Where there's smoke, there's fire: Insights from murine models on the effect of cigarette smoke in rheumatoid arthritis development

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by joint inflammation and damage, leading to disability and pain. The etiology of RA is undefined but considered multifactorial, as interactions between genetics and environmental factors lead to the generation of autoantibodies that target synovial joints. Smoking is a wellestablished and widely studied risk factor for RA development and is associated with a reduced response to treatments and poor clinical outcomes. Murine models of inflammatory arthritis have provided many insights into the pathogenesis of RA and have recently been used to explore the relationship between cigarette smoking and RA. In this review, we comprehensively appraise the current literature investigating cigarette smoke exposure in murine models of inflammatory arthritis, focused on RA. The current literature indicates that the influence of smoke exposure on molecular and disease outcomes depends on the timepoint of exposure and genetic background of the mice. Further, dose-dependent increases in disease manifestations reproduce human clinical data that the intensity of smoking is linked to disease but demosntrate that there may be a plateau effect. Finally, we consolidate mechanistic findings to describe a potential mechanism through which cigarette smoke exacerbates murine arthritis. Understanding how these factors, genetics, timing, and intensity of exposure modulate response to CS in inflammatory arthritis models may lead to better drug development and personalized treatment strategies, ultimately improving outcomes for RA patients with a smoking history.