Overview: What this real-world evidence reveals about HAE with Normal C1 Inhibitor
Hereditary angioedema (HAE) can present with normal C1 inhibitor levels, a subtype that varies in origin and response to treatment. A recent national study analyzed 116 symptomatic patients within a hereditary angioedema network to describe how clinicians identify, diagnose, and manage HAE with normal C1 inhibitor. The cohort was predominantly female and most commonly reported abdominal symptoms. Importantly, diagnostic timing has improved in newer generations, indicating rising clinician awareness and greater access to subtype testing. These findings provide a practical guide for clinicians navigating a condition that often hinges on recognizing hormonal and genetic nuances.
Key driver: Hormonal modulation in HAE-FXII
In the subset known as HAE-FXII, hormonal factors play a central role. The study found that withdrawing combined oral contraceptives, especially formulations with progestins, led to marked reductions in attack frequency. In many cases, this alone produced meaningful control. When progestins were added or used in conjunction with other strategies, some patients achieved complete responses. The data show a dramatic improvement: median attack days dropped from about four and a half to one, and attack-free intervals lengthened after hormonal changes.
However, the experience was not uniform for every patient. A small portion experienced relapse after extended remission, often tied to hormonal changes such as life stage transitions or new exposures that alter the hormonal milieu. This underscores the necessity of long-term follow-up and anticipatory management around events like menstruation, pregnancy, and menopause, where hormone levels shift and attack risk may change.
Subtype-oriented options beyond hormonal measures
Beyond hormonal strategies, the study highlights a spectrum of options tailored to individual subtype profiles within HAE with normal C1 inhibitor. Tranexamic acid showed variable results, ranging from complete cessation of attacks to no response, reflecting heterogeneity among patients. Lanadelumab, a monoclonal antibody targeting kallikrein, demonstrated clinical benefit in a small number of patients with unknown genetic causes or with ANGPT1 variants, suggesting that targeted biologic therapy can be effective for select subgroups. Androgens, once used in some HAE subtypes, yielded only partial reductions in attack frequency in this cohort, further supporting a move toward precision medicine guided by subtype testing and patient history.
The overarching takeaway is clear: treatment plans should be individualized, taking into account the patient’s specific subtype, triggers, prior responses, and life circumstances. This approach helps clinicians optimize prophylaxis while minimizing side effects and maintaining quality of life.
Clinical implications for U.S. practice
For patients with suspected HAE with normal C1 inhibitor, clinicians should consider hormonal contributions early, particularly for those with suspected HAE-FXII. Early recognition of hormonal drivers can accelerate effective control of attacks. Subtype confirmation—supported by genetic and functional testing—facilitates targeted use of hormonal strategies, antifibrinolytic agents, and monoclonal prophylaxis such as lanadelumab, when appropriate. As patients navigate hormonal life events, ongoing surveillance and adaptable management plans remain essential.
These findings align with a pragmatic, patient-centered care model: diagnose accurately, tailor treatment to subtype, and maintain vigilant follow-up during periods of hormonal fluctuation. Shared decision-making with patients about risks, benefits, and personal preferences is central to optimizing outcomes in HAE with normal C1 inhibitor.
Bottom line for clinicians and patients
The study by Lobão et al. (2025) emphasizes hormone sensitivity as a pivotal factor in HAE-FXII and demonstrates that real-world management often benefits from a staged, subtype-informed approach. By combining hormonal adjustments, antifibrinolytics, and selective monoclonal therapies, clinicians can improve attack control while addressing individual patient needs. Continued research and long-term follow-up will refine guidelines and support patients through hormonal transitions across the lifespan.
