FcRn antagonists in ITP

Abstract

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. It is a diagnosis of exclusion and is associated with a persistent platelet count of <100×109/L without identifiable cause. In almost two thirds of patients, immunoglobulin G (IgG) autoantibodies directed against platelet receptors can be detected. They are associated with increased platelet clearance and destruction, inhibition of platelet production, and are also thought to impair platelet function. The clinical impact in many patients is an increased risk of bleeding and impaired quality of life. Current treatments have limited efficacy and significant side effects. Additionally, although current guidelines can educate treatment decisions, there is no real treatment paradigm which exists ('trial and error' approach), and optimal treatment decisions for each patient need to be individualised and remain a challenge in many cases, highlighting the current unmet needs. A novel approach to treatment is based on lowering levels of pathogenic IgG autoantibodies and is explored in this review. The neonatal Fc receptor (FcRn) is a major regulator in the homeostasis of IgG and albumin protecting them from degradation. FcRn-mediated extension of the half-life for IgG antibody responses is beneficial in the protection against pathogens, it will also prolong the serum half-life of IgG autoantibodies therefore promoting autoimmune diseases and their chronicity. It is postulated that targeted reduction of IgGs through FcRn blockade may either prevent or reduce the pathogenic actions of IgG autoantibodies and represents an exciting novel treatment modality in ITP. In this review article, we discuss the role of FcRn as the central regulator of IgG homeostasis, the therapeutic approaches involving IgG reduction, and the clinical trial results of two FcRn antagonists currently investigated in patients with ITP, efgartigimod and rozanolixizumab.