We aimed to determine whether adipokines are associated with pain and polysymptomatic distress in patients with rheumatoid arthritis (RA) over time in a large patient registry. The cohort study was conducted in a subset of Forward; a patient-based multi-disease, multi-purpose rheumatic disease registry with patients enrolled from community-based rheumatology practices across the U.S. Adipokines (adiponectin, leptin, and fibroblast growth factor[FGF]-21) were measured on stored serum as part of a multi-analyte panel. Body mass index (BMI), pain, polysymptomatic distress, and other patient-reported outcomes (PROs) were reported on bi-annual questionnaires. Linear regression was used to evaluate independent associations between BMI, adipokines, and PROs. Cox proportional hazards models evaluated independent associations between adipokines and clinically meaningful changes in pain over time (change in numerical rating >1.1 [range 0-10], sustained over 1 year). Among 645 patients included in these analyses, there were significant differences in RA characteristics, comorbidity, PROs, and adipokines across obesity categories. Of note, severely obese patients were more likely to experience greater pain, polysymptomatic distress, and fatigue. Patients with higher FGF-21 levels had higher pain and polysymptomatic stress at baseline, were more likely to use opioids, and were more likely to have sustained worsening pain over time [HR (per 1 SD) (95% CI): 1.22 (1.02,1.46) p=0.03]] independent of BMI. Obesity and elevated levels of FGF-21 are associated with pain and polysymptomatic distress in RA. Elevated FGF-21 levels may help identify those at risk of worsening pain trajectories over time, independent of BMI. PERSPECTIVE: This study characterizes the relationship between severe obesity and pain and polysymptomatic distress in patients with rheumatoid arthritis and demonstrates that the adipocytokine Fibroblast Growth Factor-21 is independently associated with pain and predicts a worsening trajectory over time. Further mechanistic studies are needed.