Identification of Dual Super-Response in Patients With Asthma and CRSwNP Treated With Mepolizumab

Abstract

[EN]Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) are both type 2 (T2) inflammatory diseases that frequently co-occur and are interconnected through shared immunological pathways. The anti-IL-5 monoclonal antibody mepolizumab has shown efficacy in reducing eosinophilic inflammation and improving clinical outcomes. However, the molecular mechanisms underlying response to treatment, particularly at the transcriptomic level, remain underexplored. We aimed to investigate peripheral blood transcriptomic changes and identify potential biomarkers associated with dual super-response to mepolizumab in patients with severe asthma and CRSwNP. The study population comprised 29 participants (19 patients with severe asthma and CRSwNP and 10 healthy controls). Whole blood RNA sequencing was performed before and after treatment with mepolizumab in 6 patients, followed by validation of candidate genes using qPCR. Clinical responses were assessed using the FEOS score (FEV1, exacerbations, oral corticosteroids, symptoms) and lung function measurements, and the 22-item Sino-Nasal Outcome Test (SNOT-22) score. Mepolizumab significantly improved clinical parameters, including exacerbation rates, asthma control, and the SNOT-22 score. Transcriptomic analysis identified 156 differentially expressed genes after treatment with mepolizumab, significantly enriching immune and inflammatory pathways. Twelve candidate genes were studied. Three of these genes (PNPLA1, C3AR1, and RGS1) were validated as potential predictors of super-response to treatment of asthma and CRSwNP. Baseline expression levels of RGS1 were associated with dual super-response in asthma and CRSwNP. This study provides new insights into transcriptomic changes following mepolizumab treatment and highlights RGS1 as a potential biomarker for predicting dual super-response in asthma and CRSwNP. Our findings contribute to precision medicine approaches and support the identification of optimal candidates for anti-IL-5 therapy.