Understanding Hereditary Angioedema with Normal C1 Inhibitor
Hereditary angioedema (HAE) is a rare condition defined by recurrent swelling attacks. In cases with a normal C1 esterase inhibitor (C1-INH), the clinical picture and management can differ from classic C1-INH–deficient forms. The latest real-world evidence, drawn from a national HAE network, highlights how certain subtypes—especially HAE with FXII variants (HAE-FXII)—are markedly influenced by hormonal status. The study analyzed 116 symptomatic patients, most of whom were female and reported predominant abdominal symptoms. Importantly, diagnostic delays have shortened in recent generations, suggesting improved clinician awareness and broader access to subtype testing.
Key Real-World Findings at a Glance
Among patients with HAE and normal C1 inhibitor, hormonal modulation emerged as a central theme. The withdrawal of combined oral contraceptives (COCs), often containing progestins, was associated with substantial reductions in attack frequency. In the HAE-FXII subset, stopping COCs led to dramatic improvements across the cohort, and the addition of progestins aided complete responses in many cases. Post-withdrawal, the median number of attack days decreased from about 4.5 days per month to roughly 1 day, while the intervals between attacks lengthened, indicating meaningful, clinically relevant control.
Clinical Course and the Need for Long-Term Surveillance
Although most patients responded to hormonal modification, a small portion experienced relapse during extended remission that correlated with hormonal changes (for example during life stages with shifting estrogen levels). This observation underscores the importance of ongoing follow-up and anticipatory management as patients encounter such hormonal transitions. Clinicians should prepare for potential re-emergence of attacks during pregnancy, perimenopause, or changes in contraceptive use.
Subtype-Oriented Options Beyond Hormonal Measures
While hormonal strategies form a cornerstone for many patients with HAE-FXII, other subtype-guided therapies offer additional options. Tranexamic acid showed variable efficacy, ranging from complete attack cessation to little or no benefit, reflecting the heterogeneity within HAE with normal C1 inhibitor. Lanadelumab, a monoclonal antibody, demonstrated clinical benefit in patients with less common genetic causes or ANGPT1 variants, though data was limited due to smaller subgroups. Androgens were associated with only partial reductions in attack frequency in this real-world cohort, suggesting that their use should be individualized and carefully weighed against potential adverse effects.
The overarching message is clear: management should be tailored to the patient’s specific subtype, triggering profile, and historical response pattern. Shared decision making, guided by confirmed subtype information, enables targeted use of hormonal therapy, antifibrinolytics, and biologic prophylaxis when appropriate.
Practical Implications for U.S. Practice
For patients suspected of having HAE with normal C1 inhibitor, clinicians should consider hormonal contributors early in the diagnostic and treatment process, particularly for the HAE-FXII subtype. Early hormonal assessment can accelerate control of attacks and reduce the need for exploratory therapies. Subtype confirmation, ongoing surveillance, and collaborative care are essential during periods of physiological change—such as puberty, pregnancy, or menopause—when hormone levels fluctuate and attack patterns may shift.
Looking Forward
The study by Lobão et al. (2025) underscores the value of real-world data in refining management of HAE with normal C1 inhibitor. As genetic and phenotypic subtyping becomes more accessible, clinicians can optimize combinations of hormonal strategies, antifibrinolytics, and monoclonal therapies to align with each patient’s trajectory and life stage. Continued follow-up and adaptive care remain critical to maintaining attack control over time.
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.
