use icatibant for hereditary angioedema
- related: Allergy and Immunology
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The pathophysiology of edemagenesis in patients with hereditary angioedema (HAE) and either a deficiency or dysfunction of C1 inhibitor involves activation of the plasma contact system and consequent excessive generation of bradykinin, which mediates an increase in vascular permeability. This understanding of the underlying cause of edema formation in HAE, which has been investigated in detail over the last decade, has provided a number of targets for newer treatments as both prophylaxis preventing acute attacks and treating acute attacks themselves. Prior treatments used for HAE that largely modify allergic phenomena mediated via mast cell activation—including β-agonists and corticosteroids, which were largely ineffective—have been replaced by specific and more effective treatments. Icatibant, a bradykinin receptor antagonist, is such a new therapy employed for acute attacks in patients with HAE.
HAE is a rare autosomal dominant genetic disorder that produces episodic cutaneous angioedema and bouts of severe abdominal pain in affected individuals. While laryngeal edema with a risk for life-threatening airway obstruction occurs in only a small fraction of episodes, the fact that HAE patients in the past experienced so many episodes over their lives resulted in more than half of patients experiencing airway compromise. It is during these episodes that HAE patients are often managed by pulmonary and critical care physicians.
Two types of HA have been identified, and in both there are low levels of serum C4, a component of the complement cascade for which C1 inhibitor is a key regulatory protein. Type I HA patients (about 85% of HAE cases) have both low antigen and functional levels of C1 esterase, indicating diminished esterase production. Type II HAE patients (about 15% of HAE cases) have normal antigen levels but low C1 inhibitor function as a result of mutations affecting the reactive loop of the molecule and, hence, enzyme functionality.
In the past, long-term management of patients with HA often involved the use of antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) and androgens such as danazol. The mechanisms of action of these agents were not clear, avoidance of acute episodes was far from ideal, and significant side effects were encountered. During acute attacks, fresh frozen plasma was sometimes added to treatment to provide absent functional C1 esterase inhibitor, but instances of worsening with fresh frozen plasma infusion were noted as well. Beginning a decade ago, more specific and effective treatments were developed for both prophylactic and acute treatment. IV plasma-derived C1 inhibitor was the first of these new treatments, but it did require frequent treatment at infusion centers and/or placement of long-term IV access. A significant advance in treatment was the development of subcutaneous treatments that could be administered at home. These included plasma-derived C1 inhibitor as well as lanadelumab, a human monoclonal inhibitor of plasma kallikrein, a precursor to bradykinin formation. The patient described here had been managed with lanadelumab as her primary prophylactic treatment.
Advances have also been made in the treatment of acute or breakthrough episodes. These treatments include replacement of plasma-derived C1 inhibitor (not a choice here), inhibition of the bradykinin receptor (icatibant), or inactivation of plasma kallikrein (ecallantide, not a choice here). All of these therapies have been shown to confer benefit and to be safe in randomized controlled trials. Icatibant is administered subcutaneously and has a rapid onset of action. Doses may need to be repeated, usually at 6-h intervals, with no more than three doses in a 24-h period. In the past, availability of this agent for use in a rare disease has been a problem, but generic forms of the drug are likely to be available in the near future.1