A potential role for chlamydial infection in rheumatoid arthritis development.

Objectives: To assess the relationship between self-reported and serological evidence of prior chlamydial infection, rheumatoid arthritis (RA)-related autoantibodies and risk of RA development.

Methods: This is a nested study within a prospective Swiss-based cohort including all first-degree relatives of RA patients (RA-FDR) who answered a questionnaire on past chlamydial infections. Primary outcome was systemic autoimmunity associated with RA (RA autoimmunity) defined as positivity for anti-citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF). Secondary outcomes were high levels of RA autoimmunity, RA-associated symptoms and RA autoimmunity, and subsequent seropositive RA diagnosis. We conducted a nested case-control analysis by measuring the serological status against the major outer membrane protein of Chlamydia trachomatis. We replicated our analysis in an independent USA-based RA-FDR cohort.

Results: Among 1231 RA-FDRs, 168 (13.6%) developed RA autoimmunity. Prevalence of self-reported chlamydial infection was significantly higher in individuals with RA autoimmunity compared with controls (17.9% vs 9.8%, odds ratio [OR] = 2.00; 95% CI: 1.27, 3.09; P < 0.01). This association remained significant after adjustments (OR = 1.91; 95% CI: 1.20, 2.95). Stronger effect sizes were observed in later stages of RA development. There was a similar trend between a positive C. trachomatis serology and high levels of RA autoimmunity (OR = 3.05; 95% CI: 1.10, 8.46; P = 0.032). In the replication cohort, there were significant associations between chlamydial infection and RF positivity and incident RA, but not anti-CCP positivity.

Conclusion: Self-reported chlamydial infections are associated with elevated RA autoimmunity in at-risk individuals. The differing association of chlamydial infections and ACPA/RF between cohorts will need to be explored in future studies, but is consistent with a role of mucosal origin of RA-related autoimmunity.