The Neuropsychological Dimensions to Pathogenesis of Chronic Spontaneous Urticaria Beyond Autoallergy – A Brief Narrative Review

Chronic spontaneous urticaria (CSU) is a burdensome dermatological condition with a complex, multifactorial pathogenesis involving intricate immune, neurological, and psychological interactions. While traditional models primarily emphasize auto-allergic mechanisms, evidence highlights the critical role of neuroimmune interaction in the chronicity and exacerbation of disease. This review examines the neuroimmune contributions to CSU pathogenesis, focusing on mast cell (MC)-sensory neuron interactions, autonomic nervous system dysregulation, neuroinflammatory pathways, and psychological comorbidities that perpetuate disease activity. A comprehensive narrative review of the literature was undertaken, evaluating mechanisms such as MC activation through immunoglobulin-E (IgE)-independent pathways, neuropeptide-mediated inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and psychiatric associations with CSU. Findings indicate that beyond the classical IgE-mediated MC degranulation, neurogenic inflammation via Mas-Related G-Protein Coupled Receptor X2 (MRGPRX2) receptors-triggered by neuropeptides such as substance P and vasoactive intestinal peptide-plays a pivotal role. Chronic psychological stress activates the HPA axis, contributing to MC hyperactivity and reinforcing the pruritus-stress cycle. Furthermore, a high prevalence of psychiatric comorbidities, including anxiety and depression, contributes to central sensitization and worsens disease severity. The interplay of T cells, basophils, eosinophils, and endothelial cells further amplifies the neuroimmune-inflammatory network. These insights suggest that optimal CSU management requires an integrated approach encompassing dermatological, immunological, and psychological interventions. Emerging therapies targeting neuroimmune pathways, such as MRGPRX2 antagonists, beta-adrenergic blockers, and cognitive-behavioral strategies, show promise. Future research should prioritize the development of personalized neuroimmune-directed therapies to enhance disease control in CSU.