Causal Effects of Inflammatory Arthritis Subtypes on Fibromyalgia: A Comprehensive Mendelian Randomization Study

Fibromyalgia (FM) is a chronic pain disorder characterized by widespread musculoskeletal pain and central sensitization, often co-occurring with inflammatory arthritis (IA) in clinical presentation. While observational studies suggest a higher prevalence of FM among IA patients, the causal relationship between IA and FM remains uncertain due to potential confounding factors and the possibility of reverse causation. We employed a two-sample Mendelian randomization (TSMR) approach to evaluate the causal effect of nine IA subtypes on FM, utilizing genetic summary data from large-scale genome-wide association studies (GWAS) encompassing up to 201,581 participants (exposure: IA phenotypes) and 168,378 participants (outcome: FM). The primary analysis was conducted using the Inverse-Variance Weighted (IVW) method, with sensitivity analyses assessing robustness and pleiotropy. MR analysis revealed significant causal links between several IA subtypes and FM. Rheumatoid arthritis (OR 1.105, 95% CI 1.020-1.198), enteropathic arthritis (OR 1.207, 95% CI 1.123-1.299), Juvenile Idiopathic Arthritis (OR 1.307, 95% CI 1.183-1.445), and other IA subtypes showed an increased risk of FM (all p<0.0001). Psoriatic arthritis demonstrated no significant association with FM (OR 1.006, 95% CI 0.909-1.112, p=0.911). Sensitivity analyses confirmed no significant heterogeneity and consistent results, despite minor horizontal pleiotropy observed in MR-Egger regression. This study provides genetic evidence supporting a causal relationship between IA subtypes and an increased risk of FM. However, no significant causal link was found between psoriatic arthritis and FM. These findings emphasize the role of immune-mediated inflammation in FM pathogenesis and highlight the differential impact of various IA subtypes on FM risk.