Mechanisms and Therapeutic Advances in Antihistamine‐Refractory Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is a common autoimmune skin disorder characterized by recurrent wheals and/or angioedema lasting more than 6 weeks. A substantial proportion of patients remain symptomatic despite treatment with standard or high‐dose H1‐antihistamines, defined as antihistamine‐refractory CSU. This condition is associated with significant disease burden, reduced quality of life, and limited therapeutic options. The pathogenesis of refractory CSU is complex and heterogeneous, involving aberrant mast cell activation through IgE‐dependent and IgE‐independent pathways, dysregulated cytokine networks, and contributions from basophils, eosinophils, and T cells. Such immune imbalance underlies variable responses to conventional therapies. Current management primarily relies on omalizumab and cyclosporine, but their efficacy is limited in a subset of patients. Advances in understanding the disease mechanisms have led to the development of novel therapeutic strategies, including biologics targeting interleukins (IL‐4, IL‐5, IL‐17, and TSLP), Bruton’s tyrosine kinase inhibitors, anti‐KIT antibodies, MRGPRX2 antagonists, and Janus kinase inhibitors. These emerging agents show promising efficacy in clinical trials and may help refine individualized treatment approaches. Further large‐scale studies are warranted to validate their safety and effectiveness, ultimately improving outcomes for patients with refractory CSU.