Hereditary angioedema

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Hereditary angioedema (HAE) is a rare genetic disorder characterized by debilitating, disfiguring, and potentially fatal attacks of edema. There are three types of HAE: type I HAE (HAE-1) and type II HAE (HAE-2), the most common forms, are autosomal dominantly inherited with a prevalence of 1:50,000 due to mutations in the C1-esterase inhibitor (C1-INH) gene on chromosome 11q12-q13.1. De novo mutations of the gene controlling C1-INH ( SERPING1 ) can occur, accounting for approximately 25% of C1-INH-HAE cases. HAE-1 is characterized by a quantitative abnormality of the C1-INH (low antigen and low functional levels), which accounts for 85% of HAE patients. HAE-2 is due to a functional defect of the inhibitor of the C1-INH (with normal protein concentration); this comprises about 15% of patients. HAE-1/2 are mediated by the protease kallikrein and the nonapeptide bradykinin, acting on B ₂ receptors and 98% of cases have low C4, rising to nearly 100% during attacks. The third type of HAE, previously known as HAE type III (or the estrogen-dependent type), is now referred to as HAE with normal C1-INH (HAE nC1-INH) . Less prevalent than HAE-1/2, this type is associated with a positive family history, occurring predominantly in women, with no detectable abnormality of C1-INH or other complement components. A mutation in the gene encoding for factor 12 (F12 ), which encodes for the coagulation factor XII (FXII or Hageman factor), has been identified in some of these families. HAE attacks are characterized by sudden, unpredictable swellings of subcutaneous and submucosal tissues, including abdominal organs, genitals, face, and the upper airway. The angioedema is often asymmetrical and may sometimes be painful rather than pruritic. HAE is not associated with urticarial wheals, as it is not mast cell mediated, but a prodromal erythema marginatum rash can occur. Acute abdominal pain simulating an ‘acute abdomen’ is an important presentation in any type of HAE, and fatalities are possible due to laryngeal obstruction.

Management Strategy

Therapy for HAE is dependent on three considerations:

Relief of acute angioedema attacks especially preservation of the airway (also known as on-demand therapy)
Long-term prophylaxis for minimizing overall frequency and/or severity of attacks
Short-term prophylaxis for the prevention of relapse due to dental and surgical interventions

Acute Angioedema

Acute presentations of HAE are treated optimally with intravenous (IV) plasma-derived (pd) C1-INH concentrate (Berinert, Cinryze). This treatment is safe, and no proven cases of viral transmission have been reported. Reduction in swelling is usually significant within minutes and substantial within 2–3 hours. A recombinant C1-INH preparation (Ruconest) is now available. Patients should be taught to self-administer for a more rapid resolution of symptoms and to prevent further progression of the attack. The kallikrein–bradykinin mediator pathway is the target of current approaches to treatment of acute HAE. The swellings of HAE are mediated by bradykinin, a product of the action of kallikrein on its substrate kininogen. Bradykinin acts on B2 receptors, and its specific antagonist icatibant subcutaneously has been proven effective in acute attacks of HAE. Icatibant may be the preferred therapy because it is given subcutaneously, preferably in the abdominal area, and can be administered in a domiciliary setting by health care professionals or even by self-administration after appropriate training. Ecallantide , a kallikrein inhibitor administered as subcutaneous injections, has been proven to be safe and effective for acute attacks. Fresh frozen plasma (FFP) , which contains C1-INH, can be used in an emergency if concentrate is unavailable. However, FFP carries a higher risk of inadvertent viral transmission (HIV, hepatitis) and theoretically could exacerbate angioedema due to the presence of C1-esterase substrate. Laryngeal edema may require tracheostomy , intubation , and/or other life-support measures . Patients are routinely admitted for 24 hours after acute episodes, as life-threatening relapses are common.

Long-Term Prophylaxis

Long-term prophylaxis should be considered in those patients with at least one or more attacks of angioedema per month and in those with severe symptoms. However, patients could have infrequent attacks and still present with laryngeal edema. Even first-episode angioedema can be fatal. Prophylactic treatment with IV pd C1-INH (Cinryze) is currently the first-line therapy and can lead to less severe symptoms and even attack prevention. Pd C1-INH is also now available as a subcutaneous therapy (Haegarda), which may be preferred as a more convenient method than IV with superior steady state plasma concentrations of C1-INH. Other treatments include the 17α-alkylated ‘attenuated’ androgens ( danazol ) used as second-line prophylactic medications that may be effective in preventing angioedema in some patients with HAE-1/2. The lowest effective dose of androgen should be used to obtain clinical remission. Side effects include hirsutism, deepening of voice, and menorrhagia. These attenuated androgens are unsuitable for long-term treatment of HAE in children and pregnant women, or the treatment of acute attacks. However, they are safe and effective in adults, provided they are closely supervised with clinical biochemical and radiologic assessments. Liver function tests and lipid levels should be monitored, with liver ultrasound scans performed every 2 years. Other less effective prophylactic therapies have included antifibrinolytics (tranexamic acid ) but should be avoided in patients with a history of thrombotic diseases. They are useful for short-term prophylaxis, especially for those where C1-INH is not available or other therapies are contraindicated. In patients with mild infrequent attacks, avoidance of provoking factors, including estrogens and angiotensin-converting enzyme (ACE) inhibitors, may be sufficient.

Lanadelumab, a fully human monoclonal antibody that provides targeted inhibition of plasma kallikrein, is now approved for prevention of HAE attacks.

A newer treatment currently under review, berotralstat (BCX7353), is a potent synthetic small molecule inhibitor of plasma kallikrein that offers the distinct advantage of oral administration. It has been shown to lower rates of HAE attacks and would be the first targeted oral therapy licensed for prophylaxis of HAE, representing a major advance in therapy.

Short-Term Prophylaxis (STP) for Prevention of Relapse Due to Dental and Surgical Interventions

In all patients, prior to elective surgical, dental, or other invasive procedures, prophylaxis with pdC1-INH concentrate before the procedure is recommended. Due to the possibility of breakthrough attacks, additional on-demand treatment should be available. Second-line STP could include short courses of attenuated androgens when C1-INH is not available. If an emergency procedure is necessary, C1-INH concentrate or FFP can be administered beforehand. Patients with HAE should all wear a MedicAlert disk stating the diagnosis and emergency treatment.

Specific Investigations

Complement C4 level

C1-INH protein

C1-INH function

Busse PJ, Christiansen SC. N Engl J Med 2020; 382(12): 1136–48.

Both types HAE-1/2 are characterized by low serum C4 levels from activation of the complement cascade. The C4 level is typically reduced between attacks, and nearly undetectable during an attack; therefore, all patients with suspected HAE-1/2 should have serum C4 measured as an initial screening test. However, normal or high C4 level cannot exclude HAE. To confirm the diagnosis, tests include C1 inhibitor antigen levels and C1 inhibitor function. In HAE-1 the C1-INH protein level is low, while in HAE-2, the C1-INH protein level can be normal while C1 inhibitor function is low. C1q plasma levels are characteristically normal in HAE.

Acute Angioedema

First-Line Therapies

C1-INH concentrate	A
Icatibant	A
Ecallantide	A

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks – final results of the I.M.P.A.C.T.2 study

Craig TJ, Bewtra AK, Bahna SL, et al. Allergy 2011; 66(12): 1604–11.

A group of 57 patients were treated for a total of 1085 attacks in various areas of the body during a 24-month study period. The median time to onset of symptom relief was 0.46 hours (h) and the median time to complete resolution of symptoms was 15.5 h. No inhibitory anti-C1-INH antibodies were detected in patients, and no other treatment related safety concerns. The study concluded that 20 U-kg C1-INH is a consistent, reliable, and safe treatment of successive HAE attacks in any area of the body.

Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial

Riedl MA, Bernstein JA, Li H, et al. Ann Allergy Asthma Immunol 2014; 112(2): 163–9.

In this trial 75 patients undergoing acute laryngeal, abdominal, facial, or peripheral attacks were randomized to treatment with recombinant human C1-INH ( n = 44) or saline placebo ( n = 31). In the rhC1-INH-treated patients, median time to beginning of symptom relief was 75 min vs. 303 min in placebo-treated patients ( p = 0.003). The median time to minimal symptoms was 240 min in the rhC1-INH-treated group vs. 362 min in the placebo-treated group ( p = 0.005). RhC1-INH was well tolerated, with no thromboembolic events or observations of neutralizing antibodies or anaphylaxis.

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