New Treatments for Hereditary Angioedema

Nathan M. Johnson, MD; Mariana A. Phillips, MD


Skin Therapy Letter. 2018;23(1) 

In This Article

Abstract and Introduction


Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.


Hereditary angioedema (HA) is a rare genetic disease characterized by repeated episodes of non-pitting edema that can affect any cutaneous or mucosal surface. Swelling of the face, larynx, tongue, extremities, stomach, bowels, and genitals is common and can be associated with significant morbidity and mortality. The most common form of HA is autosomal dominant and results from a loss-of-function mutation in the gene that codes for C1 inhibitor protein. Under normal circumstances, a functional level of C1 inhibitor in plasma prevents over-activation of the complement system and over-production of the vasoactive mediator, bradykinin. Deficiency of C1 inhibitor allows for excessive release of bradykinin and complement anaphylatoxins, which results in increased endothelial permeability and edema.[1,2]

In terms of disease management, synthetic androgens and protease inhibitors are useful in preventing episodes of angioedema through the stimulation of endogenous synthesis and reduced degradation of functional C1 inhibitor, respectively. Unfortunately, these agents are associated with significant adverse effects that limit their use.[3,4] Acute attacks are treated quite effectively by serum supplementation with exogenous humanderived C1 inhibitor, as initially demonstrated by Agostoni and colleagues in 1976.[5] Human derived C1 inhibitor is not available in the United States, despite acceptance in Europe, due to concerns over possible virus transmission.

Relatively new developments have led to vast improvements in prevention and acute management of HA (Table 1). This paper reviews advances in the production of safer forms of humanderived C1 inhibitor (Berinert®, Cinryze®), the development of a recombinant form of C1 inhibitor (conestat alfa, Ruconest®/Rhucin®) and drugs that decrease the production of bradykinin (ecallantide, Kalbitor®) or block its activity at the receptor level (icatibant, Firazyr®).