HEREDITÆRT ANGIOØDEM - Legeforeningen€¦ · Hereditært angioødem - HAE • Prevalens 1/50000....
Transcript of HEREDITÆRT ANGIOØDEM - Legeforeningen€¦ · Hereditært angioødem - HAE • Prevalens 1/50000....
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