Interventions for Persistent Pain Despite Low Inflammatory Activity in Rheumatoid Arthritis: A Systematic Review.

Persistent pain remains a significant clinical challenge in patients with rheumatoid arthritis (RA), even after achieving normal or low inflammatory activity. This discordance between inflammation control and pain relief suggests the involvement of mechanisms beyond active synovitis, yet the effectiveness of available interventions in this population has not been fully clarified. We conducted a systematic review to synthesize evidence on pharmacological and non-pharmacological interventions for persistent pain in RA patients with controlled inflammatory activity. Major biomedical databases were searched for studies reporting pain-related outcomes in adult RA patients, including randomized controlled trials, post hoc analyses of clinical trials, and prospective observational studies. Owing to heterogeneity in study design, interventions, and outcome measures, a narrative synthesis was performed. Eight studies met the inclusion criteria. Pharmacological interventions targeting inflammatory pathways, including conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic agents such as tumor necrosis factor and interleukin-6 receptor inhibitors, and targeted synthetic DMARDs such as Janus kinase inhibitors, demonstrated heterogeneous and generally limited effects on pain reduction once inflammation was controlled, with clinically meaningful pain frequently persisting despite improvements in disease activity. In contrast, non-pharmacological interventions, particularly exercise-based and physical therapy-oriented approaches such as nerve mobilization and structured physical activity programs, showed more consistent reductions in pain intensity independent of inflammatory markers and were often accompanied by functional improvement. Observational evidence also suggested that lifestyle-related factors, including dietary intake of omega-3 fatty acids, may be associated with pain outcomes independently of inflammatory control. Overall, these findings indicate that persistent pain in RA patients with normal or low inflammatory activity is only partially responsive to inflammation-targeted pharmacological therapy, supporting the integration of pharmacological treatment with exercise-based and lifestyle-oriented strategies within comprehensive, mechanism-informed pain management approaches.