Abstract Rationale Responses to biologic therapies in severe asthma vary widely, and improvements in lung function are likely influenced by multiple factors, including airway structure and inflammatory profiles. However, patterns of lung function improvement with biologics and their predictors remain insufficiently defined. To classify early (8-week) response patterns based on changes in spirometric indices after dupilumab initiation and to characterize the clinical features of each pattern. Methods In a prospective, multicenter observational study across 13 sites in Japan, 84 patients with severe asthma received dupilumab. Changes at 8 weeks in six spirometric indices (FVC, %FVC, FEV₁, %FEV₁, FEV₁/FVC, %FEF25-75%) were used for hierarchical clustering. Baseline clinical characteristics, biomarkers, and symptom scores were compared across clusters. Results Four distinct clusters were identified: Cluster 1 (lung-volume-predominant improvement), Cluster 2 (non-responder), Cluster 3 (small-airway-predominant improvement), and Cluster 4 (global improvement). The non-responder Cluster 2 exhibited the youngest mean age and age at onset with the longest disease duration, consistent with an early-onset phenotype; total IgE was highest, whereas FeNO and blood eosinophils were lowest, indicating an IgE-centric Th2 profile. Cluster 1 showed marked improvements in FVC and %FVC; Cluster 3 demonstrated clear gains in small-airway function, typified by increases in %FEF25-75%; Cluster 4 had the most severe large- and small-airway dysfunction at baseline yet showed broad improvements across lung volumes, airflow, and small-airway measures. Responder clusters (1, 3, and 4) shared higher baseline FeNO and blood eosinophil counts—features of IL-5/IL-13-type Th2 inflammation—along with poorer lung function and greater symptom burden/exacerbation history. Conclusion Phenotyping based on 8-week changes in lung function after dupilumab suggests limited improvement in early-onset, IgE-centric Th2 asthma, whereas IL-5/IL-13-type Th2 inflammation is associated with multidimensional gains, including lung volume and small-airway function. Early functional response patterns may help optimize individualized dupilumab therapy. This abstract is funded by: None
Mizumura et al. (Fri,) studied this question.