Dupilumab‐Related Adverse Events and Intolerance in Aspirin‐Exacerbated Respiratory Disease Patients

Aspirin-exacerbated respiratory disease (AERD), also known as Samter's triad, is a chronic inflammatory condition characterized by asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and respiratory reactions to cyclooxygenase-1 inhibitors. Patients with AERD frequently experience severe, treatment-refractory disease marked by rapid nasal polyp recurrence, frequent asthma exacerbations, impaired olfaction, and reduced quality of life despite multimodal medical and surgical management [1]. Disease severity and recurrence following endoscopic sinus surgery contribute to substantial healthcare utilization in this population [1]. Aspirin therapy after desensitization (ATAD) represents an established disease-modifying treatment option for AERD, though long-term tolerance and adherence vary across patients [2]. The emergence of biologic therapies targeting type 2 inflammation has expanded treatment options for patients with CRSwNP and asthma [3]. Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit to inhibit IL-4 and IL-13 signaling, has demonstrated efficacy in reducing nasal polyp burden and improving asthma control in patients with chronic rhinosinusitis with nasal polyposis, including those with AERD [3, 4]. However, patients with AERD remain underrepresented in dupilumab clinical trials, limiting the generalizability of safety data to this subgroup [4, 5]. Emerging reports suggest that dupilumab may be associated with distinct adverse events (AEs), including hypereosinophilia, musculoskeletal symptoms, dermatologic reactions, and autoimmune phenomena [5, 6]. When selecting between treatment options such as aspiration therapy after desensitization and biologic therapy, both treatment efficacy and tolerance are central considerations. Recent data report an overall ATAD tolerance rate of 82.7%, with tolerance varying by sex, menopausal status, and race [7]. To meaningfully compare these therapeutic pathways and identify which patients may benefit most from each, it is essential to define dupilumab-related adverse events, dupilumab tolerability, and discontinuation rates in real-world AERD cohorts [2]. This study aims to quantify and characterize dupilumab-related AEs in AERD patients treated at a tertiary care center, providing insight into its real-world safety profile and informing individualized treatment decisions. This retrospective chart review was conducted at the University of Pennsylvania and was determined to be Institutional Review Board-exempt. Adult patients with a clinical diagnosis of AERD, defined according to international consensus criteria, who received at least one dose of dupilumab between November 2018 and June 2025 were included [8]. Diagnosis was confirmed using ICD-10 coding and allergist documentation. Patients were excluded if post-treatment follow-up data were unavailable. Collected variables included age, sex, race and ethnicity, autoimmune disease history, dupilumab treatment duration, documented AEs, and reasons for treatment discontinuation. AEs were attributed to dupilumab based on treating physician documentation in the medical record. Statistical analyses were performed using R version 4.0.3. Continuous variables were assessed for normality and compared using ANOVA or Kruskal–Wallis testing as appropriate. Categorical variables were analyzed using Fisher exact testing. A two-tailed hypothesis was adopted, and a p-value ≤0.05 was considered statistically significant. When overall tests were significant, post hoc analyses were performed using Bonferroni correction. Among 104 patients with AERD treated with dupilumab, 26 (25.0%) experienced at least one dupilumab-related AE. Eighteen patients (17.3% of the total cohort; 69.2% of those with AEs) discontinued dupilumab because of an AE (Table 1). Four additional patients discontinued therapy for non-AE reasons, including cost, pregnancy, and lack of effectiveness. After adverse event-related discontinuation, 12 patients switched to another biologic therapy, most commonly mepolizumab or tezepelumab, while one patient underwent aspirin desensitization (Table 2). The remaining patients did not pursue additional biologic therapy. The most common AEs leading to discontinuation were joint pain, hypereosinophilia, dermatologic reactions, and vision changes (Table 1). Rare severe AEs included drug-induced systemic lupus erythematosus and Sweet's syndrome with eosinophilic myocarditis (Table 2). Clinical and demographic characteristics by AE status are shown in Table 1. Age and sex did not differ significantly between groups. Autoimmune disease history and race demonstrated trends toward association with AE-related discontinuation without reaching statistical significance. Adverse event-related dupilumab discontinuation has not been adequately characterized in AERD, an important gap given underrepresentation in CRSwNP trials, heightened baseline type 2 inflammation compared to CRSwNP, and the availability of ATAD as an alternative, making tolerability central to individualized treatment selection [4, 5]. In this real-world AERD cohort, 17.3% discontinued dupilumab due to AEs, exceeding rates reported in Phase III clinical trials and real-world studies of broader CRSwNP populations [3, 9]. The most common AEs prompting discontinuation in this cohort were musculoskeletal symptoms, hypereosinophilia, dermatologic reactions, and vision changes, consistent with prior real-world and pharmacovigilance reports [5, 6]. Rare but severe autoimmune complications were observed. One possible mechanism is immune dysregulation following IL-4 and IL-13 blockade, resulting in Th17-skewed inflammatory responses and eosinophil-mediated tissue injury. Bridgewood et al. reported that IL-4/IL-13 antagonism was associated with Th17-skewed immune responses, manifesting as increased inflammatory skin and joint disease, as well as IL-5-mediated eosinophilic disorders [10]. The higher rate of AE-related dupilumab discontinuation in our AERD cohort may reflect a higher baseline type 2 inflammatory burden than CRSwNP, possibly leading to more pronounced inflammatory shifts after IL-4/IL-13 blockade and a higher likelihood of clinically significant adverse events requiring discontinuation. This study is limited by its retrospective design, single-center setting, and modest sample size, which may limit the power to detect predictors of intolerance. Higher AEs and discontinuation rates may reflect ascertainment bias via closer tertiary center monitoring and easier access to alternative therapies. Nonetheless, it provides clinically meaningful insight into dupilumab tolerability in AERD and underscores the need for larger, multi-institutional studies to better define risk factors and mechanisms of AEs. This research was supported by the Thomas B. McCabe and Jeannette E. Laws McCabe Fund at the University of Pennsylvania. The authors declare no conflicts of interest.