HEREDITÆRT ANGIOØDEM Robert Brudevold Seksjonsoverlege hematologi Medisinsk avd Ålesund sjukehus

Kilder

• Up to date • Clinical Key •  International WAO guidelines. • WHO guidelines

HAE

• Epidemiologi • Patofysiologi • Klinikk •  Livskvalitet • Utredning • Behandling

Figur 2 Inddeling av og hyppigste årsager til angioødem

Tidsskr Nor Legeforen 2012; 132: 2391-5

© Tidsskrift for Den norske legeforening

Hereditært angioødem - HAE

• Prevalens 1/50000. • Mutasjon i Serping1-gen, kromosom 11 • Autosomal dominant arv • C1- inhibitor funksjon redusert pga av defekt

transkripsjon eller defekt protein - type 1/2. • C1-inhibitor funksjon normal – type3 • C1- inh : regulerer klassisk komplementakt, aktivering

av kallikrein , plasmin og koag faktor XI, XII.

Björkander J, Bygum A, Nielsen EW. Hereditärt angioödem – svår sjukdom med nya terapialternativ. Läkartidningen. 2012 Jan 17;109(3):99–103.

Two primary forms of HAE

C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema Lumry WR. Am J Manag Care 2013;19:S103–S110

Type I: 85% of cases

Type II: 15% of cases

Type I – Deficiency of C1-INH •  Caused by a mutation in the C1-INH

gene leading to low plasma levels of antigenic and functional C1-INH

•  Accounts for ~85% cases

Type II –Dysfunctional C1-INH •  Caused by mutations that cause the

production of a dysfunctional C1-INH protein resulting in low C1-INH function despite normal levels of antigenic C1-INH

Primary Types of HAE

• Plasminogenmutasjon • Angiopoetinmutasjon •  Faktor XII mutasjon • U-HAE

HAE type III

Patofysiologi

Plasmaproteiner involvert • Koagulasjon •  Fibrinolyse • Kontaktsystem • Komplementsystem

=> Hematologi

Dr Heinrich Quincke beskrev tilstanden 1882 Hematologisk forskning påviste C1 INH mangel som årsak

Mutasjoner – kromosom 11

• Serping1 gen (300 stk) •  Faktor XII • Angiopoetin • Plasminogen •  ? • Arvet 75% • Nyoppstått 25%

Contact system activation generates bradykinin. Contact system activation is initiated by assembly of the contact system components high-molecular-weight kininogen ( HMWK ), the zymogen plasma prekallikrein ( PK ), and the zymogen coagulation factor XII (fXII) on an appropriate surface. Activation is initiated by either autoactivation of factor XII to active factor XIIa or prolylcarboxypeptidase-mediated activation of plasma prekallikrein to active plasma kallikrein ( Kall ). Zymogen proteases are shown as circles and active proteases as circles with a small pie-shaped section deleted . Factor XIIa and plasma kallikrein can reciprocally activate each other, thereby rapidly amplifying contact system activation. Plasma kallikrein has two additional effects on the contact system: It cleaves factor fXIIa to active fXIIf, and it cleaves high-molecular-weight kininogen to release the mediator bradykinin ( BK ). Factor XIIf can cleave plasma prekallikrein to plasma kallikrein, as well as activate the complement C1 zymogen proteases, which can then cleave C4. Proteolytic activity inhibited by C1INH is shown by grey ovals. Hereditary Angioedema and Bradykinin-Mediated Angioedema Zuraw, Bruce L., Middleton's Allergy: Principles and Practice, 37, 588-601 Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc.

In the Kallikrein-kinin Pathway, Uncontrolled Plasma Kallikrein Activity due to a reduced activity of C1-INH leads to Excess Bradykinin Production1-3

Prekallikrein

Kallikrein

Kallikrein-kinin Pathway

XII

XIIa

Auto-activation

C1-INH C1-INH

C1-INH

C1-IN

H

HMWK

HMWK

Kallikrein HMWK

Hypothetical mode of action, Bowen T, et al. J Allergy Clin Immunol. 2004;114:629-37. Adapted from Zuraw BL. Clin Immunol. 2005;114:10-6.

Endothelial Cell

Bradykinin

Fibrinolytic Pathway

Plasminogen

Plasmin

Fibrin Degradation

XII XIIa HMWK

Factor XII (Hageman Factor) Activated Factor XII High molecular weight kininogen Bradykinin receptor B2

1. Kaplan & Joseph. Ann Allergy Asthma Immunol. 2010;104:193–204 2. Zuraw & Christiansen. Clinic Rev Allerg Immunol. 2016;51:216–29

3. Reshef et al. Clinic Rev Allerg Immunol. 2016;51:121–39

HMWK; high molecular weight kininogen

Copyrights apply

Bradykinin increases vascular permeability. A, Paracellular fluid movement in endothelial cells is restricted by homo- and heterodimers of VE-cadherin that make up the adherens junction. VE-cadherin consists of five extracellular (EC) repeats, a trans membrane domain, and a cytoplasmic tail. The EC repeats mediate cis and trans associations between different VE-cadherin molecules. The cytoplasmic domain binds to intracellular partners β-catenin and p120-catenin, which stabilize the VE-cadherin. B, Binding of bradykinin ( BK ) to the B2 BKR results in an increase in intracellular calcium. Activated protein kinase C ( PKC ) phosphorylates VE-cadherin, as well as β-catenin and p120-catenin, leading to internalization and degradation of VE-cadherin. Activation of the small GTPase RhoA, as well as myosin light chain kinase, results in polymerization and contraction of the actin cytoskeleton. As a consequence, the endothelial cells retract, and gaps increase between adjacent endothelial cells, with loss of the barrier to transcellular fluid movement. B2 BKR, B2 bradykinin receptor; DAG, decay accelerating factor; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; P, phosphate; PG12, prostaglandin I2 [prostacyclin]; PLA2, phospholipase A2; PLC, phospholipase C. Hereditary Angioedema and Bradykinin-Mediated Angioedema Zuraw, Bruce L., Middleton's Allergy: Principles and Practice, 37, 588-601 Copyright © 2014 Copyright © 2014 by Saunders, an imprint of Elsevier Inc.

Bradykinin

• Vasodilatasjon • Økt karpermeabilitet

Klinikk

Særtrekk ved HAE • Hevelse i hud/slimhinner (G-I trakt/luftveier) • Anfallsvis •  Trigger (Fysisk/psykisk) • Smertefull • Utseendeforandring •  Livstruende • Uforutsigbar • Store variasjoner • Sjelden sykdom - begrenset kunnskap •  Tidligere begrenset behandlingsmuligheter

Most common locations:1-3

•  Face

•  Abdominal

•  Genitalia

•  Extremities

•  Angioedema attacks vary in location, frequency, duration, and severity1,2

HAE anfall - hud og mukosa

HAE, hereditary angioedema

1. Lumry WR. Am J Manag Care 2013;19:S111–S118 2. Farkas H. Allergy Asthma Clin Immunol 2010;6:18 3. Nygren A, et al. Acta Paediatr 2016;105:529–534

4. Lumry WR. Am J Manag Care 2013;19:S103–S110 5. Agostoni A, et al. J Allergy Clin Immunol 2004:114:S51-S131

Less common:1 •  Laryngeal

•  50% of patients will have ≥1 laryngeal attack in their lifetime4,5

•  Death may result due to airway obstruction and asphyxiation1,5

•  Asphyxia may ensue more rapidly in children than adults4

Trigger factors of HAE attacks in children and adults

ACE, angiotensin converting enzyme; HAE, hereditary angioedema; HRT, hormone replacement therapy

1. Farkas H, et al. Allergy 2017;72:300–313 2. Nygren A, et al. Acta Paediatr 2016;105:529–434

3. Lumry WR. Am J Manag Care 2013;19:S103–S110 4. Zotter Z, et al. Orphanet J Rare Dis 2014;9:44

Children1,2 •  Most attacks occur without a clear trigger •  Common triggers reported include:

-  Mechanical trauma -  Mental stress -  Upper airway infections -  Sporting activity

•  Dental eruption may trigger HAE attacks in some children

•  Menstruation and ovulation are common triggers in adolescent girls

Adults3,4 •  Weather changes, exposure to cold •  Minor trauma •  Dental/medical procedures •  Prolonged sitting or standing •  Physical exertion •  Exposure to certain foods or chemicals •  Medications (e.g., ACE inhibitors, estrogen-

containing contraceptives, HRT) •  Infection •  Emotional stress, fatigue/exhaustion •  Menstruation and pregnancy

Many attacks occur without an obvious trigger, and the same trigger may not always provoke an attack2

Course of a typical untreated HAE attack

Trig

ger e

vent

(s

ome

case

s)

Pro

drom

al

sym

ptom

s (s

ome

case

s)

Sym

ptom

ons

et

Sym

ptom

inte

nsity

Hours to days Increasing intensity 12–36 hours

Slow resolution 2–5 days Time from onset4

•  Prior to an attack, patients may experience a tingling sensation and/or non-raised rash (erythema marginatum)1

•  Prodromal symptoms occur in 42–58% of pediatric patients with HAE2

•  Symptoms typically worsen over the first 24 hours and subside over the next 48–72 hours3

•  Attacks can last up to 5 days1 and may spread to another location before resolving3

HAE anfall

HAE, hereditary angioedema

1.  MacGinnitie AJ. Pediatr Allergy Immunol 2014;25:420–427 2. Farkas H. Allergy Asthma Clin Immunol 2010;6:18

3. Zuraw BL. N Engl J Med 2008;359:1027–1036 4. Banerji A, et al. Ann Allergy Asthma Immunol 2013;111:329–336

HAE anfall

• Prodromalfase 1 døgn • Anfall 2-5 døgn (Hud-GI-luftveier) •  Tid mellom anfall?

Prodromalfase •  Fatigue • Myalgi • Kvalme • G-I symptomer • Utslett – erytema marginatum

Copyrights apply

Anfall - hud

• Ødem • Non-pitting • Ekstremiteter • Ansikt • Genitalia • NB Ikke kløe- ofte smertefulle • Varighet 2-5 døgn

Copyrights apply

Swelling of the lips (A) and normal state (B) in a woman with HAE-FXII. Hereditary angioedema caused by missense mutations in the factor XII gene: Clinical features, trigger factors, and therapy Bork, Konrad, MD, Journal of Allergy and Clinical Immunology, The, Volume 124, Issue 1, 129-134 Copyright © 2009 American Academy of Allergy, Asthma & Immunology

A 19-year-old Caucasian woman who presented with diffuse urticarial rash with very subtle facial and neck edema that was nonreponsive to typical urticarial treatment with H2 -blockers, antihistamines, and steroids. She was subsequently diagnosed with Type I hereditary angioedema. Hereditary angioedema presenting as refractory urticaria: a case report Wall, Matthew, DO, Osteopathic Family Physician, Volume 4, Issue 1, 24-28 Copyright © 2012

Anfall G-I trakt

• Kvalme • Kolikk • Oppkast • Diare • Hypotensjon/Synkope • Sterke smerter VAS 8-9 • Ofte feildiagnostisert – kirurgi •  Ikke feber, peritonitt eller labavvik • UL/CT: Ødem i tarmvegg. Ascites i sluttfasen.

CT and MRI of the Upper Gastrointestinal Tract Torigian, Drew A., MD, MA, FSAR, Radiology Secrets Plus, Chapter 25, 240-254 “Target” sign of small bowel on CT. Note moderate wall thickening of multiple loops of small bowel ( arrows ) in right abdomen and mild perienteric fat stranding. Also note associated bright soft tissue attenuation inner layer, dark low-attenuatio... Copyright © 2017 Copyright © 2017 by Elsevier, Inc. All rights reserved.

M015 ANGIOTENSIN CONVERTING ENZYME INHIBITOR-INDUCED ISOLATED ABDOMINAL ANGIOEDEMA Diaz-Menindez, M., Annals of Allergy, Asthma & Immunology, Volume 123, Issue 5, Supplement, S68-S68 (no summary available) Copyright © 2019

Anfall larynx/luftveier

• Hevelse lepper,tunge,gane • Globulus • Stemmeforandring • Stridor • Dyspne • Bevissthetstap

Hereditary angioedema attacks can be disfiguring, debilitating, and life threatening. Depicted is a patient experiencing hereditary angioedema attacks. Source: Bygum et al. The burden of illness in patients with hereditary angioedema Banerji, Aleena, MD, Annals of Allergy, Asthma & Immunology, Volume 111, Issue 5, 329-336 Copyright © 2013 American College of Allergy, Asthma & Immunology

ACEI 5år Ak hevelse ansikt Hoven tunge Dyspne Ingen effekt antihistamin, adrenalin Sc Firazyr 30mg

Diff diagnoser • Allergi? • Autoimmune sykdommer (SLE/DM/SSS/SS) •  Thyroideasykd • Vena cava sup syndrom • Cheilitis granulomatosa • Melkersson-Rosenthal syndrom • Ak kirurgiske tilstander (Peritonitt)

Livskvalitet

Særtrekk ved HAE • Hevelse i hud/slimhinner (G-I trakt/luftveier) • Anfallsvis •  Trigger (Fysisk/psykisk) • Smertefull • Utseendeforandring •  Livstruende • Uforutsigbar • Store variasjoner • Sjelden sykdom - begrenset kunnskap •  Tidligere begrenset behandlingsmuligheter

Emotional impact of HAE

HAE, hereditary angioedema; HAE-BOIS, Hereditary Angioedema Burden of Illness Study

Caballero T, et al. Allergy Asthma Proc 2014;35:47–53

The greatest source of anxiety in patients with HAE is the risk of passing the disease to their children, regrdless of pain severity

A great deal

No anxiety

10

9

8

7

6

5

4 3

2

1

0

No pain (n=17) Mild pain (n=37) Moderate pain (n=74) Severe pain (n=36)

Anxiety about future attacks

Anxiety about passing HAE

to children

Prevented from travelling

Sudden feelings of

panic

Current distress about

HAE

HAE-specific anxiety by pain severity of most recent attack: HAE-BOIS EU study (Spain, Germany and Denmark) (N=186)

0

2

4

6

8

10

12 M

ean

HD

I-SF

scor

e (±

SD

)

There is a high prevalence of depression among patients with HAE

*HAE patients significantly more likely to experience depression than population norms (p<0.0001 based on t-test); †Based on Reynolds & Koback2 HAE, hereditary angioedema; HDI-SF, Hamilton Depression Inventory-Short Form; SD, standard deviation

1. Lumry WR, et al. Allergy Asthma Proc 2010;31:407–414 2. Reynolds WM, Kobak KA. Hamilton Depression Inventory Professional Manual.

Lutz, FlL: Psychological assessment Resources, Inc. 1995

Population norm†

HAE patients

Mild

Moderate

Severe

3.1 ±3.0

8.1 ±6.5*

5.6 ±6.2

10.1 ±7.3

HAE attack severity

Depression scores: web-based survey of patients with HAE (N=457)1

7.8 ±5.9

Incr

ease

d de

pres

sion

N=457 n=71 n=256 n=130

Depression increased with HAE attack severity

29 % 26 %

59 % 64 %

82 %

69 %

0 %

10 %

20 %

30 %

40 %

50 %

60 %

70 %

80 %

90 %

Patients Caregivers

% w

ho re

porte

d m

isse

d tim

e (>

0 da

ys)

No/mild pain Moderate pain Severe pain

Impact of HAE attacks on patient and caregiver absenteeism from work/school

Percentages based on 72 patients employed or in school; caregivers based on full sample (N = 164). Note: Means based on number of patients (n = 40) and caregivers (n = 86) who missed time (including leisure time). Data missing for 31 caregivers. HAE-BOIS, Hereditary Angioedema Burden of Illness Study

Aygören-Pürsün E, et al. Orphanet J Rare Dis 2014;9:99

Work/school absenteeism during last attack by pain severity: HAE-BOIS EU study (Spain, Germany and Denmark) (N=164)

1.5 days

1.9 days

5.1 days

1.2 days

1.0 day

2.1 days

0

10

20

30

40

50

60

Work time missed Impairment while working

Overall work impairment

Activity impairment

Mea

n im

pairm

ent (

% ±

SD

)

HAE Severe asthma Crohn's disease

Reduced productivity due to HAE is comparable to other chronic conditions*

*As reported in the literature2,3 HAE, hereditary angioedema; WPAI-GH, Work Productivity and Activity Impairment – General Health

1. Lumry WR, et al. Allergy Asthma Proc 2010;31:407–414 2. Chen H, et al. Value Health 2008;11:231-239

3. Reilly MC, et al. Clin Ther 2008;30:393-404

Impact of HAE on productivity: mean impairment as determined by the WPAI-GH questionnaire (N=457)1

9.4 ±19.2 7.0

±21.0

18.3 ±29.3

33.5 ±25.8

26.0 ±28.0

40.5 ±25.2

33.6 ±29.1

28.0 ±31.0

45.9 ±26.5

45.0 ±30.2 41.0

±31.0

52.0 ±25.2

9 %

10 %

36 %

40 %

42 %

58 %

63 %

69 %

48 %

55 %

41 %

0 % 10 % 20 % 30 % 40 % 50 % 60 % 70 % 80 %

Switched positions within a company

Left a position permanently

Prevented from career advancement

HAE impacted career choices

Prevented from applying to certain jobs

HAE hindered educational attainment

HAE impacted educational choices

Hindered educational advancement

Burden of HAE USA

HAE-BOIS EU

Impact of HAE on education and career progression: data from US and EU burden of illness studies1,2

HAE, hereditary angioedema; HAE-BOIS, Hereditary Angioedema Burden of Illness Study; NR, not reported

1. Lumry WR, et al. Allergy Asthma Proc 2010;31:407−414 2. Aygören-Pürsün E, et al. Orphanet J Rare Dis 2014;9:99

Impact of HAE on education and career progression: data from the Burden of HAE- assessed in USA (N=457) and HAE-BOIS EU (N=164) studies1,2

A high proportion of participants in both studies revealed that HAE had hindered their career and/or educational advancement, and prevented them from applying for certain

jobs

NR

NR

NR

NR

NR

Median level of current health and HRQoL for children with symptomatic HAE was rated as good

Overall HRQoL in children generally perceived to be good despite HAE symptoms but many parents take parental leave due to their child’s symptoms

. ‡Mainly abdominal attacks and skin swelling. HAE, hereditary angioedema; HRQoL; health-related quality of life; SD, standard deviation; VAS, visual analogue scale

Nygren A, et al. Acta Paediatr 2016;105:529–534

73% of parents had taken parental leave to care for their children due to HAE symptoms‡

•  The most common reasons for taking leave were due to their child’s abdominal attacks (n=15), followed by skin swelling (n=7)

•  The mean (± SD) rating for the 23 children was 4.26 (0.79)

•  The 12 boys had a mean of 4.42 (0.64) •  The 11 girls had a mean of 4.09 (0.90)

•  The outcome was based on findings from a retrospective questionnaire sent to 36 children with a diagnosis of HAE and with follow-up telephone interviews

- The child’s quality of life the preceding week was assessed with a single-item seven-step visual analogue scale (VAS), using facial expressions (1=sad; 7=happy).

Depression Anxiety

Social activities Travel

Work/school Hospitalization

Burden of HAE

Disease course

Nature of attacks

Treatment QoL

Costs

HAE is associated with a substantial and multifaceted burden of illness

ED, emergency department; HAE, hereditary angioedema; QoL, quality of life Banerji A, et al. Ann Allergy Asthma Immunol 2013;111:329–336

Acute/chronic treatment

Direct medical

Hospitalization ED visits

Indirect

Work/school productivity

Prolonged Frequency Disfiguring Painful Debilitating

Unpredictable

Life threatening

Limited options Accessibility Side effects

Early onset

Delayed diagnosis Misdiagnosis

Chronic

Burden-QoL

Physical Psycological

Social

Utredning

HAE Types

85%

15%

Rare

Type I Low serum C1-INH

Low functional C1-INH

Type II Normal serum C1-INH Low functional C1-INH

HAE with Normal C1-INH

Primarily in women Normal serum C1-INH

Normal functional C1-INH

HAE1-4

1. Adapted from Levy JH, et al. Expert Opin Investig Drugs. 2006;15(9):1077-1090. 2. Dewald G, et al. Biochem Biophys Res Commun. 2006:343(4):1286-1289. 3. Agostoni A, et al. J Allergy Clin Immunol. 2004;114(3 suppl): S51-S131. 4. Cichon S, et al. Am J Hum Genet. 2006;79(6):1098-1104. 5. Zuraw BL, Bork K, E Binkley K, Banerji A,Christiansen SC, Castaldo A, Kaplan A, Riedl M, Kirkpatrick C, Magerl M, Drouet C, Cacardi M. Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy Asthma Proc. 2012 Dec 13.

HAE - Utredning

• C4 • C1-inh ag • C1-inh funksjon • C1q

Lab HAE

C1-INH Level

C1-INH Function

C4 Level

C1q Level

HAE type I <30% <30% Low Normal

HAE type II Normal/High <30% Low Normal

HAE type III Normal Normal Normal Normal

HAE type I <30% <30% Low

C1q=component of complement protein C1.

HAE type II Normal/High <30% Low

HAE type III Normal Normal Normal

Agostoni A, et al. J Allergy Clin Immunol. 2004;114(3 suppl):S51-S131.

Clinical symptoms: • recurrent angioedema without urticaria • recurrent episodes of abdominal pain & vomiting • laryngeal oedema • postivie family history

Laboratory measures: • C4 levels • C1-INH antigenic protein • C1q levels

C4; C1-INH low C1q normal

C1-INH function normal

Diagnosis: HAE-I confirm with 2nd measure of C4, C1-INH levels and function

Other disease? e.g. autoimmune

C4 low C1-INH; C1q normal

C1-INH function low

Determine: • C1-INH function

Diagnosis: HAE-II confirm with 2nd measure of C4, C1-INH levels and function

C4; C1-INH; C1q all normal

all normal (even during attack)

Determine: • C1-INH function • repeat C4 levels (during attack)

Consider other forms of angioedema • HAE type III • ACEi-AE • IAE

C4; C1q low C1-INH normal/low

C1-INH function low

Determine: • C1-INH function

Diagnosis: AAE determine anti-C1-INH antibody

T Bowen et al. Am Acad Allergy Asthma Immunol 2004; 114(3): 629-637. Diagnostic Algorithm

HAE utredning

•  Type III? Forsøke behandling med Antihistamin+/- steroider (cetirizin 20mgx2 +/- prednisolon 30mg v/anfall)

- NGS (mutasjoner?)

Faktor XII mutasjon U-HAE Angiopoetinmutasjon Plasminogenmutasjon

Akvirert /ervervet Angioødem? •  Idiopatisk histaminergt Angioødem? • Medikamenter?

-ACEI -A2-blokker -Neprilysinhemmer (Entresto) -NSAID -Østrogener

•  Immunologisk? (C1q lav, C4 lav, C1inh lav) -Hematologisk malignitet (lymfom? MGUS?) -Autoimmun sykdom

•  HAE symptoms can manifest at any age but typically appear during childhood, worsen during puberty (especially in females) and persist throughout life1,2

•  Clinical symptoms are rare during infancy2

•  Reported age of onset: 4–18 years (mean age of first attack: 10 years)2

•  Early onset may predict a more severe course of disease2,3

Age of symptom onset

HAE, hereditary angioedema

1. Lumry WR. Am J Manag Care 2013;19:S103–S110 2. Farkas H, et al. Allergy 2017;72:300–313

3. Christiansen SC, et al. Clin Pediatr 2016;55:935–942

Age at onset of first swelling: retrospective questionnaire study of US patients with HAE (N=581)3

Age at time of first swelling

Mean age of onset: 11 years3

50

40

30

20

10

0 C

ount

60

2 4 6 8 10 12 14 16 18 20

•  Although onset commonly occurs during childhood, accurate diagnosis of HAE is often not made until adulthood1,2

•  The time between onset of symptoms and accurate diagnosis averages 8.5 years1

•  Long delays in diagnosis are significantly correlated with early onset of HAE2

Diagnosis

HAE, hereditary angioedema 1. Farkas H, et al. Allergy 2017;72:300–313

2. Christiansen SC, et al. Clin Pediatr 2016;55:935–942

Age at time of diagnosis: retrospective study of US patients with HAE (N=581)2

120

100

80

60

40

20

0 0 10 20 30 40 50 60 70

Cou

nt

Mean age of diagnosis: 19 years (range 1–60)2

Median delay in diagnosis: 8 years (range 0–55 years)2

Age at time of diagnosis

•  Due its rarity and overlap of symptoms with other conditions, HAE is frequently under-recognized and misdiagnosed1,2

•  Abdominal pain is common among patients with HAE but is also a frequent symptom in the general population1

•  Misdiagnosis can result in unnecessary treatment or surgery2

HAE is frequently misdiagnosed

HAE, hereditary angioedema

1. Farkas H, et al. Allergy 2017;72:300–313 2. Banerji A. Ann Allergy Asthma Immunol 2013;111:329–336

3. Farkas H. Allergy Asthma Clin Immunol 2010;6:18

Symptom location Potential misdiagnosis

Subcutaneous Allergic reaction

Abdominal Acute appendicitis Irritable bowel syndrome Mesenteric lymphadenitis Intussusception Strangulation ileus Meckel’s diverticulum Polycystic ovarian syndrome Ovarian or testicular torsion Intestinal hemorrhage or infarction Recurrent peritonitis of familial Mediterranean fever

Laryngeal Allergic food reactions Allergic asthma Croup/pseudocroup Foreign body aspiration Acute epiglottitis

Prodromal Urticaria

Differential diagnoses of HAE symptoms among pediatric patients1-3

Behandling

Targets of HAE Treatment: Current and Potential Therapies

1.  Zuraw BL. Immunol Allergy Clin North Am. 2006, 26(4), 691-708 2.  CINRYZE® [package insert]. Lexington, MA: Shire ViroPharma Inc; 2014

3.  Kalbitor [package insert]. Cambridge, MA: Dyax Corp; 2009 4.  FIRAZYR® [package insert]. Lexington, MA: Shire Orphan Therapies, Inc; 2013

5.  Levy JH, et al. Expert Opin Investig Drugs. 2006, 15(9), 1077-90 6.  Berinert [package insert]. Kankakee, IL: CSL Behring LLC; 2012.

7.  Ruconest [package insert]. Raleigh, NC; Salix Pharmaceuticals; 2014 8.  Craig T. World Allergy Organ J. 2012, 5(12), 182-99 9.  Haegarda (C1-esterase inhibitor [human]) PI. 2017

10.  Banerji A et al. NEJM, 2017, 376 (8), 717-728

B2R; bradykinin B2 receptor BK; bradykinin FXIIa; factor XIIa

Vasodilation and increase in vascular permeability1

Active kallikrein

Active FXIIa

Inhibits

Replaces/increases

Fresh-frozen plasma1

Antifibrinolytics5

(Not recommended for treating HAE)8

Androgens1,5

C1-INH2,6,7,9 (concentrate or

recombinant)

Kallikrein inhibitors3,10

BK B2R antagonist4

BK B2R

Bradykinin

C1-INH dysfunction

54 %

16 % 14 %

8 % 8 % 5 % 5 %

0 %

10 %

20 %

30 %

40 %

50 %

60 %

Emergency department

Family doctor office visit

Overnight hospital stay

HAE specialist office visit

Doctor home visit

Acute/urgent care clinic

Nurse home visit

Patie

nts

Emergency department visits are common in some countries

Note: Four patients had more than one type of treatment visit for the attack. HAE-BOIS, Hereditary Angioedema Burden of Illness Study

Aygören-Pürsün E, et al. Orphanet J Rare Dis 2014;9:99

Types of treatment facility visits for most recent HAE attack: HAE-BOIS EU study (Spain, Germany and Denmark) (N=37 patients)

Behandling

• Generell • Anfallsbehandling •  Forebyggende behandling

Generell behandling • Opplæring/utdanning av pasient og pårørende •  Informasjon om arv og evt testing av 1.grads slektninger •  ”Emergency card” • Kontakt med FL/Lokalsykehus, sikre tilgang på

medikament • Unngå trigger

Akutt behandling

Akuttbehandling •  Icatibant (Firazyr): 30mg sc ved start av anfall ny dose

etter 6 evt 12 t. • PdC1-inhibitor (Berinert/Cinryze): 20E/kg iv. •  rhC1-inhibitor (Ruconest): 50E/kg iv • Plasma (Octaplas) 2-4 E hvis ikke annet tilgjengelig • NB! Ved tegn til økende larynxødem sikre luftveier først/

samtidig.

ACEI 5år Ak hevelse ansikt Hoven tunge Dyspne Ingen effekt antihistamin, adrenalin Sc Firazyr 30mg

NB! Ikke effekt av:

• Adrenalin • Steroider • Antihistamin

Profylakse – forebyggende behandling

Korttids

•  Forbigående trigger -eksamen -jobb

Langtids

• Permanent trigger

Copyrights apply

Forebyggende behandling • Cyklokapron 1-3g/dag. • Androgener f eks Danol 50-100mg/d •  pdC1-inhibitor iv

-Cinryze 1000E x2/u -Berinert 1000-1500Ex2/u

•  pdC1-inhibitor sc -Berinert 60E/kg

•  Lanadelumab(Takhzyro) 300mg sc hver 2-4u

Pålina

HAE Ålesund •  3 important persons • Dr Ivar Franck Local GP • Dr Arvid Nilsen (Haukeland University Hospital) • Dr Erik Waage Nilsen (Norlandssykehuset/Rikshospitalet)

HAE in Ålesund •  32 patients •  11 patients on C1inh prophylaxis/maintenance •  21 with on demand treatment

#1 •  Female born 1964 • HAE type 1 with symptoms from 1980 • No effective treatment •  Tried a few inj with C1 inh but no obvious effect •  From 1986 morfin only effective treatment •  From 1990 increasingly disabled •  2005 hospitalised due to continuous pain and on

Morphine infusion •  Tried C1 inh x 3-4/week (to maintain normal C4) and

thereafter tapering morphine ( only p.o) •  Today no Morphine. C1 inh 4 days a week.

HAE-kasus S-C4 0,2 0,1

okt nov des jan feb mar apr mai juni juli aug

sympt sympt

C1-inh x2 C1-inh x3

#2 •  Female born 1944 •  Type 1 HAE • Edema and abdominal attacks. Sometimes laryngeal

attacks. •  Frequent attacks ( 2-3/week) and difficult job situation. • Anxiety/depression/isolation • Oral treatment without effect. Icatibant with variable effect. •  From 2012 C1 inh maintenance x 2/week. •  «Normal life»

#4 •  Female born 1965 •  type 1 with increasing edema/abdominal attacks from

1985 • Problems at work and home • Endometriosis? • After pregnancy disease changed from attacks to more

continuous tiredness/loss of energi. Periods up to 2-3 weeks

• After C1 inh maintenance from 2013 life has normalised •  100% job/ 100% mother

Vår erfaring •  Individuell variasjon •  Fatigue • Sosioøkonomiske problem •  Tid mellom anfall? •  Fra anfallsbeh til mer profylakse •  Tett oppfølging spes i start • Årlig kontroll

Hva er HAE? symptom

time

Goal

Physical Psycological

Social

Take home message HAE

• Sjelden sykdom 1/50000 • Anfall med ikke- histaminergt angioødem • Arvelig • Klinikk 3 typer (Hud/abd/luftveier) •  Ikke effekt av antihistamin/adrenalin/steroider • Enkel diagnostikk • God behandling • Majoriteten profylakse • Brakutansenteret- hudavd RH