Analyzing the clinical profile and potential biomarkers to differentiate idiopathic angioedema from hereditary or mast cell-mediated angioedema

Purpose Idiopathic angioedema (AE-UN) is a heterogeneous, exclusion-based clinical category rather than a single disease entity. The clinical characteristics and potential exploratory markers in patients currently classified as AE-UN remain poorly understood. This study aimed to evaluate clinical features and laboratory mediators in a selected cohort of patients fulfilling the current diagnostic definition of AE-UN. Methods We compared 16 patients classified as AE-UN according to a stepwise diagnostic approach with 20 patients with hereditary angioedema (HAE), 20 patients with mast cell-mediated angioedema (AE-MC), and 24 healthy controls. AE-MC classification required recurrent angioedema with or without wheals, normal C4 and C1-inhibitor levels, and a convincing clinical response to mast cell-directed therapy, including H1-antihistamines up to four-fold standard dose when clinically indicated, corticosteroids, or standard-dose omalizumab (4–6 months). Patients without such a response and without confirmed HAE, drug-induced angioedema, or other recognized causes were classified as AE-UN. Baseline features, treatments, and laboratory factors were analyzed, including serum markers of inflammation, endothelial dysfunction, and serine proteases, as determined by ELISA. Results AE-UN showed shorter disease duration compared to AE-MC and HAE (2.26 vs. 3.02 vs. 15.78, p < 0.0001), but experienced a relatively higher frequency of life-threatening attacks than AE-MC (25% vs. 10%). Meanwhile, facial edema was most common in AE-UN (68.75%). We did not find a significant difference regarding age and sex among all angioedema (AE) subtypes. IgG4 levels were increased in AE-UN rather than other AE groups, and demonstrated a statistical difference with HAE (p = 0.049). Besides, Ang-1, Ang-2, and Tie-2 were significantly elevated in all AE compared to controls. By contrast, the Ang-2/Ang-1 ratio was decreased in AE patients. Notably, in AE-UN compared to AE-MC and HAE, Fibroblast Activation Protein (FAP) concentration was significantly reduced, whereas for tPA and PLA2G7, the difference was not significant compared to controls and among AE subtypes. Conclusions Lower FAP levels may represent an exploratory biomarker candidate in this selected AE-UN cohort, rather than a diagnostic marker for a homogeneous disease. Ang-1, Ang-2, and Tie-2 were increased across angioedema groups. Because of the small sample size, the exclusion-based nature of AE-UN, and the possibility of diagnostic reclassification, these findings should be interpreted as hypothesis-generating.