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what is HAE?

what is hereditary angioedema?

Get to know the signs and symptoms and how to identify hereditary angioedema (HAE) in your patients so that together you can take action.

HAE is a rare autosomal dominant disease affecting approximately 1 in 10,000 to 1 in 50,000 individuals worldwide.1-3

It causes spontaneous attacks of swelling in various parts of the body.3,4

Attacks of swelling are unpredictable in frequency and severity, and they can be life threatening when they occur in the throat.4,5

Common attack locations3,4

The mouth, throat, abdomen, genitals, hands, and feet are common attack locations

good to know

The disease burden of HAE may extend beyond attacks into everyday life. Due to its unpredictable nature, HAE can cause substantial emotional, psychosocial, and quality-of-life impairments for some patients and their caregivers.2,6

overview of hereditary angioedema

Share this fact sheet with others in your practice to help familiarise them with the signs and symptoms of HAE

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Common attack locations3,4

The mouth, throat, abdomen, genitals, hands, and feet are common attack locations

what can cause hereditary angioedema attacks?

There are several different forms of HAE that are currently recognised and genetically identifiable. The two most common are:

C1-INH deficiency (Type 1 HAE, HAE-1):
characterised by low antigenic and functional C1-INH levels7

C1-INH dysfunction (Type 2 HAE, HAE-2):
characterised by normal or elevated antigenic but low functional C1-INH levels7

Types of HAE4

Graph showing 85% of patients have Type 1 HAE and 15% of patients have Type 2 HAE

Within the kallikrein-kinin system, C1-INH inhibits the production of bradykinin by interfering with plasma kallikrein activity. Dysregulation of plasma kallikrein activity within the kallikrein-kinin system leads to the cleavage of high-molecular-weight kininogen and excess bradykinin production, which can lead to attacks.8,9

Types of HAE4

Graph showing 85% of patients have Type 1 HAE and 15% of patients have Type 2 HAE

Other forms of HAE that do not involve mutations of C1-INH include:

  • F12 gene mutation (HAE-FXII)7
  • Angiopoietin-1 gene mutation (HAE-ANGPTI)7
  • Plasminogen gene mutation (HAE-PLG)7

triggers and prodromal symptoms

While many occur with no identifiable trigger, some swelling attacks may be associated with10:

  • Emotional distress
  • Physical trauma
  • Changes in hormone levels
  • Infection
  • Medication
  • Exposure to cold
  • Non-traumatic tissue compression
  • Prolonged sitting or standing
  • Certain foods

Prodromes can be predictive of an attack in some cases and are often described as11-13:

  • Fatigue or malaise
  • Restlessness
  • Nausea
  • Joint pain
  • Cramps
  • Anxiety or mood changes

The patient may also experience a prickling sensation, tightness in the skin, or nonpruritic rash called erythema marginatum.12-14

Laryngeal swelling is a potential symptom of hereditary angioedema attacks

good to know

Attack history is not a predictor of future attack frequency, severity, or location.5

diagnosing HAE

how is hereditary angioedema diagnosed?

When diagnosing HAE, a combination of factors should be considered, including symptoms, family history, and laboratory testing.1

Testing Testing for C1-INH deficiency or dysfunction

Patients suspected of having HAE Type 1 or Type 2 should be assessed for blood levels of C1-INH function, C1-INH protein, and C4. Using complement testing, a patient’s peripheral blood test will show low C4 levels, in addition to low C1-INH activity or levels. If any of the levels are abnormally low, the tests should be repeated to confirm the diagnosis.1,15,16

Other forms of HAE have been described that do not involve mutations of C1-INH, and are rare. However, it is possible for patients with this type of HAE to have clinical symptoms that are indistinguishable from Types 1 and 2 and have normal plasma levels and functional C1-INH. This has been referred to as Type 3 HAE.7,16

delays to diagnosis

HAE is often misdiagnosed, even among patients with a family history17:

- In a real-world registry study of patients with HAE Type 1 or Type 2, almost half of patients had initially received 1 or more misdiagnoses (185/418)17

- Patients who received a misdiagnosis experienced a mean diagnostic delay of 15 years17

- In general, misdiagnosis can result in increased health resource use, including unnecessary abdominal surgeries and increased risk of death from laryngeal attacks2,18,19

good to know

Genetic testing increases diagnostic reliability in children. It may be helpful if the mutation of the parent is known, or if biochemical measurements are inconclusive.15,16

treating HAE

how is hereditary angioedema treated?

If left untreated, attacks gradually worsen over 12 to 36 hours and typically subside in 1 to 5 days. Treatment for HAE should be individualised to your patient’s needs and lifestyle to help reduce the burden of disease by preventing or attenuating attacks.6,8

According to the 2017 World Allergy Organization (WAO) Treatment Guideline, HAE can be managed with:

on-demand therapy

WAO/EAACI recommendation:
“We recommend that all attacks are:

  • Considered for on-demand treatment, and that any attack affecting or potentially affecting the upper airway is treated.
  • Treated as early as possible.
  • Treated with either C1-INH, ecallantide, or icatibant.”1

short-term preventive (prophylactic) therapy

WAO/EAACI recommendation:
“We recommend short-term prophylaxis before procedures that can induce an attack.”1

long-term preventive (prophylactic) therapy

WAO/EAACI recommendation:
“We recommend that patients are evaluated for long-term prophylaxis at every visit. Disease burden and patient preference should be taken into consideration.”1

Availability of therapies differs by country.

HAE management guideline fact sheet

See the latest WAO/EAACI recommendations on how to manage your patients’ HAE.

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Watch and learn:

New Views on Prevention & On-Demand Therapy: Highlights from the 2017 WAO/EAACI Guideline

Watch Dr Marcus Maurer review some updates to the treatment guideline

Please note that current treatment guidelines are for patients with Type 1 and Type 2 HAE only; the pathogenesis of other forms of HAE is not well-characterised, and therefore, therapeutic options may not be similarly effective.1

Get to know more about current treatment approaches

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References: 1. Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update. Allergy. 2018. doi: 10.1111/all.13384. 2. Longhurst H, Bygum A. The humanistic, societal, and pharmaco-economic burden of angioedema. Clin Rev Allerg Immunol. 2016;51(2):230-239. 3. Longhurst HJ, Bork K. Hereditary angioedema: causes, manifestations and treatment. Br J Hosp Med (Lond). 2006;67(12):654-657. 4. Banerji A, Busse P, Christiansen SC, et al. Current state of hereditary angioedema management: a patient survey. Allergy Asthma Proc. 2015;36(3):213-217. 5. Farkas H, Martinez-Saguer I, Bork K, et al. International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. Allergy. 2017;72(2):300-313. 6. Bygum A, Aygören-Pürsün E, Beusterien K, et al. Burden of illness in hereditary angioedema: a conceptual model. Acta Derm Venereol. 2015;95(6):706-710. 7. Zuraw B. Hereditary angioedema with normal C1 inhibitor. Four types and counting. J Allergy Clin Immunol. 2018;141(3):884-885. 8. Longhurst H, Cicardi M. Hereditary angioedema. Lancet. 2012;379(9814):474-481. 9. Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy. 2014;44(12):1503-1514. 10. Caballero T, Maurer M, Longhurst HJ, et al. Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema. J Investig Allergol Clin Immunol. 2016;26(6):383-386. 11. Prematta MJ, Kemp JG, Gibbs JG, Mende C, Rhoads C, Craig TJ. Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks. Allergy Asthma Proc. 2009;30(5):506-511. 12. Rasmussen ER, de Freitas PV, Bygum A. Urticaria and prodromal symptoms including erythema marginatum in Danish patients with hereditary angioedema. Acta Derm Venereol. 2016;96(3):373-376. 13. Magerl M, Doumoulakis G, Kalkounou I, et al. Characterization of prodromal symptoms in a large population of patients with hereditary angio-oedema. Clin Exp Dermatol. 2014;39(3);298-303. 14. Johnston D. Diagnosis and management of hereditary angioedema. J Am Osteopath Assoc. 2011;111(1):28-36. 15. Zuraw BL. Clinical Practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036. 16. Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602-616. 17. Zanichelli A, Longhurst HJ, Maurer M, et al. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016;117(4):394-398. 18. Patel N, Suarez LD, Kapur S, Bielory L. Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Reports Immunol. 2015;2015:925861. 19. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol. 2012;130(3):692-697.