Overview: Real-World Insights into HAE with Normal C1 Inhibitor
Hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) remains a clinically challenging condition. Real-world data from a national HAE network highlight that many patients are hormone-sensitive, particularly in the HAE-FXII subtype. The pattern observed: cessation of hormonal contraception often leads to a marked drop in attack frequency, with adjunctive therapies providing additional control for selected patients. This article synthesizes current findings and practical implications for clinicians managing HAE with normal C1 inhibitor.
Hormonal Modulation as a First-Line Strategy in HAE-FXII
In the subset of HAE-FXII, withdrawal of combined oral contraceptives (COCs) — and often progestin-containing regimens — shows high effectiveness. Across evaluated patients, most experienced improvement after cessation, and the addition of progestins contributed to complete responses in many cases. Key metrics include a reduction in median attack days—from about 4.5 days to 1 day—and longer attack-free intervals after hormonal withdrawal. Notably, a small portion relapsed during prolonged remission, usually coinciding with hormonal changes (life stages such as menstruation, pregnancy, or menopause) that alter hormone levels. These observations underscore the need for long-term follow-up and anticipatory management during periods of hormonal fluctuation.
Subtype-Oriented Options Beyond Hormonal Measures
The management of HAE with normal C1 inhibitor is heterogeneous, reflecting diverse underlying subtypes. Tranexamic acid offered variable benefit, ranging from complete symptom control to little or no effect, illustrating that antifibrinolytics are not universally effective. Lanadelumab demonstrated clinical benefit in the limited patients with HAE of unknown genetic cause and in those with ANGPT1 variants, suggesting a role for monoclonal prophylaxis in select subtypes. Androgens yielded only partial reductions in attack frequency in this cohort. Overall, these data support a personalized approach that accounts for the specific subtype, triggers, and prior response history when selecting preventive strategies.
Clinical Implications for Practice
For clinicians assessing suspected HAE with normal C1 inhibitor, it is prudent to consider hormonal contributors early, especially if HAE-FXII is suspected. Confirming the subtype through targeted testing and engaging in shared decision making enables targeted use of hormonal strategies, antifibrinolytics, and monoclonal prophylaxis. Ongoing surveillance is essential during life stages associated with physiological changes that can influence hormone levels and attack patterns.
Summary for Clinicians
Real-world evidence underscores the importance of a personalized, hormone-aware management plan for HAE with normal C1 inhibitor. By integrating hormonal modulation with subtype-directed options such as tranexamic acid or lanadelumab, clinicians can improve attack control while tailoring therapy to individual patient needs and life stages.
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.
