Immunological Basis of Chronic Spontaneous Urticaria: Immunoglobulin E and Beyond

Abstract

Chronic spontaneous urticaria (CSU) is associated with a substantial disease burden due to its prolonged course and significant impairment of quality of life. The diagnostic process for CSU involves confirming the diagnosis itself and identifying disease phenotypes or endotypes, cofactors, and comorbid conditions, which may affect disease activity and severity. Immunoglobulin E (IgE) and non-IgE-mediated mast cell degranulation are the major pathogenic mechanisms of CSU, where Fc epsilon RI alpha, a high-affinity IgE receptor, is the critical therapeutic target. Although the first-line treatment for CSU is typically second-generation H1-antihistamines, anti-IgE antibodies are recommended for patients who are refractory to up-dosed antihistamines. However, some patients with autoimmune phenotypes show incomplete responses. Recently, dupilumab, an anti-interleukin (IL)-4/IL-13 receptor antibody that inhibits type 2 inflammation, was approved by the US Food and Drug Administration. Patients with autoimmune phenotypes treated with Bruton's tyrosine kinase inhibitors have shown promising efficacy. Additionally, emerging biological agents, such as anti-KIT antibodies targeting mast cell activation and survival, and novel anti-IgE therapies (e.g., YH35324), are currently under investigation and are anticipated to become potential therapeutic options. This review provides an update on the pathogenic mechanisms of CSU, including IgE-and non-IgE-mediated mechanisms, and suggests potential therapeutic targets for improving clinical remission rates.