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Indication of Anti-IgE
treatment in children
Matthias Kopp
Pediatric Pulmonology and Allergology
University of Lübeck
Annual meeting of the Danish Society of
Paediatric Allergology and Pulmonology
Kolding, 15th of January 2010
severe asthmatic attack after
a ride with a horse-drawn
carriage
history of allergy to horses
one week ago: transfusion of
600 ml blood from a man with
a known allergy to horses
factor in the blood is able to transfer allergic complaints
reagine = immunglobuline IgE
Anecdotic Case Report
Ramirez MA, JAMA 1919
Johansson SG, Lancet 1967
Antigen-presenting
cells
TH2-cells
naive T-cell
sensitis
ation
mastcells basophils
YY
effe
cto
r-phase
F FF
IgE
IL-4
IL-13IL-5
eosinophils
Pathophysiology
effector cells
B-cells
Allergic reaction
Allergen
IgE
IgE-receptor
effector cells
histamine
leukotriene, IL-4, IL-5
Omalizumab
Anti-IgE
IgE and Anti-IgE
allergen
Kopp MV, JACI 2002
Omalizumab: Leukotrienes
before - after before - after0
1000
2000
3000
4000
5000Grass Allergen
Birch Allergen
Leukotr
iene r
ele
ase [
ng/L
]
therapy therapy
SIT-Grass + Anti IgE
p = 0.0001
p = 0.0002
before - after before - after0
1000
2000
3000
4000
5000Grass Allergen
Birch Allergen
Leuko
trie
ne r
ele
ase [
ng/L
]
therapy therapy
SIT-Grass + Placebo
SIT + Omalizumab SIT + Placebo
IgE
IgE-receptor
effector cells
histamine
leukotriene, IL-4, IL-5
Omalizumab
Anti-IgE
IgE and Anti-IgE
allergen
MacGlashan, J Immunol 1997
Lin H, J Allergy Clin Immunol 2004
Prussin C, J Allergy Clin Immunol 2003
expression of Fc R1 on
basophils before (open bar)
and after therapy (shaded
bar) with omalizumab
Omalizumab reduce the
expression of the high
affinity IgE receptor
(Fc R1) on basophils and
mastcells as well as
dendritic cells significantly
within 14 days
Anti-IgE: Fc R1
Omalizumab is able to
attenuate the eosinophilic
inflammation in patients
with allergic
rhinokonjunctivitis (AR)
during the pollen season
eosinophils before and during
the pollen season in patients
with a birch pollen induced AR
treated with omalizumab
(right) or placebo (left)
Plewako H, J Allergy Clin Immunol 2002
Bez C, Clin Exp Allergy 2004
Anti-IgE : Eosinophils
Omalizumab
Possibilities and Indication
Allergic diseases
allergic rhinitis – allergic asthma – severe
allergic asthma – food allergy – atopic dermatitis
– bee venom allergy – wasp venom allergy –
urticaria – latex allergy – drug allergy – contact
allergy – allergic rhinokonjunctivitis – allergic
rhinitis - allergic asthma – drug allergy – urticaria
- severe allergic asthma – food allergy – atopic
dermatitis – bee venom allergy – wasp venom
allergy – urticaria – latex allergy – drug allergy –
contact allergy – allergic rhinokonjunctivitis
allergic rhinitis – allergic asthma – severe
allergic asthma – food allergy – atopic dermatitis
– bee venom allergy – wasp venom allergy –
urticaria – latex allergy – drug allergy – contact
allergy – allergic rhinokonjunctivitis allergic
rhinitis – allergic asthma – severe allergic
asthma – food allergy – atopic dermatitis – bee
venom allergy – wasp venom allergy – urticaria
Indication of Anti-IgE
Xolair (Omalizumab) is indicated for
1. adults and children (> 6 y) with
2. severe persistent allergic asthma
3. who have a positive skin test or in vitro
reactivity to a perennial aeroallergen
4. > 12 y: FEV1 < 80%
5. IgE > 30 - 700 kU/l (< 12 y: - 12000)
6. whose symptoms are inadequately
controlled despite optimal therapy.
age > 12 13-year old boy
symptoms since his first year of life
optimal therapy budesonide 400 – 800 µg 2 x daily
salmeterol
montelukast
IgE 30 – 700 kU/l
peren. allergen
IgE 468 kU/l
mites (Der p) CAP-class 3; grass
pollen 2; birch pollen 3
special notes 5 x hospitalisation nesecessary
physical fatigue currently
Case Report
• Bronchiolitis obliterans
• good clinical response to
high doses of systemic
steroids
• Omalizumab not indicated
Recomendation:
The diagnosis of severe asthma must
be critically reviewed!
Case Report
COPD,
BO
CF
α1-AT- deficiency
cardiomyoptahy
VCD
31%: other or additional pulmonary disease!Robinson DS, Eur Respir J 2003
Difficult-to-treat asthma
Systematic assesment
1. sensitization to a perennial
aeroallergen ?
2. safety and efficacy of anti-IgE
treatment in young children with
sever asthma ?
3. use of Anti-IgE in case of other
allergic diseases ?
Anti-IgE in children
n age duration symptoms allergen
Casale TB, JAMA 2001 536 12 - 75 3 mo ragweed
Ädelroth E, JACI 2000 251 17 - 66 4 mo. birch
Kuehr J, JACI 2002 225 6 - 17 9 mo birch and grass
Casale TB, JACI 2006 123 18 - 50 20 we ragweed
Okubo K, Allergol Int 2006 100 20 - 64 24 we cedar
Kopp MV, 2008 sub. 140 12 - 46 18 we grass
Perennial allergens
Inhalant steroids (ICS)
+ placebo
4 w 16 w 8 w 4 w
primary outcome: number of asthma exacerbations
28 weeks
Trials: Anti-IgE & asthma
+ omalizumab
stepwise
reduction
of ICS
lowest
tolerated
ICS dose
Clinical Trials in children 6 - 12 years:
p< 0.001
18
38
0
10
20
30
40
50
60
Omalizumab Placebo
asthma exacerbation (%)
Milgrom H, Pediatrics 2001
Adolescents > 12 y
55
39
0
10
20
30
40
50
60
70
Omalizumab Placebo
children without ICS (%)
p< 0.001
0.77
0.29
0.63
0.42
Num
ber
of
clin
ical re
levant exacerb
ations
1.2
1.0
0.8
0.6
0.4
0.2
0Omalizumab
(n=159)
Placebo
(n=76)
1.2
1.0
0.8
0.6
0.4
0.2
0
24 weeks: stable ICS dose 28 weeks: ICS reduction phase
Omalizumab
(n=159)Placebo
(n=76)
–34%
p=0.047
–63%
p<0.001
Asthma exazerbations
Num
ber
of
clin
ical re
levant exacerb
ations
ERS, Vienna 2009 (Poster)
IA05
high dose
ICS + LABA
(n=235)
IA05 total
(n=576)
INNOVATE
(n=419)
Clinical relevant
exacerbations 1,4 1,7 2,7
Number needed to treat
ERS, Vienna 2009 (Poster)
…to prevent asthma exacerbation
number of adverse
events
causal relationship:
Urtikaria
anaphylactic reaction
?
Anti-IgE-AK
Komplementaktivierung
Immunkomplexablagerung
local reaction:
mild- moderat
severe adverse
events
Safety (n > 5200 patients)
Limb SL, JACI 2007
Risk of anaphylaxis
• June 2003 – December 2006; 77.300 patients
• 124 cases of anaphylaxis (1:625)
• mean age 43 y (9 – 78); 82% females
• pulmonary involvement 89%; hypotension or syncope 17%
• 39% first-dose; 19% second-dose; 33% > third dose reaction
• time to onset < 30 min 35%; < 60 min 26%; < 120 min 8%;
> 24 h up to 4 days 5%
Delayed onset and protracted progression of
symptoms!
effective
safety
Allergic Rhinitis
Anti-IgE + SIT
ABPAfood-allergyAtopic
DermatitisUrticaria
Indication and Perspectives
Krathen RA , J Am Acad Dermatol 2005
Vigo PG, J Am Acad Dermatol 2006
Some case reports show that Anti-IgE might be effective in AD
Lane JE, J Am Acad Dermatol 2006
effects:
Atopic Dermatitis & Anti-IgE
Lane Krathen Vigo recommendation0
400
800
2500
7500
12500
17500
22500
IgE
[ku
/l]
only case reports!
good satisfying +/- 0
worse
Atopic Dermatitis & Anti-IgE
11 patients
IgE levels:
1.343 – 39.534 IU/ml
Results:
6/11 satisfying –
good
Belloni B, JACI 2007
150 mg omalizumab every second week over 10 weeks
=> effect in selected patients
No data from randomized controlled trials
available
No recommendation for standard use
based on case series.
Atopic Dermatitis & Anti-IgE
Aspergillus fumigatus: fungi
• Allergic bronchopulmonary
aspergillosis: pulmonary
complication in CF patients
• CF: ~ 50% colonized with
Aspergillus fumigatus
• CF: prevalence of ABPA in
Europe ~7.8%
• Therapy: systemic
steroids & antimycotic
drugs
Mastella G, Eur Respir J 2000
Thia LP, Pediatric Respir Rev 2009
inhalation of fungi => TH2-
driven inflammationIgE
mastcells
complement
ABPA
ABPA + Anti-IgE
• are there additive therapeutic effects of omalizumab in CF
patients with ABPA treated with steroids?
• is omalizumab a steroid-saving therapeutic option?
Patient
age
Genotyp ABPA Therapy:
Itraconazol + …
Outcome afetr Xolair 300 mg sc
every other week:
13-y
boy
F508/
A141D
7 y Prednison 4 weeks 1
mg/kg KG
Weaning impossible
0.5 mg/kg every
other day
Prednison-Weaning
Stop of steroids after 9 m
FEV1 77% => 87%
13-y
Boy
F508/
F508
6 y Prednison 20 mg/ Tag
Weaning impossible
1 mg/kg every other
day
Prednison-Weaning
Stop of steroids after 18
months
17-y
boy
F508/
F508
6 y Prednison 20 mg/
every other day
Prednison-Weaning
Stop of steroids after 4 m
FEV1 83% => 102%
Zirbes JM, Pediatric Pulmonology 2008
Summary: effective Steroid-saving
ABPA + Anti-IgE
Case report: Maria, 12 years
• CF, F-508/ F-508; FEV1 pred. 92%
• cough exercise tolerance
• Serratia marescens => i.v. antibiotics, no improvement
• tentative diagnosis: ABPA
- 27% eosinophils; absolut 3180/µl
- IgE increased 133 kU/l => 524 kU/l
- rAsp. f. 4: 3,27 kU/l; IgG-AK
- Sputum: Asp. fumigatus
- SPT positive
- expirium , rhonchi
- shortness of breath
=> ABPA confirmed
• therapy: steroids – Itraconazol - Xolair
• rapid improvement
• symptom free: 10 days after start of Xolair
• normal exercise tolerance after 4 weeks, LuFu
1,00
1,20
1,40
1,60
1,80
2,00
2,20
2,40
2,60
2,80
May October January
FEV1
FVC predicted
predicted
Case report: Maria, 12 years
• only published case reports
• open issues:
- How effective is omalizumab?
- Responder and non responder?
- Steroid-saving effect?
- Therapy without steroids possible?
- Early or late therapy with omalizumab?
ABPA & Omalizumab
Anti-IgE & SIT
1. Are additional clinical benefits of
omalizumab + SIT?
2. Is the number of adverse events of
SIT reduced by pretreatment of
omalizumab?
3. SIT + omalizumab: enhanced long-
lasting effects?
Allergic Rhinitis
• Grass- and birch pollen Kühr 2002
• ragweed Casale 2006
Saisonal asthma
• grasspollen Kopp 2009
Anti-IgE & SIT
35%
P=0.01*
0.30
0.46 45%
P=0.011*
0.38
0.21
0
0,2
0,4
0,1
0,3
0,5
symptom load - score (median)
*=Wilcoxon Test
n=53
SIT grass +
placebo
n=59
SIT grass +
omalizumab
n=55
SIT birch +
omalizumab
n=54
SIT birch +
placebo
Kühr J, JACI 2002
6 - 17 years
sensitization:
birch + grass
SIT
+ placebo
+ placebo
+ Anti-IgE
+ Anti-IgE
Anti-IgE & SIT
start of the
ragweed season
9 weeks
Omalizumab
Visit 0
Rush-SIT
8 weeks
> 3 weeks
Rush-IT: 6 injections in 3 h Build-up Maintenance
0.012–1.2 µg Amb a 1 2-4-6-8 µg 12 µg
12 weeks4 weeks
Anti-IgE & SIT
Placebo
Omalizumab + Placebo
Omalizumab + SIT
Placebo + SIT
n= 11 (29.7%)
n= 12 (33%)
n= 22 (56%) *
n= 7 (18.9%)
all adverse events
n= 1 (2.7%)
n= 2 (5.6%)
n= 10 (25.6%) *
n= 1 (2.7%)
anaphylaxis
Placebo + SIT: 20.5% received epinephrine
Casale, JACI 2006
120 ragweed-sensitized patients (18–50 y) with allergic rhinitis
Anti-IgE prior to SIT
Omalizumab
Placebo
8 w season 18 w pre2 w
w 0 w 2 w 10 w 18
2006
+ Rush-SIT
+ Rush-SIT
2007 2008
SIT
SIT
s 2 s 3
Anti-IgE & SIT: DUAL
- Population: n= 132 (2006) and n= 119 (2007; 92% )
- 12 – 45 years; allergic rhinitis + seasonal asthma
- endpoint: symptom load (symptoms + medication)
0,0
0,1
0,2
0,3
0,4
0,5
SIT + Placebo SIT + Omalizumab
Sym
pto
m s
eve
rity
sc
ore
(m
ed
ian
)
p = 0.01
0.42
0.29
Allergic Rhinitis and Asthma
Kopp MV, Clin Exp Allergy 2009
Asthma Control
Questionnaire
SIT + Omalizumab: asthma control significantly improved
Asthma Quality of
Life Questionnaire
1,0
1,2
1,4
1,6
1,8
2,0
2,2
SIT + Placebo SIT + Omalizumab
LS
mean
s
1.96
1.63
p = 0.03
5,7
5,8
5,9
6,0
6,1
6,2
6,3
6,4
6,5
6,6
SIT + Placebo SIT + OmalizumabL
S m
ean
s
6.07
6.41
p = 0.029
Kopp MV, Clin Exp Allergy 2009
Quality of life improved
Kissing decreases IgE
production
Kimata H, J Psychosom Res 2006
Control study Kissing study
before after before after
IgE [ng/ml] 2.3 2.5 2.6 1.1 *
IL-4 [pg/ml] 152 135 286 143*
IFN-γ [pg/ml] 203 235 209 134*
Patients with atopic dermatitis or allergic rhinitis spent 30
minutes with their partner without kissing (control study)
or with kissing while listening to music (kissing study)