Comorbidities in Chronic Spontaneous Urticaria: Integrating Disease Drivers and Systemic Consequences

Chronic spontaneous urticaria (CSU) is a mast cell-driven inflammatory skin disorder traditionally considered self-limiting and non-life-threatening. However, accumulating evidence suggests that CSU is associated with multiple comorbidities, reflecting systemic immune and neuroinflammatory dysregulation. These comorbidities may act as both triggers and consequences of disease activity, forming a complex network centered on mast cell activation. Autoimmune diseases, particularly autoimmune thyroid disease, are strongly associated with CSU, especially in the type IIb autoimmune endotype. By contrast, type I autoallergic CSU is associated with immunoglobulin E (IgE) autoantibodies. Atopic diseases, neuroimmune interactions, and psychiatric conditions may further contribute to disease persistence through mechanisms involving IgE signaling and substance P-mediated mast cell activation via Mas-related G protein-coupled receptor X2. Metabolic and cardiovascular comorbidities have also been reported, with recent large-scale cohort studies strengthening the evidence for an association with cardiovascular risk, although causality remains unestablished. Associations with malignancy remain uncertain, whereas recent real-world studies suggest increased mortality among patients with CSU, potentially reflecting the underlying comorbidity burden rather than direct disease effects. Importantly, effective disease control may improve CSU outcomes and associated comorbidities. A comprehensive, mechanism-based approach that integrates comorbidity assessment into clinical management is essential for optimizing patient care.