Physical Activity Moderates Inflammatory Gene Expression in Rheumatoid Arthritis

Abstract

Background: While general population studies have shown associations between greater physical activity and lower inflammatory markers, effects of physical activity on systemic inflammation in immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) are unknown. We examined whether physical activity associates with differential expression of inflammatory genes in RA. Methods: Data derived from an observational RA cohort. Physical activity was measured with the GT9X ActiGraph Link for 7 consecutive 24-hour periods. Clinical data and peripheral whole blood for RNA sequencing were collected. Physical activity groups were defined by the highest and lowest tertiles of moderate/vigorous activity (metabolic equivalent level ≥2.00). RNA extraction, library preparation, Illumina sequencing, and gene expression data processing were performed using established methods. Genes differentially expressed in the most versus least active groups were identified using DESeq2 with the Independent Hypothesis Weighting (IHW) multiple testing procedure and adjusting for sex, age, and race/ethnicity. Ingenuity Pathway Analysis (IPA) Canonical Pathway and Upstream Regulator Analyses were employed on differentially expressed genes with a P<0·1 ranked by log2-fold change to identify biological pathways affected by physical activity. Findings: 35 participants were included (mean age 56±12 years; 91% female; race/ethnicity 31% white, 9% African American, 9% Asian, 40% Hispanic). 767 genes were differentially expressed (padj<0.1) between high versus low activity groups. The high activity group exhibited downregulation of innate and adaptive immune signaling pathways implicated in RA pathogenesis including CD40, STAT3, TREM-1, IL-17a, IL-8, toll-like receptor and interferon signaling. Upstream cytokine activation states demonstrated lower TNF-alpha and interferon among individuals in the high vs. low activity group. Interpretation: RA patients who were more physically active had lower expression of genes involved in innate and adaptive immune signaling compared to those who were more sedentary, providing mechanistic evidence that physical activity may confer protective effects on RA disease outcomes. Funding: This work is supported by NIH/NIAMS R01 AR069616 and NIH/NHLBI K23HL138461-01A1. Additional support from the Rheumatology Research Foundation. Declaration of Interest: None to declare. Ethical Approval: The UCSF Institutional Review Board approved all procedures (UCSF IRB protocol #17-21790) and all participants provided written informed consent.