The Atopic Dermatitis Pathogenesis, and Implications for Alopecia Areata Emma Guttman-Yassky, MD PhD Sol and Clara Kest Professor, and Vice Chair Dermatology, Icahn School of Medicine at Mount Sinai Medical Center, NY President, International Eczema Council Not for Distribution
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The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E.
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The Atopic Dermatitis Pathogenesis, and Implications for Alopecia Areata
Emma Guttman-Yassky, MD PhDSol and Clara Kest Professor, and Vice Chair
Dermatology, Icahn School of Medicine at Mount Sinai Medical Center, NY
President, International Eczema Council
Not for Distribution
Atopic Dermatitis
Most common inflammatory skin disease (3-7%of adults, 15-25% of children)
20-30% of patients have moderate-to severedisease
Large Unmet Need for long-term disease control
The therapeutic drought is finally ending!
Not for Distribution
AD Has A Complex Multifactorial Pathogenesis
AD PathogenesisType 2 (Th2)(IL-4, IL-13, IL-5, IL-31)
Th22 (IL-22)
“Inside-Out” “Outside-In”
EpithelialDefects
GeneralInflammation
Th2 and Th22AdaptiveImmunity
Microbiome
Itch
Skin BarrierDefects
BarrierHypothesisImmune Hypothesis
Modified with Permission from Beck LA
Not for Distribution
The abnormal epidermal phenotype in lesional AD skin is initiated by increased expression of cytokines that induce the epidermal abnormalities
AD is a disease of fixed (genetic) epidermal barrier defects that may trigger abnormal keratinocyte hyperplasia and secondary immune activation*Supported by the FLG gene mutation in 2006.
Two Proposed Pathogenic Hypotheses
Immune-based model (“Inside-out”)
Epidermal-based model (“Outside-in”)
1. Leung DYM, et al. J Allergy Clin Immunol. 2014;134(4):769-779. 2. Barker JN, et al. J Invest Dermatol. 2007;127(3):564-567. 3. Woźniak M, et al. Postepy Dermatol Alergol. 2016;33(2):128-133. 4. Palmer CN, et al. Nat Genet. 2006;38(4):441-446. 5. Suárez-Fariñas M, et al. J Allergy Clin Immunol. 2011;127(4):954-964. 6. Dhingra N, et al. J Invest Dermatol. 2014;134(8):2071-2074.
• 1. Guttman-Yassky E. New frontiers and pivotal clinical advances for the pathoimmunobiology of atopic dermatitis. The translational path in atopic dermatitis and the implications for dermatology practice. http://clinicalwebcasts.com/slidecasts/2017/ISDS_Atopic_Dermatitis_SlideCAST-285.pdf. Accessed August 2, 2018.
Lichenification: Epidermal hyperplasia characterizes chronic lesional AD skin
Barrier Defects in AD (and Clinical Correlations)Not for Distribution
Terminal Differentiation, Tight Junction, and Lipid Defects
Guttman-Yassky, et al
J Allergy Clin Immunol 2009
De Benedetto A et al JACI
2011; 127: 773-786
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De Benedetto A et al JACI 2011; 127: 773-786
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The Type 2 Cytokines IL-4 and IL-13 Downregulate Epidermal Differentiation Proteins In Vitro
Howell MD et al. J Invest Derm 2008;128:2248–2258; Kim BE et al. Clin Immunol 2008;126:332–337.
Filaggrin Loricrin Involucrin
Not for Distribution
IL-22 promotes hyperplasia and impairs
terminal differentiation
Nograles KE et al, British Journal of Dermatology, 2008
Full thickness skin rafts (epidermis + fibroblasts/dermis)
*S100As FCH
S100A7 psoriasin 458.87
Terminal Differentiation
LOR Loricrin 0.084
FLG Filaggrin 0.032
CALML5 Calmodulin 5 0.326
KRT1 keartin 1 0.022
KRT10 keratin 10 0.499
Genes up/down-regulated by IL-22 in keratinocytes
IL-22
Keratin 16
S100A7 (psoriasin)
Effects:
Acanthosis of
epidermis
Keratin 16
synthesis
S100A7
synthesis
Sa SM et al, J Immunol, 2007
Media
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A paradigm shift in pathogenesis of AD
Gittler J….Guttman-Yassky E Allergy Clin Immunol 2012
Staph
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Noda S...Guttman-Yassky E. J Allergy Clin Immunol. 2015;136(5):1254-64
Brunner P....Paller AS, and Guttman-Yassky E. J Allergy Clin Immunol 2016
Wen H.C...Guttman-Yassky E. J Allergy Clin Immunol. 2018
Brunner P..Guttman-Yassky E. J Allergy Clin Immunol. 2018
Is AD A Single Disease Across The Spectrum?
Czarnowicki T, He H, Krueger JG, Guttman-Yassky E JACI IN Press 2018
All AD subtypes share robust Th2 activation
But, stratification of biomarkers specific to different AD
phenotypes may be important for developing a
personalized medicine approach for AD
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Atopic Dermatitis Emerges as a
Systemic Disease Systemic Inflammation is well established in psoriasis
Higher immune activation has been recently reported in peripheral
GWAS studies: IL-13, CTLA4, IL-2RA, IL-2/IL-21, ULBP3/ULBP6, PRDX5, STX17, and IKZF4/ERBB3 identified in the 1st North American study
Authors concluded that IL-13 is also a susceptibility loci for other atopic diseases, supporting the hypothesis of shared pathways of susceptibility
Genetic polymorphisms of IL-4, IL-16, ICOS, IL-18, FAS/FASL were also associated with AA
Jagielska D et al. J Invest Dermatol. 2012 Sep;132(9):2192-7.
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AA is a highly inflammatory skin disease with increased Th1, IL-23 and Th2 cytokine circuits
Suarez-Farinas, M….Guttman-Yassky, E. JACI August 2015.
* * * * * * * ** ** ** ** ** ** **
* * * * * * *
n=3 n=22 n=17 n=4 n=2 n=10 n=10−9.5
−9
−8.5
−8
−7.5
−7
−6.5
−6
Normal Scalp AA AD PsO
Group
log 2
(Exp
ress
ion/
hAR
P)
Tissue
Normal
NL
LS
CCL5
Th1
IL-23 Th2
IFNγ CXCL9 CXCL10
IL-23p19 IL-12/IL-23p40 IL-13
N Scalp
AA AD PSO N Skin
N Scalp AA AD PSO N SkinN Scalp
AA AD PSO N Skin
N Scalp
AA AD PSO N Skin
N Scalp
AA AD PSO N Skin
N Scalp
AA AD PSO N Skin
N Scalp, normal scalp, N Skin, normal skin; NL, non lesional; LS, lesional
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An Integrated Model of Alopecia Areata Scalp and Serum Biomarkers Highlights Th1 and Th2 Biomarkers
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●
●
●
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●
●
●
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r=0.79 p<0.01
25
50
75
100
40 50 60 70 80
mScore
SA
LT
IFNG_LS,IL5_LS,IL13_NL,IL10_NL
Teresa Song,….Guttman-Yassky E. JACI 2018
IFNγ LS, IL5 LS, IL13 NL, IL10 NL
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**P<0.01, ***P<0.001 vs placeboBL, baseline; CI, confidence interval; LS, least squares; SALT, Severity of Alopecia Tool.
Guttman-Yassky et al. ISDS 2018
JAK1/TYK2
JAK3
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The immune pathogenesis of AA is complex and still being elucidated
Because of more broadinhibition of multiplecytokines/pathways, JAKinhibitors cannot fully teaseout the pathogenesis of AA
Clinical trials with targetedtherapeutics against differentaxes are required to test theirpossible pathogeniccontributions
Not for Distribution
AA shares pathogenic features with AD
Similar to AD, AA is also increasingly recognized as a systemicdisease, suggesting the need for systemic treatmentapproaches for severe patients
AA might present a similar model to AD in which immunecytokines suppress formation of hair keratins
Similar to AD, AA may present different disease endotypes(subtypes) with differing immune polarizations
Specific cytokine inhibition with mechanistic correlates isneeded to dissect the mechanisms underlying AA
In SumNot for Distribution
Thank You
We are now beginning an exciting medical and scientific path for a new treatment paradigm for our atopic dermatitis patientsWe are now beginning an exciting medical and scientific path for a new treatment paradigm for our atopic dermatitis patients and beyond