Clinical and molecular aspects of managing chronic spontaneous urticaria: identifying endotypes, phenotypes, and determinants of treatment response and resistance

Abstract

Chronic spontaneous urticaria (CSU) is a clinically heterogeneous, mast cell–driven inflammatory disease in which disease expression, treatment response, and resistance are determined by distinct but overlapping immunopathogenic mechanisms. Growing evidence supports the existence of two principal molecular endotypes: type I (autoallergic) CSU, mediated by autoreactive IgE antibodies against self-antigens such as thyroid peroxidase and interleukin-24, and type IIb (autoimmune) CSU, characterized by IgG (and less frequently IgA or IgM) autoantibodies directed against IgE or its high-affinity receptor FcεRI. These endotypes differ substantially in biomarker profiles, clinical severity, and therapeutic responsiveness. Patients with type I CSU typically exhibit elevated total IgE levels, allergic comorbidities, and rapid, robust responses to omalizumab, whereas those with type IIb CSU more often present with low IgE, positive autologous serum skin test or basophil activation assays, thyroid autoantibodies, eosinopenia, basopenia, and delayed or insufficient responses to anti-IgE therapy. Importantly, accumulating data indicate that strict dichotomous classification is insufficient, as many patients display concurrent IgE- and IgG-mediated autoreactivity, supporting the concept of an immunological continuum summarized under the broader framework of \"autoreactivity.\" Beyond immunoglobulin-driven mechanisms, eosinophils, basophils, complement activation, and coagulation pathways critically contribute to disease amplification and treatment refractoriness. Biomarkers such as total IgE, anti-thyroid antibodies, eosinophil and basophil counts, C-reactive protein, and functional assays including ASST and BAT enable pragmatic endotype stratification and prediction of therapeutic outcomes. Integrating molecular endotypes with clinical phenotypes provides a rational basis for personalized management, allowing earlier identification of likely non-responders, optimization of omalizumab dosing, and timely consideration of alternative or emerging targeted therapies. This evolving endotype-guided approach represents a key step toward precision medicine in CSU.