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RA and the Mucosal Origins Hypothesis Examined

Nat Rev Rheumatol; 2018 Sep; Holers, et al

Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative and predictive patterns of RA-related autoantibodies, especially for anti-citrullinated protein antibodies (ACPAs), a recent investigation found. In addition, in serologically positive individuals without arthritis, designated ACPA-positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. Another discovery revealed that a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately, arthritis development, should provide insights into new therapeutic approaches to prevent RA.


Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: Protection turns to destruction. Nat Rev Rheumatol. 2018;14(9):542-557.