Identification of pyruvic and maleic acid as potential markers for disease activity and prognosis in chronic urticaria

Background Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of CU patients has not been reported. Objective To explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy. Methods Plasma samples from 80 CU patients and 82 healthy controls (HCs) were collected for metabolomics quantification and performed bioinformatics analysis. Another independent cohort consisting of 144 CU patients was studied to validate the findings. Bone marrow-derived mast cells (BMMCs) and IgE-induced passive cutaneous anaphylaxis (PCA) mice were utilized for in vitro and in vivo experiments, respectively. Results We observed clear metabolomics difference between CU and HC. Meanwhile, differential metabolites N6-acetyl-l-lysine, L-aspartate, maleic acid and pyruvic acid were used to respectively construct random forest classifiers, and achieved AUCs greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H1-antihistamines (sgAHs), and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cells activation in vitro and in vivo. Conclusions The combination of plasma pyruvic acid and maleic acid may be effective biomarkers for predicting the disease activity, therapeutic efficacy as well as prognosis for CU patients.