Наследственный ангионевротический отек: типы, диагностика и лечение.

Disorder resulting in severe swelling
Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur. while type III affects females more often than males.

There are three types of hereditary angioedema (HAE). HAE types I and II are both caused by a deficiency of complement C1 inhibitor (C1 INH), a plasma protein that is an important inhibitor of several serine proteases, specially of the complement system and the contact activation/kallikrein kinin pathway, but also the fibrinolytic system. In HAE type I, there is a quantitative C1 inhibitor deficiency, antigenic as well as functional C1 inhibitor levels in plasma are decreased. This type accounts for approximately 85% of HAE cases with C1 inhibitor deficiency. C1 inhibitor deficiency is caused by mutations of the SERPING1 gene, the gene encoding complement C1 inhibitor. More than 700 different mutations have been described. Another type of hereditary angioedema, originally named HAE type III, has been observed. In contrast to HAE types I and II, this type of the disease is characterized by normal C1 inhibitor measurements. Thus, the term "hereditary angioedema with normal C1 inhibitor" is now generally used for this HAE type. Normal C1 inhibitor level hereditary angioedema is thought to involve various mutations that increased bradykinin activity and cause a decreased threshold for activation of the plasma contact system thus leading to the symptoms of angioedema. All four mutations known so far, the two originally described missense mutations in exon 9 as well as the two additional, very rare mutations described later, affect the proline rich region of coagulation factor XII. Clinical manifestation of hereditary angioedema due to a F12 mutation occurs preferably, but not exclusively in female mutation carriers. The remarkable estrogen sensitivity is a characteristic feature of the HAE type caused by a F12 mutation. For example, estrogen containing oral contraceptives play an important role in triggering angioedema attacks. Exacerbation of symptoms during pregnancy is also a common observation. The mutation creates a new lysine binding site within the kringle 3 domain and alters the glycosylation of plasminogen. Tongue swellings are a very frequent and characterizing symptom in patients with hereditary angioedema due to a plasminogen mutation.

People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of pdC1INH in many parts of the world; bradykinin receptor antagonists (icatibant) in Europe; kallikrein inhibitors (ecallantide and lanadelumab) in the United States; and recombinant C1 INH replacement therapy (rhC1INH; conestat alfa) in Europe. Tranexamic acid has been shown to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events. For people requiring long term prophylaxis, home therapy which allows people to self administer the product, is considered an integral part of allowing patients a normal quality of life. In 2018, the U. S. Food and Drug Administration (FDA) approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people over age 12. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II. Berotralstat was approved in the US in December 2020, for the prevention of attacks of hereditary angioedema in people over twelve years of age.

Short term prevention is normally administered before surgery or dental treatment. In Germany, C1 INH concentrate is used for this and given 1–1.5 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.

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 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor. 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. Several C1 inhibitor treatments are now available in the U. S. Food and Drug Administration and two C1 inhibitor products are now available in Canada. 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. Ruconest (Pharming) is a recombinant C1 inhibitor approved in the US and Europe that does not carry the risk of infectious disease transmission due to human blood borne pathogens. The medication ecallantide inhibits plasma kallikrein and was approved by the F. D. A. (but not in Europe) for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in Europe and the USA. In HAE, 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. In February 2023, the FDA approved the expanded use of lanadelumab (Takhzyro) to prevent attacks of hereditary angioedema in children aged 2 to 12 years of age.

About 25% of those affected die in the first two decades of life, mainly due to lack of treatment.

Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.

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 conestat alfa (trade name Ruconest), 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 Europe and was approved in the US by the FDA in Aug 2011. 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.