UNIVERSITÄTSMEDIZIN BERLIN
June 2011
Atopic urticaria:
Different phenotypes
and diverse treatment
Marcus Maurer
Allergie-Centrum-Charité
Department of Dermatology and Allergy
Charité - Universitätsmedizin Berlin
Urticaria
Wheal and flare
Angioedema
EAACI / GA2LEN / EDF / WAO Guidelines
3rd International Consensus Meeting on Urticaria
Urticaria 2008
EAACI / GA2LEN / EDF / WAO Guidelines
Allergy 2009; 64: 1417-1426 & 1427 -1443
Chronic urticaria is
a disabling disease.
Treat it until it is gone!
Allergy 2009; 64: 1417-1426 & 1427 -1443
Urticaria – Pathogenesis
PRURITUS
ERYTHEMA
WHEAL
INFILTRATE
Urticaria – Pathogenesis
Activation
Vasodilation
PRURITUS
ERYTHEMA
Extravasation
WHEAL
Recruitment
INFILTRATE
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,
chondroitinsulfate,
chymase,
tryptase, CPA
Activation
Vasodilation
PRURITUS
ERYTHEMA
Extravasation
WHEAL
Recruitment
INFILTRATE
Urticaria – Pathogenesis
Mast cells are the key effector cells
in the induction of urticaria symptoms
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,
chondroitinsulfate,
chymase,
tryptase, CPA
Activation
Vasodilation
PRURITUS
ERYTHEMA
Extravasation
WHEAL
Recruitment
INFILTRATE
Urticaria – Pathogenesis
Mast cells are the key effector cells
in the induction of urticaria symptoms
IgE
Fcε RI
SCF
Kit
IgG
Fc γR
LPS
TLRs
Complement
CR1/2, CR3
Anaphylatoxins
C3aR, C5aR
Neuropeptides
NK1
Endothelin-1
ETA /ETB
Bacteria
CD48
Interleukins
IL-3,4,15R
Chemokines
CCR3
Oxytocine
OTRs
Leukotriene
CysLT1R
POMCs
MC-1/MC5
Prostaglandins
EP1/EP3
Cannabinoids
CB1/CB2
Adenosine
A2b/A3
Urokinase
uPAR
Capsaicin
VR
?
PIRA/PIRB
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,
chondroitinsulfate,
chymase,
tryptase, CPA
Activation
Vasodilation
PRURITUS
ERYTHEMA
Extravasation
WHEAL
Recruitment
INFILTRATE
Urticaria – Pathogenesis
Mast cells are the key effector cells
in the induction of urticaria symptoms
C
A
U
S
E
IgE
Fcε RI
SCF
Kit
IgG
Fc γR
LPS
TLRs
Complement
CR1/2, CR3
Anaphylatoxins
C3aR, C5aR
Neuropeptides
NK1
Endothelin-1
ETA /ETB
Bacteria
CD48
Interleukins
IL-3,4,15R
Chemokines
CCR3
Oxytocine
OTRs
Leukotriene
CysLT1R
POMCs
MC-1/MC5
Prostaglandins
EP1/EP3
Cannabinoids
CB1/CB2
Adenosine
A2b/A3
Urokinase
uPAR
Capsaicin
VR
?
PIRA/PIRB
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,
chondroitinsulfate,
chymase,
tryptase, CPA
Activation
Vasodilation
PRURITUS
ERYTHEMA
Extravasation
WHEAL
Recruitment
INFILTRATE
Urticaria - Therapeutic strategies
Trigger
Cause
causal
Mast cellactivating
signal
Mast cell
activation
Mast cell
mediators
symptomatic
Urticaria
reaction
Urticaria - Therapeutic strategies
Trigger
Cause
causal
Mast cellactivating
signal
Mast cell
activation
Mast cell
mediators
symptomatic
Urticaria
reaction
Chronic Spontaneous Urticaria
Identify underlying cause
once cause is found
Treat underlying cause
Allergy 2009; 64: 1417-1426 & 1427 -1443
Urticaria - Therapeutic strategies
Trigger
Cause
causal
Mast cellactivating
signal
Mast cell
activation
Mast cell
mediators
symptomatic
Urticaria
reaction
Non sedating H1-Antihistamine (nsAH)
Allergy 2009; 64: 1417-1426 & 1427 -1443
Progress in antihistamine
development and availability
Second Generation
First Generation
<1970
Chlorpheniramine
Diphenhydramine
Hydroxyzine
1980s
1990s
Rupatadine
2003
Desloratadine
2002
Fexofenadine Levocetirizine
2002
1995
Cetirizine
1987
Ebastine
1992
Terfenadine Loratadine
1987
1979
2000+
Cold contact urticaria
Cold contact urticaria
TempTest® 3.0
Critical temperature thresholds
Improvement
P=0.0006
Baseline
Placebo
Non sedating
Antihistamine
Metz, ..., and Maurer, Ann All Asthma Immunol 2010: 104; 86-92
Critical temperature thresholds
Non-sedating AH
26
26
24
24
Temperature threshold (°C)
Temperature threshold (°C)
Placebo
22
20
18
16
14
12
10
8
6
4
22
20
18
16
14
12
10
8
6
4
2
2
0
0
Before
After
Before
After
Metz, ..., and Maurer, Ann All Asthma Immunol 2010: 104; 86-92
BUT:
<50% of urticaria patients show
complete response to nsAHs !
Non sedating H1-Antihistamine (nsAH)
If symptoms persist
after 2 weeks
nsAH updosing (up to 4x)
Allergy 2009; 64: 1417-1426 & 1427 -1443
Cold contact urticaria
TempTest® 3.0
Does updosing work?
Critical Temperature Threshold (°C)
30
25
20
15
10
5
0
Baseline
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Does updosing work?
Critical Temperature Threshold (°C)
30
25
20
15
10
5
0
Baseline
Placebo
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Does updosing work?
Critical Temperature Threshold (°C)
30
***
25
20
15
10
5
0
Baseline
Placebo
Standard dose
Non sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Updosing works!
***
Critical Temperature Threshold (°C)
30
***
***
25
20
15
10
5
0
Baseline
Placebo
Standard
4x Standard
Non sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Patient #24: Volumetric changes under treatment
Placebo
0 min
5 min
10 min
20min
Patient #24: Volumetric changes under treatment
Placebo
Standard dosed nsAH
4 x Standard dosed nsAH
0 min
5 min
10 min
20min
Wheal volume (mm³)
1200
Updosing works in cold urticaria!
Urticaria Skin Symptoms
***
***
1000
800
600
***
400
200
0
Baseline
Placebo
Standard
4x Standard
Non sedating AH
Siebenhaar, …, and Maurer. JACI 2009; 123: 672-9
Non sedating H1-Antihistamine (nsAH)
If symptoms persist
after 2 weeks
nsAH updosing (up to 4x)
If symptoms persist
after 1-4 weeks
+Leukotrieneantagonist, change nsAH
If symptoms persist
after 1-4 weeks
+H2-Antihistamine, Cyclosporine A, Dapsone, anti-IgE
Allergy 2009; 64: 1417-1426 & 1427 -1443
Reduction of disease activity
P=0.009
100
UAS7 (%)
100
100
80
72.8
60
40
27.6
20
0
Anti-IgE
Placebo
0
24
0
24
Week
Maurer et al., unpublished data
Change in disease activity
7.0
6.5
6.0
5.5
5.0
Anti-IgE
4.5
Placebo
4.0
3.5
3.0
UAS
2.5
2.0
p=0.0002
1.5
1.0
0.5
0.0
0
10
20
30
40
50
60
70
80
90
100 110 120 130 140 150 160 170 180 190
Day
Maurer et al., unpublished data
Patients without wheals (in %)
Patients with Complete Disease Control
(no more wheals …)
80
70.4
70
60
50
40
30
20
4.5
10
0
Anti-IgE
Placebo
Maurer et al., unpublished data
Quality of Life (QoL)
Improvement in QoL (in %)
70
60
55
50
50
45
40
30
20
11
10
6
6
0
Anti-IgE
Placebo
CU-Q2oL
DLQI
SKINDEX
Maurer et al., unpublished data
Use of rescue medication
Loratadine (tablets / week)
5
4
3
3.5
3.3
2.9
2
1
0.3
0
0
Anti-IgE
Placebo
24
Week
Maurer et al., unpublished data
We recommend against the long
term use of systemic cortisone.
Allergy 2009; 64: 1417-1426 & 1427 -1443
We recommend against the long
term use of systemic cortisone.
We recommend against the routine use of
old sedating first generation antihistamines.
Allergy 2009; 64: 1417-1426 & 1427 -1443
Awake
First
Generation
Antihistamine
Drowsy
Awake
Asleep
REM Sleep
delayed and
reduced
REM Sleep
Night
Day
Night
Day
Church, Maurer, ..., Zuberbier. Allergy 2010, in press
Non sedating H1-Antihistamine (nsAH)
If symptoms persist
after 2 weeks
nsAH updosing (up to 4x)
If symptoms persist
after 1-4 weeks
+Leukotrieneantagonist, change nsAH
If symptoms persist
after 1-4 weeks
+H2-Antihistamine, Cyclosporine A, Dapsone, anti-IgE
Allergy 2009; 64: 1417-1426 & 1427 -1443
Unmet Clinical Needs in Chronic
Spontaneous Urticaria - A GA2LEN
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
Chronic urticaria is
a disabling disease
Treat it until it is gone!
Allergy 2009; 64: 1417-1426 & 1427 -1443
Clinics for Mast Cell-driven Diseases
and Dermatological Allergology Lab
www.allergie-centrum-charite.de
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.