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

RationaleNon-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 mediators causing acute symptoms when driving the hypersensitivity reaction to acetylsalicylic acid (ASA) ingestion, remain poorly defined. ObjectivesTo investigate the dynamics of nasal mediators during ASA provocation in N-ERD patients before and twenty-four weeks after therapy with the IL-4 receptor alpha-blocking antibody dupilumab. MethodsNasal mucosal lining fluids of patients with N-ERD, chronic rhinosinusitis patients with nasal polyp (CRSwNP) and healthy disease controls were collected at selected time points up to two hours after ASA provocation. Analysis of thirty-three different inflammatory mediators as well as transcriptomic profiling was performed. In N-ERD patients, provocation was repeated after twenty-four weeks of dupilumab therapy. Measurements and Main ResultsSixty minutes after provocation with ASA, N-ERD patients showed a significant increase in type 2 associated cytokines (i.e., TSLP, IL-5, and eotaxin-3) 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 (i.e., AREG) as well as enhanced downregulation of lipid (i.e., ALOX15) and peroxisome metabolisms (i.e., NOS2) at ASA provocation after dupilumab therapy. ConclusionsTreatment with dupilumab leads to reduced nasal type 2 cytokine secretion and distinct changes in transcriptomic profile during ASA provocation, but changes in type 2 mediators show no association with tolerance development.