Key Findings at a Glance
REAL-WORLD evidence indicates that hereditary angioedema with normal C1 inhibitor is frequently hormone sensitive. In HAE-FXII, withdrawal of combined oral contraceptives, often with progestins, is associated with marked reductions in attack frequency, and adjunctive options include tranexamic acid and lanadelumab for selected subtypes.
Hereditary Angioedema with Normal C1 Inhibitor: Study Overview
Investigators analyzed 116 symptomatic patients through a national hereditary angioedema network to characterize clinical features and management patterns in HAE with normal C1 inhibitor. Most participants were female and reported predominant abdominal symptoms. Diagnostic delay improved in more recent generations, suggesting increased clinician awareness and access to subtype testing.
Hormonal Modulation and First-Line Strategy in HAE-FXII
In HAE-FXII, combined oral contraceptive withdrawal showed high effectiveness. Nearly all patients improved after cessation, and the addition of progestins supported complete response in the evaluated group. Following withdrawal, median attack days fell from four and a half to one, and attack-free intervals lengthened. A small number of patients experienced relapse after prolonged remission that coincided with hormonal change, underscoring the need for long-term follow up and anticipatory management during life stages with fluctuating hormone levels.
Subtype-Oriented Options Beyond Hormonal Measures
Tranexamic acid produced variable benefit, ranging from complete cessation to no response, highlighting heterogeneity within HAE with normal C1 inhibitor. Lanadelumab demonstrated clinical efficacy in the limited number of patients with HAE of unknown genetic cause and with ANGPT1 variants. Androgens achieved only partial reductions in attack frequency in this cohort. These patterns support individualized decision making that considers the patient’s subtype, triggers, and response history.
Clinical Implications for U.S. Practice
For patients with suspected HAE with normal C1 inhibitor, early consideration of hormonal contributors can accelerate control of attacks, particularly in HAE-FXII. Subtype confirmation and shared decision making enable targeted use of hormonal strategies, antifibrinolytics, and monoclonal prophylaxis, with ongoing surveillance through periods of physiological change.
Reference: Lobão NT et al. Real-World Evidence on the Management of Hereditary Angioedema with Normal C1 Inhibitor. J Allergy Clin Immunol Pract. 2025;10:S2213-2198(25)00936-5.
