Type 2 Inflammation in Chronic Spontaneous Urticaria: Presentation, Role, and Management

Chronic spontaneous urticaria (CSU) is a heterogeneous inflammatory skin disease characterized by recurrent wheals, angioedema, and pruritus, with substantial effects on quality of life. Although mast-cell activation remains the central effector event, increasing evidence implicates type 2 inflammatory pathways in CSU and suggests that the disease shares biological features with established type 2 inflammatory disorders, including atopic dermatitis, asthma, chronic prurigo, and chronic rhinosinusitis with nasal polyps. This review examines the contribution of type 2 inflammation to CSU, its relationship with established autoimmune endotypes, associated biomarkers, and implications for current and emerging therapies. Type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31, together with epithelial alarmins and neuroimmune pathways, interact with IgE-dependent, autoimmune, and other mechanisms to amplify mast-cell activation, inflammation, and pruritus. Importantly, type 2 inflammation should not be regarded as an alternative to the established type I autoallergic/type IIb autoimmune classification, but rather as a partly overlapping and variably expressed inflammatory axis. No validated biomarker currently defines a type 2-high CSU endotype or reliably guides individual treatment selection; total IgE, eosinophils, basophils, autoantibodies, and functional basophil assays provide complementary mechanistic or prognostic information but remain insufficient for precision prescribing. The expanding therapeutic landscape reflects this biological complexity. Omalizumab targets IgE-dependent activation, dupilumab directly inhibits IL-4/IL-13 signaling, whereas BTK inhibitors such as remibrutinib interfere with intracellular mast-cell and basophil signaling across multiple upstream mechanisms. Emerging KIT-directed therapies extend this strategy through direct targeting of the mast-cell compartment. Nevertheless, heterogeneous cytokine signatures and variable therapeutic responses argue against defining CSU as a uniformly type 2-driven disease. Future progress will require prospectively validated biomarker signatures, biomarker-stratified trials, comparative studies of emerging therapies, and long-term evaluation of treatment-free remission and potential disease modification. Defining the contribution and boundaries of type 2 inflammation within the broader pathobiology of CSU may ultimately facilitate the transition from mechanistic understanding to clinically actionable precision medicine in CSU.