Background/Purpose: The preclinical period of rheumatoid arthritis (RA) development is characterized by elevations of serum RA-related autoantibodies (Abs) including Abs to citrullinated protein antigens (ACPA) and rheumatoid factor (RF). Serum ACPAs are highly predictive of future inflammatory arthritis (IA) classifiable as RA, and recent data suggesting that ACPAs are directly pathogenic in joint disease highlight the need to understand the etiology of ACPA development. In addition, it remains unknown why RA disproportionately impacts women compared to men, and data suggest hormonal factors may influence the risk of developing RA. Importantly, prior data from our group identified that oral contraceptive pill (OCP) use was associated with a decreased risk for serum RF positivity in the absence of IA (Bhatia 2007). Therefore, we hypothesize that contraceptive factors will be associated with serum ACPA positivity among arthritis-free women at increased risk for RA.

Methods: In the Studies of the Etiology of RA (SERA) project, 1243 first degree relatives (FDR) of probands with RA are enrolled who are women. Of these FDRs, we studied women who at their baseline visit had serum ELISA testing for ACPA using anti-CCP3.1 (IgG/IgA, INOVA) and a detailed prior contraceptive and pregnancy history obtained using a standardized questionnaire (N=336). To avoid familial correlation, we also randomly selected only one subject per family; therefore, our final analyses included 297 FDRs.  All subjects were without clinical IA at the time of serum testing. In cross-section, associations of ACPA and subject factors were analyzed using chi-squared and logistic regression.

Results: In multivariate analyses, prior use of OCPs was associated with a decreased risk of serum ACPA positivity (OR=0.34; 95% CI 0.15-0.79; adjusted for age, race and smoking). In addition, there was an increased risk of ACPA positivity in women who had a history of intrauterine device (IUD) use (OR=2.68; 95% CI 1.11-6.47; adjusted for age, race and smoking). ACPA(+) FDRs were slightly older than ACPA(-) FDRs, but were similar in race, smoking and shared epitope status (Table). No significant association was seen between ACPA positivity and pregnancy or breastfeeding.

Conclusion: Prior OCP use was associated with a decreased risk of ACPA positivity in these FDRs, and these results are in line with our prior findings of OCP use associated with a decreased risk of RF positivity. Of interest was the association of an increased risk of ACPA positivity with IUD use. While the mechanisms that link contraceptive factors to ACPA generation are unknown, unlike OCPs, IUDs have been shown to generate endometrial inflammatory responses. Therefore, the association of IUD use and ACPA suggest that IUD-induced endometrial inflammation may be a potential mucosal trigger of RA-related Abs. Mechanisms by which OCPs could protect and IUDs could increase risk for RA-related autoimmunity need further study.