Serum MRGPRX2 and substance P levels are biomarkers of disease activity rather than an antihistamine response in chronic spontaneous urticaria

Abstract

In chronic spontaneous urticaria (CSU), the role of Mas-related G protein-coupled receptor X2 (MRGPRX2) and substance P (SP) as biomarkers of disease severity and the antihistamine response remains unclear. The study aims to examine the correlations between serum MRGPRX2 and SP levels, disease severity, and antihistamine response in patients with CSU. This study included 120 CSU patients and 30 healthy controls. Based on the Urticaria Activity Score over 7 days (UAS7), the patients with CSU were divided into two categories: severe (UAS7 ≥ 28) and non-severe (UAS7 < 28). Severe CSU patients received 20 mg of bilastine, titrated up to 80 mg based on Urticaria Control Test (UCT) results at days 15, 30, and 60. Serum MRGPRX2 and SP levels were measured at baseline for all participants and after two months in severe CSU patients. The Kruskal-Wallis test and Dunn's corrections were used to examine differences in multiple comparisons. Spearman's correlation assessed the relationships between MRGPRX2 and SP levels, age, and urticaria duration. Receiver Operating Characteristic (ROC) curves were created to identify the optimal serum levels of MRGPRX2 and SP for distinguishing severe CSU. Additionally, univariate and multivariate logistic regression analyses were conducted to identify risk factors associated with severe CSU. Serum levels of MRGPRX2 and SP were significantly higher in patients with severe CSU compared to non-severe patients (P < 0.001 and P = 0.01) but were comparable to controls (P > 0.05). These levels were positively correlated with the UAS7 (P < 0.001 and P = 0.01), with no correlation between MRGPRX2 and SP levels (P = 0.28). MRGPRX2 ≥ 11.67 ng/mL and SP ≥ 97.66 pg/mL were identified as independent risk factors for severe CSU (OR 48.21 95%CI 13.00-178.82; P < 0.001 and OR 3.19 95% CI 1.10-9.24, P = 0.03). Among the severe CSU patients, the baseline MRGPRX2 and SP levels did not significantly differ across the antihistamine response groups (P > 0.05); serum MRGRPX2 levels remained consistent over time after antihistamine treatment (P = 0.41), whereas serum SP concentrations significantly decreased (P < 0.001). Serum MRGPRX2 and SP levels are associated with disease severity in CSU patients but do not predict antihistamine response in severe cases.

Keywords: Antihistamine response; Biomarkers; Chronic spontaneous urticaria; Disease severity; MRGPRX2; Substance P.

Fig. 1

Flowchart depicting the study outline. ASST autologous serum skin test, CBC complete blood count, CRP C-reactive protein, CSU chronic spontaneous urticaria, EAACI European Academy of Allergy and Clinical Immunology, ELISA Enzyme-linked immunosorbent assay, IgE immunoglobulin E, IgG immunoglobulin G, MRGPRX2 Mas-related G-protein-coupled receptor-X2, SP Substance P, TPO Thyroid Peroxidase, UAS7 urticaria activity score over 7 days, UCT Urticaria control test.

Fig. 2

Serum MRGPRX2 and SP concentrations between severe, non-severe CSU and controls (Kruskal-Wallis test with Dunn’s multiple comparison test). CSU Chronic spontaneous urticaria, MRGPRX2 Mas-related G-protein-coupled receptor-X2, ng/mL nanogram/milliliter, NC normal healthy controls, pg/mL picogram/milliliter, SP Substance P.

Fig. 3

Correlation between serum MRGPRX2 and SP concentrations and CSU disease activity by Spearman correlation and ROC curve analysis. CSU Chronic spontaneous urticaria, MRGPRX2 Mas-related G-protein-coupled receptor-X2, ng/mL nanogram/milliliter, pg/mL picogram/milliliter, SP Substance P, UAS7 Urticaria activity score over 7 days.

Fig. 4

Baseline serum MRGPRX2 and SP concentrations among treatment response groups to antihistamine in the severe CSU (Kruskal–Wallis test). CSU Chronic spontaneous urticarial, MRGPRX2 Mas-related G-protein-coupled receptor-X2, ng/mL nanogram/milliliter, pg/mL picogram/milliliter, SP Substance P.

Fig. 5

Changes in serum MRGPRX2 and SP levels before and after treatment with antihistamine in the severe CSU. CSU Chronic spontaneous urticaria, MRGPRX2 Mas-related G-protein-coupled receptor-X2, ng/mL nanogram/milliliter, SP Substance P.