Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology · 2025
Dupilumab Dampens Mucosal Type 2 Response During Acetylsalicylic Acid Challenge in N-ERD Patients.
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Eckl-Dorna Julia, Morgenstern Christina, Poglitsch Katharina, Arnoldner Tamara, Gangl Katharina, Bartosik Tina J, Campion Nicholas J, Tu Aldine, Stanek Victoria, Schneider Sven, Bangert Christine
Аннотация
BACKGROUND: Non-steroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is characterised 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.
OBJECTIVE: To investigate the dynamics of nasal mediators during ASA provocation in N-ERD patients before and 24 weeks after therapy with the IL-4 receptor alpha-blocking antibody dupilumab (EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256)).
METHODS: Nasal 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 2 h 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 24 weeks of dupilumab therapy.
RESULTS: Sixty 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 24 weeks of dupilumab therapy and was independent of the development of ASA tolerance. Transcriptomics revealed dampened upregulation of type 2 associated pathway 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.
CONCLUSION AND CLINICAL RELEVANCE: Treatment 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.
TRIAL REGISTRATION: EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256).
OBJECTIVE: To investigate the dynamics of nasal mediators during ASA provocation in N-ERD patients before and 24 weeks after therapy with the IL-4 receptor alpha-blocking antibody dupilumab (EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256)).
METHODS: Nasal 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 2 h 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 24 weeks of dupilumab therapy.
RESULTS: Sixty 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 24 weeks of dupilumab therapy and was independent of the development of ASA tolerance. Transcriptomics revealed dampened upregulation of type 2 associated pathway 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.
CONCLUSION AND CLINICAL RELEVANCE: Treatment 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.
TRIAL REGISTRATION: EudraCT (2019-004889-18) and ClinicalTrials.gov (NCT04442256).