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U N I V E R S I T Ä T S M E D I Z I N B E R L I N
Markus Magerl
Anti-histaminiques dans l’UC:nouvelles stratégies
URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi 21 janvier 2010
Allergie-Centrum-CharitéKlinik für Dermatologie, Venerologie und Allergologie
Charité - Universitätsmedizin Berlin
Allergie-Centrum-CharitéDepartment of Dermatology and Allergy
Charité - Universitätsmedizin Berlin
Anti-histaminiques dans l’UC:nouvelles stratégies
Anti-histamines in chronic urticaria:new strategies
URTICAIRE CHRONIQUE – Actualités et controverses Lyon, jeudi 21 janvier 2010
Allergie-Centrum-CharitéKlinik für Dermatologie, Venerologie und Allergologie
Charité - Universitätsmedizin Berlin
Allergie-Centrum-CharitéDepartment of Dermatology and Allergy
Charité - Universitätsmedizin Berlin
EAACI/WAO/GA 2LEN/EDF Guidelines
Urticaria 20083333rdrdrdrd International Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on Urticaria
Non sedating H 1-Antihistamine (nsAH)
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA 2LEN/EDF guideline: management of urticaria
Non sedating H 1-Antihistamine ( nsAH )
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA2LEN/EDF guideline: management of urticaria
Step 1: Non sedating H1-Antihistamines (nsAH)
level of evidence: 1++
grade of recommendation: A
most pts. are treated this way
sounds good, but:
> 40% affecting partnership
> 50% impairment of sleep
> 50% influence on cognitive functioning/concentration
> 55% interferes with execution of daily work load
> 60% short tempered and bad mood
> 75% impairment of leisure time/activities
n = 362
Implications of urticaria
www.urtikaria.net
CU patients
healthy control
Staubach et al., Br J Dermatol 2006; 154: 294-8
0
20
40
60
SK
IND
EX
Sco
re
80
***
n = 196
Chronic urticaria = bad quality of life
Chronic urticaria = bad quality of life
Basra MK et al. Br J Dermatol. 2008 Nov;159(5):997-1035
DLQ
I
number of nights per week
Impairment of sleep
n = 321
0%
10%
20%
30%
0 <1 1 2 3 4 5 6 7
patie
nts
Maurer, Ortonne and Zuberbier. Br J Dermatol. 2008
0%
20%
40%
60%
80%
100%
prescrmed lotions
doc
OTC
bath ice
others
nothing
cover
Impatient patients: Wait and see is no option
patie
nts
n = 321 Maurer, Ortonne and Zuberbier. Br J Dermatol. 2008
0
20
40
60
80
100
very satisfied
satisfiedmodest
not satisfiedvery unsatisfied
Are you satisfied with the treatment?P
atie
nten
(%
)
total
n = 321
WHY?
Patients are not enthusiastic
16 of 37 CU studies report responder rates.
Only 42.5% (range: 4% to 68%) of patients show complete symptom control.
Complete symptom control
WHY?
What can be improved?
Patients are not enthusiastic
Daily vs As-Needed Desloratadine in Chronic Spontaneous Urticaria
• Randomized, double-blind, parallel-group study at 35 centers in France
• Patients initially received desloratadine 5 mg for 28 days
• Responders received 2-month therapy with either:– Desloratadine 5 mg continuous treatment, or– Desloratadine 5 mg as needed, i.e. when patients had wheals
• Assessments– Primary: Change in quality of life– Secondary: Change in pruritus symptoms and in overall condition
Grob et al., Allergy 2009
Improvement of Quality of Life
Grob et al., Allergy 2009
Improvement of Quality of Life
50
40
30
20
10
0
QoL
Impa
irmen
t
ContinuousPRN
P = 0.091
P = 0.007
P = 0.005
P = 0.044
P = NS
P = NS
P = 0.077
P = 0.016
Self-perception
Daily lifeactivities
Mood Social life Leisureactivities
Limitationdue to
treatment
Physicalpains
Global VQ-Dermato
index
Grob et al., Allergy 2009
VQ
-Der
mat
o D
imen
sion
Sco
re
Days with Moderate/Severe Pruritus
P=0.012
Day
s w
ith M
oder
ate
/ Sev
ere
Pru
ritus
Daily As needed
6.3 days
12.7 days
0
5
10
15
6.3 days
12.7 days
Grob et al., Allergy 2009
Complete Relief
P=0.097
Pat
ient
s w
ith C
ompl
ete
Rel
ief (
%)
Daily As needed
52.5%
30.8%
0
20
40
60
52.5%
30.8%
Grob et al., Allergy 2009
Conclusions
Continuous / daily use of antihistamineis superior to treatment as needed
Non sedating H 1-Antihistamine ( nsAH )
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA2LEN/EDF guideline: management of urticaria
Testing the effects of desloratadine updosing:
Aerius updosing in acquired cold urticaria
(AUDACU)
The AUDACU trial
Phase IV
RandomisedDouble-blind
Placebo controlledCrossover study5mg vs. 20mg Desloratadine
Acquired cold urticaria (ACU)n = 30
Acquired Cold Urticaria: Symptoms after cold shower
Parameters assessed
Wheal volume (Volumetry)
Hyperthermic skin area (Thermography)
Critical Temperature Threshold (TempTest 2.0)
The AUDACU trial
Study design
▼▼▼▼ ▼▼▼▼ ▼▼▼▼ ▼▼▼▼
▼▼▼▼ Cold provocation
ScreeningDay0
Visit 1Week 2
Visit 2Week 5
Visit 3Week 8
Treatment7 days
Washout14 days
+Treatment
7 days
Washout14 days
+Treatment
7 days
Cold provocation with TempTest 2.0 at 4°C for 5 minutes
The AUDACU trial
TempTest 2.1 TempTest 2.0
Volumetry
• 3D in vivo skin measurement
• readings of wheal volume, area, and height
Volumetry
Volumetry
Volumetry
Volumetry
Volumetry
Volumetry
Volumetry
Thermography
•Visualization of thermal energy (heat)at site of inflammation• Assessment of hyperthermic skin area after cold provocation
Thermography in a cold urticaria patient
Thermography in a healthy control person
Critical temperature thresholds (CTT) at baseline
Critical Temperature Threshold (CTT)
Num
ber
of P
atie
nts
12
10
8
6
4
2
028-31°°°°C23-27°°°°C18-22°°°°C13-17°°°°C4-7°°°°C 8-12°°°°C
28°C: Swimming in indoor pool
4°C: snowball fight, cold drink
20°C: Using normal toilet seat
16°C: Swimming in Atlantic Ocean, France
10°C: Preparing food, skiing
30
25
20
15
10
5
0
Critical Temperature Threshold (CTT)
Crit
ical
Tem
pera
ture
Thr
esho
ld (
°C)
******
***
20mg5mgPlaceboBaselineDesloratadine
Critical Stimulation Time Threshold (CSTT)
DL 20mgDL 5mgPlaceboBaseline
6
5
4
3
2
1
0
Crit
ical
Stim
ulat
ion
Tim
e T
hres
hold
(m
in)
**
***
***
AUDACU-Patient #24: Knut, S. 62y
DL 20mgDL 5mgPlaceboBaseline
Patient #24: Volumetric changes under treatment
Desloratadine 5mg
Desloratadine 20mg
0 min 5 min 10 min 20min
Placebo
Patient #24: Volumetric changes under treatment
Desloratadine 5mg
Desloratadine 20mg
0 min 5 min 10 min 20min
Placebo
Updosing of Desloratadine Improves Urticaria Skin Symptoms
DL 20mgDL 5mgPlaceboBaseline
Whe
al v
olum
e (m
m³)
1200
1000
800
600
400
200
0
***
*** ***
Patient #18: Thermographic changes under treatment
Desloratadine 5mg
Desloratadine 20mg
0 min 5 min 10 min 20min
Placebo
DL 20mgDL 5mgPlaceboBaseline
Hyp
erth
erm
ic s
kin
area
(m
m²)
4000
3000
2000
1000
0
Updosing of desloratadine improves urticaria skin symptoms
*
*
*
DL 20mgDL 5mgPlaceboBaseline
Whe
al v
olum
e (m
m³)
1200
1000
800
600
400
200
0
***
*** ***
Updosing of desloratadine improves urticaria skin symptoms
No
of c
ompl
ete
resp
onde
rs
Updosing of desloratadine improves urticaria skin symptoms
What about updosing of antihistamines in chronic spontaneous urticaria?
The AUD2OCU trial
Chronic spontaneous urticaria
RandomisedDouble-blind
Parallel group5mg vs. 20mg Desloratadinen = 29
week 1 week 2 week 3screening
V1 V2 V3
Group A
Group B
desloratadine 20 mg
desloratadine 5 mg
Planimetric Morphometry , Volumetric and Thermographic Assessment
no antihistamines
no antihistamines
*
***
Desloratadine
20 mg5 mg
*
Red
uctio
n of
whe
al n
umbe
rat
5 h
ours
(in
%)
*
***
Desloratadine
20 mg5 mg
*
Red
uctio
n of
whe
al n
umbe
rat
5 h
ours
(in
%)
p = 0.008
0 1 2 3 4 5h
5 mgDL
spontaneousresolution
20 mgDL
Time to significant reduction of number of wheals
5h0h
Nothing
5h0h
0h 5h
Nothing
5mg Desloratadine
5h0h
Nothing
5h0h
0h 5h
Nothing
20 mg Desloratadine
Standard dose of DL works in chronic spontaneous urticaria
and cold urticaria.
UPDOSING (using 4x the standard dose) results in even
better total symptom control .
UPDOSING is safe.
Updosing of antihistamines
Non sedating H 1-Antihistamine ( nsAH )
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA2LEN/EDF guideline: management of urticaria
Non sedating H 1-Antihistamine ( nsAH )
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA2LEN/EDF guideline: management of urticaria
Non sedating H 1-Antihistamine ( nsAH )
Antihistamines are the basis of CU treatment
+
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
+Leukotrieneantagonist, change nsAH
nsAH updosing (up to 4x)
+H2-Antihistamine, Ciclosporine A, Dapsone, anti-IgE
EAACI/GA2LEN/EDF guideline: management of urticaria
Study Aim and Design
Is anti-IgE (Omalizumab) effective and safe in patients with moderate to severe chronic urticaria?
Study Aim and Design
Is anti-IgE (Omalizumab) effective and safe in patients with moderate to severe chronic urticaria?
27-week, randomized, double-blind, placebo-controll ed, multicenter parallel-group study
Prescreening-Visit
Placebo
Omalizumab
24 weeksTreatment
3 weeksScreening
w -3 w 0 w 24
• Moderate to severe chronic spontaneous urticaria• „Antihistamine-resistant“ (UAS7 ≥ 10)• 18-70 years
• ≥ 20 kg and ≤ 150 kg KG• Total-IgE ≥ 30 and ≤700 I.E./ml
• IgE-anti-TPO-level > 8 IU/mL
Study population
Outcome parameters
Disease activity (urticaria activity score, UAS7)
Symptom loadWhealsPruritusErythemasAngioedemasSystemic symptoms
Quality of lifeDLQISkindexCU-Q2oL
Rescue medication
Combined score:pruritus intensity and number of wheals
UAS per day is between 0 and 6 points
UAS (Urticaria Activity Score)
+
• UAS7 = UAS of 7 days
• UAS7: between 0 and 42 points
• Time of UAS7 determination:– baseline (Screening-Phase � day -14 to -1 before
randomization)– End of treatment (week 22 to 24 after randomization)
UAS7
Xolair Dosing
>20-25
>25-30
>30-40
>40-50
>50-60
>60-70
>70-80
>80-90
>90-125
>125-150
>=30–100 75 75 75 150 150 150 150 150 300 300
>100–200 150 150 150 300 300 300 300 300 450 600
>200–300 150 150 225 300 300 450 450 450 600 750
>300–400 225 225 300 450 450 450 600 600
>400–500 225 300 450 450 600 600 750 750
>500–600 300 300 450 600 600 750
>600–700 300 450 450 600 750
Body Weight (kg)
Dosage ≤ 300 mg will be administered every 4 weeks
Dosage >300 mg will be split in two doses and admin isterd every 2 weeks
Body Weight (kg) T
otal
IgE
(IU
/ml)
Demographic Data
Omalizumab (n=27)
Placebo (n=22)
Age (years) mean ± SD 39.1 ± 9.0 42.3 ± 15.0
Gender female n (%) 19 (70.4) 19 (86.4)
Race caucasian n (%) 27 (100) 22 (100)
Height (cm) mean ± SD 171.0 ± 7.2 164.1 ± 6.6
Weight (kg) mean ± SD 81.9 ± 20.2 71.2 ± 12.4
IgE-anti-TPO mean ± SD 7.3 ± 4.6 6.2 ± 3.7
Omalizumab Placebo
n (%) n (%)
Study completion treated 27 (100.0) 22 (100.0)
discontinued 2 (7.4) 5 (22.7)
completed 25 (92.6) 17 (77.3)
Reason for discontinuation
Adverse event(s) 0 (0.0) 1 (4.5)
Unsatisfactory therapeutic effect
1 (3.7) 4 (18.2)
Administrative problem 1 (3.7) 0 (0.0)
Drop outs
0
5
10
15
20
25
30
0 24 0 24
Change in disease activity
UA
S7
P=0.009
Week XolairPlacebo
Omalizumab Placebo
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
Day0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190
UA
S p=0.0002
Change in disease activity
Responder analysis (UAS7)
Res
pond
er r
ates
(in
%)
100 % ≥ 90% ≥ 75%XolairPlacebo
48
56
71
0
10
20
30
40
50
60
70
80
90
Patients with Complete Disease Control (no more wheals …)
Pat
ient
s w
ithou
t whe
als
(in %
)
Xolair Placebo
70.4
4.5
0
10
20
30
40
50
60
70
80
XolairPlacebo
Quality of Life (QoL)
Impr
ovem
ent i
n Q
oL (
in %
)
CU-Q2oL DLQI SKINDEX
55
45
50
6
11
6
0
10
20
30
40
50
60
70
XolairPlacebo
Use of rescue medication
Lora
tadi
ne (
tabl
ets
/ wee
k)
WeekXolairPlacebo
2.9
0.3
3.53.3
0
1
2
3
4
5
0 24
Adverse Events
n % of patients n % of patients
Cardiovascular Disorder 0 0.0 1 4.5
Injection Site Irritation 0 0.0 1 4.5
Injection Site Pain 0 0.0 1 4.5
Anaphylactic Reaction 1 3.7 0 0.0
Nasopharyngitis 1 3.7 0 0.0
Vulvitis 1 3.7 0 0.0
Headache 2 7.4 2 9.1
Hypoaesthesia 0 0.0 1 4.5
Alopecia 0 0.0 1 4.5
Skin Burning Sensation 1 3.7 0 0.0
Haematoma 1 3.7 0 0.0
Omalizumab Placebo
First Results of the X-CUISITE Study
• Effective and safe in autoallergic CU patients
• High rate of “complete responders”
• Significant impact on QoL
• Fast onset of action
Pending Questions
• Efficacy in different types of urticaria?
• Mode of action?
• Dosing?
www.allergie-centrum-charite.de
b2
Diapositive 144
b2 bschinze; 13/02/2008
Woche 1
Randomisierung / Versand der
Prüfmedikation
Screening
DL 20mgGruppe A
Visit 1
DL 5mg
Visit 2
PlaceboWash out Wash out
Woche 2 Woche 5 Woche 8
DL 5mgGruppe B Placebo DL 20mgWash out Wash out
PlaceboGruppe C DL 20mg DL 5mgWash out Wash out
Visit 3
PlaceboGruppe D DL 5mg DL 20mgWash out Wash out
DL 20mgGruppe E Placebo DL 5mgWash out Wash out
DL 5mgGruppe F DL 20mg PlaceboWash out Wash out
Details of study design
week 1 week 2 week 5 week 8
Group B
Group C
Group D
Group E
Group F
Group A
Placebo daily + DL 5mg PRN (n=60)
DL 5mg daily + placebo PRN (n=46)
DL 5mg daily(N=126)
Month 1 2 3 4 5
DL 5 mg PRN (n=93)
Randomisation
V2 V3 V4 V5
TreatmentStart
Daily vs As-Needed Desloratadine in Chronic Spontaneous Urticaria
Grob et al., Allergy 2009
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