Hereditary angioedema

Hereditary angioedema (types I and II) (also known as "Quincke edema" after discoverer Heinrich Quincke) presents in the second to fourth decade, and is characterized by local swelling in subcutaneous tissues.

Hereditary angioedema is caused by a deficiency of the C1 esterase inhibitor, a protein of the complement system, a part of the immune system. Some mutations produce low levels of C1 inhibitor (type I); others produce normal levels of ineffective C1 protein (type II).

C1 inhibitor is needed to control the coagulation cascade in blood clotting, the complement cascade in the immune system, and the contact cascade which is also part of the inflammatory system.

Pathogenesis
Deficiency of C1 inhibitor causes hereditary angioedema types I and II. This autosomal dominant disorder is more common than complement deficiency states. C1 inhibitor inhibits C1, factor XII, and kallikrein, thus when these go unregulated they can give rise to vasoactive substances.

Hereditary angioedema type III has separate pathogenesis, being caused by mutations in F12 gene coding for a serine protease called Factor XII.

Diagnosis
A blood test, ideally taken during an episode, can be used to diagnose the condition.

Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.

Acute treatment
The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1-INH concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1-INH concentrate is only available to patients who are participating in special programs. In emergency situations where C1-INH concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1-INH.

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in Europe since 1979, but the U.S. Food and Drug Administration did not license it for fear of contamination with hepatitis C and other viruses. Consequently, death rates from hereditary angioma are high in the U.S. but rare in Europe. Older and newer preparations have used different purification techniques and demonstrated safety, and the F.D.A. is now approving some of them. Berinert P (CSL Behring), which is pasteurized, was approved by the F.D.A. in 2009 for acute attacks. Cinryze (ViroPharma), which is nanofiltered, was approved by the F.D.A. in 2008 for prophylaxis. Rhucin (Pharming) is a recombinant C1 inhibitor under development, but is more expensive than traditional products.

Newer treatments attack the contact cascade. Ecallantide (Kalbitor, Dyax) inhibits plasma kallikrein, and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant (Firazyr, Jerini) inhibits the bradykinin B2 receptor, and was approved in Europe. . Approved by the FDA on August 25, 2011. In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine.

Prophylaxis
Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. This often involves male sex hormones (androgens), which increase production of C1-INH in the liver through an as yet unknown mechanism. Danazol is the most commonly used. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.
 * Long-term prophylaxis

As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid, are used, although their effect is comparatively weak and their potential for side effects is questionable.

Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-11/2 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.
 * Short-term prophylaxis

In those with frequent or unpredictable attacks, regular infusions of plasma or inhibitor concentrate may be used. C1-INH concentrate is not available in the US, so sometimes fresh frozen plasma is used. C1inh concentrate is currently under late-stage development for both acute and prophylactic use.
 * Long-term prophylaxis

New treatment options
Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.

Pharming Group NV announced on 24 June 2010 that the European Medicines Agency has adopted a positive opinion on Ruconest (Rhucin), a C1-inhibitor for the treatment of acute angioedema attacks.

Ecallantide, a peptide inhibitor of kallikrein, has received orphan status for HAE and has shown positive results in phase III trials.

Icatibant (marketed as Firazyr) is a selective bradykinin receptor antagonist, which has been approved in only Europe and not in the USA. After initial borderline results this drug was shown to be effective in phase III trials.

Cinryze has been approved by the FDA in October 2008.

No studies have been done on these agents in relation to HAE type III.