Angioedema hereditary edema. Patients with a rare hereditary disease will be issued another passport

With this disease, it is observed very rarely and resembles erythema annulare. It is localized on the limbs, trunk, neck, persists for 2-4 days. Hereditary angioedema occurs with periodic exacerbations, manifested by painful swelling of the skin, mucous membranes of the upper respiratory tract and gastrointestinal tract. In 26% of patients, laryngeal edema leads to death. An exacerbation can be triggered by a small injury, emotional overstrain, infection, a sharp change in temperature. The disease is inherited in an autosomal dominant manner. It is due to a deficiency of the C1-esterase inhibitor. Complement activation in this case leads to excessive accumulation of C-kinin and other mediators, which cause edema.

Hereditary angioedema should be suspected if there is a history of frequent edema, especially after injury. In 80% of cases, the disease is familial. During an attack C4 in serum is not determined. In the interictal period, its level is reduced. The level of C2 during an attack is reduced. In the interictal period, it is usually normal. It is possible to reduce the hemolytic activity of complement, but this indicator is not informative enough. The most accurate diagnostic method is to determine the level of the C1-esterase inhibitor, which is significantly reduced in almost all patients. In 15% of patients, the level of the C1-esterase inhibitor is normal, and its activity is reduced. Functional assays are used to assess the activity of a C1-esterase inhibitor. In patients with acquired deficiency of the Cl-esterase inhibitor, its serum content is reduced. In hereditary Quincke's edema, the level of C1-esterase inhibitor is normal.

In mild cases, with exacerbations, NSAIDs and intravenous fluids are prescribed. Adrenaline is used only in severe cases. H1 blockers and corticosteroids are not prescribed. With severe pain, narcotic analgesics are indicated in low doses. To restore the patency of the respiratory tract, tracheal intubation is performed, if necessary, a tracheostomy. Concentrated preparations of the C1-esterase inhibitor are not available in the USA; if necessary, fresh frozen plasma is used as its source. It should be noted that sometimes after its administration, the condition of patients worsens, this is due to an increase in the concentration of complement components in the serum. In Europe, tranexamic acid, a potent inhibitor of proteases, including C1-esterase, is used as an experimental agent for the treatment of hereditary Quincke's edema. During exacerbation, this drug is prescribed at a dose of 1 g orally every 2 hours (no more than 4 g / day). For prophylaxis 1 g orally 3 times a day. In the US, tranexamic acid is not yet approved by the FDA for use in hereditary angioedema. Another protease inhibitor, aprotinin, is not available in the US.

To prevent exacerbations of hereditary Quincke's edema, 2 doses of fresh frozen plasma are prescribed before surgery before surgery. In severe, frequent exacerbations, prophylactic administration of danazol is indicated, 200 mg orally 1-3 times a day for a long time. In the absence of exacerbations, the dose of the drug is reduced to 50 mg every other day. Stanozolol is also used for the same purpose. It is prescribed first at a dose of 1-4 mg / day inside, then reduce it to the minimum effective. During treatment, the patient is carefully monitored. Androgens are contraindicated in children, adolescents and pregnant women. Stanozolol is better to appoint men, because it has a virilizing effect, and danazol - women. Danazol is also indicated for the prevention of angioedema due to overconsumption

1. C1 Inhibitor Concentrate (C1-INHIBITOR).
   a) native C1 inhibitor (isolated from plasma): Berinert, Cinryze(in adolescents and adults) Cetor;
   b) recombinant C1 inhibitor (obtained from the milk of genetically modified rabbits): Rhucin.
2. Bradykinin receptor antagonists: Firazyr (Icatibant) .
   Only for adults. Research in pediatrics is ongoing.
3. Kallikrein inhibitor: Kalbitor (Ecallantide)
4. Fresh frozen plasma if it is not possible to use C1 inhibitor drugs and other modern drugs.

Long-term prevention of hereditary angioedema

According to Craig et al. (2009), patients require long-term prophylaxis if:

• the frequency of exacerbations of HAE more than one exacerbation per month;
• ever had swelling of the larynx;
• have ever required tracheal intubation or hospitalization in the intensive care unit / intensive care unit;
• attacks of HAE are accompanied by temporary disability or absenteeism for more than 10 days a year;
• due to attacks of HAE, there is a significant decrease in the quality of life;
• the patient has any drug addiction;
• the patient's contact with health centers is limited;
• the patient has a sharp development of exacerbations of HAE;
• if the so-called. on-demand therapy(therapy on demand).

For long-term prevention, the experts of the International Consensus on the Treatment of HAE (2010) recommend the following groups of drugs:

1. so-called. "lightweight" androgens: Stanozolol, Danazol, Oxandrolone.
   This group of drugs is quite effective, but has a large number of serious side effects. And, if a dose of more than 200 mg / day (according to Danazol) is necessary to obtain a clinical effect (state of control), then the expected benefit and the possible risk of side effects should be weighed.
2. Fibrinolysis inhibitors (antifibrinolytics): ε-aminocaproic and Tranexamic acids.
   These drugs can be effective for long-term prophylaxis, but have numerous side effects, and therefore experts prefer the use of androgens, as more effective agents, than the appointment of this group.
3. C-1 inhibitor
   a) native (plasma): Cinryze(in adolescents and adults) Berinert, Cetor,
   b) recombinant: Rhucin, Ruconest– while undergoing clinical trials for approval of use as a prophylactic agent). Its effectiveness has been shown in multicenter studies.

Short-term prevention of hereditary angioedema

The drugs used to treat exacerbations of HAE are used. In case of symptoms of the prodromal period (harbingers), it can be effective Tranexamic acid or Danazol within 2-3 days to prevent the development of an exacerbation.

Drugs used to treat and prevent hereditary angioedema

1. "Aminokapronka", most likely, will not help. It generally helps few of the HAE patients, but still, it happens that it helps. It is a pity that our doctors (due to a lack of other effective drugs, as well as a lack of knowledge about HAE) are still prescribing it.
2. Better pay attention to TRANEXAMIC ACID. In Russia and Ukraine there is such a drug TRANEKSAM. However, unfortunately, this medicine is also considered ineffective. But you can try.
3. Further, from the available there is "Danazol" with the trade names Danoval, Danol, Danazol. Typically HAE patients take this drug at 50 mg to 200 mg per day and increase the dose if there is a possibility of an attack (and attacks do occur, but usually much less frequently). Attention! Danazol has a whole range of bad side effects, especially for women, especially if taken in high doses. But, with all the "buts", the drug works for many HAE patients.
4. There is also a drug called Stanozolol. It is effective, like Danazol, but there are much fewer side effects. Pay attention to it. In children, according to the literature, treatment with low doses of oxandrolone is more preferable.
5. During acute attacks of edema (larynx, abdomen, face) abroad (there, they have), drugs are used:
   + C1 inhibitor concentrate (Berinert, Cinryze, Cetor);
   + Recombinant C1 inhibitor concentrate (Ruconest/Rhucin);
   + B2 receptor antagonists (Firazyr).

   All these medicines are very expensive. Patients rarely pay for them themselves. The state, insurance organizations, charitable foundations help people by paying either the full cost of drugs or part of them. Very often, such expensive drugs are stored in refrigerators and "wait" for acute attacks of their owners. In order for these medicines to become available in the CIS countries, patients must take an active part in the process of treatment and diagnosis. To optimize partnerships between patients with HAE and doctors, there are associations or groups of patients with HAE in many Western countries around the world.

   Please note that Firazyr is officially registered in Russia, which means it should be available to patients. At least in the clinics of large cities for the relief of acute edema.

If none of the above in paragraph 5 is available, and there is a dangerous edema, then urgent hospitalization to the intensive care unit is necessary (it is desirable that the patient is known there, therefore, it should be agreed in advance) and the introduction of fresh frozen plasma rich in C1-inhibitor (it is better to choose in advance own one and store it, for example, in the refrigerator). Caution: Recent studies on the treatment of exacerbations of HAE have shown that fresh frozen plasma may contain kininogens (precursors of bradykinin), and therefore the patient's condition may worsen.

I would like to express special gratitude to Daria Aleksandrovna Yartseva (assistant of the Department of Faculty Pediatrics, Ph.D. of Zaporozhye State Medical University, Department of Faculty Pediatrics) for her help in writing this section.

Note. Berinert P, Cinryze, Ruconest and Icatibant (Firazyr) instructions reprinted from website

Human blood contains proteins that provide immunity. A group of these proteins is called the complement system. They contain a C1-esterase inhibitor. It controls the synthesis of another protein - bradykinin, which is responsible for the expansion of blood vessels in order to lower blood pressure.

Violations of the C1 inhibitor are associated with a mutated C1NH gene. As a result, control over the production of the bradykinin protein is lost. Because of this, a person can develop a very rare disease - hereditary angioedema, abbreviated as HAE.

Description and symptoms of the disease

HAE - recurring edema associated with the work of the peripheral vascular system. Uncontrollably produced bradykinin causes vasodilation, a decrease in the permeability of their walls. The result is the accumulation of fluid in the deep layers of the skin or submucosal layer.

In 60% of patients, the first attack of the disease is recorded in childhood or adolescence. In many, the first edema appears in adulthood, in units - in the elderly.

The reasons provoking the first angioedema are as follows.

1. Hormonal surge of transitional age.
2. Prolonged stressful situation.
3. Any, even a small, injury.
4. Surgical intervention.
5. Dental treatment.
6. chronic infection.
7. Hypothermia.
8. Taking certain medications (oral contraceptives, ACE inhibitors).

Locations:

• with angioedema of soft tissues, tumors appear on the face, arms, legs, abdomen, back;
• on the mucous membranes of the upper respiratory tract, gastrointestinal tract.

Symptoms of angioedema:

1. Various sizes of tumors on the body, usually painless, not itchy, not discolored. They feel like bursting, they are quite dense to the touch.
2. Can significantly increase the size of the lips, ears, eyelids, fingers.
3. Sometimes, before the onset of edema, a rash of the type of urticaria appears.
4. With swelling of the upper respiratory tract, the voice changes, a dry cough, wheezing appears, breathing becomes difficult up to suffocation.
5. Tumors of the gastrointestinal tract give severe pain, nausea, vomiting, anorexia, diarrhea.

Cause the appearance of recurring angioedema (or Quincke's edema) not only the factors that provoked the onset of the disease. Sometimes a little pressure is enough during a dental or gynecological examination. But most often, edema develops spontaneously, and antiallergic drugs are ineffective.

If you seem to have the same symptoms as above but have no idea what it is, the photo in our article shows what it looks like. And in the event that the swelling in the photo is similar to your swelling, it is advised to contact a specialist.

It is often difficult to determine that a patient has a congenital nature of the disease. For decades in a row, doctors can make incorrect diagnoses, suspecting allergic angioedema, anaphylaxis, appendicitis, intestinal obstruction, liver and kidney diseases, gynecological pathologies, even meningitis. The disease can occur without obvious and external edema, which further complicates its diagnosis.

The most dangerous is angioedema of the larynx. It blocks the access of air to the lungs, and the person suffocates. The sudden onset, rapid development of such a condition leads to death in two out of five cases.

Types of congenital angioedema

The disease is inherited. If at least one of the parents suffers from it, then the child with a probability of 50% will also receive a mutated gene. But sometimes it happens that a baby with HAE is born in a healthy family. He becomes the first carrier of a hereditary disease.

Doctors diagnose three types of HAE.

1. A decrease in the concentration of C1-inhibitor in complement is observed in the vast majority of patients (85%).
2. The concentration is normal or elevated, but at the same time, the functionality of the protein is minimal.
3. Concentration and functionality are within normal limits, but symptoms of the disease are present.

There are few such cases, experts suggest the presence of a mutation that has not yet been studied.

For an accurate diagnosis, the doctor finds out how long and how often edema appears, whether there is a heredity factor. In the stage of exacerbation, an examination is carried out. Based on a blood test from a vein, the immune status is determined, and specifically, the concentration and functionality of the C1 inhibitor. Along the way, the presence of other similar diseases is excluded.

It is important that the next of kin must be screened. In its absence, the probability of a critical situation increases to 35%. That is, every third case of edema can affect the larynx and cause death.

Treatment of hereditary angioedema

Medicine does not have a method for correcting mutations. But there are ways to compensate for their influence, thereby controlling the disease. The main methods of treating angioedema are used in the acute stage. At the same time, corticosteroid drugs, antihistamines are ineffective.
Applied methods:

• prophylactic hormone therapy - used for frequent edema, rarely used due to side effects (androgens are synthetic substitutes for male hormones);
• drugs that reduce the effect of bradykinin (introduced in the form of solutions, swelling disappears in a maximum of an hour and a half);
• drugs that replace the missing amount of protein: synthetic (injectable solutions) and donor (fresh frozen plasma, aminocaproic acid).

Examples of modern drugs for angioedema:

Popular:

Traditional medicine does not know the means capable of restoring violations of the primary immune function.

A reader from the Vitebsk region, Regina Kh., called the editorial office with a request to print information for doctors of various specializations about a rare disease that she has been suffering from for many years - hereditary angioedema.

“I always warn about my diagnosis of a dentist, an otorhinolaryngologist,” the woman explained. - I say that manipulations on soft tissues can provoke severe edema, which is not easy to deal with. Some are perplexed. And some even take me for a simulator or a hypochondriac.

Tell us about the features of this disease, the prevention of manifestations and treatment.

Tatyana Uglova, Head of the Clinical Research Laboratory of the Scientific Department of the Republican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology, Ph.D. sciences, associate professor.

Hereditary angioedema (HAE) is a rare, potentially life-threatening, genetically determined disease with an autosomal dominant inheritance pattern and incomplete penetrance. Diagnosis of HAE is not difficult, but, unfortunately, due to the lack of alertness of doctors, pathology can remain unrecognized for many years. Patients are seen by various specialists. Anaphylaxis, angioedema, or allergic angioedema are often diagnosed. However, approaches to treatment are fundamentally different: antihistamines, glucocorticosteroids, epinephrine, which are successfully used in allergic angioedema, are ineffective in HAE.

HAE is a primary (congenital) immunodeficiency without an infectious syndrome. A key role in pathogenesis is played by a decrease in the amount and/or activity of the C1 esterase inhibitor (C1 inhibitor) due to a defect in the SERPING gene (C1 INH), which is mapped on the 11th chromosome (11q12-q13.1) and encodes the synthesis of the C1 inhibitor . Approximately 300 gene mutations have been described in HAE patients, most of which involve exon 8.

C1-inhibitor is produced in hepatocytes and monocytes. It inactivates the C1 component of complement and the classical pathway of complement activation, by binding to C1r and C1s, it prevents the transition of prekallikrein to kallikrein, plasminogen to plasmin, and activation of coagulation factor XII. With its deficiency, the content of bradykinin increases, followed by an increase in the permeability of the vascular wall and the development of edema. Histamine is not involved in the development of edema in HAE.

Women have more swelling

The prevalence of HAE is 1:10,000 to 1:50,000 of the population. Men and women are equally often ill, although in the fair sex the disease occurs in a more severe form.

In 40% of patients, the first episode of HAE occurs before the age of 5 years, in 75% - before the age of 15 years. Patients with early onset of HAE attacks have a worse prognosis. In 5% of adults, the nature of the disease is asymptomatic, they were diagnosed after the discovery of the disease in their children.

How to recognize

Approximately 33% of patients have seizures more than once a month, 40% - 6-11 times a year. And only 22% have them from time to time.

As a rule, edema is localized on the skin of the face (lips, eyelids); often the genitals are involved. There is no itch. The patient feels "enlargement" and thickening of the skin or tingling in the affected area, in some cases - pain.

The swelling builds up over 12 to 24 hours and usually lasts 72 hours. In some, the symptoms persist for 5 days, and the edema migrates.

70-80% of patients with HAE complain of abdominal pain. In a quarter, it is dominant and is due to swelling of the mucous membrane of any part of the gastrointestinal tract. The intensity of pain - as in the "acute abdomen"; sometimes accompanied by nausea, vomiting, diarrhea, occasionally - constipation and intestinal obstruction.

The absence of inflammatory changes in the analysis of peripheral blood, ultrasound of the abdominal cavity help in differential diagnosis.

When the urinary system is affected, pain, urinary retention or anuria are noted.

In rare cases, when the meningeal membranes are involved, meningeal symptoms (stiff neck, severe headache, vomiting), diplopia, ataxia are recorded. With the defeat of the labyrinth systems, Meniere's syndrome develops. Very rarely - an epileptic seizure, Raynaud's syndrome.

Edema of the mucous membranes of the larynx, nose, tongue is potentially life-threatening (risk of asphyxia). Harbingers - difficulty swallowing, hoarseness, dysphonia, aphonia, anxiety, shortness of breath. In this situation, urgent hospitalization and urgent medical interventions are indicated, since an urgent condition develops, as a rule, within 8–12 hours, but may be faster.

Diagnosis of HAE

1. Anamnesis data: family cases of edema of various localization; death of relatives from laryngeal edema; hospitalizations for "acute abdomen" without subsequently establishing a topical diagnosis; connection of edema with trauma, emotional stress, taking ACE inhibitors or angiotensin II receptor blockers; the presence in the family of a patient with HAE.
2. The results of the physical examination: pale, dense swelling, no itching, the presence of precursors, clinical presentation, ineffectiveness of antihistamines and glucocorticosteroids.
3. Laboratory examination data:

• in the general blood test, an increase in hematocrit is possible, there are no eosinophilia and leukocytosis;
• C4 component of complement in blood serum - less than 14 mg/l;
• C1q - more than 77 mg/l;
• C1 antigenic inhibitor - below 199 mg/l;
• functional activity of the C1 inhibitor - up to 72% of the reference values;
• CH 50;
• fragments of prothrombin (F1+2) and D-dimers during an attack.

HAE classification

I type- characterized by a decrease in the C1 inhibitor in the blood serum and the C4 component of the complement (the latter is a screening factor). C1q level is normal. Occurs in 80-85% of patients. Caused by a mutation in the SERPING gene.

II type- decreased activity of the C1 inhibitor at normal or elevated concentrations. The level of the C4 component of the complement is low. The level of C1q is not changed. Occurs in 10-15% of cases. Caused by point mutations in the SERPING gene.

III type- normal levels of C1 inhibitor, C4 and C1q complement components. The reason is mutations in the F12 gene encoding coagulation factor XII (c.1032C->A, c.1032C->G, Thr309 Lys). Women get sick. A low level of angiotensin I is characteristic.

Deficiency of C1-inhibitor can be acquired and observed in patients with lymphoproliferative diseases (type I), with autoimmune, oncological pathology, liver diseases (type II). A sign of acquired forms (unlike HAE) is a low level of C1q.

Differential diagnosis should also be carried out with angioedema, the mediator of which is histamine. In this case, edema is hot, hyperemic, itchy, occurs quickly (from several minutes to an hour), and is often accompanied by urticaria. Harbingers are not typical. Serum C4 level is normal.
Effective antihistamines.

Therapeutic tactics. Options

Continuous lifelong prevention of acute manifestations of the disease is required. When they occur - cupping. At the III International Congress on HAE in Toronto (2010), an international consensus on the diagnosis, treatment and management of HAE was adopted: indications and principles for the treatment of acute attacks, short-term and long-term prevention were determined.

A. Relief of acute attacks
1. Mild peripheral edema does not require emergency treatment.
2. In the presence of severe peripheral edema, causing a decrease in functional activity, -
1st line therapy:

• intravenous

• antifibrinolytics (tranexamic acid at a dose of 1-1.5 g orally every 3-4 hours, -aminocaproic acid 7-10 g / day.

• hospitalization;
• consultation with a surgeon to exclude acute surgical pathology;
• bradykinin inhibitors (ikatibant) - under 18 years of age are contraindicated;
• administration of C1 inhibitor concentrate (donor or recombinant) according to the instructions for use;
• native or fresh frozen plasma.

• hospitalization;
• bradykinin inhibitors (ikatibant) - under 18 years of age are contraindicated;
• administration of C1 inhibitor concentrate (donor or recombinant) according to the instructions for use;
• native or fresh frozen plasma;
• antifibrinolytics (tranexamic acid at a dose of 1–1.5 g orally every 3–4 hours), -aminocaproic acid intravenously at a dose of 5–10 g (100–200 ml of a 5% solution), then at a dose of 5 g (100 ml of 5 % solution) every 4 hours;
• inhalation of β-agonists;
• with inefficiency - intubation, conicotomy, tracheostomy.

• bradykinin inhibitors (ikatibant) - under 18 years of age are contraindicated;
• the introduction of ε-aminocaproic acid according to the instructions for use;
• native or fresh frozen plasma;
• antifibrinolytics (tranexamic acid at a dose of 1-1.5 g orally every 3-4 hours; -aminocaproic acid intravenously at a dose of 5-10 g (100-200 ml of 5% solution), then at a dose of 5 g (100 ml of 5% solution) every 4 hours;
• inhalation of β-agonists.

• exacerbations more than once a month;
• if you have ever had swelling of the larynx;
• if you have ever needed tracheal intubation or hospitalization in the intensive care unit (intensive care unit);
• attacks are accompanied by temporary disability or missing classes for more than 5 days a month;
• a significant decrease in the quality of life;
• remoteness of the place of residence from health care institutions;
• seizures are usually rare.

When preparing women with HAE for pregnancy and the entire period of gestation, only C1 inhibitor concentrate (donor or recombinant), native or fresh frozen plasma, antifibrinolytics (with caution, coagulogram control once every 2 weeks) can be used. Observation by an immunologist throughout the entire period of pregnancy with the definition of an algorithm for accompanying childbirth is shown.

It is advisable for people with HAE to carry a “passport of a patient with HAE” or a medical bracelet that contains information about the disease and recommendations for emergency care.

Hereditary angioedema (HAE)- a rare disease associated with a quantitative deficiency (type HAO - 1) or insufficient activity (type HAO - 2) of a C1 inhibitor (English) Russian human complement system, which leads to uncontrolled internal reactions in the blood and manifests itself in the form of edema on the body. Most often, edema occurs on the arms, legs, face, in the abdominal cavity, and also in the larynx.

Swelling of the larynx often makes it difficult for air to enter the body, which in turn can lead to suffocation. Therefore, in case of laryngeal edema, hospitalization is mandatory. Edema in the abdominal cavity is accompanied by acute pain and severe vomiting and also requires hospitalization.

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K. Bork - Hereditary angioedema

Angioedema of the larynx - symptoms and treatment

Subtitles

Pathogenesis

C1 inhibitor is a highly glycosylated serum protein synthesized in the liver and inhibits the proteolytic activity of the Clr and Cls subcomponents, thus preventing the activation of the C4 and C2 components of the complement. Deficiency of the C1 inhibitor leads to uncontrolled activation of early complement components. Moreover, in 15% of cases, the concentration of C1-inhibitor remains normal, and only its functional activity is reduced. Determining the cause of the deficiency is critical to the choice of treatment for this autoimmune disease.

The pathogenesis of HAE is similar to the pathogenesis of urticaria and is associated with dilation and increased vascular permeability (mainly venules) of the deep (unlike urticaria) layers of the dermis and submucosal layer, caused by complement components and kinins of the kallikrein-bradykinin chain. In addition, these vasoactive peptides cause spasm of the smooth muscles of the digestive tract and hollow organs.

Types of HAE

The structure of the C1 inhibitor is encoded on the 11th chromosome, this protein is alpha-2-globulin and is produced mainly in hepatocytes, although activated monocytes, megakaryocytes, endothelial cells and fibroblasts are able to synthesize it in small quantities. There are three types of HAE that are phenotypically identical.

HAE type 1

HAE type 1 (85% of cases). C1 inhibitor deficiency is due to a non-functioning gene. The mutation consists of a variety of inclusions or deletions of one or more nucleotides in the region of the gene encoding the C1 inhibitor. The mutation is inherited as an autosomal dominant, Mendelian trait, although approximately 25% of HAE cases are due to a spontaneous mutation.

HAE type 2

HAE type 2 (15% of cases). The patient produces a normal or elevated amount of a malfunctioning C1 inhibitor. A common cause is a point mutation at the position of the Arginine 444 locus, which encodes for a "reactive center" - an active binding/separating site on the molecule. A non-functioning C1 inhibitor is not consumed, resulting in a higher than normal serum concentration.

HAE type 3

HAE type 3 (prevalence unknown) is a recently described disease. The concentration of C1-inhibitor in blood plasma is normal, the mechanism of the disease is unknown and probably not related to the C1-inhibitor. Until recently, it was believed that this type of HAE occurs only in women (the nature of the pedigrees suggests an X-linked dominant type of inheritance), however, families were identified in which this type of HAE was also diagnosed in men.

Acquired angioedema due to C1 inhibitor deficiency occurs in the elderly and is often associated with lymphoproliferative disorders, anti-C1 antibodies, or chronic infection.

History of the NAO

The beginning of the history of hereditary angioedema was laid by a German general practitioner and surgeon, the author of a large number of discoveries and innovations in the field of medicine Ireneus Quincke.

1882 - Ireneus Quincke first describes Quincke's edema.
1888 - W. Osier observes and describes the hereditary form of Quincke's edema. Edema appears intermittently in a 24-year-old woman. Osier draws attention to the family form of this disease, since similar symptoms were observed in five previous generations of the patient's family. The edema is first described as hereditary angioedema.
1917 - The autosomal dominant nature of the disease becomes known
1963 - Donaldson and Evans described the cause of this disease as a biochemical defect - the absence of a C1 inhibitor (C1INH deficiency).
1986 - This gene defect was found to be associated with chromosome 11.
1972 - Caldwell first described the relationship of C1-esterase inhibitor deficiency with lymphoproliferative diseases (acquired angioedema)
1987 - Alsenz, Bork and Loos discovered IgG1 antibodies to C1-esterase inhibitor (acquired angioedema).
2000 - estrogen-dependent edema is described.

Treatment of hereditary angioedema

Treatment during acute attacks of hereditary angioedema

Treatment should be started as early as possible!

1. C1 inhibitor concentrate.
   1. native C1 inhibitor (isolated from plasma): Berinert, Cinryze (in adolescents and adults), Cetor;
   2. recombinant C1 inhibitor (derived from the milk of genetically modified rabbits): Rhucin.
2. Bradykinin receptor antagonists: incatibant.
3. Only for adults. Research in pediatrics is ongoing.
4. Kallikrein inhibitor: Kalbitor (Ecallantide)
5. Fresh frozen plasma, if C1-inhibitor preparations and other modern drugs are not available.

Long-term prevention of hereditary angioedema

Long-term prophylaxis is required for patients if:

• the frequency of exacerbations of HAE more than one exacerbation per month;
• ever had swelling of the larynx;
• have ever required tracheal intubation or hospitalization in the intensive care unit / intensive care unit;
• attacks of HAE are accompanied by temporary disability or absenteeism for more than 10 days a year;
• due to attacks of HAE, there is a significant decrease in the quality of life;
• the patient has any drug addiction;
• the patient's contact with health centers is limited;
• the patient has a sharp development of exacerbations of HAE;
• if the so-called. on-demand therapy (on-demand therapy).

For long-term prevention, the experts of the International Consensus on the Treatment of HAE (2010) recommend the following groups of drugs:

1. T. n. "light" androgens: Stanozolol, Danazol, Oxandrolone.
   This group of drugs is quite effective, but has a large number of serious side effects. And, if a dose of more than 200 mg / day (according to Danazol) is necessary to obtain a clinical effect (state of control), then the expected benefit and the possible risk of side effects should be weighed.
2. Fibrinolysis inhibitors (antifibrinolytics): ε-aminocaproic and Tranexamic acids.
   These drugs can be effective for long-term prophylaxis, but have numerous side effects, and therefore experts prefer the use of androgens, as more effective agents, than the appointment of this group.
3. C-1 inhibitor
   a) native (plasma): Cinryze (in adolescents and adults), Berinert, Cetor,
   b) recombinant: Rhucin, Ruconest - while undergoing clinical trials for permission to use as a prophylactic agent). Its effectiveness has been shown in multicenter studies.

Short-term prevention of hereditary angioedema

The drugs used to treat exacerbations of HAE are used. In the presence of symptoms of the prodromal period (harbingers), Tranexamic acid or Danazol may be effective for 2-3 days to prevent the development of an exacerbation.

Drugs used to treat and prevent hereditary angioedema

• Incatibant -  B2 receptor antagonist (English) Russian. Manufacturer: Shire Human Genetic Therapies (HGT).
• Berinert is a C1 inhibitor concentrate. Manufacturer: CSL Behring.
• Cinryze is a C1 inhibitor concentrate. Manufacturer: Viropharma.
• Cetor is a C1 inhibitor concentrate. Manufacturer: Sanquin.
• Kalbitor - Kallikrein inhibitor - Ecallantide (DX-88). Manufacturer: Dyax Corp.
• Ruconest - Recombinant C1 inhibitor. Manufacturer: Swedish Orphan Biovitrum (Sobi).
• Rhucin - Recombinant C1 inhibitor. Producer: Pharming Group N.V.
• Stanozolol is an anabolic steroid drug, a derivative of androstane (dihydrotestosterone). Brand names: Winstrol (oral), Tenabol and Winstrol Depot (intramuscular).
• Danazol is an antigonadotropic agent, which is a synthetic androgen derived from ethisterone. Trade names: Danazol, Danoval, Danol, Danocrine.
• Oxandrolone is an anabolic steroid derived from dihydrotestosterone. Trade names: Oxandrin, Anavar