1. Hereditary Angioedema
Amin Kanani, MD FRCPC
Clinical Assistant Professor
The University of British Columbia
Division of Allergy and Clinical Immunology
St. Paul’s Hospital

2. HAE
Hereditary Angioedema (HAE) is a rare and potentially life-threatening genetic condition.
Occurs in about 1 in 10,000 to 1 in 50,000 people.
Up to 3374 of the Canadian population
Disease does not discriminate between race, ethnic groups or gender.

3. HAE Symptoms
Episodes of angioedema (swelling) in various body parts including the hands, feet, face and throat.
Swelling in the intestinal wall can cause excruciating abdominal pain, nausea and vomiting
Airway swelling is particularly dangerous and can lead to death by asphyxiation.
Normal
Swelling

4. HAE Untreated angioedema events can last over 48 to 96 hours.
Increase frequency of attacks in puberty
Attacks varying from periodic, clustering, and variable periods of remission

5. History of Hereditary Angioedema
First article published by Osler describing hereditary nature
First description by Graves
With a better understand the condition, the term ‘neurotic’ has been removed from its name.
Hereditary angioedema (HAE) is now the accepted named
1882
1963
1888
1840
Donaldson and Evans describe the absence of C1 inhibitor
Quincke assigned the term angioneurotic edema

6. HAE Most commonly, symptoms begin at school age
Review of 209 patients mean age at onset of the disease was 11.2 years
American Journal of Medicine 2006; 119:

7. HAE
Because the disease is rare, it is not uncommon for patients to remain undiagnosed for many years.
Unnecessary surgery has been performed on patients experiencing abdominal attacks

8. Common Triggers of HAE Attacks
Trauma
Menstruation
Angioedema
Angioedema attack
Surgical/dental
procedures
Pregnancy
Infection
Medications
Estrogen
ACE Inhibitor
Stress
Many are spontaneous

9. Prodromal symptoms experienced by some patients include one or more of the following:
Non-itchy red rash (Erythema marginatum)
Paresthesia (tingling, tightness, or pain)
Flu-like symptoms
Headache
Abdominal discomfort
Nausea
Fatigue
Malaise
Irritability
Mood changes
Thirst

10. HAE Burden of Illness Web-based survey of 457 HAE patients found:
100% felt disease prevented them from advancing in school
69% felt unable to consider certain jobs
58% affected career advancement
Impact of last HAE attack:
51% missed ≥1 work day
44% missed ≥1 school day
59% missed ≥1 leisure day
1Castaldo AJ, et al. Ann Allergy Asthma Immunol. 2009;102:A92.
2Moore GP, et al. Ann Emergency Med. 1988;133:
3Santos C, et al. Ann Allergy Asthma Immunol .2009;102:A38.

11. HAE Burden of Illness
Attacks result in days of incapacitation annually
Approximately 15,000 to 30,000 ER visits/yr
Untreated patients can lose up to days of work per year and have morbidity rates approaching 30-40%
Unpredictability of attacks causes significant psychological burden
1Castaldo AJ, et al. Ann Allergy Asthma Immunol. 2009;102:A92.
2Moore GP, et al. Ann Emergency Med. 1988;133:
3Santos C, et al. Ann Allergy Asthma Immunol .2009;102:A38.

12. C1 inhibitor

13. 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.

14. HAE Type 1 Type 2 Abnormal level of C1 inhibitor 85%
Abnormal function of C1 inhibitor
15%

15. Diagnostic tests HAE C1-INH level and/or function <50% of normal
Complement levels C4
C1 INH level
C1 INH function
Type 1
(85%)
Type 2
(15%)
Low
Normal/
elevated
C1-INH level and/or function <50% of normal
C4 is low
Measurements should be performed twice, at an interval of at least 1 month
Testing under one year of age may not be reliable (unless genetic typing)
Genetic testing

16. Treatment of HAE Education Trigger avoidance
Trigger avoidance
Carry information about condition

17. Canadian Hereditary Angioedema Guideline 2014
Meeting in Toronto November 2013
Canadian Hereditary Angioedema Network (CHAEN)/ Canadien d'angioédème héréditaire (RCAH)
HAE Canada
Invited most of the world experts in HAE
Reviewed all the current medical literature

18. Canadian Hereditary Angioedema Guideline 2014
Treatment of Acute Attacks
Short-Term Prophylaxis
Long-Term Prophylaxis
Self-Administration
Approach to Individualized Therapy
Quality of Life
Comprehensive Care

19. Treatment of HAE Acute treatment Treating an attack
Prophylactic treatment Preventing an attack

20. Acute Attacks C1 INH replacement (intravenous, blood product)
Berinert 20U/kg ( U)
Cinryze 1000 U (not approved in Canada for acute, only prophylaxis)
Icatibant (Firazyr) is a bradykinin receptor blocker.
Will be approved soon in Canada
Dose is 30 mg subcutaneously in adults
Local pain, swelling and redness at site of injection
Repeat injection 6 hours apart
Age 18 or older
Ecallantide (Kalbitor) is an inhibitor of plasma kallikrein (the enzyme that releases bradykinin)
Only approved in US not Canada

21. Acute Attacks
All attacks of angioedema involving the upper airway (throat) are medical emergencies and must be treated immediately.
In addition, we recommend emergency department assessment.
Laryngeal (throat)
Face, neck
Abdominal
Genital
Extremity

22. Acute Attacks
All patients should be trained on self-administration of HAE-specific therapies if they are suitable candidates. If patients cannot self-administer therapy, provisions should be made to ensure timely access to all appropriate therapies.
Danazol and Tranexamic acid should not be used to treat acute attacks.

23. Short-term Prophylaxis
To prevent an attack during a medical/dental procedure
Patient-specific trigger e.g. emotional stressor
Danazol 600 mg 5 days prior and 2-5 days after procedure
C1 inhibitor prior and second available after procedure

24. Long-term Prophylaxis
May be appropriate for some patients to reduce frequency, duration and severity of attacks.
Danazol
C1 inhibitor
Cinryze 1000 U times/week
Berinert 500 U U times/week (not approved in Canada for prophylaxis, only acute)
Tranexamic Acid – children
It is not necessary to fail other long-term prophylaxis therapies before use of C1-inhibitor for long-term prophylaxis is considered.

25. Treatment of HAE Side effects may include : virilization weight gain
Danazol can not be used: pregnancy, breast feeding, cancer, hepatitis, and childhood
Side effects may include :
virilization
weight gain
acne
hair growth
voice deepening
decreased breast size
menstrual irregularities
hypertension
elevated cholesterol
altered liver enzymes
liver damage
liver neoplasms (hepatocellular adenomas or carcinomas)

26. Safety of C1 inhibitor products
Blood product
The specific steps of the CINRYZE and BERINERT purification process that help minimize the risk of transmitting an infectious agent include:
careful donor screening
testing for the presence of viruses
pasteurization
Nanofiltration / chromatography

27. Treatment of HAE
The decision to start or stop long-term prophylaxis depends on multiple factors and should be made by the patient and an HAE specialist.

28. Treatment of HAE
Health care providers should specifically address factors known to affect quality of life with HAE patients. Management of HAE should aim to improve patients' quality of life.
Comprehensive care should be available for all patients with HAE.

29. Comprehensive Care Clinic for HAE
It is recommended that HAE patients be linked with comprehensive care clinic program
bringing together clinical care, education and research
to facilitate diagnosis, therapy, management
facilitate home self infusion with C1 INH
facilitate data base registries
allow rigorous safety efficacy monitoring of emerging therapies

30. Emerging Therapies
Subcutaneous infusion with C1 inhibitor instead of current IV infusion
Recombinant C1-INH (Rhucin, Ruconest)
Recombinant human C1-INH produced in transgenic rabbit milk
Currently under review in the USA and Europe
BCX4161 (plasma kallikrein inhibitor) is being developed as an oral prophylactic treatment for patients suffering from Hereditary Angioedema (HAE)

31. What Can you Do? Don't let the disease become your identity
You can manage an illness, or it can manage you
Understand your condition and know all the options available to you
Advocate for better treatments
National program
Self infusion programs
Comprehensive care
Emerging therapies
HAE Canada

33. Women and HAE
Female sex hormones are known to affect the synthesis of many proteins
Estrogen sensitive: the symptoms in these subjects are worsened by taking combined contraceptive medication, HRT or during pregnancy
Estrogen-independent: the use of the combined contraceptive pill or pregnancy does not exacerbate the symptoms. These individuals represent a minority of HAE patients

34. Women and HAE Contraception Pregnancy
Progestogen pill, Depo-Provera (injection) or intra-uterine device is recommended
Pregnancy
Fertility and the rate of spontaneous abortion are the same as those found in the normal population.
Rule of thirds
1/3 pregnancy worsens symptoms
1/3 symptoms are improved
1/3 remain the same
Attack rates increase during the third trimester

35. Women and HAE Pregnancy In the past treatment with tranexamic acid
Danazol is contra-indicated.
C1 INH used to treat of severe attacks
C1 INH used prophylactically if frequent attacks
The management of labour depends on how the pregnancy has progressed.
If the patient has suffered worsening of the condition then labour must be covered with C1 INH
If the disease has been less severe, there is no need for prophylaxis but C1 INH should be available
Epidural analgesia is recommended

36. Women and HAE Breast feeding Menopause
Tranexamic acid, danazol and icatibant should be avoided as they are secreted in maternal milk.
Only C1 INH should be used
Menopause
In most patients (55%) the menopause does not alter the disease.
One third is worse while only 13% improve
Menopausal hormone replacement therapy should not be given because estrogen can exacerbate the condition

37. Women and HAE IVF with pre-implantation genetic diagnosis
Embryo from in vitro fertilization is screened for genetic abnormalities before it is transferred into uterus