Algorithms in Allergy: Hereditary Angioedema

Angioedema is a clinical sign of various hereditary and acquired conditions (Supporting Information) 1, 2. The most common type of hereditary angioedema (HAE) results from a genetic C1INH deficiency (HAE-C1INH) leading to a low plasma activity of C1INH, which is considered to be a rare disease with a prevalence of approximately 1:50,000. It is classified as HAE-C1INH type I with low C1INH protein concentration (80% of the cases) and in type 2 with normal or elevated C1INH protein concentration in plasma (20% of the cases). In 2000, a novel type of HAE without wheals was identified 3, 4. This type was not associated with a deficiency of C1INH and was termed “HAE with normal C1INH” (HAE-nC1INH or HAE type III). In 2006, missense mutations in the coagulation factor XII gene (F12) were identified as the underlying genetic defect 5. Between 2018 and today (2025), further types of HAE-nC1INH were detected. Currently, gene mutations in six different genes (F12, PLG, ANGPT-1, KNG1, MYOF, HS3ST6) linked with the expression of HAE-nC1INH have been reported. Another two gene variants in CPN1 and DAB2IP are candidate genes under investigation due to their co-expression with urticaria. HAE–FXII and HAE due to mutations in the plasminogen gene (HAE-PLG) seem to be the most common types of HAE-nC1INH; however, these also occur much less frequently than HAE-C1INH. In a major number of families with HAE-nC1INH, a basic genetic defect has not yet been identified up to now (HAE-unknown; HAE-UNK) 1, 2. Clinical symptoms of HAE may include swelling of the skin and tongue, abdominal pain attacks, as well as pharyngeal and laryngeal edema that can lead to asphyxiation 6. HAE-associated angioedema usually does not occur with urticaria, nor does it respond to high-dose anti-allergic medications. There are a number of clinical conditions (“masqueraders”) that are occasionally mistaken for angioedema. Clinical classification of the various forms of angioedema begins with noting the presence or absence of recurrent wheals as a sign of urticaria 1. This allows many, but by no means all, cases of recurrent angioedema to be clinically ruled out as chronic spontaneous urticaria. Diagnosis of HAE can be established based on the family history, clinical symptoms, complement and genetic testing (Figure 1, Supporting Information). Treatment goals encompass preventing asphyxiation, preventing attacks, and controlling disease activity (frequency, severity, and duration of attacks) and enhancing the quality of life (Supporting Information) 7, 8. Due to the severe symptoms (gastrointestinal attacks, risk of asphyxiation), managing and treating patients with HAE represents a considerable responsibility. It is mandatory to provide patients with comprehensive and detailed information on symptoms, in particular initial symptoms of laryngeal edema, as well as trigger factors. Family screening of first-degree relatives is obligatory. Patients and their families need a clear plan for managing symptoms. This includes educating family members about the disease and necessary interventions. Patients should also carry an emergency medical ID (identity) card. Given the importance and time-intensive nature of these measures, it is recommended to refer patients to an HAE treatment center, such as the Angioedema Center of Reference and Excellence (ACARE) to leverage their extensive experience 9. Ideally, patients are treated close to where they live by their family physician or treating physician in close cooperation with an HAE treatment center. Patients should also be referred to patient self-help organizations, which make a significant contribution to the care of patients with HAE. For treating patients with HAE-C1INH, there is a number of highly effective and safe drugs available (Supporting Information). They include drugs for treating attacks, for short-term prophylaxis, and for preventing attacks (long-term prophylaxis) (Tables 1 and 2) 7, 8. Drugs for treatment of attacks include icatibant (bradykinin B2 receptor antagonist), human plasma-derived (pd) or recombinant human (rh) C1INH, and the plasma kallikrein-inhibitors sebetralstat and ecallantide (ecallantide is not licensed for Europe). For long-term prophylaxis in HAE-C1INH, the recommended drugs include pdC1INH, the kallikrein inhibitors lanadelumab and berotralstat, pre-kallikrein inhibitor donidalorsen and the activated FXII blocker garadacimab. Androgens and antifibrinolytics are not considered first-line drugs for this treatment. Treatment experience in patients with one of the various types of HAE-nC1INH is limited, mainly due to the rarity of these conditions 2. Icatibant and pd. C1INH have been reported to be efficacious in many patients with HAE-FXII and HAE-PLG although a significant number of patients reported about little benefit. A similarly inconsistent pattern can be seen in long-term prophylaxis. While modern therapies for long-term prophylaxis in HAE-C1INH have a good to very good efficacy profile, the number of partial or non-responders in all types of HAE-nC1INH is comparably high. Plasma-derived C1-INH CSL: “Pediatric” No age limit Takeda: No ≥ 2 years CSL: Yes No age limit Takeda: No Yes Recombinant C1-INH No ≥ 2 years Yes Yes No ≥ 2 years No (≥ 18 years) Yes No No ≥ 12 years No No No ≥ 12 years ≥ 12 years IV plasma-derived C1-INH Takeda: ≥ 6 years ≥ 6 years Takeda: Yes Yes SC plasma-derived C1-INH CSL: ≥ 6 years No CSL: Yes Yes ≥ 2 years ≥ 2 years Yes Yes No No ≥ 12 years ≥ 12 years No No ≥ 12 years ≥ 12 years K.B. conceptualized the manuscript, literature review and material preparation; M.M. writing: material preparation, review and editing; E.A.-P. writing: material preparation, review and editing; H.F. conceptualized the manuscript, literature review and material preparation. The authors have nothing to report. K.B. has received honoraria and/or research funding, and/or has served as a consultant and/or participated in advisory boards for CSL Behring, Pharvaris, and Takeda. M.M. has served as an advisor/consultant/speaker for Argo, Astria, BioCryst, CSL Behring, Intellia Therapeutics, KalVista Pharmaceuticals, Otsuka, Pharvaris, and Takeda, and been a speaker for CSL Behring, Pharming, and Takeda. E.A.-P. has served as an advisor/consultant/speaker for Astria, BioCryst, Biomarin Europe, CSL Behring, Intellia Therapeutics, KalVista Pharmaceuticals, Otsuka, Pharvaris, and Takeda, and has been a speaker for Biocryst, CSL Behring, Pharming, and Takeda. H.F. has received research grant from CSL Behring and Pharvaris; speaker fee from Biocryst, CSL Behring, Pharming, Pharvaris, and Takeda, travel grants from Astria, Biocryst, CSL Behring, Intellia, Ionis, KalVista, ONO Pharmaceutical, Pharming, Pharvaris, and Takeda; served as an advisor/consultant for Astria, Biocryst, CSL Behring, Intellia, Ionis, KalVista, ONO Pharmaceutical, Pharming, Pharvaris, and Takeda. No data was generated for this article. Data S1: all70241-sup-0001-Supinfo.docx. 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