Mechanism-Based Drug Repurposing Strategies for Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder characterized by persistent synovial inflammation, progressive joint destruction, and systemic complications. Despite advances in disease-modifying antirheumatic drugs (DMARDs), therapeutic heterogeneity, incomplete response, safety concerns, and high treatment costs continue to limit optimal disease control. This chapter presents a mechanism-based narrative review of drug repurposing strategies in RA, emphasizing the pharmacological rationale for repositioning approved or clinically investigated agents based on shared pathogenic mechanisms. Key inflammatory pathways, including cytokine signaling, JAK–STAT, NF-κB, MAPK, and immunometabolic networks, are critically examined as therapeutic targets. The chapter integrates evidence from pharmacological studies, network pharmacology, molecular docking, multi-omics approaches, and translational clinical research to evaluate repurposing candidates originating from oncology, metabolic, cardiovascular, anti-infective, and neuropharmacological indications. Clinically supported therapies are distinguished from exploratory candidates supported primarily by preclinical or computational evidence. Major translational barriers, including inconsistent clinical validation, safety concerns, economic constraints, and regulatory challenges, are discussed. The importance of biomarker-guided patient stratification, precision rheumatology, and integrated multi-omics approaches is highlighted to improve translational success. Although mechanism-based repurposing offers considerable promise in RA, robust experimental and clinical validation remains essential before computational predictions can be translated into meaningful therapeutic outcomes.