Dupilumab improves outcomes in aspirin-exacerbated respiratory disease

By inhibiting IL-4R alpha in aspirin-exacerbated respiratory disease, dupilumab improved respiratory symptoms and smell among other positive outcomes, according to a study published in The Journal of Allergy and Clinical Immunology.

These therapeutic effects likely are due to decreased IL-4R alpha signaling on respiratory tissue granulocytes, epithelial cells and B cells, Kathleen M. Buchheit, MD, assistant professor of medicine in the division of allergy and clinical immunology at Harvard Medical School and assistant program director of the allergy/immunology fellowship at Brigham and Women’s Hospital, and colleagues wrote.

The observational study involved 22 patients (mean age, 52.6 years; age range, 18-75 years; 54.5% women; 86.4% white) with aspirin-exacerbated respiratory disease (AERD) who were treated for severe asthma and/or chronic rhinosinusitis with nasal polyps for 3 months with dupilumab (Dupixent, Regeneron/Sanofi).

These patients had been prescribed 300 mg of dupilumab to be taken subcutaneously every other week to treat their moderate to severe eosinophilic asthma or CRSwNP from the Allergy and Immunology Clinics at Brigham and Women’s Hospital between 2018 and 2020.

Patients took part in a baseline visit immediately prior to their first dose of dupilumab, which is a fully human monoclonal antibody that targets IL-4R alpha and inhibits the signaling of IL-4 and IL-13, with follow-up visits 1 month and 3 months later.

During each visit, clinicians assessed sense of smell via the University of Pennsylvania Smell Identification Test (UPSIT), and they measured peak nasal inspiratory flow (PNIF), nasal polyp size and spirometry, in addition to sino-nasal outcome test and Asthma Control Questionnaire 6 (ACQ-Q) scores. They also collected urine, blood, nasal fluid and nasal cells from the inferior turbinate at each visit.

Eight patients had been on daily aspirin therapy after they had been desensitized to aspirin for 6 months or more before beginning dupilumab, although aspirin therapy had not helped them achieve sufficient control of their asthma or CRSwNP.

UPSIT scores improved by a mean of 11.3 after 1 month of dupilumab treatment and by a mean of 11.9 after 3 months (both, P < .0001). Also, 16 participants were anosmic with UPSIT scores less than 19 at baseline, which dropped to four patients after 1 month (OR = 0.12; 95% CI, 0.04-0.36) with sustained effects at 3 months (OR = 0.08; 95% CI, 0.02-0.28).

Similarly, SNOT-22 scores improved beyond what the researchers called the minimally clinically important difference of 8.9 points after 1 month, with a mean change of –34.4, and scores were sustained at 3 months with a mean change of –34.5 (both, P < .0001).

PNIF increased with a mean change of 31.4 mL (P = .0023) at 1 month and 36.5 mL (P = .0007) at 3 months. The researchers observed significant reductions in nasal polyp burden after 1 month of treatment (P < .0001).

FEV₁ percentages improved by a mean of 12.6% (P = .0002) at 1 month and 12.1% (P = .0015) at 3 months, with the researchers noting significant improvements in total liters of FEV₁ and forced vital capacity as well.

Based on ACQ-6 scores, patient-reported asthma control saw a mean change of –1.3 (P < .0001) that was sustained at 3 months.

There additionally were significant decreases in urinary LTE4 at 1 month (P < .0001) and 3 months (P = .0095), while nasal LTE4 decreased sevenfold at 1 month (P = .0256) and further at 3 months (P = .002).

But there was a significant increase in nasal fluid prostaglandin E2 (PGE2) induced by dupilumab, the researchers continued, nearly doubling after 1 month (P = .0103) and 3 months (P = .0063) of treatment.

The researchers further found an association between baseline nasal PGE2 levels and UPSIT scores but not between LTE4 levels and UPSIT scores. The 16 anosmic patients had a mean nasal PGE2 level of 1.6 ng/mL at baseline compared with 5.11 ng/mL among the six normosmic/hyposmic patients (P = .0168).

Also, there was a positive correlation between baseline UPSIT scores and nasal PGE2 levels (Spearman’s correlation coefficient = 0.503; P = .0171) and a trend toward positive correlation between the dupilumab-induced change in nasal PGE2 from baseline to the first month and the corresponding change in UPSIT.

After 1 month of dupilumab, nasal albumin levels significantly fell (P = .0149), and this change persisted through the 3-month visit (P = .016), with a slight trend toward decreased nasal eosinophilic cationic protein at the 1-month and 3-month visits, the researchers wrote.

There were decreases in serum (P < .0001) and nasal IgE (P = .0003) levels after 1 month that were sustained through 3 months (both, P < .0001) as well.

Finally, the researchers found 32 upregulated and 25 downregulated transcripts after 1 month of treatment during their analysis of the inferior turbinate scraping RNA-seq samples, with 34 upregulated and 86 downregulated transcripts after 3 months.

MUC5B, which is a transcript related to mucus overproduction, and PTHLH, which is related to epithelial dysfunction, were significantly downregulated after 1 month of dupilumab treatment, the researchers found.

By inhibiting IL-4R alpha, the researchers wrote, dupilumab significantly improved smell, nasal congestion, nasal polyp size, asthma symptoms and lung function among adult patients with AERD.

These rapid clinical improvements likely are due to several concomitant mechanistic changes, the researchers added, with changes in eicosanoids possibly underlying most of these clinical benefits.