Clinical Improvement of AERD Achieved With Dupilumab Use for Asthma, CRS With Nasal Polyps

Patients with aspirin-exacerbated respiratory disease (AERD) who initiated treatment with dupilumab as an add-on asthma or chronic rhinosinusitis with nasal polyps (CRSwNP) therapy reported rapid clinical improvement that was sustained after 3 months. Results were published recently in the Journal of Allergy and Clinical Immunology.

For conditions such as asthma and CRSwNP, prior research on the use of dupilumab, a fully human monoclonal antibody against the interleukin (IL)-4 receptor α-subunit (IL-4Rα) that inhibits IL-4 and IL-13 signaling, has demonstrated significant improvement in disease control and patient quality of life.

Moreover, researchers highlight that the drug has shown robust improvements in upper and lower respiratory tract symptoms among patients with AERD, which is often difficult to treat as many patients fail first-line therapies.

“Elucidating which dupilumab-induced cellular changes lead to the drug’s dramatic clinical benefit in AERD will allow for increased understanding of the underlying pathobiology of the disease and may help teach us which effector cell(s) cause the chronic inflammation in AERD,” they said.

The study authors conducted an observational study to determine the impact of IL-4Rα blockade in AERD, with parallel examination of early treatment timepoints (1 month and 3 months) for both clinical and mechanistic outcomes. Participants aged 18-75 years with AERD who met criteria for dupilumab (300 mg subcutaneously) for the treatment of moderate-to-severe eosinophilic asthma or CRSwNP were recruited from the Brigham and Women's Hospital in Boston, Massachussetts (N = 22).

Clinical outcomes were assessed at baseline and at one and 3 months after initiation of dupilumab, including sense of smell (University of Pennsylvania Smell Identification Test [UPSIT]), peak nasal inspiratory flow (PNIF), nasal polyp size, spirometry (forced expiratory volume in 1 second [FEV₁] and forced vital capacity [FVC]), and patient-reported outcome measures of sinonasal outcome test (SNOT)-22 and Asthma Control Questionnaire-6 (ACQ-6) scores.

Biological specimens of nasal fluid, urine, blood, and inferior turbinate scrapings were also collected at the 3 time points for mediator levels, cellular assays, and RNA-sequencing.

Research showed that participants experienced significantly rapid improvement in clinical measures after 1 month of dupilumab, which were sustained after 3 months of dupilumab:

• sense of smell (UPSIT; mean change of 11.3 and 11.9 at month 1 and 3, respectively; all P < .0001)
• sinonasal symptoms (SNOT-22; mean change of –34.4 and –34.5 at month 1 and 3, respectively; all P < .0001)
• peak nasal inspiratory flow (PNIF; mean change of –31.4 milliliter [mL] [P = .0023] and 36.5 mL [P = .0007) at month 1 and 3, respectively)
• lung function  (FEV₁; predicted improvement by a mean of 12.6% (P = .0002) and 12.1% (P = .0015) at months 1 and 3, respectively)
• asthma control (ACQ-6; mean change of –1.3 at 1 month that was sustained after 3 months; P < .0001)

Further findings indicated that baseline severity of smell loss correlated with lower nasal prostaglandin E₂ levels, with dupilumab found to increase nasal prostaglandin E₂ and decrease levels of nasal albumin, nasal and urinary leukotriene E₄, and serum and nasal immunoglobulin E (IgE).

Transcripts related to epithelial dysfunction and leukocyte activation/migration were noted to be downregulated in inferior turbinate tissue after treatment with dupilumab. No dupilumab-induced changes in nasal eosinophilia were observed.

“While there are multiple potential mechanisms by which dupilumab may lead to clinical improvement in patients with AERD, we cannot yet determine which mechanistic changes are the principal drivers of disease resolution, nor which are the result of direct vs indirect effects of IL-4Rα blockade,” concluded the study authors.

Reference

Buchheit KM, Sohail A, Hacker J, et al. Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2022 Apr 20;S0091-6749(22)00542-5. doi:10.1016/j.jaci.2022.04.007