A potential role for chlamydial infection in rheumatoid arthritis development

SUMMARY

The authors of this article, led by GCIR Professor Axel Finckh, assessed the relationship between self-reported and serologic evidence of prior chlamydial infection, rheumatoid arthritis (RA)-related autoantibodies and risk of RA-development.
This is a nested study within a prospective Swiss-based cohort including all first-degree relatives of RA patients (RA-FDR) who answered a question 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. The authors conducted a nested case-control analysis by measuring the serological status against Chlamydia trachomatis' major outer membrane protein. They replicated their analysis in an independent United States-based RA-FDR cohort.
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%, 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.
In 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.

Link to full article: https://doi.org/10.1093/rheumatology/kead682

Funding: This work was supported by the Swiss National Science Foundation, the Warnery Foundation and Rheumasearch Foundation. This work was also partially supported by an unrestricted IMUL research fund. The work from the US-SERA project was supported by NIH/NIAMS.

Why is it important?

The development of rheumatoid arthritis (RA) is believed to begin with an infection at a mucosal site, leading to widespread autoimmunity. This hypothesis is supported by studies in populations at-risk of RA by demonstrating the concurrent presence of inflammation, RA-associated autoantibody production and/or mucosal dysbiosis. Currently, research has concentrated on three mucosal sites: the lung, the gut and the gingiva. However, the initiation of autoimmunity in RA may occur also at the genital tract. By analysing a large prospective cohort of individuals at risk for RA, the authors of this article discovered a significant higher prevalence of self-reported chlamydial infection among individuals with RA autoimmunity. Therefore, the authors recommend assessing Chlamydial infections in future epidemiological and mechanistic studies as a potential risk factor for RA development.

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