Abstract
Chronic spontaneous urticaria (CSU) is a mast cell-driven disease that impairs health-related quality of life. Although omalizumab is a cornerstone treatment for patients uncontrolled with up-dosed second-generation H1-antihistamines, some patients remain partially responsive or refractory. This narrative review summarizes current concepts in defining, predicting, and managing omalizumab-refractory CSU. Response assessment should rely on validated patient-reported outcome measures, particularly the 7-day Urticaria Activity Score (UAS7) and Urticaria Control Test (UCT), to distinguish complete response, partial response, and true non-response, while also helping to identify pseudo-resistance related to poor adherence or misdiagnosis. Emerging biomarker data support an endotype-driven approach: higher total immunoglobulin E (IgE) is generally associated with type I autoallergic CSU and a better response to omalizumab, whereas low total IgE, basopenia, positive basophil histamine release assay (BHRA) or basophil activation test (BAT) results, and other autoimmune markers suggest type IIb autoimmune CSU and a greater likelihood of inadequate anti-IgE response. For patients with persistent disease despite omalizumab, cyclosporine A remains an evidence-based option, while newer targeted therapies, including dupilumab, Bruton's tyrosine kinase inhibitors, and anti-KIT antibodies, are expanding the treatment landscape. Overall, management of omalizumab-refractory CSU is shifting toward precision medicine that integrates validated outcome measures, biomarker-informed endotyping, comorbidities, access, safety, and patient preferences. However, standardized switching algorithms, comparative effectiveness data, and validated predictive biomarkers are still needed to optimize individualized care.