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Print this pageHAE Frequently Asked Questions
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What is Hereditary Angioedema?What causes Hereditary Angioedema attacks?
How is Hereditary Angioedema diagnosed?
At what age do attacks of Hereditary Angioedema start?
How long do Hereditary Angioedema attacks last?
When are Hereditary Angioedema attacks considered serious?
How is Hereditary Angioedema treated?
Are there any new treatments on the horizon?
What treatments are available for children who have Hereditary Angioedema?
What medicine should HAE patients avoid?
What is Hereditary Angioedema?
Hereditary Angioedema (HAE) is a very rare and potentially life threatening genetic condition that occurs in about 1/10,000 to 1/50,000 people. HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face, and airway.
HAE is called hereditary because the genetic defect is passed on in families. A child has a 50 percent chance of inheriting this disease if one of his or her parents has it. The absence of family history does not rule out the HAE diagnosis, however. Scientists report that as many as 20 percent of HAE cases result from patients who had a spontaneous mutation of the C1-inhibitor gene at conception. These patients can pass the defective gene to their offspring. Because the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years. Many patients report that their frequent and severe abdominal pain was inappropriately diagnosed as psychosomatic, resulting in referral for psychiatric evaluation. Unnecessary exploratory surgery has been performed on patients experiencing gastrointestinal edema because abdominal HAE attacks mimic a surgical abdomen. Before therapy became available, the mortality rate from airway obstruction was reportedly as high as 30%.
Hereditary Angioedema (HAE) is a very rare and potentially life threatening genetic condition that occurs in about 1/10,000 to 1/50,000 people. HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face, and airway.
HAE is called hereditary because the genetic defect is passed on in families. A child has a 50 percent chance of inheriting this disease if one of his or her parents has it. The absence of family history does not rule out the HAE diagnosis, however. Scientists report that as many as 20 percent of HAE cases result from patients who had a spontaneous mutation of the C1-inhibitor gene at conception. These patients can pass the defective gene to their offspring. Because the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years. Many patients report that their frequent and severe abdominal pain was inappropriately diagnosed as psychosomatic, resulting in referral for psychiatric evaluation. Unnecessary exploratory surgery has been performed on patients experiencing gastrointestinal edema because abdominal HAE attacks mimic a surgical abdomen. Before therapy became available, the mortality rate from airway obstruction was reportedly as high as 30%.
What causes Hereditary Angioedema attacks?
Most attacks occur spontaneously with no apparent reason, however anxiety, stress, minor trauma, surgery, and illnesses such as colds and flu have been cited as triggers. Trauma to the oral cavity caused by dental procedures make HAE patients particularly vulnerable to airway attacks. Patients have also reported swelling in extremities following typing, prolonged writing, pushing a lawn mower, hammering, shoveling, and other physical activities.
In women, menstruation and pregnancy seem to have a major effect on disease activity. Some women patients report a definite increase in the number of attacks during their menstrual periods. During pregnancy, some patients note an increase in the frequency of attacks, while others have reported a decrease. Use of oral contraceptives and hormone replacement therapy is associated with an increase in the frequency and severity of attacks.
Most attacks occur spontaneously with no apparent reason, however anxiety, stress, minor trauma, surgery, and illnesses such as colds and flu have been cited as triggers. Trauma to the oral cavity caused by dental procedures make HAE patients particularly vulnerable to airway attacks. Patients have also reported swelling in extremities following typing, prolonged writing, pushing a lawn mower, hammering, shoveling, and other physical activities.
In women, menstruation and pregnancy seem to have a major effect on disease activity. Some women patients report a definite increase in the number of attacks during their menstrual periods. During pregnancy, some patients note an increase in the frequency of attacks, while others have reported a decrease. Use of oral contraceptives and hormone replacement therapy is associated with an increase in the frequency and severity of attacks.
How is Hereditary Angioedema diagnosed?
Most cases of angioedema are not HAE because swelling attacks are typically caused by something other than C1-inhibitor deficiency, usually an allergic reaction. Laboratory analysis of blood samples or genetic testing is required to establish the HAE diagnosis. There are two specific blood tests that confirm HAE:
Most cases of angioedema are not HAE because swelling attacks are typically caused by something other than C1-inhibitor deficiency, usually an allergic reaction. Laboratory analysis of blood samples or genetic testing is required to establish the HAE diagnosis. There are two specific blood tests that confirm HAE:
- C1-inhibitor quantitative (antigenic)
- C1-inhibitor functional
At what age do attacks of Hereditary Angioedema start?
The age of HAE onset varies considerably, however, in one study, half of the patients reported onset of their symptoms by the age of seven, and over two thirds became symptomatic by the age of thirteen. There also seems to be an increased frequency of attacks during puberty or adolescence.
The age of HAE onset varies considerably, however, in one study, half of the patients reported onset of their symptoms by the age of seven, and over two thirds became symptomatic by the age of thirteen. There also seems to be an increased frequency of attacks during puberty or adolescence.
How long do Hereditary Angioedema attacks last?
Patients often report tingling or tightness at the site where edema will occur thirty minutes to several hours later. In some cases, this sensation can be present twelve to twenty four hours before the onset of swelling. Approximately one fourth of HAE patients experience a flat, non itching red blotchy rash both before and during an attack.
Patients often report tingling or tightness at the site where edema will occur thirty minutes to several hours later. In some cases, this sensation can be present twelve to twenty four hours before the onset of swelling. Approximately one fourth of HAE patients experience a flat, non itching red blotchy rash both before and during an attack.
When are Hereditary Angioedema attacks considered serious?
Swelling of the extremities is uncomfortable and, according to some patients, can be painful and debilitating depending on the location of the edema. Attacks that involve the face and throat must be taken seriously and medical treatment should be sought without delay. Swelling of the throat can close the air passage and cause death by suffocation. The symptoms of an impending airway obstruction include difficulty swallowing and a change in voice pitch.
Abdominal attacks cause severe pain, nausea, vomiting, and watery diarrhea. Some patients require hospitalization for low blood pressure, dehydration, and pain management. As noted above, abdominal attacks can mimic a surgical abdomen and many patients have been subjected to unnecessary exploratory surgery.
Swelling of the extremities is uncomfortable and, according to some patients, can be painful and debilitating depending on the location of the edema. Attacks that involve the face and throat must be taken seriously and medical treatment should be sought without delay. Swelling of the throat can close the air passage and cause death by suffocation. The symptoms of an impending airway obstruction include difficulty swallowing and a change in voice pitch.
Abdominal attacks cause severe pain, nausea, vomiting, and watery diarrhea. Some patients require hospitalization for low blood pressure, dehydration, and pain management. As noted above, abdominal attacks can mimic a surgical abdomen and many patients have been subjected to unnecessary exploratory surgery.
How is Hereditary Angioedema treated?
There are three types of therapy for HAE patients.
Winstrol (stanozolol) was a widely used HAE therapy until the company producing the product ran into manufacturing problems and decided to discontinue manufacturing the drug. To accommodate anyone who would like to continue using Winstrol (stanozolol), the HAE Association has made arrangements for patients to purchase the drug from pharmacies equipped to make the drug in-house.
Some patients report success with a class of drugs called antifibrinolytics (epsilon aminocaproic acid is available in the US), but their use has largely been abandoned because androgens have proven to be much more effective.
The medical literature and practitioner experience confirms that corticosteriods (prednisone), antihistamines, and epinephrine are not effective in treating angioedema caused by C1-inhibitor deficiency. Short-term therapy is necessary for patients who do not require ongoing preventive treatment, but are facing dental procedures or elective surgery. Current practice calls for daily high dose androgen therapy (600-800 mgs of danazol) for at least five days prior to surgery and four days afterward. For emergency procedures, fresh frozen plasma can be used to prevent attacks. There have been reports of acute attacks getting worse after fresh frozen plasma was administered. The threat of this complication only exists during an acute attack, and is not a concern when fresh frozen plasma is given as a preventive measure.
Currently, there is no approved treatment for acute HAE attacks available in the United States. Some clinicians use fresh frozen plasma effectively, but (as noted above) this therapy is considered controversial because of reports that it caused attacks to worsen. C1-inhibitor concentrate is the treatment of choice for acute attacks of HAE, and has been available to patients in Europe for over a decade. C1 inhibitor concentrate treatment resolves the angioedema in thirty minutes to two hours with complete remission in twenty-four hours. C1-inhibitor concentrate is not available in the United States. To the dismay of US HAE patients, a poorly designed C1-inhibitor concentrate phase III clinical trial sponsored by a major multinational pharmaceutical company did not result in a US license for this life saving product. C1INH concentrate can be purchased under the FDA’s Personal Importation guidelines. As noted on our website, http://www. haea.org, The HAE Association provides patients with technical assistance on personal importation of C1INH concentrate.
The absence of an effective acute attack therapy limits clinicians to providing supportive care. Maintaining an open airway is the primary concern for patients with laryngeal edema. Because gastrointestinal edema usually involves excruciating pain and frequent vomiting, therapy should include aggressive pain management and fluid replacement. Clinicians report that Zofran, compazine, and phernergan are effective in reducing nausea and vomiting, while either morphine, dilaudid, darvocet, or other narcotics can be used to relieve attack related abdominal pain.
Unfortunately, the HAE literature in the mid seventies made reference to patients who developed narcotic dependency and this observation was repeated in subsequent papers. Many HAE patients have noted that physicians are often wary of prescribing pain medicine for painful abdominal attacks, and this could be due to reports contained in the literature. Any notion that the HAE population suffers from widespread narcotics addiction has been discredited by the experience of researchers who have treated relatively large numbers of patients.
There are three types of therapy for HAE patients.
- Long term preventive treatment
- Short term preventive treatment
- Treatment of acute attacks
Winstrol (stanozolol) was a widely used HAE therapy until the company producing the product ran into manufacturing problems and decided to discontinue manufacturing the drug. To accommodate anyone who would like to continue using Winstrol (stanozolol), the HAE Association has made arrangements for patients to purchase the drug from pharmacies equipped to make the drug in-house.
Some patients report success with a class of drugs called antifibrinolytics (epsilon aminocaproic acid is available in the US), but their use has largely been abandoned because androgens have proven to be much more effective.
The medical literature and practitioner experience confirms that corticosteriods (prednisone), antihistamines, and epinephrine are not effective in treating angioedema caused by C1-inhibitor deficiency. Short-term therapy is necessary for patients who do not require ongoing preventive treatment, but are facing dental procedures or elective surgery. Current practice calls for daily high dose androgen therapy (600-800 mgs of danazol) for at least five days prior to surgery and four days afterward. For emergency procedures, fresh frozen plasma can be used to prevent attacks. There have been reports of acute attacks getting worse after fresh frozen plasma was administered. The threat of this complication only exists during an acute attack, and is not a concern when fresh frozen plasma is given as a preventive measure.
Currently, there is no approved treatment for acute HAE attacks available in the United States. Some clinicians use fresh frozen plasma effectively, but (as noted above) this therapy is considered controversial because of reports that it caused attacks to worsen. C1-inhibitor concentrate is the treatment of choice for acute attacks of HAE, and has been available to patients in Europe for over a decade. C1 inhibitor concentrate treatment resolves the angioedema in thirty minutes to two hours with complete remission in twenty-four hours. C1-inhibitor concentrate is not available in the United States. To the dismay of US HAE patients, a poorly designed C1-inhibitor concentrate phase III clinical trial sponsored by a major multinational pharmaceutical company did not result in a US license for this life saving product. C1INH concentrate can be purchased under the FDA’s Personal Importation guidelines. As noted on our website, http://www. haea.org, The HAE Association provides patients with technical assistance on personal importation of C1INH concentrate.
The absence of an effective acute attack therapy limits clinicians to providing supportive care. Maintaining an open airway is the primary concern for patients with laryngeal edema. Because gastrointestinal edema usually involves excruciating pain and frequent vomiting, therapy should include aggressive pain management and fluid replacement. Clinicians report that Zofran, compazine, and phernergan are effective in reducing nausea and vomiting, while either morphine, dilaudid, darvocet, or other narcotics can be used to relieve attack related abdominal pain.
Unfortunately, the HAE literature in the mid seventies made reference to patients who developed narcotic dependency and this observation was repeated in subsequent papers. Many HAE patients have noted that physicians are often wary of prescribing pain medicine for painful abdominal attacks, and this could be due to reports contained in the literature. Any notion that the HAE population suffers from widespread narcotics addiction has been discredited by the experience of researchers who have treated relatively large numbers of patients.
Are there any new treatments on the horizon?
There are five companies who are testing their products in the United States.
On November of 2006, Dyax announced that it completed its 72-patient, placebo-controlled, multi-center trial that will provide data on the efficacy of its drug—a kallikrein inhibitor name ecallantide—to treat patients suffering from moderate to severe acute HAE attacks. The Company is now gearing up to perform another confirmatory placebo-controlled trial that the FDA requested to further validate the patient reported outcome (PRO) instrument used for demonstrating efficacy in the phase 3 trial. The company projects FDA approval by mid 2008.
The German biotechnology company Jerini AG has completed their US clinical trial of their B2 bradykinin receptor antagonist--Icatibant. Jerini reported that although the results of this trial were clinically relevant, the focus of the study--median time to onset of symptom relief of drug versus that of placebo did not reach statistical significance. A separate concurrent study conducted mostly in Europe did show a statistically significant difference between Icatibant and Tranexamic Acid (which is used by some European doctors). Jerini plans to submit data from the two studies, and expects Icatibant to receive a US license in 2007.
Lev Pharma is conducting a Phase III pivotal trial with a C1-INH product that is manufactured from US source plasma by the Sanquin Blood Supply Foundation ("Sanquin"), a not-for-profit organization based in the Netherlands. Sanquin has been producing and selling successive generations of human plasma derived C1-INH in the Netherlands for over 30 years. The drug's historical safety record is impeccable. Patient recruitment is ongoing.
On January 17, 2007, Lev Pharma announced that it completed the acute attack treatment portion of its pivotal Phase III clinical trial. Patients enrolled in this study will continue to receive open label treatment for attacks. The results for this component of the trial are expected to be announced by the end of the first quarter of 2007, and Lev Pharma anticipates submitting their licensing application to the FDA during the first half of 2007.
The other component of the Lev Pharma trial is examining the effectiveness of C1- INH in preventing inflammatory attacks in more severely affected HAE patients. This prophylactic study is ongoing and is expected to conclude in the second half of 2007.
The Dutch biotechnology company, Pharming NV is testing their recombinant C1INH concentrate product in the US. Pharming has perfected a futuristic technology that features genetically altering rabbits to produce the human C1INH protein in their milk. The drug has been tested in European patients with results that are reportedly similar to what is observed in patients treated with plasma derived C1INH concentrate. Patient recruitment is ongoing.
CSL Behring is conducting a Phase III pivotal study of Berinert-P, a C1INH concentrate product that is manufactured in Marburg, Germany and sold throughout the world. Berinert-P has an impressive long term safety record and, in countries where available, is the drug of choice for acute HAE attacks. Several dozen US HAE patients have been purchasing Berinert-P under the auspices of the FDA’s Personal Importation Guideline for over three years. Patient recruitment is ongoing.
There are five companies who are testing their products in the United States.
On November of 2006, Dyax announced that it completed its 72-patient, placebo-controlled, multi-center trial that will provide data on the efficacy of its drug—a kallikrein inhibitor name ecallantide—to treat patients suffering from moderate to severe acute HAE attacks. The Company is now gearing up to perform another confirmatory placebo-controlled trial that the FDA requested to further validate the patient reported outcome (PRO) instrument used for demonstrating efficacy in the phase 3 trial. The company projects FDA approval by mid 2008.
The German biotechnology company Jerini AG has completed their US clinical trial of their B2 bradykinin receptor antagonist--Icatibant. Jerini reported that although the results of this trial were clinically relevant, the focus of the study--median time to onset of symptom relief of drug versus that of placebo did not reach statistical significance. A separate concurrent study conducted mostly in Europe did show a statistically significant difference between Icatibant and Tranexamic Acid (which is used by some European doctors). Jerini plans to submit data from the two studies, and expects Icatibant to receive a US license in 2007.
Lev Pharma is conducting a Phase III pivotal trial with a C1-INH product that is manufactured from US source plasma by the Sanquin Blood Supply Foundation ("Sanquin"), a not-for-profit organization based in the Netherlands. Sanquin has been producing and selling successive generations of human plasma derived C1-INH in the Netherlands for over 30 years. The drug's historical safety record is impeccable. Patient recruitment is ongoing.
On January 17, 2007, Lev Pharma announced that it completed the acute attack treatment portion of its pivotal Phase III clinical trial. Patients enrolled in this study will continue to receive open label treatment for attacks. The results for this component of the trial are expected to be announced by the end of the first quarter of 2007, and Lev Pharma anticipates submitting their licensing application to the FDA during the first half of 2007.
The other component of the Lev Pharma trial is examining the effectiveness of C1- INH in preventing inflammatory attacks in more severely affected HAE patients. This prophylactic study is ongoing and is expected to conclude in the second half of 2007.
The Dutch biotechnology company, Pharming NV is testing their recombinant C1INH concentrate product in the US. Pharming has perfected a futuristic technology that features genetically altering rabbits to produce the human C1INH protein in their milk. The drug has been tested in European patients with results that are reportedly similar to what is observed in patients treated with plasma derived C1INH concentrate. Patient recruitment is ongoing.
CSL Behring is conducting a Phase III pivotal study of Berinert-P, a C1INH concentrate product that is manufactured in Marburg, Germany and sold throughout the world. Berinert-P has an impressive long term safety record and, in countries where available, is the drug of choice for acute HAE attacks. Several dozen US HAE patients have been purchasing Berinert-P under the auspices of the FDA’s Personal Importation Guideline for over three years. Patient recruitment is ongoing.
What treatments are available for children who have Hereditary Angioedema?
Fortunately, most prepubescent children with HAE do not suffer from frequent attacks and infrequent flares affecting the abdomen can be managed by using pain relievers and anti nausea agents. The small number of severely affected children who experience frequent and severe attacks must be managed on a case by case basis.
The HAE literature suggests that a class of drugs called antifibrinolytics (Amicar is the only drug in this class available in the US) should be the first drug tried if the parents and physician agree that ongoing treatment is warranted. There are a few reports in the literature of children who did not respond to antifibrinolytics, but have been treated successfully with androgens. Two studies done in the US indicate that oxandrin is the androgen of choice for children with HAE so severe that treatment is warranted.
Fortunately, most prepubescent children with HAE do not suffer from frequent attacks and infrequent flares affecting the abdomen can be managed by using pain relievers and anti nausea agents. The small number of severely affected children who experience frequent and severe attacks must be managed on a case by case basis.
The HAE literature suggests that a class of drugs called antifibrinolytics (Amicar is the only drug in this class available in the US) should be the first drug tried if the parents and physician agree that ongoing treatment is warranted. There are a few reports in the literature of children who did not respond to antifibrinolytics, but have been treated successfully with androgens. Two studies done in the US indicate that oxandrin is the androgen of choice for children with HAE so severe that treatment is warranted.
What medicine should HAE patients avoid?
ACE Inhibitors and estrogen-derived medications (birth control pills and hormone replacement drugs) have been known to increase the frequency and intensity of HAE attacks.
ACE Inhibitors are often prescribed to treat high blood pressure. Below is a list of some of the ACE Inhibitors licensed in the US:
ACE Inhibitors and estrogen-derived medications (birth control pills and hormone replacement drugs) have been known to increase the frequency and intensity of HAE attacks.
ACE Inhibitors are often prescribed to treat high blood pressure. Below is a list of some of the ACE Inhibitors licensed in the US:
- captopril (Capoten)
- benazepril (Lotensin)
- enalapril (Vasotec)
- lisinopril (Prinivil, Zestril)
- fosinopril (Monopril)
- ramipril (Altace)
- perindopril (Aceon)
- quinapril (Accupril)
- moexipril (Univasc)
- and trandolapril (Mavik)
Disclaimer: The information, including opinions and recommendations, contained in this document is for educational purposes only. Such information is not intended to be a substitute for professional medical advice, diagnosis or treatment. No one should act upon any information provided in this document without first seeking medical advice from a qualified medical physician. Information derived from the internet or emails, no matter how accurate or relevant are no substitute for competent medical care.
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