Physical Activity Associates with Lower Systemic Inflammatory Gene Expression in Rheumatoid Arthritis

Objective While general population studies have shown inverse associations between physical activity and common inflammatory biomarkers, the effects of physical activity on inflammatory gene expression and signaling pathways in rheumatoid arthritis (RA) remain unknown. We aimed to determine whether physical activity independently associates with expression of inflammatory genes among people with RA.

Methods This was a prospective observational study of adults with RA. Physical activity was measured by quantitative actigraphy over 7 consecutive days, and peripheral blood collected during the same time period was used for RNA sequencing followed by differential gene expression, pathway, and network analyses.

Results Actigraphy and RNA sequencing data was evaluated on 35 patients. The cohort mean age was 56±12 years, 91% female, 31% white, 9% African American, 9% Asian, 40% Hispanic. We found 767 genes differentially expressed (padj<0.1) between patients in the greatest versus lowest physical activity tertiles, after adjusting for sex, age, race, and ethnicity. The most active patients exhibited dose-dependent downregulation of several immune signaling pathways implicated in RA pathogenesis. These included CD40, STAT3, TREM-1, IL-17a, IL-8, toll-like receptor and interferon signaling pathways. Upstream cytokine activation state analysis predicted reduced activation of TNF-alpha and interferon in the most active group. In sensitivity analyses we adjusted for RA disease activity and physical function and found consistent results.

Conclusion RA patients who were more physically active had lower expression of immune signaling pathways implicated in RA pathogenesis, even after adjusting for disease activity, suggesting that physical activity may confer a protective effect in RA.