Top Causes of Angioedema: Insights for 2025

Summary and Overview of Angioedema

Angioedema is sudden, localized swelling of deeper skin and mucous membranes, often affecting the face, lips, airway, extremities, and gastrointestinal tract. It results from increased vascular permeability triggered by vasoactive mediators and ranges from mild discomfort to life-threatening airway obstruction. Angioedema is classified into histamine-mediated (allergic) and bradykinin-mediated types, each with distinct triggers and treatments. Common causes include allergic reactions to foods, medications, insect stings, NSAIDs, and ACE inhibitors, with hereditary angioedema (HAE) being a rare genetic form caused by C1 esterase inhibitor deficiency or dysfunction. Advances in diagnostics and targeted therapies, including C1-inhibitor concentrates, bradykinin receptor antagonists, and monoclonal antibodies like garadacimab, have improved management. Despite progress, angioedema remains complex with significant morbidity and mortality risks.

Epidemiology and Causes

Allergic angioedema is the most common form, often involving periorbital and lip swelling, sometimes without urticaria. ACE inhibitor-induced angioedema, prevalent in Western countries, accounts for many emergency cases, while NSAIDs like ibuprofen are common triggers in some populations. HAE is rare, variable in severity, and often underdiagnosed. Angioedema causes include IgE-mediated allergic reactions, bradykinin-mediated mechanisms (HAE, acquired angioedema, ACE inhibitor-related), and idiopathic or acquired forms linked to autoimmune or neoplastic conditions.

Pathophysiology

Angioedema arises from increased vascular permeability due to mast cell degranulation or bradykinin excess. Mast cell–mediated angioedema involves histamine release triggering rapid swelling with urticaria and itching. Bradykinin-mediated angioedema lacks urticaria and develops more slowly; it results from excessive bradykinin production or impaired degradation, activating bradykinin B2 receptors. Recent findings reveal mutant plasminogen can generate bradykinin independently, offering new therapeutic targets like garadacimab, which inhibits activated Factor XII.

Clinical Presentation and Diagnosis

Angioedema presents as abrupt, nonpitting swelling of skin or mucosa, often affecting the face, airway, and gastrointestinal tract. Allergic forms onset rapidly with urticaria and itching; bradykinin-mediated forms have slower onset, longer duration, and no urticaria. Hereditary angioedema may show erythema marginatum rash and is often triggered by trauma or stress. Diagnosis involves clinical history, family history, and laboratory tests including complement C4, C1 esterase inhibitor levels and function. Genetic testing identifies mutations in genes like SERPING1 and others for normal C1-INH HAE. Differentiating types guides treatment.

Treatment and Management

Histamine-mediated angioedema responds to antihistamines, corticosteroids, and epinephrine. Bradykinin-mediated angioedema, including HAE, requires specific therapies such as C1-INH concentrates, kallikrein inhibitors, and bradykinin B2 receptor antagonists like icatibant. Long-term prophylaxis options include monoclonal antibodies like garadacimab targeting Factor XIIa, offering monthly dosing and improved quality of life. Emerging RNA-based and gene therapies are under investigation. Avoidance of triggers, especially ACE inhibitors and estrogen-containing contraceptives, is crucial. Individualized care plans enhance disease control and patient outcomes.

Clinical Efficacy and Recent Advances

Garadacimab has demonstrated sustained efficacy and safety in reducing HAE attacks and improving quality of life in phase 2 and 3 trials. Investigational drugs like deucrictibant, a bradykinin B2 receptor antagonist, show promise with rapid action and good tolerability. Advances in genetics reveal multiple gene mutations causing HAE with normal C1-INH, improving diagnostic accuracy through next-generation sequencing. RNA interference therapies targeting kallikrein and gene therapy approaches are in early clinical development. These innovations simplify treatment and enhance patient adherence, though long-term safety data remain under study.

Prevention and Prognosis

Prevention centers on identifying and avoiding triggers such as allergens, ACE inhibitors, NSAIDs, and estrogen. Prophylactic therapies have improved quality of life and reduced emergency care needs in HAE. Prognosis has improved with newer treatments like garadacimab, which reduce attack frequency and severity. Laboratory monitoring of complement and C1-INH levels aids disease management. Despite advances, some patients require therapy adjustments due to efficacy or side effects.

Societal and Economic Impact

Angioedema imposes significant healthcare and economic burdens due to unpredictable attacks and treatment costs. Novel therapies have reduced hospitalizations and improved patient quality of life, though indirect costs like lost productivity and psychological stress persist. Pharmacovigilance using databases such as FDA’s FAERS helps monitor drug-induced angioedema risks. Continued development of safe, effective, and convenient treatments is essential to lessen the societal and economic impact of angioedema globally.

The content is provided by Avery Redwood, Scopewires