Eosinophilic Granulomatosis with Polyangiitis: Latest Findings and Updated Treatment Recommendations

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) causes necrotizing vasculitis and eosinophil-rich granulomatous inflammation in small- to medium-sized vessels, resulting in multiple organ damage. EGPA is classified as an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, with myeloperoxidase-ANCA detected in approximately one-third of the patients. Conventional treatment of EGPA relies on systemic glucocorticoids (GCs) in combination with cyclophosphamide when poor prognostic factors are present; however, the dilemma between disease control and drug-related adverse effects has long been a challenge. Recent studies have revealed that the genetic background, pathophysiology, and clinical manifestations differ between ANCA-positive and ANCA-negative patients; however, mepolizumab, an interleukin (IL)-5 inhibitor, is effective in both groups, suggesting that the IL-5-eosinophil axis is deeply involved in the pathogenesis of both ANCA-positive and ANCA-negative EGPA. This review summarizes the latest knowledge on the pathophysiology of EGPA and focuses on the roles of eosinophils and ANCA. We then introduce the current treatment recommendations and accumulated evidence for mepolizumab on EGPA. Based on current unmet clinical needs, we discuss potential future therapeutic strategies for EGPA.

Keywords: antineutrophil cytoplasmic antibody; eosinophil; eosinophilic granulomatosis with polyangiitis; interleukin-5; mepolizumab.

Figure 1

Eosinophils matured in the bone marrow migrate to the peripheral blood and are mobilized to tissues. Eosinophils are differentiated from CD34-positive hematopoietic stem cells in the bone marrow by transcription factors, such as GATA-1, PU.1, and C/EBP, and mature in the presence of granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin (IL)-5, and IL-3. Mature eosinophils are released from the bone marrow into the peripheral blood by IL-5. In the peripheral blood, eosinophils circulate, roll around on the endothelial cells, and leak out from blood vessels by binding eosinophil surface adhesion molecules (β1 and β2 integrins) to vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1) expressed on vascular endothelial cells. Type 2 innate lymphoid cells (ILC2s) abundantly produce IL-5 in response to IL-33 from epithelial and endothelial cells during allergic inflammation. Eotaxin produced by epithelial and stromal cells cooperates with IL-5 to selectively mobilize eosinophils to sites of eotaxin expression. In addition, cytokines such as IL-4, IL-5, and IL-13 and eotaxins also contribute to the migration of eosinophils into inflammatory tissues.

Figure 2

Clinical manifestations differ between ANCA-positive and ANCA-negative EGPA. In antineutrophil cytoplasmic antibody (ANCA)-positive cases of eosinophilic granulomatosis with polyangiitis (EGPA), rapidly progressive glomerulonephritis and peripheral neuropathy are more likely to occur. In contrast, ANCA-negative cases are more likely to develop cardiac and pulmonary involvement. Gastrointestinal lesions, purpura, and alveolar hemorrhage are observed regardless of ANCA status.

Figure 3

Genetic differences between ANCA-positive and ANCA-negative EGPA lead to different pathophysiology. Antineutrophil cytoplasmic antibody (ANCA)-negative eosinophilic granulomatosis with polyangiitis (EGPA) is genetically associated with GPA33 and IRF1/IL5. In this group, the interleukin (IL)-5-eosinophil axis plays a central role in the pathogenesis. Specifically, IL-5 produced by T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) promotes eosinophil maturation and proliferation in the bone marrow and extravasation from the peripheral blood to the site of inflammation in concert with eotaxins. Eosinophils that reach to the tissues initiate degranulation, and cytoplasmic granules, such as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), exhibit cytotoxicity, causing eosinophilic inflammation. In contrast, ANCA-positive EGPA is genetically associated with HLA-DQ. In this group, circulating neutrophils are primed by inflammatory cytokines and complement C5a. Primed neutrophils expose cytoplasmic ANCA antigens to the cell surface, allowing circulating ANCA produced by activated B cells to bind to ANCA antigens. The Fc fragments of ANCA further activate neutrophils via Fcγ receptor (FcγR), which result in the overproduction of reactive oxygen species and the formation of neutrophil extracellular traps. Thus, neutrophil-mediated vasculitis represents the main pathology in ANCA-positive EGPA. Both ANCA-positive and ANCA-negative EGPA share genetic variants in TSLP, BCL2L11, CDK6, GATA3, BACH2, and LPP/BCL6, which may lower the activation threshold of Th2 cells and eosinophils.

Figure 4

The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA).