Background/Purpose: Serum anti-CCP antibodies are specific for RA in the setting of inflammatory arthritis (IA) and can be elevated for several years prior to the onset of IA during the preclinical period of autoimmunity in RA. Understanding the origins of anti-CCP is critical to understanding the etiology of RA. Prior studies demonstrate that positivity of autoantibodies (e.g. RF and ANA) increase with increasing age. Similar associations have not been reported for anti-CCP. We sought to further evaluate the association of age and anti-CCP3.1 that detects IgG and IgA reactivity in subjects without RA.

Methods: From the Studies of the Etiology of RA (SERA) cohort, we included 1037 RA-free first-degree relatives (FDRs) of probands with RA, and from the Myogenic and Osteogenic Responses to Exercise and Ibuprofen (MOXI) Study, we included the baseline sample of 187 subjects aged 59-75 years without RA. Serum was tested by ELISA for CCP2 (IgG, Axis-Shield) and CCP3.1 (IgG/IgA, Inova) with positivity based on manufacturerÕs recommendations. A random subset of 279 FDRs also had serum testing by ELISA on a CCP3 substrate using isotype-specific IgA (CCP-IgA) and IgG (CCP-IgG) secondary reagents (Inova, for research only) with positivity based on a cut-off level that was positive in <5% of 154 anonymous blood donors. Analyses included logistic regression and McNemarÕs test. 

Results: FDRs were 81% female, 76% white, 40% ever smokers and 53% shared epitope (SE) positive. MOXI Subjects were 66% female, 82% white and 47% ever smokers. Overall in FDRs, anti-CCP3.1 positivity was more prevalent than CCP2 (8.2 v. 2.7%, p<0.01). There was an association between increasing age (per year) and anti-CCP3.1 positivity (OR=1.03 95% CI 1.02-1.05) that remained significant after adjusting for sex, race, smoking and SE. When stratified by age group, the higher prevalence of anti-CCP3.1 was significant after age 50 (Figure). In MOXI Subjects, anti-CCP3.1 positivity was also more prevalent than CCP2 (23.5 v. 1.6%, p<0.01). When considering specific isotypes, in FDRs ³50 years, anti-CCP-IgA positivity was more prevalent than CCP-IgG (17.3 v. 8.3%, p=0.04). Anti-CCP-IgA positivity was also associated with increasing age (per year) (OR=1.04 95% CI 1.02-1.07). There was no association of age and anti-CCP2 (p=0.78) or CCP-IgG (p=0.24).

Conclusion: This is the first study to demonstrate increasing anti-CCP3.1 positivity with increasing age in subjects without RA. This association appears to be driven by IgA reactivity, and may reflect an ongoing mucosal immune process. Additional studies are needed to determine potential pathogenicity or other phenotypic associations of anti-CCP-IgA in older adults, but these findings have important clinical and research implications. Age should be considered in the clinical interpretation of anti-CCP3.1 in subjects without IA, and identifying mechanisms of anti-CCP-IgA generation in older adults could provide insight into the etiology of RA.