Transcript Angioedema - (HAE) Canada

Hereditary Angioedema
Amin Kanani, MD FRCPC
Clinical Assistant Professor
The University of British Columbia
Division of Allergy and Clinical Immunology
St. Paul’s Hospital
HAE
• Hereditary Angioedema (HAE) is a rare and potentially lifethreatening 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.
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
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
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
1963
1882
1888
1840
Quincke
assigned the
term
angioneurotic
edema
Donaldson and
Evans describe
the absence of
C1 inhibitor
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; 119:267-274
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
Common Triggers of HAE
Attacks
Trauma
Menstruation
Surgical/dental
procedures
Pregnancy
Angioedema
Angioedema
attack
Infection
Medications
Estrogen
ACE Inhibitor
Stress
• Many are spontaneous
Prodromal symptoms experienced by some patients
include one or more of the following:
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Non-itchy red rash (Erythema marginatum)
Paresthesia (tingling, tightness, or pain)
Flu-like symptoms
Headache
Abdominal discomfort
Nausea
Fatigue
Malaise
Irritability
Mood changes
Thirst
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.
GP, et al. Ann Emergency Med. 1988;133:1082-1086.
3Santos C, et al. Ann Allergy Asthma Immunol .2009;102:A38.
2Moore
HAE Burden of Illness
• Attacks result in 20-100 days of incapacitation annually
• Approximately 15,000 to 30,000 ER visits/yr
• Untreated patients can lose up to 100-150 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.
GP, et al. Ann Emergency Med. 1988;133:1082-1086.
3Santos C, et al. Ann Allergy Asthma Immunol .2009;102:A38.
2Moore
C1 inhibitor
• 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.
HAE
• Type 1
• Abnormal level of C1 inhibitor
• 85%
• Type 2
• Abnormal function of C1 inhibitor
• 15%
Diagnostic tests
HAE
Complement levels
C4
C1 INH level
C1 INH function
Type 1
(85%)
Low
Low
Low
Type 2
(15%)
Low
Normal/
elevated
Low
• 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
Treatment of HAE
• Education
• www.haecanada.org
• www.haea.org
• Trigger avoidance
• Carry information about condition
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
Canadian Hereditary Angioedema Guideline 2014
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Treatment of Acute Attacks
Short-Term Prophylaxis
Long-Term Prophylaxis
Self-Administration
Approach to Individualized Therapy
Quality of Life
Comprehensive Care
Treatment of HAE
• Acute treatment
Treating an attack
• Prophylactic treatment
Preventing an attack
Acute Attacks
• C1 INH replacement (intravenous, blood product)
• Berinert 20U/kg (1000-2000 U)
• Cinryze 1000 U (not approved in Canada for acute, only prophylaxis)
• Icatibant (Firazyr) is a bradykinin receptor blocker.
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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
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.
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Laryngeal (throat)
Face, neck
Abdominal
Genital
Extremity
Acute Attacks
• All patients should be trained on self-administration of HAEspecific 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.
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
Long-term Prophylaxis
• May be appropriate for some patients to reduce frequency,
duration and severity of attacks.
• Danazol
• C1 inhibitor
• Cinryze 1000 U 2-3 times/week
• Berinert 500 U - 1000 U 2-3 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.
Treatment of HAE
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
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hypertension
elevated cholesterol
altered liver enzymes
liver damage
liver neoplasms
(hepatocellular adenomas
or carcinomas)
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
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.
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.
Comprehensive Care Clinic for HAE
• It is recommended that HAE patients be linked with
comprehensive care clinic program
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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
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)
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
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National program
Self infusion programs
Comprehensive care
Emerging therapies
HAE Canada
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
Women and HAE
• Contraception
• 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
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
Women and HAE
• Breast feeding
• 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
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