Beyond Antihistamines: How Biologic and Small-Molecule Therapies Are Transforming Chronic Spontaneous Urticaria Care in Adults

Chronic urticaria (CU) is a complex, disabling skin disease characterized by recurrent, pruritic wheals and frequently angioedema lasting for 6 weeks or more. Although non-sedating H1-antihistamines remain the first-line therapy, a significant subset of patients (50%) remains symptomatic despite antihistamines, underscoring an unmet need for more targeted treatments. Recent advances in our understanding of CU pathophysiology have led to the development of biologic agents-most notably omalizumab and dupilumab-as well as an expanding pipeline of small-molecule therapies targeting key intracellular signaling pathways (e.g., Bruton's tyrosine kinase [BTK] and Janus kinase [JAK] inhibitors). Therapeutic targets for biologics in chronic spontaneous urticaria (CSU) include IgE, IL-4/IL-13, and IL-5 pathways. This review provides a comprehensive overview of the underlying immunopathogenesis of CSU in adults, critically examines the limitations of conventional therapy (primarily second-generation H1-antihistamines), and reviews the current status and future prospects of biologic and small-molecule treatments. It synthesizes the rapidly evolving landscape of these therapies focusing on therapeutic mechanisms of biologic and small-molecule therapies, recent clinical trial data, and potential for personalized treatment, building on and extending prior reviews. We also discuss practical considerations-including endotyping, cost-effectiveness, and long-term safety, and outline future research directions toward personalized management of chronic urticaria.