Advances in Pathophysiology and Therapeutic Paradigm Shifts in Chronic Spontaneous Urticaria: A Narrative Review

Chronic spontaneous urticaria (CSU) is a debilitating inflammatory skin disorder characterized by recurrent wheals and/or angioedema lasting beyond 6 weeks without identifiable triggers. Recent advances have shifted the understanding of CSU from a historically idiopathic condition to one increasingly recognized as an immune-mediated disease with distinct endotypes, including type I (autoallergic) and type IIb (autoimmune). This narrative review synthesizes contemporary insights into CSU pathophysiology, endotype classification, and systemic manifestations, while highlighting the substantial impact on quality of life, sleep, and psychological health. Advances in biomarker research, including total serum immunoglobulin E (IgE) levels, basophil activation tests (BAT), and eosinophil counts, support progress toward personalized treatment approaches. Therapeutically, management of CSU has evolved from empirical symptom control with H1 antihistamines toward mechanism-based precision medicine. Omalizumab remains the established second-line therapy, and dupilumab received US Food and Drug Administration (FDA) approval in 2025 for antihistamine-refractory disease. In parallel, several targeted therapies are under investigation, including Bruton's tyrosine kinase (BTK) inhibitors, anti-KIT antibodies, and Janus kinase (JAK) inhibitors. These therapeutic mechanisms may offer sustained benefit, though long-term outcomes require validation through controlled trials. Integration of psychological interventions, such as cognitive behavioral therapy combined with pharmacotherapy, underscores the need for holistic patient care. Despite these advances, challenges remain in biomarker validation, sequencing of new therapies, and bridging clinical trial evidence with real-world practice. Future directions include refining endotype-driven personalized care, conducting long-term real-world studies, and developing cost-effective, globally accessible treatment strategies to optimize patient outcomes.