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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 June 2011
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Atopic urticaria: Different phenotypes and diverse treatment
Marcus Maurer
Allergie-Centrum-CharitéDepartment of Dermatology and Allergy
Charité - Universitätsmedizin Berlin
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Urticaria
Wheal and flare Angioedema
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EAACI / GA 2LEN / EDF / WAO Guidelines
Urticaria 2008Urticaria 2008Urticaria 2008Urticaria 20083333rdrdrdrd International Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on UrticariaInternational Consensus Meeting on Urticaria
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EAACI / GA 2LEN / EDF / WAO Guidelines
Allergy 2009; 64: 1417-1426 & 1427 -1443
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Chronic urticaria is
a disabling disease.
Treat it until it is gone!
Allergy 2009; 64: 1417-1426 & 1427 -1443
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PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
Urticaria – Pathogenesis
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Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
Urticaria – Pathogenesis
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Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-γ,
GM-CSF, TGF-β, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine,serotonine,
heparin,chondroitin-
sulfate,chymase,
tryptase, CPA
Urticaria – Pathogenesis
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Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
MC
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-γ,
GM-CSF, TGF-β, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine,serotonine,
heparin,chondroitin-
sulfate,chymase,
tryptase, CPA
Mast cells are the key effector cells in the induction of urticaria symptoms
Urticaria – Pathogenesis
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Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
Fcε RIKit
Fc γRTLRs
CR1/2, CR3C3aR, C5aR
NK1ETA /ETB
CD48IL-3,4,15RCCR3OTRsCysLT1R
MC-1/MC5EP1/EP3CB1/CB2
A2b/A3uPAR
VRPIRA/PIRB
IgESCF
IgGLPS
ComplementAnaphylatoxinsNeuropeptidesEndothelin-1
BacteriaInterleukinsChemokines
OxytocineLeukotriene
POMCsProstaglandins
CannabinoidsAdenosine
UrokinaseCapsaicin
?
MC
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-γ,
GM-CSF, TGF-β, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine,serotonine,
heparin,chondroitin-
sulfate,chymase,
tryptase, CPA
Mast cells are the key effector cells in the induction of urticaria symptoms
Urticaria – Pathogenesis
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Recruitment
Extravasation
Vasodilation
Activation PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
CAUSE
Fcε RIKit
Fc γRTLRs
CR1/2, CR3C3aR, C5aR
NK1ETA /ETB
CD48IL-3,4,15RCCR3OTRsCysLT1R
MC-1/MC5EP1/EP3CB1/CB2
A2b/A3uPAR
VRPIRA/PIRB
IgESCF
IgGLPS
ComplementAnaphylatoxinsNeuropeptidesEndothelin-1
BacteriaInterleukinsChemokines
OxytocineLeukotriene
POMCsProstaglandins
CannabinoidsAdenosine
UrokinaseCapsaicin
?
MC
Mast cells are the key effector cells in the induction of urticaria symptoms
Urticaria – Pathogenesis
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-γ,
GM-CSF, TGF-β, bFGF,
VPF/VEGF, PGD2, LTB4, LTC4, PAF, histamine,serotonine,
heparin,chondroitin-
sulfate,chymase,
tryptase, CPA
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Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic strategies
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Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic strategies
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Identify underlying cause
once cause is found
Treat underlying cause
Chronic Spontaneous Urticaria
Allergy 2009; 64: 1417-1426 & 1427 -1443
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Trigger
CauseMast cell-activating
signal
Mast cellactivation
Mast cellmediators
Urticaria reaction
causal symptomatic
Urticaria - Therapeutic strategies
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Non sedating H1-Antihistamine (nsAH)
Allergy 2009; 64: 1417-1426 & 1427 -1443
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Progress in antihistamine
development and availability
ChlorpheniramineDiphenhydramine
Hydroxyzine
Terfenadine1979
Second Generation
First Generation
Desloratadine2002
Levocetirizine2002
Ebastine1992
Fexofenadine1995
Loratadine1987
Cetirizine1987
<1970 1980s 1990s 2000+
Rupatadine2003
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Cold contact urticaria
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TempTest® 3.0
Cold contact urticaria
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Critical temperature thresholdsIm
prov
emen
t
P=0.0006
Baseline Placebo Non sedating Antihistamine
Metz, ..., and Maurer, Ann All Asthma Immunol 2010: 104; 86-92
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0
2
4
6
8
10
12
14
16
18
20
22
24
26
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Before After
Tem
pera
ture
thre
shol
d (°C
)
Placebo Non-sedating AH
Critical temperature thresholds
Tem
pera
ture
thre
shol
d (°C
)
Before After
Metz, ..., and Maurer, Ann All Asthma Immunol 2010: 104; 86-92
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BUT:
<50% of urticaria patients show
complete response to nsAHs !
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Non sedating H1-Antihistamine (nsAH)
nsAH updosing (up to 4x)
If symptoms persistafter 2 weeks
Allergy 2009; 64: 1417-1426 & 1427 -1443
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TempTest® 3.0
Cold contact urticaria
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30
25
20
15
10
5
0
Does updosing work?C
ritic
al T
empe
ratu
re T
hres
hold
(°C
)
Baseline
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
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30
25
20
15
10
5
0
Crit
ical
Tem
pera
ture
Thr
esho
ld (
°C)
PlaceboBaseline
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Does updosing work?
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30
25
20
15
10
5
0
Crit
ical
Tem
pera
ture
Thr
esho
ld (
°C)
***
Standard dosePlaceboBaselineNon sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Does updosing work?
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30
25
20
15
10
5
0
Crit
ical
Tem
pera
ture
Thr
esho
ld (
°C)
******
***
4x StandardPlaceboBaseline StandardNon sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Updosing works!
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Patient #24: Volumetric changes under treatment
0 min 5 min 10 min 20min
Placebo
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Patient #24: Volumetric changes under treatment
Standard dosed nsAH
4 x Standard dosed nsAH
0 min 5 min 10 min 20min
Placebo
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Updosing works in cold urticaria!Urticaria Skin Symptoms
PlaceboBaseline
Whe
al v
olum
e (m
m³)
1200
1000
800
600
400
200
0
***
******
4x StandardStandardNon sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
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Non sedating H1-Antihistamine (nsAH)
nsAH updosing (up to 4x)
+Leukotrieneantagonist, change nsAH
+H2-Antihistamine, Cyclosporine A, Dapsone, anti-IgE
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
Allergy 2009; 64: 1417-1426 & 1427 -1443
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0 24 0 24
Reduction of disease activityU
AS
7 (%
)
Week Anti-IgEPlacebo
0
20
40
60
80
100100
27.6
100
72.8
P=0.009
Maurer et al., unpublished data
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Anti-IgE 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
Maurer et al., unpublished data
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Patients with Complete Disease Control (no more wheals …)
Pat
ient
s w
ithou
t whe
als
(in %
)
Anti-IgE Placebo
70.4
4.5
0
10
20
30
40
50
60
70
80
Maurer et al., unpublished data
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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
Anti-IgEPlacebo
Maurer et al., unpublished data
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Use of rescue medication
Lora
tadi
ne (
tabl
ets
/ wee
k)
WeekAnti-IgEPlacebo
2.9
0.3
3.53.3
0
1
2
3
4
5
0 24
Maurer et al., unpublished data
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We recommend against the longterm use of systemic cortisone.
Allergy 2009; 64: 1417-1426 & 1427 -1443
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We recommend against the longterm use of systemic cortisone.
We recommend against the routine use of
old sedating first generation antihistamines.
Allergy 2009; 64: 1417-1426 & 1427 -1443
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REM Sleep
Drowsy
REM Sleep delayed and
reduced
Awake
First Generation
Antihistamine
Night Day Night Day
Aw
ake
Asl
eep
Church, Maurer, ..., Zuberbier. Allergy 2010, in press
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Non sedating H1-Antihistamine (nsAH)
nsAH updosing (up to 4x)
+Leukotrieneantagonist, change nsAH
+H2-Antihistamine, Cyclosporine A, Dapsone, anti-IgE
If symptoms persistafter 2 weeks
If symptoms persistafter 1-4 weeks
If symptoms persistafter 1-4 weeks
Allergy 2009; 64: 1417-1426 & 1427 -1443
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Unmet Clinical Needs in Chronic Spontaneous Urticaria - A GA 2LEN
Task Force Report
M. Maurer, K. Weller, C. Bindslev-Jensen, A. Giménez-Arnau, P. Bousquet, J. Bousquet, G. W. Canonica, M. K. Church, K. V. Godse,
C. E. H. Grattan, M. W. Greaves, M. Hide, D. Kalogeromitros, A. P. Kaplan, S. S. Saini, X. J. Zhu, T. Zuberbier
Allergy 2010; in press
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Chronic urticaria is
a disabling disease
Treat it until it is gone!
Allergy 2009; 64: 1417-1426 & 1427 -1443
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www.allergie-centrum-charite.de
Clinics for Mast Cell-driven Diseasesand Dermatological Allergology Lab
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Disclosure of Significant Relationships with Commercial Companies and Organizations
Funding of Research by Almirall, Bayer Bioscience, Biobasal AG, Biofrontera, BMWi (ProInno), Carstens Stiftung, DBV Winterthur, Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe, Eppenauer Gutzeit Stiftung, Essex Pharma, EU (Europäischer Fond für Regionale Entwicklung, EFRE), European Centre of Allergy Research Foundation (ECARF), FAES Pharma, GA2LEN, Hans Sauer Stiftung, Investitionsbank Berlin (PROfit), Italfarmaco, Jado Labs, Jerini, Jürgen Manchot Stiftung, Jung Stiftung für Wissenschaft und Forschung, L. van Heek Textiles, Maruho, Novartis, Pharmacia Diagnostics, Schering-Plough, Shire, Stiftung Rheinland Pfalz für Innovation, Symbiopharm, UCB, Unna-Stiftung, Urticaria Network e.V. (UNEV), and Volkswagen Stiftung.
Speaker and/or Advisor for Almirall Hermal, Bayer Schering Pharma, Biofrontera, Essex Pharma, Genentech, JADO Technologies, Jerini, Merckle Recordati, Novartis, Sanofi Aventis, Schering-Plough, Leo, MSD, Merck, Shire, Symbiopharm, UCB, and Uriach.