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

Atopic urticaria: Different phenotypes and diverse treatment

Marcus Maurer

Allergie-Centrum-CharitéDepartment of Dermatology and Allergy

Charité - Universitätsmedizin Berlin

Urticaria

Wheal and flare Angioedema

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

EAACI / GA 2LEN / 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

PRURITUS

ERYTHEMA

WHEAL

INFILTRATE

Urticaria – Pathogenesis

Recruitment

Extravasation

Vasodilation

Activation PRURITUS

ERYTHEMA

WHEAL

INFILTRATE

Urticaria – Pathogenesis

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

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

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

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

Trigger

CauseMast cell-activating

signal

Mast cellactivation

Mast cellmediators

Urticaria reaction

causal symptomatic

Urticaria - Therapeutic strategies

Trigger

CauseMast cell-activating

signal

Mast cellactivation

Mast cellmediators

Urticaria reaction

causal symptomatic

Urticaria - Therapeutic strategies

Identify underlying cause

once cause is found

Treat underlying cause

Chronic Spontaneous Urticaria

Allergy 2009; 64: 1417-1426 & 1427 -1443

Trigger

CauseMast cell-activating

signal

Mast cellactivation

Mast cellmediators

Urticaria reaction

causal symptomatic

Urticaria - Therapeutic strategies

Non sedating H1-Antihistamine (nsAH)

Allergy 2009; 64: 1417-1426 & 1427 -1443

Progress in antihistamine

development and availability

ChlorpheniramineDiphenhydramine

Hydroxyzine

Terfenadine1979

Second Generation

First Generation

Desloratadine2002

Levocetirizine2002

Ebastine1992

Fexofenadine1995

Loratadine1987

Cetirizine1987

<1970 1980s 1990s 2000+

Rupatadine2003

Cold contact urticaria

TempTest® 3.0

Cold contact urticaria

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

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

BUT:

<50% of urticaria patients show

complete response to nsAHs !

Non sedating H1-Antihistamine (nsAH)

nsAH updosing (up to 4x)

If symptoms persistafter 2 weeks

Allergy 2009; 64: 1417-1426 & 1427 -1443

TempTest® 3.0

Cold contact urticaria

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

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?

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?

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!

Patient #24: Volumetric changes under treatment

0 min 5 min 10 min 20min

Placebo

Patient #24: Volumetric changes under treatment

Standard dosed nsAH

4 x Standard dosed nsAH

0 min 5 min 10 min 20min

Placebo

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

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

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

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

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

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

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

We recommend against the longterm use of systemic cortisone.

Allergy 2009; 64: 1417-1426 & 1427 -1443

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

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

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

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

Chronic urticaria is

a disabling disease

Treat it until it is gone!

Allergy 2009; 64: 1417-1426 & 1427 -1443

www.allergie-centrum-charite.de

Clinics for Mast Cell-driven Diseasesand Dermatological Allergology Lab

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.