Mechanisms of dupilumab in aspirin-exacerbated respiratory disease
Published: April 19, 2022
Aspirin-exacerbated respiratory disease (AERD) is a severe chronic respiratory disease characterized by chronic rhinosinusitis with nasal polyps and eosinophilic asthma. The nasal polyps and asthma in AERD can be difficult to treat, but the advent of targeted respiratory biologic therapy for asthma and nasal polyps has led to improvement in control of these diseases and patient quality of life. Dupilumab, respiratory biologic therapy targeting the interleukin 4 receptor alpha, is efficacious for treating both nasal polyps and asthma in patients with aspirin-exacerbated respiratory disease, but the mechanisms by which treatment with dupilumab lead to clinical improvement is not completely understood.
In a recent issue of The Journal of Allergy and Clinical Immunology (JACI), Buchheit and colleagues conducted an open label study of dupilumab for treatment of chronic rhinosinusitis with nasal polyps and asthma in patients with AERD. Twenty-two adult patients with AERD were treated with dupilumab for three months. Clinical outcomes were assessed prior to the start of dupilumab and at 1 and 3 months after starting dupilumab. They also collected nasal fluid, urine, blood, and nasal inferior turbinate cells at the three time points for mediator levels, cellular assays, and RNA sequencing. They analyzed upper and lower airway clinical response to dupilumab in patients with AERD and biomarkers associated with the clinical response to dupilumab.
After one month of treatment with dupilumab, the participants with AERD had improvement in upper and lower airway symptoms, asthma control, sense of smell, and lung function, which were sustained after three months of treatment with dupilumab. The clinical improvements corresponded with mechanistic changes in nasal and urinary eicosanoids, specifically an increase in nasal prostaglandin E2, and a decrease in nasal and urinary leukotriene E4. The authors found that the baseline nasal fluid prostaglandin E2 levels of participants who could not smell at the start of the study were significantly lower than in patients with a normal sense of smell. Further, the baseline levels of nasal fluid prostaglandin E2 corelated positively with the number of scents each participant could identify. Dupilumab treatment also led to reductions in serum and nasal IgE levels and nasal albumin levels, a marker of epithelial barrier dysfunction.
In summary, treatment with dupilumab led to rapid improvement in respiratory symptoms and smell for patients with AERD. The findings of this study suggest that changes in anti-inflammatory eicosanoids (prostaglandin E2) and inflammatory cysteinyl leukotrienes induced by interleukin receptor inhibition with dupilumab in patients with AERD are due to the combined effects of decreased interleukin 4 and 13 signaling on local respiratory tissue granulocytes, epithelial cells, and B cells.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
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