Improvement of Mixed Inflammatory Environment in Nasal Secretions of Diffuse Type 2 Chronic Rhinosinusitis With Nasal Polyps Under Dupilumab

BACKGROUND: In Western countries, Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is predominantly associated with a type 2 inflammatory endotype. While nasal secretion analysis shows promise for disease endotyping, current biomarkers remain limited for accurate stratification, disease monitoring, and prediction of treatment response. OBJECTIVE: This study aimed to investigate the inflammatory patterns in nasal secretions of patients with type 2 Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) undergoing treatment with dupilumab, an anti-IL4Rα antibody. A second objective was to evaluate markers for therapy response and monitoring. METHODS: Nasal secretions and blood samples were collected at four time points from 23 patients with histological type 2 CRSwNP undergoing dupilumab treatment and compared with 10 healthy controls. Samples were analysed using proximity extension assay method by Olink. RESULTS: Proteomic analysis of nasal secretions revealed 50 differentially expressed proteins in type 2 CRSwNP compared to healthy controls. Nasal secretions of most patients revealed a mixed inflammatory endotype. Under dupilumab treatment, cytokines of all different endotypes decreased. The cytokines with the highest mean change (MCP-4, CCL23, GDNF and CCL11) showed good associations with clinical variables and were effective predictors of dupilumab response and disease control. CONCLUSION: The inflammatory environment of the nasal mucosa in histological type 2 CRSwNP is most often characterized by a mixed type 1, 2, and 3 inflammatory endotype. Targeting type 2 inflammation with dupilumab reduces inflammation markers of all three types of inflammation. GDNF has emerged as a valuable marker for stratifying therapy and monitoring success in type 2 CRSwNP under dupilumab treatment.