Targeting FcRn for immunomodulation: a promising therapy in autoimmune inflammatory rheumatic diseases

Autoimmune inflammatory rheumatic diseases (AIIRD) are systemic disorders characterized by breakdown of immune tolerance and production of pathogenic IgG autoantibodies, leading to chronic inflammation and tissue damage. The rapid and selective lowering of pathogenic IgG therefore has therapeutic appeal. The neonatal Fc receptor (FcRn) is a key regulator of IgG homeostasis, which mediates the IgG half-life extension and transportation across cell barriers, while also facilitating antigen presentation. Targeting FcRn offers a novel, precision medicine approach to reduce pathogenic IgG burden and regulate immunity without inducing broad immunosuppression.

This review summarizes FcRn biology, discusses the therapeutic rationale for FcRn inhibition, maps the evolving pipeline of FcRn inhibitors, and integrates key preclinical and clinical evidence across rheumatic indications. It also addresses practical considerations for clinical implementation and pharmacoeconomics, together with future directions for the field.

FcRn inhibition accelerates IgG catabolism and potentially dampens downstream inflammatory circuits by reducing immune-complex-mediated activation and related immune signaling. This rationale is supported by multiple preclinical models and emerging clinical data. Several FcRn-targeted agents, including efgartigimod, nipocalimab, and IMVT-1402, are currently in clinical development for various indications encompassing idiopathic inflammatory myopathies (IIM), Sjögren's disease (SjD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA).

FcRn blockade represents a promising precision-medicine strategy for IgG-driven AIIRD. Future studies should define optimal patient populations, identify predictive biomarkers, optimize next-generation molecules, and clarify long-term safety, pharmacoeconomic value, and opportunities for indication expansion.