Angioedema Therapies Are Advancing Fast, But Diagnosis Still Lags Behind
Angioedema, in its autoimmune and hereditary forms, is a condition that causes sudden, painful swelling in the skin, lips, face, throat, hands, and abdomen. Unlike the more commonly known allergic swelling that responds to antihistamines, the form caused by dysfunction of a protein called C1 inhibitor follows a different biological pathway, one driven by a molecule called bradykinin rather than histamine. This distinction matters enormously for treatment, because antihistamines and epinephrine, the typical tools for allergic reactions, simply do not work in bradykinin-mediated angioedema attacks.
A 2025 review in Frontiers in Immunology, authored by researchers F. Johnson and B. Hofauer, examines both the diagnostic challenges and the wave of new therapies now available for this group of rare but potentially life-threatening disorders. Hereditary angioedema, or HAE, is the best-characterized form, caused by either a deficiency of C1 inhibitor protein (Type I) or a dysfunctional version of it (Type II). Acquired forms linked to autoimmune conditions also exist, where the immune system destroys the C1 inhibitor, and these can be more difficult to identify and treat.
Diagnosis remains a major challenge for patients with angioedema. The condition is frequently misdiagnosed as allergic reactions, abdominal emergencies, or even psychiatric symptoms when intestinal swelling causes cramping and nausea. Many patients spend years seeking answers before receiving a correct diagnosis. The review highlights that low C4 complement levels in blood, combined with reduced C1 inhibitor activity, are key diagnostic markers, but that clinician awareness of non-allergic angioedema types remains limited outside of specialist settings.
On the treatment front, the past few years have brought remarkable progress. Garadacimab, recently approved under the brand name ANDEMBRY for patients aged 12 and older, works by blocking a protein called Factor XIIa that sits at the top of the bradykinin production pathway. Given as a once-monthly injection, it has shown strong results in preventing attacks. Sebetralstat, an oral plasma kallikrein inhibitor approved by the European Medicines Agency in 2025, offers on-demand treatment for acute attacks, with trials showing a meaningful reduction in attack severity compared to placebo.
For longer-term prevention, established therapies include C1 inhibitor replacement products, lanadelumab (a monthly injection), and berotralstat (a daily oral pill). The expanding menu of options means clinicians can increasingly tailor prevention strategies to individual patients based on attack frequency, route preference, and lifestyle factors.
For patients with autoimmune-driven acquired angioedema, treatment is more complex and typically involves addressing the underlying autoimmune condition. This may include immunosuppressive agents, B cell depletion therapies like rituximab, and, in some cases, the same bradykinin-pathway therapies used in hereditary forms. The review underscores the importance of specialist referral for anyone whose angioedema does not clearly respond to antihistamines, as proper subtyping is the key to effective management.