Dupilumab dampens mucosal type 2 response during acetylsalicylic acid challenge in N-ERD patients

Non-steroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is characterized by the clinical triad of hypersensitivity to NSAIDs, nasal polyposis, and asthma. The cells and immune mediators causing acute symptoms when driving the hypersensitivity reaction to acetylsalicylic acid (ASA) ingestion, remain poorly defined. Here we investigate the dynamics of nasal immune mediators during ASA provocation in N-ERD patients before and twenty-four weeks after therapy with the IL-4 receptor alpha-blocking antibody dupilumab. Nasal mucosal lining fluids of patients with N-ERD, chronic rhinosinusitis patients with nasal polyps (CRSwNP) and healthy disease controls were collected at defined time points up to two hours after ASA provocation and analysis of thirty-three different inflammatory mediators as well as transcriptomic profiling was performed. We observed that N-ERD patients showed a significant increase in type 2 associated cytokines sixty minutes after ASA provocation as compared to the other patient groups. This effect was diminished after twenty-four weeks of dupilumab therapy and was independent of the development of ASA tolerance. Transcriptomics revealed dampened upregulation of type 2 associated pathways genes as well as enhanced downregulation of lipid and peroxisome metabolisms at ASA provocation after dupilumab therapy. Thus, treatment with dupilumab leads to reduced nasal type 2 cytokine secretion and distinct changes in the transcriptomic profile during ASA provocation, but changes in type 2 mediators show no association with tolerance development.