TARGETING COMPLEMENT AND PROTEASOME PATHWAYS IN RHEUMATOID ARTHRITIS: EMERGING THERAPEUTIC STRATEGIES

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial inflammation, cartilage destruction, and bone erosion, leading to disability and reduced quality of life. Although conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have improved outcomes, many patients remain refractory or develop adverse effects, necessitating exploration of novel therapeutic strategies. The complement and proteasome pathways play pivotal roles in RA pathogenesis by sustaining immune activation, cytokine amplification, and NF-κB–mediated inflammatory signaling. Pharmacological interventions targeting these pathways, including complement inhibitors (C3, C5, C5aR antagonists) and proteasome inhibitors (Bortezomib, Carfilzomib, Immunoproteasome-selective agents), have demonstrated promising efficacy in preclinical and early clinical studies. Furthermore, combination regimens and dual-targeting approaches provide synergistic effects by simultaneously disrupting extracellular and intracellular inflammatory mechanisms. Advances in immunoproteasome-selective molecules, oral small-molecule inhibitors, nanoparticle-based delivery, and biomarker-driven patient selection are expected to enhance both safety and therapeutic outcomes. Collectively, targeting the complement and proteasome pathways represents an innovative and promising frontier in RA management, particularly for difficult-to-treat and refractory cases.