Background/Purpose: EGPA variably presents eosinophil (EOS)-related features and vasculitic manifestations. Recent introduction of mepolizumab (MEP) has revolutionized the treatment of EOS manifestations of EGPA. However, the efficacy of MEP also in vasculitic phenotypes suggests direct interactions between EOS and neutrophilic inflammation in EGPA. Extracellular traps formed by neutrophils (NETs) are an important innate immune response and are involved in ANCA-associated vasculitis pathogenesis. Similarly, EOS produce extracellular traps (EETs), recently detected in tissues of EGPA patients.Our study aims to evaluate the efficacy of MEP in EGPA and the potential role of this treatment on NETs and EETs formation in different disease phenotypes.

Methods: Patients classified as EGPA according to MIRRA trial and/or ACR/EULAR 2022 criteria and eligible for therapy with MEP were consecutively enrolled. Clinical and routine blood chemistry data were collected before (T0) and after 6 (T1) and 12 (T2) months of treatment with MEP 300 mg/4 weeks. Oral steroid was tapered according to clinical judgement, therapy with immunosuppressants, if taken, was unchanged during the study. In parallel, we evaluated NETs and EETs on peripheral blood by immunofluorescence staining (Petretto et al., 2019). NETs and EETs were expressed as percentage of the total area of cells in the fields. Patients were stratified by disease phenotype according to the presence/absence of MPO-ANCA, asthma and nasal polyposis (CRSwNP) and organ involvement.

Results: 17 patients with EGPA and eligible for MEP were enrolled (53% female (9/17)). MPO-ANCA were detected in 29.4% of patients (5/17). 88% (15/17) were asthmatic, 60% of them had severe asthma. 53% (9/17) were atopic and 82% had CRSwNP. At T0 94% (16/17) were taking prednisone therapy (5.83±4.18 mg, average dose). Distribution of organ involvement is reported in Figure 1. Following MEP introduction, EOS blood count reduced from T0 to T1 (p=0.036) but not from T1 to T2, while neutrophils did not vary in any period. Steroid dose was reduced to 1.04±2.59 mg at T2 (p=0.003), with 10 patients (58.8%) being steroid-free. No relapse was observed during the study. At T0, NETs and EETs levels did not vary by ANCA status, organ involvement, EOS peak count, asthma or CRSwNP presence/severity. NETs levels were negatively correlated to total IgE titre (r=-0.52, p=0.05). EETs values are higher in atopic patients (p=0.017) regardless of steroid dose and EOS blood count. NETs and EETs decreased at T1 (respectively p=0,001 and p=0,014) but were stable between T1 and T2 in the overall group (Figure 2). After stratification for ANCA status, NETs significantly decreased only in ANCA positive patients at T1 (p=0.01), while EETs only in ANCA negative patients at T1 (p=0,025), without any difference observed between T1 and T2. No difference was found according to asthma and CRSwNP presence.

Conclusion: In a small but representative cohort of EGPA patients, NETs and EETs vary by atopic status but not by ANCA status or organ involvement. MEP treatment, after 6 months of therapy, influences NETs and EETs formation in EGPA patients, also in relation to their ANCA profile, supporting potential utility of NETs and EETs evaluation in disease management.

Figure 1. Distribution of patients according to organ involvement.

Figure 2. NETs and EETs response to mepolizumab treatment, *p=0.001, **p=0.014

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophil-and-eosinophil-extracellular-traps-in-eosinophilic-granulomatosis-with-polyangiitis-phenotype-based-characterization-and-response-to-mepolizumab/