Rheumatology & Autoimmunity (Sep 2022)

Mechanism‐driven strategies for prevention of rheumatoid arthritis

  • V. Michael Holers,
  • Kristine A. Kuhn,
  • M. Kristen Demoruelle,
  • Jill M. Norris,
  • Gary S. Firestein,
  • Eddie A. James,
  • William H. Robinson,
  • Jane H. Buckner,
  • Kevin D. Deane

DOI
https://doi.org/10.1002/rai2.12043
Journal volume & issue
Vol. 2, no. 3
pp. 109 – 119

Abstract

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Abstract In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor. This period before clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an “at‐risk” status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at‐risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production, which should normally be transient, but instead is followed by a systemic spread of the autoimmunity as manifested by serum autoantibody elevations, ultimately driving the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial “checkpoints” that in principle should constrain or resolve autoimmunity; however, instead, the checkpoints “fail” and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt, or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at‐risk state, or approaches that target novel pathways.

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