Juan Liu, Xiangyi Cui, Nan Zhou, Yuxiang Zhi
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.
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.