Modifiable risk factors linked to the development of rheumatoid arthritis: evidence, immunological mechanisms and prevention

Abstract

Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. Of these risk factors, cigarette smoking, nutrition, obesity, occupational exposures and periodontal disease all incrementally increase RA risk. However, the precise immunological mechanisms by which these risk factors lead to RA are not well understood. Basic and translational studies have provided key insights into the relationship between inflammation, antibody production and the influence in other key cellular events such as T cell polarization in RA risk. Improving our general understanding of the mechanisms which lead to RA will help identify targets for prevention trials, which are underway in at-risk populations. Herein, we review the modifiable risk factors that are linked to RA development and describe immune mechanisms that may be involved. We highlight the few studies that have sought to understand if modification of these risk factors reduces RA risk. Finally, we speculate that modification of risk factors may be an appealing avenue for prevention for some at-risk individuals, specifically those who prefer lifestyle interventions due to safety and economic reasons.

Keywords: diet; envrionment; mucosal; prevention; rheumatoid arthritis; risk factors; smoking.

Figure 1

Modifiable risk factors for RA and their impact on autoimmunity and inflammation. Mechanistically, the influence of external risk factors converges on a number of immune cell dysfunction, including the stimulation of the innate and adaptive immune systems. Cigarette smoke has been shown to influence the development of autoantibodies such as anti-citrullinated protein antibodies (ACPA) and Rheumatoid Factor (RF), particularly in the lungs, where it also leads to enhanced citrullination possibly through the activation of neutrophils to form neutrophil extracellular traps (NETosis). Occupational exposures, such as silica dust and textile dust, drives NLRP3 inflammasome activation leading to the release of IL1β, and other cytokines such as TNF-α and IFN-γ. Similar to cigarette smoking, silica may also influence NET formation and the release of citrullinated proteins. Dietary factors such as low vitamin D and Omega-3 fatty acid intake leads to the release of pro-inflammatory cytokines, and eicosanoids such as Leukotriene B4 (LTB4). Obesity has overlapping effects on inflammatory cytokine release with other dietary factors but is also associated with the release of key adipokines such as Adiponectin, which may influence the development of erosive arthritis in RA. Periodontitis shares features with cigarette smoke and occupational exposures, mediating similar processes but in the oral mucosa rather than the lung. Interestingly many exposures strongly influence T-cell polarization, favoring an increase in Th1 and Th17 helper T-cells, which play a crucial role in RA pathogenesis. Created with BioRender.com.