Multisite Chronic Pain Reveals Neuro–Immune–Metabolic Dysregulation across Rheumatoid Arthritis and Depression

Multisite chronic pain (MCP) frequently co-occurs with immune and depressive disorders, yet whether it reflects coordinated cross-domain multi-omic dysregulation remains unknown. Using UK Biobank data (19,484 baseline participants; 32,870 to 399,476 for 15.9-year follow-up), we identified MCP-related multi-omic signatures spanning 59 biochemical measures, 168 metabolites, and 2,920 proteins. Notably, these signatures showed graded dysregulation [controls < depression < rheumatoid arthritis (RA) < comorbidity] with increasing disease burden, were associated with increased risk of incident RA and depression, and partially mediated their bidirectional association. We further identified HNMT as a depression risk factor, FGF21 as an RA risk factor, MME as a depression protective factor, and platelet count/FGF21/HNMT as shared factors using Mendelian randomization. Beyond disease outcomes, the signatures were associated with brain structural impairment and health-related behaviors (smoking/fish intake/physical activity), and aligned with polygenic liability for immune-metabolic-psychiatric traits. Together, these findings demonstrate that MCP reflects coordinated neuro-immune-metabolic dysregulation underlying RA-depression comorbidity and functions as a systems-level phenotype linking immune processes and depression.