Chronic Spontaneous Urticaria in the Era of Targeted Therapy: From Pathogenic Mechanisms to Precision Medicine.

Abstract

Chronic spontaneous urticaria (CSU) is a common and heterogeneous inflammatory skin disease characterized by recurrent wheals and/or angioedema for more than six weeks. Despite treatment with second-generation antihistamines, many patients remain symptomatic, highlighting the need for therapies targeting underlying pathogenic mechanisms.

Aim: This review summarizes current knowledge on CSU immunopathogenesis and targeted therapies, with a focus on personalized medicine.

Methods: A literature review was conducted, focusing on recent advances in CSU endotypes and clinical trial data on biologic, small-molecule, and other targeted therapies acting on key immunological pathways.

Results: CSU is increasingly recognized as a heterogeneous disease with distinct immunological endotypes, including type I (autoallergic) and type IIb (autoimmune), which may influence treatment response. Omalizumab remains the mainstay of second-line therapy, although many patients do not achieve complete disease control. Emerging therapies, including anti-IL-4Rα monoclonal antibodies (dupilumab), Bruton's tyrosine kinase inhibitors (e.g., remibrutinib), and anti-c-KIT monoclonal antibodies (e.g., barzolvolimab, briquilimab), have demonstrated promising efficacy. Some show a rapid onset of action, although preferential efficacy in specific CSU endotypes remains to be established. Several clinical and laboratory features, including total IgE, anti-TPO antibodies, ASST, basophil reactivity, basopenia, eosinopenia, and atopic comorbidities, have been investigated as potential markers of endotype and treatment response; however, their utility for treatment selection remains insufficiently validated.

Conclusions: Advances in understanding CSU pathogenesis have enabled the development of targeted therapies that may improve disease control. Predictive biomarkers and endotypic characterization may support the future development of more personalized therapeutic strategies; however, clinically validated biomarkers for treatment selection remain limited, and prospective validation of biomarker-guided approaches is still needed.