Atopic Dermatitis

Atopic Dermatitis
Prof. Dr. Petr Arenberger
Hallmarks of Atopic Dermatitis
Picture
Picture
¾ Eczema: chronic, relapsing
skin inflammation,
¾ Dry Skin: disturbance of
epidermal-barrier function
¾ Pruritus
¾ IgE-mediated sensitization to
food & environmental allergens
¾ Histology
• Spongiosis
• Perivascular infiltrate: of Ly,
Mono, MΦ, DC, Eo.
Atopic Dermatitis
GENETIC
FACTORS
Immunesystem
Environement,
Allergens,
S. Aureus, Stress
Autoallergic
AD
Innate/adapive
Immunity
Atopic
Dermatitis
Epidermal
Structure
Barrier
Dysfunction
Eczema
Pruritus
Scratching
Tissue
damage
Genetics of Atopic Dermatitis
¾ Chr 1q2: epidermal differentiation complex
¾ Chr 1q21.3: Filaggrin
¾ Chr 5q31-33: IL-4, -5, -12, -13, GM-CSF
¾ Chr 11q22: IL-18
¾ Chr 17q11: RANTES
¾ Chr 16q12: IL-4Rα
Atopic Dermatitis
¾ Immunopathogenesis
¾ Barrier Dysfunction
¾ Pruritus
Non-lesional skin in atopic eczema:
Evidence for Inflammation
¾ Hyperkeratosis and
epidermal Hyperplasia
¾ Intercellular Edema
¾ Thickening of BM
¾ Ç TEWL
¾ È Lipids (z.B. FFA)
¾ Slight dermal infiltrate (Ly)
¾ Langerhans-cells (Ç highaffinity IgE-Receptors)
Mihm jr. MC, Soter NA, Dvorak HF, Austen KF. J Invest Dermatol 1976; 67: 305-12
Wollenberg A, Bieber T. Allergy 2008; 276 - 278
Immunopathogenesis of Atopic Dermatitis
Epidermal-barrier
dysfunction
TSLP
Pollen
Th17?
Bieber T. N Engl J Med 358, 1483, 2008.
Possible Autoimmune-pathogenesis of AD
Tissue Damage, Antigen
Proteases
Histamin
Autoantigen (Hom S1-5)
Mast
LC
Valenta et al. FASEB 1998.
Valenta et al. J Allergy Clin Immunol 2000.
Altrichter et al. J Invest Dermatol 2008.
T
T
T
T
Th1/17
Atopic Dermatitis
¾ Immunopathogenesis
¾ Barrier Dysfunction
¾ Pruritus
The skin as a barrier
Classic „brick and mortar“ arrangement
Stratum corneum
Stratum granulosum
K
Stratum spinosum
Stratum basale
Corneodesmosome
Desmosome
K
Keratohyalin granule (Filaggrin)
Lipid layer
Filaggrin in atopic
dermatitis
J Allergy Clin Immunol 2006;118: 214.
Nature Genetics 2006;38: 441.
O’Regan GM et al. JACI 2008
Nature Genetics online 2007
Absence of Filaggrin leads to dermatological
conditions with exteme skin dryness
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Atopic
Dermatitis
Picture
Ichthyosis
vulgaris
Atomic Force Microscopy (AFM)
Tape stripping
¾ morphology (nm-resolution)
¾ localized cell stiffness
¾ inter-molecular force (pN)
Schneider S.W. et al. PNAS 1997 and 1999
Schneider S.W. et al. Methods Mol Med 2004
NanoLab – Dermatology Münster
Stefan W. Schneider and Thomas A. Luger
AFM of normal & atopic non lesional skin
Normal Skin
Atopic non lesional Skin
¾ Nanostructure,
adhesion- & elasticity
properties on nativ
skin
¾ Atopic skin:
- more „globular“
structures, less cellcell integrity
- tendency to show
more „clefts
Gorzelanny C. et al Exp Derm 2006
Skin Barrier Dysfunktion
¾ Filaggrin
Hydration ↓
¾ Proteases
SCCE, KLK7 
(Corneodesmosoms ↓)
¾ Protease Inhibitors
SPINK 5↓
¾ Lipids ↓
Stratum corneum
K
Stratum granulosum
Stratum spinosum
Stratum basale
Corneodesmosom
Desmosom
Keratohyalin Granule (Filaggrin)
Lipidlayer
Barrier Deficiency
(Filaggrin, Proteases,…)
Cracks in the stratum
corneum due to dryness
facilitate invasion of
¾ Allergens
¾ Irritants
¾ Microrganisms
Inflammation
Eczema
Pruritus
Atopic Dermatitis
¾ Immunopathogenesis
¾ Barrier Dysfunction
¾ Pruritus
Pruritus: Neuroreceptors & Mediators
Neuropeptides:
Pro-Pruritoceptive:
H1
Histamin
TRPV1 Vanilloid
PAR2 Tryptase
Kallikreins
EA/EB Endothelin
Substance P,
NKA, VIP, CGRP
Neurotensin,Secretin
CGRP
Contra-Pruriceptive:
TRPM8 Cold, Menthol,
Icilin
CB1/2 Cannabinoids
MOR Opioids
Prurigo
Mediators
IL-31,
IL-2, 4, 6, 31, TNFα
Leucotriens
Gastrin (Bombesin)
Bradykinin
Prostaglandins
NGF, Epinephrin
Pruritus
¾ Interleukin 31
¾ TRPV1 (Vanilloid Receptor)
Interleukin 31
¾ Location: 12q24.31
¾ Physical properties: 18 kDa 164 aa
¾ Source: Th2 cells; CD45RO+/CLA+
¾ Inducer: Staphylococcal superantigen
¾ Receptor: heterodimer of IL31RA & OSMR
monocytes, keratinocytes;
epithelial cells, dorsal root ganglia
¾ Activating STAT1, STAT3 and STAT5
Quantitative real-time PCR analysis of IL-31
mRNA expression in human skin lesions
Healthy skin
Psoriasis
AD non-lesional
AD lesional
Prurigo nodularis
Sonkoly E et al. J Allergy Clin Immunol 117, 411, 2006.
Interleukin-31
A new link between T-cells & pruritus
Pruritus
Cortex
IL-31 RA
Keratinocyte
Allergen
Spinal cord
DRG
IL-31
Superantigen
CLA+TH2
C-fiber
IL-31 RA
Dendritic cell
IL-31 RA
Staphylococcus aureus
Sonkoly A, … Steinhoff M, …, Homey B: J All Clin Immunol 2006;
Homey B, Steinhoff M et al. : J All Clin Immunol 2006
IL-31 – Role in AD
¾ IL 31 is produced by skin homing T-cells
¾ SEB upregultes T-cell IL 31 production
¾ IL 31 overexpression → Eczema, Itch (AD)
¾ IL 31 upregulated in pruritic skin lesions
¾ IL 31RA is expressed in DRG‘s
IL 31: a new target for the development
antiinflammatory & antipruritic drugs
Exp Dermatol. 18, 35-43, 2009.
(10mg/kg)
Pruritus
¾ Interleukin 31
¾ TRPV1 (Vanilloid Receptor)
Transient receptor potential channel superfamily
Ankyrin
Polycystin
Mucolipin
Vanilloid
‚NOMPC‘
Canonical
Melastatin
¾ Family of ion chanels (Ca2+)
¾ 7 main subfamilies
¾ 6 transmembrane segments, a
pore-forming loop (between S5 & S6),
intracellularly located NH2 and
COOH termini
¾ TRPV1: Heat, pH, Vanilloids,
Eicosanoids
¾ TRPV2: Heat, Mechanical, GF
¾ TRPM1: Melastatin (Melanoma ↓)
¾ TRPM8: Cold, Menthol, Icilin
¾ TRPA1: Mechanical, Bradykinin
Nilius B et al Physiol Rev 87: 165-217, 2007.
TRPVR1 is present on sensory nerve fibers
Epidermis
VR1
Substance P
¾ Mast cells
¾ Keratinocytes
Composite
Biological Functions of TRPV1
¾ Heat > 43ºC
¾ Protons [H+]
¾ Capsaicin
¾ Calcineurin Inhibitors
Pain
Pruritus
Inflammation
Vasodilatation
Neurokinin
Receptors (NKR)
Tachykinins:
Substance P
Release ⇧
Reacumulation ⇩
E. Senbaa et al. 2004, M. Steihoff et al 2006
Treatment of Atopic Eczema
a unique challenge
¾ Enormous psychosomatic
disease burden
¾ Often undertreated due to
safety concerns
¾ Patient dissatisfaction with
conventional therapy
3,0
age--adjusted
adjusted))
Family scores (age
¾ Lack of safe and effective
long-term disease
management
Paediatric atopic eczema
vs. diabetes mellitus:
The impact on the family
2,5
2,0
1,5
1,0
0,5
0,0
severe moderate mild
diabetes
eczema eczema eczema
(n=10)
(n=20) (n=18)
(n=46)
Adapted from Su JC et al. Arch Dis Child 1997;76:159–
1997;76:159–62
Atopic Dermatitis
Current Management
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Symptomatic disease
adapted treatment
¾ Education & prevention
¾ Adjuvant basic therapy
¾ Disclosure & avoidance of
trigger factors
¾ Anti-inflammatory
measurements
Allergy Prevention – Novel Aspects
Muche-Borowski et al, J Allergo J 2009; 18: 332–341; Dt Ärzteblatt 2009; 39:625-631
¾ Rejection of the previously recommended practice
of „very carefully“ exposing allergy-prone infants to
additional foods during the 1st year after end of
lactation.
¾Time window for induction of oral tolerance during
the 5th to 12th month is particularly favorable.
¾ Conclusion: Relief in the diet of allergy-prone
children in the 1st year of life.
1
Treatment Algorithm
Adjuvant basic
therapy
Emollients
AD - management:ICCAD II consensus statements: Ellis C, Luger T. International Consensus Conference on
Atopic Dermatitis II (ICCAD II) Clinical update and current treatment strategies. Br J Dermatol 2003;148: S3.
Good skin care is the first step in
the control of atopic eczema
Xerosis
‘dry skin ‘only
AD: Filaggrin loss of function mutations
Emollients
Moisturize
Maintain hydration
Relieve inflammation
Relieve pruritus
Reduce the need for CS
Sandilands et al, Nature Genetics 2007; 39:650-654
Habif TP, ed. Clinical Dermatology. Mosby 1996. Linde YW. Acta Derm Venereol Suppl 1992;177:9–13
Treatment Algorithm
Acute control of pruritus and
inflammation
¾Topical corticosteroids or
¾Topical calcineurin inhibitors
–Pimecrolimus bid or
–Tacrolimus bid
AD - management:ICCAD II consensus statements: Ellis C, Luger T. International Consensus Conference on
Atopic Dermatitis II (ICCAD II) Clinical update and current treatment strategies. Br J Dermatol 2003;148: S3.
Topical Corticosteroids:
ICCAD II Consensus Statements
¾Topical corticosteroids provide effective
acute control but provoke safety concerns,
particularly when used continuously
¾Patients do not always use steroids as
prescribed by their physician
Tacrolimus vs Pimecrolimus
Tacrolimus ointment: 0.03%
0.1%
Pimecrolimus Cream: 1.0%
¾Tacrolimus 0.03% = Pimecrolimus 1%
¾Tacrolimus 0.1% > Pimecrolimus 1%
Atopic Dermatitis
Treatment with Pimecrolimus Cream
Picture
Before Therapy
Picture
After 10 Days
Efficacy of Pimecrolimus after
pretreatment with topical steroids
Höger et al, Br J Dermatol 2009; 160:415-422.
¾ Children with head and neck eczema who are
intolerant of, or dependent on topical steroids.
¾ Pimecrolimus was effective and safe in
managing sensitive skin AD in those patients.
¾ Pimecrolimus appears to improve skin atrophy.
Topical Calcineurin Inhibitors:
Conclusions
¾ Effective short- & long-term treatment for
AD in adults & children.
¾ No impairment of the barrier function.
¾ No skin atrophy.
¾ No evidence for a causal link between the
use of TCI`s and the occurrence of
lymphomas or skin tumors.
AD - Proactive Treatment
Median time to first flare is significantly longer
CONTROL-Studies
Adults: 15
reactiv
Children: 26
25
Proactiv
Tac 2x/wk
50
75
Adults: 142
Children: 144
Days
Wollenberg A, Reitamo S, Girolomoni G, et al. (2008) Allergy 63: 742-50
Astellas Pharma EU. Data on file 2007: FG-506-06-41
100
125
150
Atopic Dermatitis
Tacrolimus 0.1% ointment
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Before therapy
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After therapy (6 mo)
Intermittent topical
anti-inflammatory therapy
Werfel et al, JDDG 2009; Suppl 1:S1-46, Wollenberg at al, Allergy 2008; 63:74250, Thaci et al, Br J Dermatol 2008; 159:1348-1356, Paller et al. Pediatrics 2008;
122:1210-1218.
¾ Intermittent therapy with topical Corticosteroids for
several months after clearence of atopic dermatitis
is effective and recomended.
¾ Intermittent topical therapy with Tacrolimus
(„proactive therapy”) is effective in children as well
as adults with atopic dermatitis.
10-12
Treatment algorithm
Emollients, education
Adjunctive
therapy
Acute control of pruritus and inflammation
Disease
remission
(no signs or
symptoms)
Flare
‹ Topical
corticosteroids or
a
‹ Topical calcineurin inhibitors
– Pimecrolimus bid or
– Tacrolimus bid
a
Always read the label
¾
Avoidance of
trigger factors
¾
Bacterial
infections:
antibiotics
¾
Viral infections:
Antiviral therapy
¾
Psychological
interventions
¾
Antihistamines
AD - management:ICCAD II consensus statements: Ellis C, Luger T. International Consensus Conference on
Atopic Dermatitis II (ICCAD II) Clinical update and current treatment strategies. Br J Dermatol 2003;148: S3.
Malassezia-Spezies - Trigger for AD
Darabi et al, J Am Acad Dermatol 2009; 60:125-136
¾ Association of Head & Neck Dermatitis with positiv
Prick-test or specific IgE-Ab for Malassezia-spezies.
¾ Head and Neck Dermatitis is associated with an
increased risk for Malassezia-Allergie; Distinct and
therapy refractory lesions during several atopic
diseases.
¾ Improvement of atopic dermatitis during antimycotic
therapy in clinical stidies (topical Ciclopirox;
systemic Ketoconazol or Itraconazol)
7
Malassezia-Spezies - Trigger for AD
Darabi et al, J Am Acad Dermatol 2009; 60:125-136
Picture
Before
Picture
After 8 weeks
100mg Itraconazol daily for 4-8 weeks, followed by
100mg Itraconazol 2 x / week
7
J Allergy Clin Immunol 2007;119:1174-80.
Conclusion: Although a preventive effect of probiotics
on infant eczema was not confirmed, the treated
infants had less IgE associated eczema at 2 years of
age and therefore possibly run a reduced risk to
develop later respiratory allergic disease. Clinical
implication: Probiotics may reduce the incidence of
IgE-associated eczema in infancy.
Treatment algorithm
Severe refractory AD
¾ Phototherrapy
¾ Potent topical CS
¾ Oral Cyclosporine
¾ Methotrexate
¾ Oral Steroids
¾ Azathioprine
¾ Psychotherapeutics
AD - management:ICCAD II consensus statements: Ellis C, Luger T. International Consensus Conference on
Atopic Dermatitis II (ICCAD II) Clinical update and current treatment strategies. Br J Dermatol 2003;148: S3.
¾9 controlled clinical trials.
¾Phototherapy with medium-dose (50 J/cm2) UVA1, if
available, should be used to control acute flares of AD
¾UVB modalities, specifically narrow-band UVB, should
be used for the management of chronic AD.
¾ 27 studies with a total of 979 patients.
¾ 11 studies showed efficacy of cyclosporine.
¾ Cyclosporine is recommended as first option for patients
with AD refractory to conventional treatment.
¾ Evidence from controlled trials exists for IFNγ and AZA.
¾ Systemic cocorticosteroids have not been assessed
adequately in studies.
¾ Mycophenolate mofetil was effective in 2 small studies.
¾ IVIG, Omalizumab, Alefacept, & Infliximab can not be
recommended.
Atopic Eczema – CsA (5mg/kg)
Picture
Before
Picture
After 4 weeks
Treatments producing poor or
unproven efficacy
¾Leucotriene antagonists
¾Antihistamines
¾Homeopathy
¾Cromoglycate
¾Ketotifen
¾Fish oil, Evening Primrose oil,
ω-3 series EFA
¾Oolong tea
ICCAD - AD Treatment Paradigms
Oral
rescue
Med.
In
te
ns
i ty
of
di
se
as
e
Step IV
Step II
Step IIIb
Step IIIa
TCI
Tac 0.1%
+
TCS
TCI Tac 0.1% ; Pim 1% (+CS)
TCI Pim 1%; Tac 0.03%
Start at first signs or symptoms
Step I Emollients
TCI: Topical Calcineurin Inhibitor
TCS: Topical Corticosteroid
Conclusion
¾ In the absence of a cure, early effective
treatment (proactive therapy) should be initiated
to reduce the signs, symptoms and recurrences,
and prevent progression of the disease.
¾ Trigger factors such as stress, irritants, microbes
and allergens should be identified and avoided.
¾ The emphasis should be on long-term control,
not just reactive management of relapses.
AD - management:ICCAD II consensus statements: Ellis C, Luger T. International
Consensus Conference on Atopic Dermatitis II (ICCAD II) Clinical update and current
treatment strategies. Br J Dermatol 2003;148: S3−10.
AD Treatment guidelines
Ellis C, Luger T. International Consensus Conference on AD II (ICCAD II)
Clinical update and current treatment strategies. Br J Dermatol 148, S3, 2003.
J Allergy Clin Immunol 118, 152, 2006.
JDDG, 7, S1 – S46, 2009.
AD Therapy: Novel developments
¾ Antihistamins: H4 blockers
¾ Corticosteroids: SEGRA
¾ HuMoAbs/FPs (IL-31,...)
¾ PAR 2 Antagonists
¾ TRP Ant/Agonists (TPRV1)
¾ Neuropeptides (SP, MSH...)
IL-31 – Role in AD
¾ IL 31 is produced by skin homing T-cells
¾ SEB upregultes T-cell IL 31 production
¾ IL 31 overexpression → Eczema, Itch (AD)
¾ IL 31 upregulated in pruritic skin lesions
¾ IL 31RA is expressed in DRG‘s
IL 31: a new target for the development
antiinflammatory & antipruritic drugs
Exp Dermatol. 18, 35-43, 2009.
(10mg/kg)
Prurigo nodularis
Overexpression of Substance P
Picture
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SP
Aprepitant (Emend)
¾ Neurokinin 1 Receptor
(NK1R) Antagonist.
MW 534.4
¾ NK1R is expressed in
CNS and PNS.
¾ Substance P (SP) is
the Ligand of NK1R.
¾ Antiemetic Drug.
Aprepitant - Pruritus
• 21 patients with pruritus
• 80 µg 1x / day / 1 week)
¾ 18/21 (85,7%) patients: CR oder PR.
¾ 3/21 (14.3%) non-responders.
¾ 65% medium decrease of pruritus.
Aprepitant: a novel strategy for the
treatment of Pruritus & Eczema
¾ Very good response
Prurigo nodularis – Atopic Dermatitis
Pruritus - Atopic Dermatitis
Pruritus - Lactoseintolerance
¾ Weak response
Pruritus & Prurigo - renal insufficiency
¾ Future: - Controlled clinical trials
- Long-term management
- New NKR Antagonists