Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
The atopic dermatitis pathogenesis and implications for alopecia areata
1. 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
2. Atopic Dermatitis
Most common inflammatory skin disease (3-7%
of adults, 15-25% of children)
20-30% of patients have moderate-to severe
disease
Large Unmet Need for long-term disease control
The therapeutic drought is finally ending!
3. 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”
Epithelial
Defects
General
Inflammation
Th2 and Th22
Adaptive
Immunity
Microbiom
e
Itch
Skin Barrier
Defects
Barrier
HypothesisImmune Hypothesis
Modified with Permission from Beck LA
4. 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.
5. H&E K16 KI-67
Normal
Psoriasis
Atopic dermatitis
• AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16.
• 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)
6. 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
N NL LS
N NL LS
De Benedetto A et al JACI 2011; 127: 773-786
8. 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
9. 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
10. A paradigm shift in pathogenesis of AD
Gittler J….Guttman-Yassky E Allergy Clin Immunol 2012
Staph
11. 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
12. Atopic Dermatitis Emerges as a
Systemic Disease
Systemic Inflammation is well established in psoriasis
Higher immune activation has been recently reported in peripheral
blood from AD vs. psoriasis patients
Increased activated T cells
Increased circulatory cytokines
and cardiovascular associated
markers
Czarnowicki T….and Guttman-Yassky E..: J Allergy Clin Immunol. 2015 Jul;136(1):208-11;
Ungar B….and Guttman-Yassky E et al.: J Invest Dermatol 2016
Brunner PM…Guttman-Yassky E. Sci Reports 2017.
13. Ungar B…Guttman-Yassky E. J Invest Dermatol Nov 2016
Systemic Cytokine Activation in AD
Serum cytokines levels were increased
in AD patients and correlated with
disease severity (SCORAD)
IL-22 CCL1
7
IL-13 CCL22 CCL1
3
CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3
FCH(log2)
-3
-2
-1
0
1
2
3
4
5
15. Allergy 2015; 70: 1300–1308
NHANES
flexural eczema in the past year was associated with significantly higher odds
of CAD (P ≤ 0.04), heart attack (P ≤ 0.01), and congestive heart failure (P ≤ 0.02),
but not with stroke (P ≥ 0.37), in survey-weighted multivariate logistic regression
models that controlled for socio-demographics, comorbid asthma, and hay fever.
NHIS 2010 and 2012
1-year history of eczema was associated with significantly higher odds of
CAD (P ≤ 0.02), angina (P ≤ 0.02), heart attack (P ≤ 0.047), other heart disease (P < 0.0001),
stroke (P ≤ 0.02), and PVD (<0.0001) in multivariate models.
16. Abnormal Cytokine Profile Already Exists in
Non-Lesional AD Skin (Unlike Psoriasis)
Suárez-Fariñas M…Guttman E. J Allergy Clin Immunol 2011;127:954-964.
Th2
NormalAD nonlesional AD lesionalTh22
The high level systemic immune activation in AD emphasizes the need
for systemic treatment approaches for moderate-to-severe AD
17. LS NL LS + NL + Blood
-60 -50 -40 -30
μScore
-70 -60 -50 -40 -30
μScore
-60 -50 -40 -30
μScore
SCORADimprovement
-60
-40
-20
IL22, IL9
-60
-40
-20
CXCL1, CCL18, IL9, IL8
r=0.91
p<0.01 -20
-40
-60
r=0.94
p<0.01
IL13[serum], CCL18[NL],
IL19[NL], IL9[NL], CCL17[serum]
r=0.73
p<0.01
Ungar B…and Guttman-Yassky E. J Invest Dermatol 2017
An Integrated Model of Therapeutic Response Biomarkers shows
much Higher Correlations with Clinical Responses to CsA
-80
SCORADimprovement
SCORADimprovement
19. 4 week study
with weekly
injections of
dupilumab
75mg, 150mg,
300mg and
placebo
A total of 67
patients, 18
participated in
the biopsy
study
Type I Receptor
B cells, T cells, Monocytes,
Eosinophils, Fibroblasts
Type II Receptor
Epithelial cells, Smooth muscle
cells, Fibroblasts, Monocytes,
Activated B cells
Beck L….Guttman-Yassky E et al, NEJM 2014
21. Keratin 16
Changes in the Atopic Dermatitis
Molecular Disease Profile in Phase 1B
Placebo DPL 300DPL 150
Down Up (Beck LA….Guttman-Yassky et.al., N Engl J Med. 2014;371:130.
Hamilton JD....and Guttman-Yassky E. J Allergy Clin Immunol 2014.
23. Meanlog2(FCH)
Dupilumab showed major
reversal of dysregulated
genes at Week 16
At Week 4, dupilumab already
showed reversal of dysregulation
while placebo had increased
dysregulation
Dupilumab reversed the
dysregulation of the AD transcriptome
Placebo Dupilumab
W0 W4 W16
Time
2
0
−2
W0 W4 W16
Both groups
showed
similar
dysregulation
at baseline
Direction of Dysregulation in AD
Down-regulated Up-regulated
Guttman-Yassky E, et al. J Allergy Clin Immunol. 2018. doi: 10.1016/j.jaci.2018.8.022
24. Epidermal thickness
Baseline NLBaseline Week 16Week 4
PlaceboDupilumab
H&E
H&E
Lesional
PlaceboDupilumab
BaselineBaseline Week 16Week 4
Lesional Non-lesional
K16
K16
Baseline LS Week 4 LS Week 16 LS
PlaceboDupilumab
Baseline LS Week 4 LS Week 16 LS
-60
-40
-20
0
20
40
60
4 16
Study week
Placebo
200 mg dpl
**
***
***§
Epidermal Thickness
FLG
FLG
Guttman-Yassky E, et al.J Allergy Clin Immunol. 2018. doi: 10.1016/j.jaci.2018.8.022
25. Dupilumab impacts both the inflammation and the barrier
dysfunction of AD
Type 2
Immune
Response
Chronic StageAcute StageInitiation
Skin Barrier DysfunctionEnvironmental
Factors/Allergens
Innate
Immune
Response
Dupilumab
Dupilumab
This establishes the Th2 axis and IL-4 and IL-13 cytokines as pathogenic in
AD and cements AD as a reversible, immune-driven disease, like psoriasis
Noda S et al. J Allergy Clin Immunol 2015;135:324–336.
26.
27. p-value for the Time x Treatment x Severity
interaction Multivariate Binary Regression
model
p-value for difference between arms
(using LS means ) using T-test
A monotherapy study with ILV-094/anti-IL-22 in AD
Guttman-Yassky E el. JAAD January 2018 (Online)
p-value for
differences
between
treatment
arms
(differences
between LS
Means)
Methods:
N=60 (2:1 to placebo)
Primary endpoint: week
12, 8 week follow up
6 IV doses until week
10
28. W4 W12 W4 W12 W4 W12 W4 W12
Much Greater Transcriptome Improvement in the High IL-22 Group
ILV-094Placebo ILV-094Placebo
Week 4
54%
82.9%
Week 12
49.9%
139.4%
Week 4
-54.6%
-29.9%
Week 12
-117.7%
-34.5%
High IL-22 Low IL-22
Brunner P, Pavel B. Ana……and Guttman-Yassky E. JACI 2018
29. Summary
AD is increasingly recognized as a systemic disease,
suggesting the need for systemic treatment approaches
for severe AD patients
The TH2 axis is central to the pathogenesis of AD but is
not solely responsible
The therapeutic pipeline for AD is robust with many
promising new targets and drugs in development
Specific cytokine targeting (with mechanistic correlates)
helps to shed light into their relative contributions to AD
30. Extending the translational revolution to AA
AA is highly associated with Atopy
Comorbidities of AA:
38.2% Atopy (allergic rhinitis, asthma, and/or eczema)
25.5% Depression or anxiety
24.5% Hyperlipidemia
21.9% Hypertension
17.3% Gastroesophageal reflux disease
14.6% Thyroid disease
11.1% Diabetes mellitus
6.3% Psoriasis and psoriatic arthritis
4.3% Systemic lupus erythematosus
3.9% Rheumatoid arthritis
2.0% Inflammatory bowel disease
Huang KP et al. JAMA
Dermatol 2013
31. Genetic Associations
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.
32. 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.
*******
0 n=10
PsO
Tissue
Normal
NL
LS
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
33. An Integrated Model of Alopecia Areata Scalp and Serum
Biomarkers Highlights Th1 and Th2 Biomarkers
●
●
●
●
●
●●
●
●
●
●
●
r=0.79 p<0.01
25
50
75
100
40 50 60 70 80
mScore
SALT
IFNG_LS,IL5_LS,IL13_NL,IL10_NL
Teresa Song,….Guttman-Yassky E. JACI 2018
IFNγ LS, IL5 LS, IL13 NL, IL10 NL
34. **P<0.01, ***P<0.001 vs placebo
BL, baseline; CI, confidence interval; LS, least squares; SALT, Severity of Alopecia Tool.
Guttman-Yassky et al. ISDS 2018
JAK1/TYK2
JAK3
35. The immune pathogenesis of AA
is complex and still being elucidated
Because of more broad
inhibition of multiple
cytokines/pathways, JAK
inhibitors cannot fully tease
out the pathogenesis of AA
Clinical trials with targeted
therapeutics against different
axes are required to test their
possible pathogenic
contributions
36. AA shares pathogenic features with AD
Similar to AD, AA is also increasingly recognized as a systemic
disease, suggesting the need for systemic treatment
approaches for severe patients
AA might present a similar model to AD in which immune
cytokines 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 is
needed to dissect the mechanisms underlying AA
In Sum
37. Thank You
We are now beginning an exciting medical and scientific path for a
new treatment paradigm for our atopic dermatitis patients
We are now beginning an exciting medical and
scientific path for a new treatment paradigm for our
atopic dermatitis patients and beyond