Citrullinated Autoantigen Targets as Markers of Extra-Articular Disease in Rheumatoid Arthritis

Citrullination represents an increasingly recognized posttranslational modification stemming from underlying physiological stressors that dysregulate intracellular calcium flux. Although this enzymatic process mediated by various isoforms of peptidylarginine deiminase (PAD) is fairly ubiquitous (occurring in normal as well as pathological states), the immune response to citrullinated proteins is heavily influenced by underlying HLA status and therefore highly associated with rheumatoid arthritis (RA) (Szodoray et al. 2010). Given that the humoral immune responses to citrullinated proteins may serve as an immunological “fingerprint” in RA, the question is whether delineating targets of anti-citrullinated protein antibodies (ACPAs) can provide insight regarding the site where immune tolerance is bypassed/broken or clarify the underlying pathophysiology of articular and extra-articular manifestations in this systemic autoimmune disease—even if the relative contribution of protein deimination versus citrulline-targeted immunity remains unresolved. In fact, extensive investigation over the last 10–15 years has yielded an expanded repertoire of ACPA specificities potentially linked with defined extra-articular manifestations, such as premature atherosclerosis, myocardial dysfunction, and interstitial lung disease (ILD), which negatively impact clinical outcome. Fueling these discoveries, novel approaches for identifying citrullinated autoantigen/autoantibody combinations have supported the search for additional biomarkers of extra-articular involvement that should further elucidate the immunobiology of relevant systemic disease pathways in RA.