Effect of Dupilumab on Type 2 Biomarkers in Chronic Rhinosinusitis With Nasal Polyps: SINUS-52 Study Results

Abstract

Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab’s effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study. Methods: Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks. Results: Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings. Conclusion: Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab’s therapeutic effects. Clinical Trial Registry Name: SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454 ClinicalTrials.gov Identifier: NCT02898454

Dupilumab dampens mucosal type 2 response during acetylsalicylic acid challenge in N-ERD patients

“…As dupilumab inhibits both IL-4 and IL-13 mediated signaling, it can impact a variety of mechanisms involved in N-ERD pathophysiology ranging from Th2 cell differentiation, ILC2 expansion, mast cell activation to airway smooth muscle cell proliferation 34 . We and others have previously demonstrated that dupilumab leads to a marked downregulation of type 2 mediators in serum and nasal secretions of N-ERD patients over time 14,16,35 . However, here we show for the first time that the same trend is also demonstrable during ASA provocation after twenty-four weeks of dupilumab therapy.…”

“…Although a reduction of type 2 mediators and associated cell subsets was observed in the chronic phase of the disease in patients undergoing therapy with the respective antibodies 15,16 , these studies have not addressed the impact of treatment on cytokine dynamics during acute hypersensitivity reactions. In this regards, data on immune kinetics following ASA challenges are scarce and indicate an increase in systemic proinflammatory IL-6 17 and nasal eosinophils as well as ILC2 influx as early as one hour after provocation, but no increase in serum chemotactic proteins such Eotaxin-1 18 .…”

The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps

“…Dupilumab is approved for the treatment of uncontrolled CRSwNP in adults and for other allergic diseases, including certain types of moderate-to-severe asthma, moderate-to-severe AD, eosinophilic esophagitis, and prurigo nodularis ( 74 ). Biomarker analysis has revealed that dupilumab treatment in patients with CRSwNP reduced concentrations of type 2 inflammatory biomarkers including eotaxin-3, periostin, eosinophil cationic protein (ECP), and IL-5 in nasal secretions, eotaxin-3, thymus and activation-regulated chemokine, periostin, and total IgE in blood, and leukotriene E4 in urine ( 75 , 76 ). Dupilumab has also been found to downregulate local IgE production and eosinophil homing ( 66 ), and to decrease inflammatory eicosanoid levels and increase levels of anti-inflammatory prostaglandin E 2 ( 77 ).…”

Brazilian guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps ‒ 2024 update

“…The reduction in these biomarkers is similar or greater in subgroups with asthma and AERD, as evidenced in a post-hoc analysis of the SINUS-24 study. 71 …”

“…Several randomized, placebo-controlled clinical trials have been published involving patients with uncontrolled persistent asthma despite adequate treatment with inhaled corticosteroids and long-acting beta-agonists, 71 , 72 inhaled corticosteroids +1 or 2 rescue medications, 75 or oral corticosteroids. 76 …”