Transcript ring-Imm-Dev-AE-WAC-Cancun-2011

Immune deviation in atopic eczema is crucial
Johannes Ring,
Kilian Eyerich, Stephan Weidinger, Ulf Darsow
Klinik und Poliklinik für Dermatologie und Allergologie am
Biederstein
Technische Universität München, Munich, Bavaria, Germany
GA2LEN Center of Excellence EU frame program
Christine Kühne Center for Allergy Research and Education (CKCARE)
XXII World Allergy Congress (WAC)
Suetonius,
Vita Caesarum
„catarrhus und
Brustenge zur Zeit
der
Frühlingswinde....j
uckende
Hautstellen, mit
einem Instrument
gekratzt...“
Enkel Claudius:
Rhinonkonjunktivi
tis,
Urgroßneffe
Britannicus:
Pferdeallergie
(Ring, Hautarzt
Atopic Eczema: History
• Imperator Octavian (Augustus)
• Aetius from Amida: „ekzema“ (ek zeo = aufkochen, 600 AD)
• Mercuriali: „Lactumen“ (like burnt mild in a pot) (1571)
• Willan: „Eczema“ (1808)
• Brocq, Jacquet: „Neurodermite“ (1892)
• Besnier: „Prurigo diathésique“ (1901)
• Coca, Cooke: „Atopy“ (1923)
• Wise, Sulzberger: „Atopic dermatitis/atopic eczema“ (1933)
• Schnyder, Borelli: „Neurodermitis constitutionalis sive
atopica“ (1968)
• Atopic eczema/dermatitis syndrome AEDS (EAACI 2001)
• Eczema (WAO nomenclature 2004)
“Atopy” = Familial tendency to develop
certain diseases
(asthma, rhinoconjunctivitis, atopic eczema)
based on
hypersensitivity of skin and mucous
membranes against environmental substances
together with
increased IgE production and/or altered
non-specific reactivity
Ring J, Handbook of Atopic Eczema
1991
WAO Task Force on Allergy Nomenclature:
“Atopy” := Familial tendency to produce
IgE immune response to
low doses of allergens
and to develop
typical symptoms such as
asthma, rhinoconjunctivitis or eczema
(Johansson et al JACI 2004)
Atopic eczema: Prevalence
• 17.2% of childhood population in U.S.
Laughter et al. JAAD 2000;43:649
• 15.6% prevalence in European children
Schultz Larsen F, et al. JAAD 1996;34:760
• 24% prevalence in 56 year old Japanese
children Sugiura H, et al. Acta Derm Venereol 1998;78:293
• 6 –19 % in preschool children in Germany
Ring et al, Weißbuch Allergie in Deutschland
Hypothetical concepts to explain increase in
prevalence of atopic diseases
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
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

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Increased awareness and improved diagnostics
Psycho-social influences (acceleration of life)
Allergen exposure
Decreased stimulation of the immune system
(“jungle” or “hygiene” hypothesis)
Underlying disease
Medication (eg antacids)
Environmental pollution (tobacco smoke, traffic
exhaust)
Climate change
The Farmhouse
Story
• Protective effect for respiratory atopy,
hay fever, asthma and IgE-sensitization
(Gassner, 1981, BraunFahrländer 1999, Riedler 2000, Ernst 2000, Downs 2001)
• No protection for atopic eczema after birth
(Braun-Fahrländer 1999, Riedler 2000, Kilpelainen 2000, von
Ehrenstein 2000, Schäfer et al 2001, Ring et al 2006)
• Protective influence, when mother was working in the stable during
pregnancy
(Roduit et al, 2011)
Hygiene hypothesis does not work for atopic eczema,
only for respiratory atopy!
ETS: Atopic Eczema and Association to
Urinary Cotinine/Creatinine Ratio
MIRIAM – Study Augsburg 1996/1998
% Prevalence Atopic Eczema
8
6
6-8 years old children
N=451
Association to CCR
per 100 ng/mg
6-8 years old children
N=1132
4
N=673
4
2
2
0
6
OR (95%CI)
1
total
Parents
without Atopy
6 yrs old children
Parents
with Atopy
0
total
Parents
without Atopy
Krämer et al, Br J Dermatol (Dec) 2003
Parents
with Atopy
Traffic exposure and Allergy: Own Studies
WIKA Study NRW 1991-1997
3
Symptome einer
allergischen
Rhinitis
500
4
%-Anteil Mädchen mit
Pollen- Sensibilisierung
4
Sensibilisierung (RAST)
gegen Pollen
500
(Birke, Gras, Beifuß)
MIRIAM Augsburg 1996
3
490
2
490
2
371
371
245
1
245
1
0
40
30
20
10
339
0
<4000 Kfz
0
>=50m
Essen/ Köln
<50m
>=50m
Borken
<50m
>=50m
<50m
Essen/ Köln
>=50m
341
>4000 Kfz
>10000 Kfz
Verkehrsstärke
Borken
Traffic exposure study Düsseldorf
1996
Hellerhof
Düs s eltal
Friedrichs tadt
70
% symptoms / sensitizations
<50m
433
60
50
40
30
20
10
0
40
45
50
55
60
NO2 outdoor [µg/m]³
65
70
Determinants of Allergic Inflammation
adjuvant
Genetic susceptibility
causative
Adjuvant Factors:
DEP, VOC, Ozone, ETS
Lack of
Protective Factors
infection
vaccination
nutrition
Allergen-
Allergic Sensitisation
exposure
Hyperreactivity
Airway / Skin
Air Pollution
Irritant Gases, ETS
Exercise
Infection
Allergic Diseases
Behrendt, 2000
Pathogenesis of atopic eczema
Genetic background
Environment
Disturbed skin barrier
Physical factors: Heat, sweating
Psychosomatic
influence
Allergens/ Haptens, Irritants
Immune deviation
Microorganisms
(Malassezia furfur, Staph. aureus)
Disturbed barrier, elevated
TEWL, Xerotis cutis
Itch /scratch, hyperreactive
Immune system
Superinfection
(Impetigo, Eczema herp.)
Atopic eczema: diagnostic criteria
•1980 (Hanifin and Rajka): diagnostic criteria based on
„major“ and „minor“ clinical features
•1994 (Williams et al): UK working party‘s diagnostic
criteria
•1982 (Ring) quoted in
„Allergy in practice“,
Springer, Berlin 2005
Diagnosis of atopic eczema
(4 out of 6 positive, Ring 1982)
•
Typical morphology (IE, L, P) and age –
dependent localization
•
•
•
•
Early onset and chronic/relapsing course
Pruritus
Stigmata
Personal and/or family history of atopy
•
IgE-Sensitization (SPT or RAST)
Atopic eczema is typically the first manifestation
of atopy
Atopic
eczema
Food allergy
Asthma
Rhinitis
0
5
Age (Years)
10
15
IgE levels in blood
Atopic eczema is (in most cases) the first manifestation of the atopic disposition
Atopic eczema: Etiopathophysiology
•
•
•
•
•
•
Genetic background
Dry skin / defective barrier
Microbial colonization
Autonomic nervous system dysregulation
Psychosomatic interaction
Inflammation:
Non-immune (irritant)
Allergic DTH (Th1)
Allergic atopic (Th2, IgE)
Autoimmune (IgE against epidermal proteins)
Effects of epidermal barrier disturbance
Allergens
P
P
HDM
P
P P
P
P
P
S.aureus
LC
Th1
Th2
IL-4
B
IL-13
Atopic Diseases and IgE Sensitization
Asthma
Atopic
Eczema
Rhiniti
s
Ig
E
Atopic Eczema: Immunological findings
• Increased serum total IgE
• Specific IgE-Antibodies against common environmental
allergens
• Often positive Prick-Test-Reactions
• Tendency to microbial colonisation and infection
• Increased number and activation of eosinophile
leukocytes in blood and tissue
• Decreased cellular (Th1) immunity („minimal cutaneous
immunodeficiency“)
• Altered prevalence rates of contact allergies (allergenspecific?)
Th1/Th2-Hypothesis
Individuals with a Th2 phenotype disease
(such as atopic eczema or allergic
asthma)
are relatively protected against
development of Th1 phenotype disease
(such as diabetes mellitus, rheumatoid
arthritis or psoriasis)
Psychoneuroimmunology
Neuroendocrine System – Immune System Interactions
Hypothalamus
CRH, GHRH TRH,
LHRH
Pituitary
GH
PRL
TSH
endorphin
s
FSH
LH
Gona
ds
oestradiol
ACTH
Adren
corticol
als
testosterone
Central and
peripheral
lymphoid organs
Kuper CF et al, 2002
epinephin
e
Mechanisms of disturbed skin barrier function
• Abnormal lipid patterns (eg ceramides)
• Abnormal lipid synthesis and metabolism
(eg sphingomyelinase, glucocerebrosidase)
• Increased protease activity (eg SCCE)
• Serin protease inhibitor defect (eg LEKTI 1)
• Structural mutations (eg filaggrin, hornerin?)
Allergen uptake: Summary
Epithelial alteration
Transcytosis
(Processing)
Paracellular transit:
Enhanced uptake
Transcellular transport
Atopy patch test (APT)
•
•
•
•
Epicutaneous patch test with allergens known to elicit IgE-mediated
reactions, for the provocation of eczematous skin lesions due to these
allergens
Ring J et al. JACI 1989; 82: 195
House dust mite patch tests in atopic eczema
Mitchell E et al. Lancet 1982; 1: 127-130
Aim: evaluation of the clinical relevance of (multiple) IgE-mediated
sensitizations in patients with AE
Controlled model for inflammation in AE
Atopy Patch Test (APT): method
(European Task Force Atopic Dermatitis ETFAD)
•
•
•
•
•
•
Patients in remission phase
Lyophilized aeroallergens (house
dust mite, cat dander, grass and
birch pollen)
Allergen doses: 5.000-7.000 PNU/g
or 200 IR/g
Vehicle: petrolatum, Large Finn
Chambers
Application for 48 h on clinically
uninvolved, not pretreated back skin
(no tape stripping)
Evaluation after 48 and 72 h
(ETFAD key*),
Exclusion of questionable reactions
* Darsow, Ring. Clin Exp Dermatol 2000; 25: 544-551 / Allergo J 2001; 10: 201-209
Atopie-Patch-Test: 48 h
Contro
l
Grass
pollen
D. pter.
Cat
Allergen 200 IR/g in Vaselin
Contro
l
APT in Europe
Diagnostic methods for relevance of
aeroallergen sensitization
Test




D. pter.
Cat dander
Grass pollen
Birch pollen
Sensitivity
Specificity
SPT
sIgE
APT
SPT
sIgE
APT
68%*
79%*
80%*
69%*
72%*
80%*
84%*
73%*
45%
14%
28%*
15%
50%*
71%*
54%*
57%*
53%*
69%*
53%*
52%*
64%
91%
91%*
83%
Referring to predictive history of eczema exacerbations in pollen
season, or in direct contact with allergen, n = 314
* Agreement with history (2-sided Pr > |Z| < 0.01)
Number of grass pollen
150
0
May
1999
0.2
0.1
100
0.0
-0.1
50
-0.2
Jun
1999
Jul
1999
Aug
1999
-0.3
/ xtent of atopic eczema
Itch e
mean deviations from individual means
0.3
Life of „atopic“ skin lesions
• Initiation
Th 2
• Chronification
Th 1
• Perpetuation
Autoimmune
IgE-reactive Autoallergens in Human
Epidermis
Homologues
Hom s 1
SART-1
Hom s 2
a-NAC
Hom s 3
Bcl 7 b
Hom s 4
Calcium binding protein
(Esophageal Ca. Ag)
(nascent peptide associated complex)
Evidence-Based Treatment of
Atopic Eczema
Treatment of disturbed skin
barrier
• Emollients, barrier –
repairing agents
Antiinflammatory treatment
(topical)
• Corticosteroids
• Calcineurin inhibitors
Antimicrobial treatment
Darsow et al
JEADV 2009
Phototherapy
• UVA-1
• UVB
• PUVA
Systemic
Immunosuppressives
• Antihistamines
Educational Programs
Guidelines for diagnosis and treatment of
atopic eczema: EADV Eczema Task Force
Darsow U et al. JEADV 2010; 24: 317-328
Atopic Eczema: Management
Diagnosis
• Disease
• Elicitors/trigger factors (=allergy diagnosis)
• Severity
Treatment
• Avoidance strategies
• Basic skin care (Emollients, oilbaths)
• Antipruriginous (wet wraps, antihistamines)
• Antiinflammatory (steroids, UV, topical
immunomodulators)
• Antimicrobial (colourings, antiseptics, antibiotics)
• Psychosomatic counselling
Atopic eczema:
Avoidance strategies
• Irritants (e.g. clothing)
• Aeroallergens (e.g. encasings)
• Food allergens, pseudoallergens (e.g. diet)
• Microbial antigens (superantigens)
• Climate therapy (high altitude, sea-level)
• Psychosomatic counselling
Davos,
Progress in Allergy, Dermatology and Immunology
Congress 8 – 10 September 2012
Atopic eczema management:
3 Step Schedule
• Acute antiinflammatory treatment
• Special treament of chronic lesions
• Identification of individual provocation factors
(Allergy Diagnostics) and specific avoidance
recommendations
Topical glucocorticosteroids in atopic
eczema
•
•
•
•
•
•
Hydrocortisone
Fluocortinbutyl ester
17-Hydroxycortisone butyrate
Prednicarbate
Methylprednisolone aceponate
Momethasone furoate
• In infected skin: combined with
antiseptics or antibiotics
Immunosuppressives / Immunomodulators
Systemic
Azathioprine
Mycophenolate Mofetil
Interferon
Biologics (anti-IgE, anti-IL 5)
Cyclosporin A
Sirolimus
Topical Calcineurin Inhibitors
Tacrolimus
Pimecrolimus
Structure of eczema school
l
Six weekly meetings of 2 h each
(eg Wednesday 19.00 – 21.00)
l
Group size maximum of 6
parents/children/adolescents
l
Interdisciplinary team consisting of
Dermatologist / Pediatrician, Psychologist, Nurse,
Nutrition expert
Contents of Training Program
"medical"
clinical picture, etiology, pathophysiology
skin care/treatment: emollients, non-steroidal
ointments, antibiotics, steroids, complications
complementary therapies
provocation factors and avoidance
"psychosocial"
self-perception, itching-scratching behaviour
improvement of self-efficacy, adequate coping
stress reduction, relaxation techniques
social competence training
"nutrition"
adaequate nutrition in children
diagnostic and therapeutic diets
"train the trainer"
• Block 1
30 h: Medizin, Psychologie, Pädagogik,
Ernährung
• Block 2
10 h: Teilnahme an einer Schulung, eine
Sitzung mit Supervision
www.disa.de (allinfo, AG- Neurodermitis)
Concept of eczema school
Active Coping
Improved QoL
Better skin condition
Knowledge
Behaviour
Perception
Interdisciplinary Teamwork
TOPICAL AND
SYSTEMIC
TREATMENT
dermatologist
pediatrician
dietician
IDENTIFICATION
OF PROVOCATION
FACTORS
Practical
management
NUTRITION
HABIT
REVERSAL
TECHNIQUES
qualified
nurse
psychologist/
psychotherapeutic
medicine
SELFMANAGEMENT
RELAXATION
TECHNIQUES
The A B C of
patient management in allergy
(Ring 2006)
•
•
•
•
•
A
B
C
D
E
=
=
=
=
=
Avoidance strategies
Basic antiinflammatory treatment
Care (skin, airways)
Direct symptom relief
Empowerment of patient (Educational
programs eg „Eczema school“)
Trust yourself and your suggestive power!
• Talk more about desired effects than about side-effects
• Give hope
• Illustrate your message with real experience – even if
only anecdotal
• Motivate patient to take own responsibility
(„you will be your own skin doctor“)
• Turn off the clock!
Thanks to
Heidrun Behrendt
Carsten Schmidt-Weber
U. Darsow
K. Brockow
K. Eyerich
J. Gutermuth
M. Mempel
M. Ollert
F. Pfab
C. Schnopp
C. Traidl-Hoffmann
S. Weidinger
7th Georg Rajka
International Symposium
on Atopic Dermatitis,
Moshi, Tansania
15 – 18 January 2012