Emerging Pathophysiology and Therapeutic Targets in Chronic Urticaria

Conclusions

• Chronic spontaneous urticaria appears to be driven by a complex, dynamic network rather than a single mast-cell-only mechanism.
• IgE remains important in CSU, but autoimmune autoantibodies, basophils, and downstream signaling pathways also contribute meaningfully.
• Sensory nerves are likely key amplifiers of urticaria, linking mast-cell activation, histamine release, and itch perception.
• Itch and wheal formation can be partially uncoupled, suggesting that not all urticarial symptoms arise from the same biology.
• Patients with itch-predominant or dermatographic phenotypes may still benefit from IgE-targeted therapy such as omalizumab.
• Basophils can mediate acute itch flares and may become activated through alarmins such as IL-33 and IL-18.
• IL-18 and IL-33 emerge as promising upstream inflammatory targets across both atopic dermatitis and urticaria-like disease.
• Mast cells and basophils share several relevant features, including IgE responsiveness, but differ in tissue residency, recruitment, and receptor dynamics.
• MRGPRX2 is an important non-IgE pathway that may drive urticaria, drug reactions, and inducible whealing.
• New therapies that block IgE, BTK, IL-18, IL-33-related pathways, or MRGPRX2 could expand treatment options for chronic urticaria and related itch disorders.
• Targeting mast cells for depletion or signaling blockade may be especially useful in patients who remain symptomatic despite antihistamines.