Development and validation of a clinically applicable biomarker panel for identifying autoimmune type IIb chronic spontaneous urticaria

Background Chronic spontaneous urticaria (CSU) includes 2 autoimmune endotypes, type I (autoallergic) and type IIb (autoimmune), which differ in pathogenesis and treatment response. However, practical criteria for distinguishing these endotypes in routine clinical practice remain limited. Objective This study aimed to evaluate whether combinations of readily available clinical parameters facilitate identification of probable type IIb CSU. Methods A total of 125 CSU patients were evaluated using 3 diagnostic combinations: (1) high IgG anti–thyroid peroxidase antibodies (IgG-anti-TPO) with low total IgE; (2) high IgG-anti-TPO with a positive autologous serum skin test (ASST+); and (3) low total IgE with ASST+. Clinical and laboratory features were compared between presumed endotypes. Serum cytokine profiles were analyzed and validated in an independent cohort of 40 patients. A predictive graphical model integrating clinical and laboratory variables was developed. Results All 3 combinations identified patient subsets with features compatible with type IIb CSU, including trends toward higher disease activity (UAS7), peripheral eosinopenia and basopenia. The combination of high IgG-anti-TPO with ASST positivity was associated with the most comprehensive type IIb-compatible features. Cytokine profiles also differed between endotypes: serum IL-6 tended to be lower in possible type IIb CSU, whereas IL-17 A and TNF-α tended to be higher, compared with the remaining CSU patients. These patterns were directionally supported in the independent validation cohort. The predictive nomogram model demonstrated good discriminatory performance. Conclusions Combinations of IgG-anti-TPO, total IgE, and ASST provide practical reference tools for identifying probable type IIb CSU, with high IgG-anti-TPO plus ASST positivity showing the highest clinical relevance. Distinct cytokine patterns further support endotype-related immune differences and may aid individualized management.