (RA) [1]. Recent studies demonstrated that shared epitope (SE) alleles are strongly associated with anti-CCP-positive but not anti-CCP-negative RA [2], and indeed are more strongly associated with anti-CCP than with RA itself [3,4]. These findings lend strong support to the concept of anti-CCP-positive RA as a distinct entity [2]. Furthermore, anti-CCP has been shown to influence radiographic progression in prospective studies, with some evidence of an interaction with SE alleles [2,5]. However, the presence of anti-CCP is associated with the presence of rheumatoid factor (RF) [3], which also is an established severity factor in RA in prospective studies of progression [6] as well as longstanding disease [7].Whether associations of anti-CCP with disease severity are independent of RF remains unclear. The influence of SE alleles on disease severity appears to vary among populations, with most studies suggesting an association with erosivity [8]. Several studies have suggested that the association of SE alleles with radiographic outcome is relevant only in RF-negative individuals [8-10]. Because carriage of SE alleles is associated with anti-CCP but not RF, it was recently suggested [3] that effects of SE alleles on disease severity may be indirect and secondary to an association with anti-CCP. In the present study we determined associations between radiographic outcome in longstanding disease (as assessed by modified Larsen's score) and RF, anti-CCP and SE alleles. We report independent associations of RF and anti-CCP with radiographic severity of disease, suggesting that both of these factors may have important influence on pathways that lead to joint damage. We concur with previous studies suggesting that SE alleles are associated with radiographic outcome only in RF-negative individuals, and confirm a strong association between anti-CCP status and SE alleles, w