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Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis

Nature Reviews Rheumatology volume 8, pages 573–586 (2012)Cite this article

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Abstract

Multiple proven and potential risk factors for the development of rheumatoid arthritis (RA) have been identified, and represent interactions between genes and the environment. Proven risk factors include genetic influences on the function of the innate and adaptive immune systems, smoking, anti-citrullinated protein antibodies (ACPAs), and rheumatoid factors (RF). Potential risk factors include epigenetic control of gene expression, the microbiome and other environmental factors, Toll-like receptors, cytokines, and Fc receptors. Preclinical abnormalities such as circulating RF and ACPAs may occur more than 10 years prior to the onset of clinical disease. However, the precise mechanisms whereby these risk factors lead to clinical disease remain unclear. It is possible that, combined with activation of the innate immune system, a subset of ACPAs initiates the disease in the cartilage or synovium after binding to endogenous citrullinated proteins. Subsequent engagement of Fc receptors and complement activation would lead to secondary inflammation in the synovium with induction of a perpetuating cycle of chronic synovitis.

Key Points

  • Rheumatoid arthritis (RA) exhibits multiple predisposing factors that precede its development

  • Genetic risk factors are prominent, involving genes of the MHC as well as many non-MHC genes associated with immune responses and inflammation

  • The presence of elevated serum levels of autoantibodies such as rheumatoid factors and antibodies to citrullinated proteins may precede the clinical onset of RA by over 10 years and could, in some cases, represent a normal adaptive response to neoantigens

  • The most important environmental risk factor for RA defined to date is smoking

  • The precise mechanism of initiation of the clinical disease is unknown but may involve antibodies directed against specific citrullinated proteins and repeated activation of innate immunity

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Figure 1: Proposed mechanism of initiation of RA.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, 1775 Aurora Court, Aurora, 80045, CO, USA

    William P. Arend

  2. Division of Rheumatology, Department of Medicine, Allergy and Immunology, University of California San Diego School of Medicine, 9500 Gilman Drive MC #0656, La Jolla, 92093, CA, USA

    Gary S. Firestein

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Arend, W., Firestein, G. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol 8, 573–586 (2012). https://doi.org/10.1038/nrrheum.2012.134

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