IgG4 and Rheumatoid Arthritis: A Comprehensive Review of Its Role in Inflammation, Biomarker Potential, and Therapeutic Implications

BACKGROUND: Immunoglobulin G4 (IgG4) is the least abundant IgG subclass and has distinctive structural and functional properties, including Fab-arm exchange and limited activation of antibody-dependent effector mechanisms. These features contribute to its generally non-inflammatory and tolerogenic profile. However, the role of IgG4 in rheumatoid arthritis (RA) remains incompletely understood. OBJECTIVE: This review aims to summarize and critically evaluate the biological characteristics of IgG4, its clinical significance in RA, and the potential therapeutic implications of IgG4-mediated immune responses. EVIDENCE: Elevated serum IgG4 levels have been reported in a subset of patients with RA and have been associated with disease activity, inflammatory markers, autoantibody levels, and treatment response in some studies. IgG4 autoantibodies, including antinuclear IgG4 antibodies, have also been detected in autoimmune diseases and may influence complement activation and proinflammatory cytokine production. However, findings remain heterogeneous, and current evidence is insufficient to establish IgG4 as an independent diagnostic or prognostic biomarker in routine RA care. CONCLUSION: IgG4 may have a complex, context-dependent role in RA, potentially reflecting both immune dysregulation and compensatory anti-inflammatory responses. Further research is needed to clarify its pathogenic mechanisms, clinical utility, and potential as a therapeutic target.