Real-World Evidence on the Management of Hereditary Angioedema With Normal C1 Inhibitor

Hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1INH) is a rare and heterogeneous group of bradykinin-mediated disorders, characterized by diagnostic challenges and limited evidence-based recommendations.

To describe the clinical features and therapeutic strategies of Brazilian patients with HAE-nC1INH, supporting individualized, subtype-oriented management.

This multicenter, cross-sectional analytical study was conducted through the Brazilian Group for the Study of Hereditary Angioedema (GEBRAEH). Data were collected in December 2024 using a standardized online questionnaire and analyzed descriptively and inferentially.

A total of 116 symptomatic patients were included: 92 with HAE with mutation in coagulation factor XII, 21 with HAE of unknown genetic cause, and 3 with HAE with mutation in angiopoietin-1. Females accounted for 96%. Abdominal symptoms were predominant, and diagnostic delay decreased in more recent generations. Initial interventions most often involved isolated combined estrogen-progestin oral contraceptive (COC) withdrawal (33 of 116; 28%) or combined with progestins (35 of 116; 30%). In HAE with mutation in coagulation factor XII, COC withdrawal was effective in 97% (29 of 30), further enhanced with progestins (30 of 30; 100%). COC withdrawal reduced median attack days (4.5 to 1; P < .001) and prolonged attack-free intervals (P < .001). Four patients relapsed after more than 10 years of remission, associated with hormonal changes. Tranexamic acid demonstrated variable efficacy (2 of 10 achieved complete cessation, 5 of 10 partial reduction, and 3 of 10 no response). Lanadelumab showed clinical efficacy in HAE of unknown genetic cause (2 of 2) and HAE with mutation in angiopoietin-1 (1 of 1). Androgens showed only limited benefit (7 of 7; all partial reduction).

COC withdrawal is the most effective first-line intervention in HAE with mutation in coagulation factor XII, with greater efficacy when combined with progestins. Tranexamic acid and lanadelumab may serve as complementary options in selected cases. Late relapse highlights the need for long-term follow-up, with intensified monitoring during periods of hormonal fluctuation.