CH50 as a Clinically Useful Biomarker of Disease Activity and Antihistamine Resistance in Chronic Spontaneous Urticaria: An Observational Ambispective Single‐Center Study

BACKGROUND: Chronic spontaneous urticaria (CSU) is frequently refractory to guideline-based therapy, highlighting the need for predictive biomarkers. Dysregulation of the complement system has been implicated in CSU severity, but global complement activity has not been systematically evaluated. OBJECTIVE: The aim of this study was to assess the total hemolytic complement (CH50) assay as a biomarker for disease activity and predictor of treatment response in CSU. METHODS: This observational, ambispective, single-center study included 180 CSU patients and 45 healthy controls. CH50 levels were measured and correlated with clinical and immunological markers. Response to second-generation antihistamines and omalizumab at 3, 6, and 12 months was evaluated. RESULTS: CH50 levels were significantly higher in CSU patients than in controls (p < 0.001) and were associated with more active and prolonged disease. CH50 correlated with Weekly Urticaria Activity Scores (UAS7) (ρ = 0.30, p < 0.0001), Urticaria Control Test (UCT) scores (ρ = -0.25, p < 0.001), longer disease duration (ρ = 0.28, p = 0.0002), D-dimer (ρ = 0.31, p < 0.001), and immunoglobulin G (IgG) anti-thyroid peroxidase (anti-TPO) (ρ = 0.21, p < 0.005). Higher CH50 levels were linked to antihistamine resistance (p < 0.001), with superior predictive accuracy (area under the curve [AUC] = 0.87) over D-dimer, C4, and UAS7. CH50 was also an independent predictor of antihistamine resistance (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09-1.18). No association was observed with omalizumab response. CONCLUSION: CH50 is a novel and promising biomarker for antihistamine resistance in CSU, outperforming previously described markers. Its low cost and accessibility support integration into CSU stratification and endotype-driven therapeutic algorithms, pending validation in multicenter cohorts.