Clinical features and potential markers of disease in idiopathic non-histaminergic angioedema, a real-life study

Abstract

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease, with unknown etiology and pathogenesis, characterized by recurrent clinical manifestations and resistance to antihistamines and corticosteroids. We aim to evaluate clinical features and potential markers of disease in an Italian cohort of patients with InH-AAE. We enrolled 26 patients diagnosed with InH-AAE. Information about clinical features, treatments, routine laboratory investigations, immunological and genetic tests were collected. We assessed plasma levels of complement components, angiogenic and lymphangiogenic mediators, proinflammatory cytokines and chemokines, and activity of phospholipases A2. Finally, patients underwent nailfold videocapillaroscopy (NVC); both quantitative and qualitative capillaroscopic parameters were analyzed. Plasma levels of VEGFs were similar in healthy controls and in InH-AAE patients. ANGPT1 was decreased in InH-AAE patients compared to controls while ANGPT2 was similar to controls. Interestingly, the ANGPT2/ANGPT1 ratio (an index of vascular permeability) was increased in InH-AAE patients compared to controls. sPLA2 activity, elevated in patients with C1-INH-HAE, showed differences also when measured in InH-AAE patients. TNF-α concentration was higher in InH-AAE patients than in healthy controls, conversely, the levels of CXCL8, and IL-6 were similar in both groups. At the NVC, the capillary loops mainly appeared short and tortuous in InH-AAE patients. InH-AAE represents a diagnostic challenge. Due to the potential life-threatening character of this condition, a prompt identification of the potentially bradykinin-mediated forms is crucial. A better comprehension of the mechanism involved in InH-AAE would also lead to the development of new therapeutic approaches to improve life quality of patients affected by this disabling disease.

Keywords: Acquired angioedema; Bradykinin; C1 inhibitor; Hereditary angioedema; Icatibant; Idiopathic non-histaminergic acquired angioedema, omalizumab.

Fig. 1

Photograph of the right hand angioedema taken by a patient

Fig. 2

Plasma VEGF-A (A), VEGF-C (B), VEGF-D (C) and VEGF-A_165b (D), ANGPT1 (E), ANGPT2 (F), ANGPT2/ANGPT1 ratio (G) in controls (Healthy) and patients with idiopathic non-histaminergic acquired angioedema (InH-AAE) in remission. Median (horizontal black line), 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers) of 26 controls and 26 patients

Fig. 3

Plasma PLA₂ (A), TNF-α (B), CXCL8 (C), and IL-6 (D) in controls (Healthy) and in patients with idiopathic non-histaminergic acquired angioedema (InH-AAE) in remission. Median (horizontal black line), the 25th and 75th percentiles (boxes) and the 5th and 95th percentiles (whiskers) of 26 controls and 26 patients

Fig. 4

Images from nailfold videocapillaroscopy on recruited idiopathic non-histaminergic acquired angioedema (InH-AAE) patients. Tortuosity and decreased loop length (A). Dilated capillary (*) with apical diameter > 20 mm and < 50 mm and normal “hairpin” shapes (B, C). Presence of single and multiple (arrow) pericapillary microhemorrhages and marked interstitial edema (D). ×200 magnification

Fig. 5

Capillaroscopic parameters (A-L) in 13 controls (Healthy) and 13 patients with idiopathic non-histaminergic acquired angioedema (InH-AAE) in remission. Horizontal bars depict the median value (A-L), boxes the 25th and 75th percentiles, and whiskers the 5th and 95th percentiles (A-F)

Fig. 6

Diagnostic flowchart for recurrent angioedema. ACEi-AAE, angioedema related to angiotensin-converting enzyme inhibitor therapy; C1-INH, C1-esterase inhibitor; C1-INH-AAE, acquired C1-esterase inhibitor deficiency angioedema; C1-INH-HAE, hereditary angioedema due to C1-esterase inhibitor deficiency; HAE, hereditary angioedema; HAE-nC1-INH, hereditary angioedema with normal C1 inhibitor; NSAID, non-steroidal anti-inflammatory drugs