Pathophysiology and emerging treatments for dermographic, cholinergic and cold urticaria.

Abstract

Chronic inducible urticarias (CIndUs), including symptomatic dermographism (SD), cholinergic urticaria (CholU) and cold urticaria (ColdU), are mast cell (MC)-driven conditions triggered by subtype-specific, definite and reproducible stimuli. Although often considered self-limiting, these diseases can persist for years and significantly impair quality of life. Current evidence suggests that CIndUs involve heterogeneous underlying mechanisms, including both immunoglobulin E (IgE)-dependent and IgE-independent pathways of MC activation. These include activating receptors such as the high-affinity IgE receptor (FcεRI), Mas-related G protein-coupled receptor X2 (MRGPRX2) and muscarinic cholinergic receptor M3 (CHRM3), as well as emerging roles for neuropeptides, autoantibodies and sweat allergens. Many patients remain symptomatic despite treatment with second-generation H₁-antihistamines (sgAHs), the only approved therapy. Omalizumab, an anti-IgE monoclonal antibody, is effective in some patients with sgAH-refractory disease but remains off-label for CIndUs. A growing number of clinical trials are investigating therapies that target MCs beyond sgAHs and anti-IgE, including Bruton's tyrosine kinase (BTK) inhibitors, anti-KIT monoclonal antibodies, MRGPRX2 antagonists and blockade of the interleukin-4 receptor alpha chain (IL-4Rα). While early findings are promising, it remains unclear whether these approaches can meaningfully alter the long-term disease course. This review summarizes current understanding of the pathophysiology of SD, CholU and ColdU, and highlights emerging therapies aimed at improving patient outcomes. Improved understanding of CIndU endotypes may enable more personalized, mechanism-based treatment approaches in the future.