Urticaria and Angioedema: Understanding Complex Pathomechanisms to Facilitate Patient Communication, Disease Management, and Future Treatment

Chronic spontaneous urticaria (CSU) is primarily a T2-dominant disease with a complex genetic background. Skin mast cell activation can be induced not only via the IgE-FcεRI axis but also from several other distinct mechanisms, molecules, and receptors involved in CSU onset, persistence, and exacerbation. These include autoallergy, autoimmunity, central or peripheral neuroimmune dysregulation, activation of both extrinsic and intrinsic coagulation pathways, and microbial infections. Besides mast cells, recent reports suggest the active and direct involvement of basophils and eosinophils. Several biological characteristics or biomarkers have been linked with CSU's known endotypes and may help forecast therapeutic responses. The introduction of biologic therapy for CSU has been a major advance in the last 10 years. The cornerstone of angioedema (AE) pathogenesis is increased vascular permeability and plasma leakage into the deeper dermis and subcutis, either mediated by histamine or bradykinin (BK). C1-inhibitor deficiency, hereditary or acquired, is the primary cause of BK-mediated AE due to increased plasma BK concentration. Other complex conditions have been identified, with some likely involving contact system dysregulation and other putative mechanisms related to vascular endothelial dysfunction. The approval of multiple hereditary-AE-specific therapies for both prevention and acute attacks has revolutionized treatment of this disease. Any new knowledge of the pathogenesis of CSU and AE offers the opportunity to improve patient information, physician-patient communication, prediction of therapeutic responses, selection of precise tailor-made treatment for each patient, and exploration of novel treatment options for those who do not achieve disease control with current medications.