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It is well established that the autoantibodies that characterize both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are present systemically years before patients develop disease. In both these autoimmune rheumatic diseases, evidence is growing that local autoimmune processes occur at epithelial surfaces potentially initiating localized autoimmunity. For RA, these are mucosal surfaces including the oral mucosa, lung, and gut. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. For SLE, the skin may be integral in pathogenesis. It is proposed that defective clearance of apoptotic debris leads to initial innate immune responses preceding autoimmunity. Many tissues may be implicated but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger suggest that keratinocytes may be a key site of initiation. In both diseases, a local break in immune tolerance could lead to systemic autoimmunity, and, in the gut, bacterial organisms that colonize the intestine may influence the localized gut immune response through T-cells and promote the development of systemic autoimmunity. In this review, we discuss the evidence for localized epithelial autoimmunity in those at risk of RA and SLE and early disease. Localized autoimmunity at the oral mucosa, lung, gut, and skin will be considered as potential initiating sites of ARD-related autoimmunity.

The systemic autoantibodies that characterize rheumatoid arthritis (RA) are detectable well before patients develop disease and may originate from sites distant to the synovial joints. There is growing evidence that local autoimmune processes occur at mucosal sites in the earliest phases of RA, as well as in predisposed individuals who have not yet progressed to clinical disease. Mucosal autoimmunity has been described at the oral mucosa, lung, and gut in these subjects, and it is conceivable that different sites may provide the primary trigger for systemic autoimmunity in different individuals. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. A break in immune tolerance could lead to localized and then systemic autoimmunity, a hypothesis compatible with an etiological model for anti-citrullinated protein antibody (ACPA) positive RA. At the gut mucosa, the composition of the intestinal microbiome is central to local immune regulation. Here, there is evidence from animal models that alteration of the local microbiome can influence the balance of pro- and anti-inflammatory T cells and promote the development of autoimmune disease. In this review, we discuss the evidence for localized mucosal autoimmunity in those with preclinical and early RA. Autoimmunity at the oral mucosa, lung, and gut will be considered as potential initiating sites of RA-related autoimmunity.