Control first, tolerance second: biologics as enablers of allergen immunotherapy in severe allergic asthma

Abstract

Despite major advances in the treatment of severe asthma with biologics targeting IgE, IL-5/IL-5Rα, IL-4Rα, and thymic stromal lymphopoietin (TSLP), these agents suppress type 2 inflammation without reliably inducing durable allergen-specific tolerance. Allergen immunotherapy (AIT) remains the only disease-modifying option for IgE-mediated respiratory allergy, yet its use in severe asthma has historically been restricted by safety concerns in uncontrolled disease. We propose a “control first, tolerance second” framework, whereby biologic-induced disease control creates a window enabling safe initiation of subcutaneous or sublingual AIT. This narrative review synthesizes the immunological rationale and clinical evidence supporting sequential biologic-AIT combination, with emphasis on omalizumab as the best-studied adjunct and emerging data on dupilumab and tezepelumab. We address biomarker-guided patient selection, treatment sequencing, comorbid allergic rhinitis and chronic rhinosinusitis, corticosteroid-sparing effects, infection risk, airway antiviral immunity, and unresolved questions around long-term remission. The novelty of this framework lies in reframing biologics not merely as symptom-control agents but as facilitators that unlock a previously inaccessible disease-modifying intervention, potentially shifting severe allergic asthma management from control toward durable immunological remission. We conclude that biologic-enabled AIT is a promising but insufficiently defined strategy, and outline the prospective trials, standardized phenotyping, and safety registries needed to establish it as an evidence-based clinical pathway.