THE DISORDER — AFRS is a subtype of chronic rhinosinusitis with nasal polyps that is characterized by an inflammatory response to noninvasive fungi and accumulation of eosinophilic mucin. Symptoms include nasal polyps, nasal congestion or obstruction, loss of smell, and postnasal drainage. Moderate to severe AFRS can lead to bony erosion of sinus walls and orbital expansion. Most cases occur in places with warm, humid climates such as the southern US.4

STANDARD TREATMENT — Endoscopic sinus surgery is often recommended initially to remove nasal polyps and inflammatory mucin. Disease recurrence is common; about 30% of patients require revision surgery. Postoperative treatment with oral and/or topical corticosteroids is recommended to reduce or delay recurrence. Antifungal therapy and immunotherapy have been tried, but high-quality evidence supporting their efficacy is lacking. Omalizumab (Xolair, Omlyclo) and mepolizumab (Nucala), biologic drugs that are approved for treatment of chronic rhinosinusitis with nasal polyps, are under investigation for treatment of AFRS.5

MECHANISM OF ACTION — Dupilumab is a human IgG4 antibody that binds to the IL-4 receptor alpha subunit shared by IL-4 and IL-13. It inhibits the signaling of these cytokines, which are thought to play a role in the inflammatory pathophysiology of AFRS.

CLINICAL STUDIES — FDA approval of dupilumab for the new indication was based on the results of an unpublished randomized double-blind trial (Liberty-AFRS-AIMS; summarized in the package insert) in 62 patients ≥6 years old with AFRS, 61 of whom had a history of ≥1 sinonasal surgery. Patients received dupilumab (dosage based on age and body weight) or placebo for 52 weeks. Dupilumab significantly reduced sinus opacification, nasal congestion/obstruction, and nasal polyp size compared to placebo at week 52 (see Table 1). Patients receiving dupilumab were less likely to require oral corticosteroids (3% vs 31% with placebo) and/or sinonasal surgery (0% vs 6.9%). The proportion of patients with bone erosion in sinuses on CT scan was comparable in the dupilumab and placebo groups at baseline, but was lower in the dupilumab group at week 52.

In a retrospective cohort study, patients with presumed AFRS who were treated with dupilumab, omalizumab, or mepolizumab were compared to matched controls. Only dupilumab reduced the risk of all clinical outcomes, including sinus surgery, inpatient admission, emergency department visits, and acute sinusitis.6

ADVERSE EFFECTS — Adverse effects of dupilumab in patients with rhinosinusitis have included injection-site reactions, conjunctivitis, insomnia, gastritis, arthralgia, and toothache. Hypersensitivity reactions, including anaphylaxis, and an increase in blood eosinophil counts have been reported.

DRUG INTERACTIONS — Use of live vaccines should be avoided in patients receiving dupilumab.

DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of dupilumab for treatment of AFRS in adults is 300 mg once every 2 weeks; in patients 6-17 years old, the dosage is based on weight: 300 mg every 4 weeks (15-<30 kg), 200 mg every 2 weeks (30-<60 kg), or 300 mg every 2 weeks (≥60 kg). Dupilumab should be injected subcutaneously into the thigh, abdomen, or upper arm; patients or caregivers can be trained to administer the drug at home. A single 300-mg dose of Dupixent costs about $2000.7

CONCLUSION — The injectable interleukin (IL)-4 receptor alpha antagonist dupilumab (Dupixent) is the first drug to be approved in the US for treatment of allergic fungal rhinosinusitis (AFRS). In one clinical trial in patients with AFRS who had undergone sinonasal surgery, dupilumab was more effective than placebo in reducing sinonasal symptoms and the need for oral corticosteroids and/or sinonasal surgery for up to 52 weeks.