Introduction

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg–Strauss syndrome, is a systemic necrotizing vasculitis that predominantly affects smalland medium-sized vessels and is characterized by asthma and blood eosinophilia [1, 2]. Although anti-neutrophil cytoplasm antibody (ANCA) presence is not constant, EGPA is classi ed as a small-sized vessel, ANCA-associated vasculitis (AAV) [3]. Clinical phenotypes and pathogenic mechanisms of this rare disease have now been partly described, but gaps in our knowledge persist. Recent advances in EGPA management have included several novel immunomodulatory drugs and biotherapies, the ef cacies of which have been or are currently being evaluated. In this review, EGPA epidemiology, pathophysiology, clinical manifestations, outcomes, and the different therapeutic options now available, including therapeutic perspectives, are addressed.

Pathophysiology

EGPA pathogenesis is not yet completely understood, but genetic background and immune dysregulation seem to be implicated.

Genetic Predisposition

Genetic studies have revealed associations between speci c human leukocyte antigen (HLA) alleles and EGPA. Indeed, genetically distinct AAV–subset associations with major histocompatibility complex (MHC) and non-MHC determi-

Y. Nguyen · L. Guillevin (*)

Reference Center for Rare Systemic and Autoimmune Diseases, Department of Internal Medicine, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France

e-mail: yann.nguyen2@aphp.fr; loic.guillevin@aphp.fr

nants were identi ed in a genome-wide association study (GWAS) on granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) but not EGPA [4]. The strongest associations were with ANCA antigen speci cities but not with the clinical phenotype. Anti-myeloperoxidase (MPO) and anti-proteinase-3 (PR3)-ANCAs were associated with HLA-DQ and HLA-DP, respectively. An earlier study found an association with the HLA-DRB4 gene, for EGPA patients harboring an HLA-DRB1*04, HLA-DRB1*07, or HLA-DRB1*09 allele (odds ratio (OR) 2.49 (95% con dence interval (95% CI) 1.58–3.09)), but HLA-DRB3 gene frequency was lower in EGPA patients than that in controls (OR 0.54 (95% CI 0.35–0.84)) [5].

A more recent GWAS conducted on 676 EGPA patients and 6809 healthy controls from 9 European countries has identi ed at least 4 signi cant associations with EGPA (P < 5 × 10−8), regardless of the ANCA status [6]. The strongest association was with the MHC, supporting the hypothesis that EGPA is a polygenic disease. This study was able to differentiate two subentities genetically and clinically, according to ANCA positivity with distinct genotypes. Compared to the general population, MPO-ANCA-positive EGPA was associated with HLA-DQ (OR 5.68; P = 1.1 × 10−28), whereas ANCA-negative EGPA had no HLA. These results might suggest potential genetic differences between MPO-ANCA-positive and MPO-ANCA-­ negative EGPA.

Immune Dysregulation

Because blood and tissue eosinophilia are among the major EGPA characteristics, eosinophils are believed to be the key players in EGPA pathogenesis. Immune dysfunction results in massive eosinophilic proliferation, impaired apoptosis, and elevated tissue toxicity attributed to eosinophil products. Defective CD95 (Apo-1/Fas)-mediated apoptosis seems to be involved in eosinophil proliferation [7]. Blood eosinophils from patients with active EGPA primarily