Hereditary angioedema
Encyclopedia
Hereditary angioedema (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.
, 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.
Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.
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 antihistamine
s, corticosteroid
s, or epinephrine
.
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 (androgen
s), 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.
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
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.
Long-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.
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 http://www.pharming.com/index.php?act=show&pr=525&height=600&width=800.
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 http://www.reuters.com/article/marketsNews/idINN1040817520081010?rpc=44 has been approved by the FDA in October 2008.
No studies have been done on these agents in relation to HAE type III.
Heinrich Quincke
Heinrich Irenaeus Quincke was a German internist and surgeon. His main contribution to internal medicine was the introduction of the lumbar puncture for diagnostic and therapeutic purposes...
) 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
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, 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 XIIFactor XII
Coagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...
, and kallikrein
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
, 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
Factor XII
Coagulation factor XII also known as Hageman factor is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.- Function :...
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 edemaEdema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx
Larynx
The larynx , commonly called the voice box, is an organ in the neck of amphibians, reptiles and mammals involved in breathing, sound production, and protecting the trachea against food aspiration. It manipulates pitch and volume...
. 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
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...
(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 antihistamine
Antihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
s, corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, or epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
.
Prophylaxis
Long-term prophylaxisPatients 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 (androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s), which increase production of C1-INH in the liver through an as yet unknown mechanism. Danazol
Danazol
Danazol is a derivative of the synthetic steroid ethisterone, a modified testosterone. Also known as 17alpha-ethinyl testosterone. Before becoming available as a generic drug, Danazol was marketed as Danocrine in the United States. It was approved by the U.S. Food and Drug Administration as the...
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.
As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid
Tranexamic acid
Tranexamic acid is a drug used to treat or prevent excessive blood loss during surgery and in certain other conditions...
, are used, although their effect is comparatively weak and their potential for side effects is questionable.
Short-term prophylaxis
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.
Long-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
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...
is used. C1inh concentrate is currently under late-stage development for both acute and prophylactic use.
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
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
has adopted a positive opinion on Ruconest (Rhucin), a C1-inhibitor
C1-inhibitor
C1-inhibitor is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during...
for the treatment of acute angioedema attacks http://www.pharming.com/index.php?act=show&pr=525&height=600&width=800.
Ecallantide
Ecallantide
Ecallantide is a drug used for the treatment of hereditary angioedema and in the prevention of blood loss in cardiothoracic surgery. It is an inhibitor of the protein kallikrein and a 60-amino acid polypeptide which was developed from a Kunitz domain through phage display to mimic antibodies...
, a peptide inhibitor of kallikrein
Kallikrein
Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known homologue, while tissue kallikrein-related peptidases encode a family of fifteen closely related serine proteases...
, has received orphan status for HAE and has shown positive results in phase III trials.
Icatibant
Icatibant
Icatibant is a peptidomimetic drug consisting of ten amino acids, which is a selective and specific antagonist of bradykinin B2 receptors...
(marketed as Firazyr) is a selective bradykinin receptor
Bradykinin receptor
The bradykinin receptor family is a group of G-protein coupled receptors whose principal ligand is the protein bradykinin.There are two Bradykinin receptors: the B1 receptor and the B2 receptor.-B1 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 http://www.reuters.com/article/marketsNews/idINN1040817520081010?rpc=44 has been approved by the FDA in October 2008.
No studies have been done on these agents in relation to HAE type III.