The document discusses the complex pathogenesis of atopic dermatitis (AD), highlighting its multifactorial nature and the significant unmet need for effective long-term treatments. It outlines various cytokine responses, including Th2 and Th22 pathways, that contribute to the disease's inflammation and skin barrier defects. The study emphasizes a shift towards systemic treatment approaches and the importance of stratifying AD subtypes for personalized medicine in managing this prevalent condition.

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

7. 0
2
4
6
8
10
1
4
16
64
256
1024
IL−4
IL−5
IL−10
IL−13
IL−31
IL−33
CCL17
CCL18
CCL22
CCL5
CCL26
CCL13
CCL11
*
*
*
**
*
*
** **
*
*
**
*
*
0
2
4
6
8
10
1
4
16
64
256
1024
TSLPR
OX40L
IL−9
IL−22
S100A7
S100A8
S100A9
S100A12
IL−32
IFNg
IL−8
IL−1b
IFNa1
*
*
** *
*
*
*** **
** ** *
*
*
6
8
10
64
256
1024
*
**
*
***
*
* **
*
***
***
*
Non-lesional
Acute AD
Chronic AD
IL-4
Th2
IL-5
Th2
IL-10
Th2
IL-13
Th2
IL-31
Th2
IL-33
Th2
CCL17
Th2
CCL18
Th2
CCL22
Th2
CCL5
Th2
CCL26
Th2
CCL13
Th2
CCL11
Th2
ln(expression/hARP)
Expression/hARP
AD shows progressive Th2 and Th22 cytokine activation
with Th1 skewing in chronic disease
z
Gittler JK…and Guttman-Yassky E J Allergy Clin Immunol 2012
Z
ln(expression/hARP)
IL-22
Th22
S100A7
Th22
S100A8
Th22
S100A9
Th22
0
2
4
6
8
10
1
4
16
64
256
1024
IL−4
IL−5
IL−10
IL−13
IL−31
IL−33
CCL17
CCL18
CCL22
CCL5
CCL26
CCL13
CCL11
*
*
*
**
*
*
** **
*
*
**
*
*
0
2
4
6
8
10
1
4
16
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IL−22
S100A7
S100A8
S100A9
S100A12
IL−32
IFNg
IL−8
IL−1b
IFNa1
*
*
** *
*
*
*** **
** ** *
*
*
0
2
4
6
8
10
1
4
16
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IL−4
IL−5
IL−10
IL−13
IL−31
IL−33
CCL17
CCL18
CCL22
CCL5
CCL26
CCL13
CCL11
*
*
*
**
*
*
** **
*
*
**
*
*
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2
4
6
8
10
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16
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IL−9
IL−22
S100A7
S100A8
S100A9
S100A12
IL−32
IFNg
IL−8
IL−1b
IFNa1
*
*
** *
*
*
*** **
** ** *
*
*
10 1024
Th2
Th22
Expression/hARP
0
2
4
6
8
10
1
4
16
64
256
1024
IL−4
IL−5
IL−10
IL−13
IL−31
IL−33
CCL17
CCL18
CCL22
CCL5
CCL26
CCL13
CCL11
*
*
*
**
*
*
** **
*
*
**
*
*
0
2
4
6
8
10
1
4
16
64
256
1024
TSLPR
OX40L
IL−9
IL−22
S100A7
S100A8
S100A9
S100A12
IL−32
IFNg
IL−8
IL−1b
IFNa1
*
*
** *
*
*
*** **
** ** *
*
*
10 1024
0
2
4
6
8
10
TSLPR
OX40L
IL−9
IL−22
S100A7
S100A8
S100A9
*
*
** *
*
*** **
** **
0
2
4
6
8
10
MX1
CXCL9
CXCL10
CXCL11
IL−17A
IL−23
IL−12/IL−23
*
**
*
* **
IFN-γ
Th1
MX1
Th1
CXCL9
Th1
CXCL10
Th1
CXCL11
Th1
IL-8
Th1
0
2
4
6
8
10
1
4
16
64
256
1024
IL−4
IL−5
IL−10
IL−13
IL−31
IL−33
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CCL18
CCL22
CCL5
CCL26
CCL13
CCL11
*
*
*
**
*
*
** **
*
*
**
*
*
0
2
4
6
8
10
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16
64
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IL−22
S100A7
S100A8
S100A9
S100A12
IL−32
IFNg
IL−8
IL−1b
IFNa1
*
*
** *
*
*
*** **
** ** *
*
*
10 1024
Th1

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

14. …post CsA treatment …
Modifiable risk factors?
Ungar B…Guttman-Yassky E. J Invest Dermatol Nov 2016
IL-22 CCL1
7
IL-13 CCL22 CCL1
3
CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
FCH(log2)

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

18. Through Clinical Trials with Targeted
Treatments in AD Patients

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

20. 18.8
0
37.5
27.3
54.552.4
71.4
0
10
20
30
40
50
60
70
80
90
100
%Responders
2 4
0
Study Week
Placebo (n=16)
75 mg (n=8)
150 mg (n=22)
300 mg (n=21)
*
*
*p<0.05; †p=0.003
*
Beck L….Guttman-Yassky E et al, NEJM 2014
No differences in responses were seen between AD
patients based on IgE or FLG mutation status
†

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.

22. Patients with lower
EASI improved faster
(already resolved by
Week 4)
In a larger 16wk study Dupilumab progressively reversed the
AD transcriptome
Time
ASI.LOCF
NA..N1.Normal.
NA..N10.Normal.
NA..N11.Normal.
NA..N124.Normal.
NA..N126.Normal.
NA..N127.Normal.
NA..N129.Normal.
NA..N130.Normal.
NA..N131.Normal.
NA..N132.Normal.
NA..N133.Normal.
NA..N134.Normal.
NA..N2.Normal.
NA..N3.Normal.
NA..N4.Normal.
NA..N5.Normal.
NA..N7.Normal.
NA..N70.Normal.
NA..N8.Normal.
NA..N9.Normal.
62.6.A.23.LS.W0
62.A.15.LS.W0
60.6.A.5.LS.W0
51.8.A.12.LS.W0
45.6.A.7.LS.W0
44.2.A.10.LS.W0
43.9.A.20.LS.W0
38.9.A.61.LS.W0
38.5.A.37.LS.W0
37.6.A.52.LS.W0
37.5.A.58.LS.W0
35.2.A.27.LS.W0
33.9.A.39.LS.W0
33.4.A.41.LS.W0
31.4.A.32.LS.W0
28.6.A.46.LS.W0
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21.4.A.49.LS.W0
21.3.A.26.LS.W0
19.2.A.13.LS.W0
18.8.A.47.LS.W0
17.2.A.44.LS.W0
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16.7.A.35.LS.W0
16.2.A.4.LS.W0
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53.6.A.12.LS.W4
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42.4.A.7.LS.W4
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54.1.B.30.LS.W0
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52.2.B.21.LS.W0
49.2.B.2.LS.W0
49.2.B.3.LS.W0
48.1.B.45.LS.W0
47.6.B.36.LS.W0
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18.4.B.57.NL.W0
18.3.B.53.NL.W0
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17.8.B.59.NL.W0
16.4.B.43.NL.W0
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0.7.B.8.NL.W16
0.B.1.NL.W16
204602_at1569297_at206552_s_at215133_s_at230959_at1561754_at241175_at242206_at243929_at206941_x_at239984_at240865_at215554_at206265_s_at206264_at237076_at236963_at1556919_at1556364_at236949_at202976_s_at1563462_at243626_at239017_at1555318_at244697_at231262_at205883_at228854_at227762_at228858_at206794_at214087_s_at214774_x_at216623_x_at229151_at223859_at213307_at243681_at223836_at203824_at205979_at214053_at227803_at207981_s_at203673_at228943_at230269_at1557474_at205043_at227174_at219704_at229964_at244216_at204437_s_at227753_at227342_s_at204607_at206873_at230419_at205295_at219768_at242488_at229866_at220425_x_at224191_x_at231535_x_at203892_at209173_at230780_at232378_at222102_at237981_at235976_at232176_at232481_s_at205776_at227123_at239202_at206254_at243585_at210297_s_at207430_s_at214204_at239319_at227985_at1552365_at237301_at226438_at241412_at207326_at215129_at228503_at219115_s_at242245_at219263_at235278_at230285_at230006_s_at205259_at214598_at215271_at1554242_a_a205229_s_at1560131_at241506_at210002_at239752_at236264_at209866_s_at209867_s_at229309_at205208_at229125_at1560697_at1560698_a_a203400_s_at214063_s_at229477_at229476_s_at208510_s_at1565162_s_a231736_x_at228821_at219616_at205364_at210247_at232206_at213695_at208367_x_at205999_x_at220675_s_at233030_at205404_at205029_s_at205030_at206002_at1553605_a_a206392_s_at221872_at221295_at223605_at221142_s_at1553583_a_a220431_at1569909_at219429_at213553_x_at204416_x_at239929_at234513_at1560507_at214240_at230573_at237515_at238466_at205942_s_at210377_at243168_at227055_at232428_at205221_at210576_at231156_at220801_s_at205380_at243730_at222071_s_at234980_at239108_at235591_at239345_at238062_at203295_s_at218934_s_at219414_at229580_at220065_at232313_at203296_s_at1562321_at209614_at209612_s_at229778_at237351_at223828_s_at239523_at1558421_a_a206930_at222083_at210963_s_at238003_at1563182_at225420_at243879_at208383_s_at206955_at223727_at230463_at206243_at218865_at228409_at1555740_a_a1554044_a_a204997_at213706_at231348_s_at204424_s_at207175_at205913_at207092_at210964_s_at231050_at235129_at222049_s_at219140_s_at205478_at219398_at239262_at235110_at242181_at235708_at204154_at225424_at235978_at203548_s_at203549_s_at210155_at207317_s_at237390_at204938_s_at228202_at227827_at204939_s_at1556069_s_a222124_at219319_at207255_at207302_at223877_at239349_at230680_at243907_at232027_at229116_at213880_at220436_at227949_at206239_s_at228241_at204712_at209904_at228546_at220087_at228704_s_at228706_s_at1553211_at213925_at1560011_at1561301_at244407_at243871_at205073_at1554195_a_a219194_at1556078_at223816_at205568_at237974_at221470_s_at224555_x_at1560652_at1556936_at219895_at215228_at230964_at226145_s_at238697_at229053_at233157_x_at227480_at232547_at227217_at228806_at205325_at239547_at222362_at214156_at229201_at222722_at240433_x_at1552754_a_a238763_at239847_at222312_s_at238441_at232054_at228547_at239006_at229649_at206204_at203895_at241834_at226591_at230578_at214823_at204919_at219747_at230319_at206417_at238786_at236029_at206069_s_at206068_s_at242313_at238983_at213558_at235428_at204865_at228434_at213486_at239398_at1559952_x_a1559950_at230187_s_at236888_at207757_at1561306_s_a240014_at243880_at231088_at239556_at207417_s_at227113_at225727_at229169_at233520_s_at220064_at229006_at1555898_at228539_at228506_at210221_at203699_s_at232195_at207693_at237953_at233112_at207455_at242743_at217763_s_at219956_at222876_s_at225100_at1555214_a_a224189_x_at222932_at240304_s_at221305_s_at208596_s_at220475_at216257_at215817_at211362_s_at216258_s_at214146_s_at235400_at205476_at219270_at238741_at239586_at206912_at219836_at214763_at219554_at210445_at221009_s_at242271_at207367_at212531_at226960_at219181_at204733_at205157_s_at222774_s_at218888_s_at231033_at204751_x_at202094_at1554696_s_a211519_s_at235572_at217640_x_at209773_s_at243475_at209727_at215891_s_at1570005_at208433_s_at204750_s_at218384_at205595_at209800_at209126_x_at240507_at235372_at227598_at205554_s_at33304_at204698_at241482_at219763_at218550_s_at206277_at201249_at216202_s_at222385_x_at228066_at204638_at206008_at205724_at230859_at243955_at216670_at217315_s_at224051_at217192_s_at237296_at206877_at1554914_at226698_at232074_at214088_s_at233687_s_at219403_s_at1562098_at219159_s_at222838_at205681_at210663_s_at204385_at217388_s_at229635_at1554406_a_a1555756_a_a204465_s_at210138_at224204_x_at220658_s_at206561_s_at227735_s_at227736_at204420_at219985_at239430_at243754_at210797_s_at205660_at212942_s_at238542_at203779_s_at209772_s_at220322_at223906_s_at221627_at224239_at205513_at220664_at205863_at232220_at41469_at203691_at211906_s_at209720_s_at210413_x_at209719_x_at232082_x_at203535_at232170_at207356_at217430_x_at227860_at206134_at206039_at242809_at232224_at203936_s_at230025_at221601_s_at244057_s_at213869_x_at208850_s_at208851_s_at205119_s_at214511_x_at216950_s_at206207_at219014_at230983_at203649_s_at202637_s_at203052_at202953_at207277_at203922_s_at206206_at210152_at205098_at207697_x_at211133_x_at211135_x_at210225_x_at210784_x_at207533_at207094_at206999_at234296_s_at212909_at208600_s_at211668_s_at205479_s_at224507_s_at200951_s_at211013_x_at242624_at209652_s_at229373_at205242_at203915_at204533_at220445_s_at219684_at228230_at219716_at236285_at217497_atAFFX−HUMIS204415_at205483_s_at205552_s_at227609_at204972_at237314_at220745_at203184_at1556409_a_a219669_at239452_at228038_at235549_at221111_at222974_at236198_at1552807_a_a202018_s_at207900_at206632_s_at244748_at218960_at223541_at227975_at214226_at203256_at220468_at1560396_at228367_at226804_at203234_at231880_at205733_at220651_s_at204695_at226661_at212021_s_at209408_at207072_at227168_at206513_at206715_at229937_x_at210146_x_at229437_at216834_at202988_s_at1555638_a_a220330_s_at205680_at205943_at206343_s_at220153_at205676_at207526_s_at230973_at207351_s_at206569_at202859_x_at204475_at210873_x_at214866_at211924_s_at210845_s_at205825_at218990_s_at207602_at1559280_a_a229947_at206211_at207850_at209774_x_at209959_at220187_at204470_at206932_at202628_s_at203413_at206172_at237169_at241272_at216005_at52837_at221901_at244561_at206785_s_at205495_s_at37145_at210321_at1405_i_at204655_at211144_x_at215806_x_at205488_at206366_x_at214567_s_at205639_at202833_s_at211429_s_at214450_at1555349_a_a204118_at219045_at210140_at209083_at232234_at203828_s_at204116_at211796_s_at210915_x_at213193_x_at206025_s_at224358_s_at223344_s_at1555229_a_a1555745_a_a223809_at214467_at207238_s_at229152_at1569344_a_a214602_at229779_at1560916_a_a224399_at225647_s_at242943_at206420_at214560_at230422_at240536_at207328_at223710_at209924_at32128_at204580_at1553834_at1553835_a_a240997_at242641_at230867_at228658_at1563509_at205039_s_at205285_s_at239237_at207861_at206749_at215784_at227677_at204563_at210164_at240232_at227458_at209765_at210643_at207651_at206545_at1558972_s_a1552497_a_a227344_at231794_at206181_at239427_at210439_at236341_at211339_s_at226218_at210116_at236280_at1555687_a_a228056_s_at210313_at1556698_a_a205307_s_at206914_at1552552_s_a1554519_at207315_at204103_at205306_x_at211138_s_at205798_at206341_at240070_at209201_x_at211919_s_at235229_at205890_s_at223820_at210072_at229560_at206978_at235735_at210895_s_at205686_s_at206991_s_at210184_at205180_s_at220358_at204575_s_at221581_s_at243099_at219385_at206682_at233510_s_at1552584_at214054_at204789_at204265_s_at204923_at209879_at241819_at236787_at207085_x_at210340_s_at211286_x_at210038_at222062_at206761_at220485_s_at229597_s_at239529_at204852_s_at214219_x_at206296_x_at228055_at208450_at213539_at205831_at228869_at207339_s_at236673_at206974_at237753_at206337_at229686_at1554240_a_a213475_s_at204890_s_at230489_at202524_s_at206804_at213958_at204891_s_at205456_at
All Patients: R668 AD genes
2
W0
W4
W16
(0,7.6]
(7.6,18.9]
(18.9,35.2]
(35.2,72]
Time
SI.LOCF
NA..N1.Normal.
NA..N10.Normal.
NA..N11.Normal.
NA..N124.Normal.
NA..N126.Normal.
NA..N127.Normal.
NA..N129.Normal.
NA..N130.Normal.
NA..N131.Normal.
NA..N132.Normal.
NA..N133.Normal.
NA..N134.Normal.
NA..N2.Normal.
NA..N3.Normal.
NA..N4.Normal.
NA..N5.Normal.
NA..N7.Normal.
NA..N70.Normal.
NA..N8.Normal.
NA..N9.Normal.
62.6.A.23.LS.W0
62.A.15.LS.W0
60.6.A.5.LS.W0
51.8.A.12.LS.W0
45.6.A.7.LS.W0
44.2.A.10.LS.W0
43.9.A.20.LS.W0
38.9.A.61.LS.W0
38.5.A.37.LS.W0
37.6.A.52.LS.W0
37.5.A.58.LS.W0
35.2.A.27.LS.W0
33.9.A.39.LS.W0
33.4.A.41.LS.W0
31.4.A.32.LS.W0
28.6.A.46.LS.W0
26.3.A.56.LS.W0
21.4.A.49.LS.W0
21.3.A.26.LS.W0
19.2.A.13.LS.W0
18.8.A.47.LS.W0
17.2.A.44.LS.W0
17.A.48.LS.W0
16.7.A.35.LS.W0
16.2.A.4.LS.W0
72.A.5.LS.W4
53.6.A.12.LS.W4
50.A.49.LS.W4
42.4.A.7.LS.W4
40.3.A.23.LS.W4
36.9.A.44.LS.W4
34.4.A.37.LS.W4
33.A.58.LS.W4
32.2.A.32.LS.W4
31.2.A.56.LS.W4
29.8.A.35.LS.W4
25.A.46.LS.W4
23.4.A.41.LS.W4
20.6.A.39.LS.W4
19.8.A.20.LS.W4
18.8.A.13.LS.W4
13.8.A.47.LS.W4
11.4.A.26.LS.W4
10.6.A.48.LS.W4
7.A.4.LS.W4
43.8.A.12.LS.W16
39.8.A.58.LS.W16
29.4.A.37.LS.W16
24.A.27.LS.W16
22.8.A.23.LS.W16
13.4.A.26.LS.W16
10.7.A.48.LS.W16
6.2.A.7.LS.W16
6.A.20.LS.W16
5.A.4.LS.W16
2.9.A.47.LS.W16
44.2.A.10.NL.W0
43.9.A.20.NL.W0
38.9.A.61.NL.W0
38.5.A.37.NL.W0
37.6.A.52.NL.W0
37.5.A.58.NL.W0
35.2.A.27.NL.W0
33.9.A.39.NL.W0
33.4.A.41.NL.W0
31.4.A.32.NL.W0
28.6.A.46.NL.W0
26.3.A.56.NL.W0
21.4.A.49.NL.W0
21.3.A.26.NL.W0
19.2.A.13.NL.W0
18.8.A.47.NL.W0
17.2.A.44.NL.W0
17.A.48.NL.W0
16.7.A.35.NL.W0
16.2.A.4.NL.W0
39.8.A.58.NL.W16
29.4.A.37.NL.W16
24.A.27.NL.W16
13.4.A.26.NL.W16
10.7.A.48.NL.W16
6.A.20.NL.W16
2.9.A.47.NL.W16
62.4.B.11.LS.W0
54.8.B.17.LS.W0
54.1.B.30.LS.W0
54.B.14.LS.W0
52.2.B.21.LS.W0
49.2.B.2.LS.W0
49.2.B.3.LS.W0
48.1.B.45.LS.W0
47.6.B.36.LS.W0
41.4.B.16.LS.W0
35.2.B.38.LS.W0
31.2.B.33.LS.W0
30.3.B.8.LS.W0
26.9.B.60.LS.W0
24.2.B.51.LS.W0
20.7.B.40.LS.W0
20.2.B.19.LS.W0
18.9.B.25.LS.W0
18.8.B.24.LS.W0
18.4.B.42.LS.W0
18.4.B.57.LS.W0
18.3.B.53.LS.W0
17.8.B.1.LS.W0
17.8.B.59.LS.W0
16.4.B.43.LS.W0
16.3.B.31.LS.W0
46.2.B.14.LS.W4
40.6.B.38.LS.W4
37.8.B.21.LS.W4
20.8.B.19.LS.W4
18.8.B.17.LS.W4
18.3.B.28.LS.W4
17.9.B.3.LS.W4
16.8.B.11.LS.W4
15.B.2.LS.W4
13.9.B.45.LS.W4
12.5.B.51.LS.W4
8.5.B.33.LS.W4
7.7.B.53.LS.W4
7.1.B.24.LS.W4
6.B.57.LS.W4
5.5.B.43.LS.W4
3.9.B.31.LS.W4
2.6.B.40.LS.W4
2.4.B.59.LS.W4
1.8.B.16.LS.W4
1.8.B.42.LS.W4
1.6.B.25.LS.W4
0.9.B.1.LS.W4
0.2.B.8.LS.W4
29.2.B.14.LS.W16
8.2.B.30.LS.W16
7.6.B.59.LS.W16
6.3.B.28.LS.W16
5.9.B.16.LS.W16
5.6.B.11.LS.W16
4.8.B.24.LS.W16
4.8.B.57.LS.W16
3.8.B.43.LS.W16
3.6.B.51.LS.W16
3.1.B.21.LS.W16
2.4.B.25.LS.W16
2.1.B.19.LS.W16
1.6.B.40.LS.W16
1.2.B.17.LS.W16
0.7.B.8.LS.W16
0.B.1.LS.W16
0.B.2.LS.W16
54.8.B.17.NL.W0
54.1.B.30.NL.W0
52.2.B.21.NL.W0
48.1.B.45.NL.W0
47.6.B.36.NL.W0
41.4.B.16.NL.W0
35.2.B.38.NL.W0
31.2.B.33.NL.W0
30.3.B.8.NL.W0
26.9.B.60.NL.W0
24.2.B.51.NL.W0
20.7.B.40.NL.W0
20.2.B.19.NL.W0
18.9.B.25.NL.W0
18.8.B.24.NL.W0
18.4.B.42.NL.W0
18.4.B.57.NL.W0
18.3.B.53.NL.W0
17.8.B.1.NL.W0
17.8.B.59.NL.W0
16.4.B.43.NL.W0
16.3.B.31.NL.W0
8.2.B.30.NL.W16
7.6.B.59.NL.W16
6.3.B.28.NL.W16
5.9.B.16.NL.W16
4.8.B.24.NL.W16
4.8.B.57.NL.W16
3.8.B.43.NL.W16
3.6.B.51.NL.W16
3.1.B.21.NL.W16
2.4.B.25.NL.W16
2.1.B.19.NL.W16
1.6.B.40.NL.W16
1.2.B.17.NL.W16
0.7.B.8.NL.W16
0.B.1.NL.W16
204602_at1569297_at206552_s_at215133_s_at230959_at1561754_at241175_at242206_at243929_at206941_x_at239984_at240865_at215554_at206265_s_at206264_at237076_at236963_at1556919_at1556364_at236949_at202976_s_at1563462_at243626_at239017_at1555318_at244697_at231262_at205883_at228854_at227762_at228858_at206794_at214087_s_at214774_x_at216623_x_at229151_at223859_at213307_at243681_at223836_at203824_at205979_at214053_at227803_at207981_s_at203673_at228943_at230269_at1557474_at205043_at227174_at219704_at229964_at244216_at204437_s_at227753_at227342_s_at204607_at206873_at230419_at205295_at219768_at242488_at229866_at220425_x_at224191_x_at231535_x_at203892_at209173_at230780_at232378_at222102_at237981_at235976_at232176_at232481_s_at205776_at227123_at239202_at206254_at243585_at210297_s_at207430_s_at214204_at239319_at227985_at1552365_at237301_at226438_at241412_at207326_at215129_at228503_at219115_s_at242245_at219263_at235278_at230285_at230006_s_at205259_at214598_at215271_at1554242_a_a205229_s_at1560131_at241506_at210002_at239752_at236264_at209866_s_at209867_s_at229309_at205208_at229125_at1560697_at1560698_a_a203400_s_at214063_s_at229477_at229476_s_at208510_s_at1565162_s_a231736_x_at228821_at219616_at205364_at210247_at232206_at213695_at208367_x_at205999_x_at220675_s_at233030_at205404_at205029_s_at205030_at206002_at1553605_a_a206392_s_at221872_at221295_at223605_at221142_s_at1553583_a_a220431_at1569909_at219429_at213553_x_at204416_x_at239929_at234513_at1560507_at214240_at230573_at237515_at238466_at205942_s_at210377_at243168_at227055_at232428_at205221_at210576_at231156_at220801_s_at205380_at243730_at222071_s_at234980_at239108_at235591_at239345_at238062_at203295_s_at218934_s_at219414_at229580_at220065_at232313_at203296_s_at1562321_at209614_at209612_s_at229778_at237351_at223828_s_at239523_at1558421_a_a206930_at222083_at210963_s_at238003_at1563182_at225420_at243879_at208383_s_at206955_at223727_at230463_at206243_at218865_at228409_at1555740_a_a1554044_a_a204997_at213706_at231348_s_at204424_s_at207175_at205913_at207092_at210964_s_at231050_at235129_at222049_s_at219140_s_at205478_at219398_at239262_at235110_at242181_at235708_at204154_at225424_at235978_at203548_s_at203549_s_at210155_at207317_s_at237390_at204938_s_at228202_at227827_at204939_s_at1556069_s_a222124_at219319_at207255_at207302_at223877_at239349_at230680_at243907_at232027_at229116_at213880_at220436_at227949_at206239_s_at228241_at204712_at209904_at228546_at220087_at228704_s_at228706_s_at1553211_at213925_at1560011_at1561301_at244407_at243871_at205073_at1554195_a_a219194_at1556078_at223816_at205568_at237974_at221470_s_at224555_x_at1560652_at1556936_at219895_at215228_at230964_at226145_s_at238697_at229053_at233157_x_at227480_at232547_at227217_at228806_at205325_at239547_at222362_at214156_at229201_at222722_at240433_x_at1552754_a_a238763_at239847_at222312_s_at238441_at232054_at228547_at239006_at229649_at206204_at203895_at241834_at226591_at230578_at214823_at204919_at219747_at230319_at206417_at238786_at236029_at206069_s_at206068_s_at242313_at238983_at213558_at235428_at204865_at228434_at213486_at239398_at1559952_x_a1559950_at230187_s_at236888_at207757_at1561306_s_a240014_at243880_at231088_at239556_at207417_s_at227113_at225727_at229169_at233520_s_at220064_at229006_at1555898_at228539_at228506_at210221_at203699_s_at232195_at207693_at237953_at233112_at207455_at242743_at217763_s_at219956_at222876_s_at225100_at1555214_a_a224189_x_at222932_at240304_s_at221305_s_at208596_s_at220475_at216257_at215817_at211362_s_at216258_s_at214146_s_at235400_at205476_at219270_at238741_at239586_at206912_at219836_at214763_at219554_at210445_at221009_s_at242271_at207367_at212531_at226960_at219181_at204733_at205157_s_at222774_s_at218888_s_at231033_at204751_x_at202094_at1554696_s_a211519_s_at235572_at217640_x_at209773_s_at243475_at209727_at215891_s_at1570005_at208433_s_at204750_s_at218384_at205595_at209800_at209126_x_at240507_at235372_at227598_at205554_s_at33304_at204698_at241482_at219763_at218550_s_at206277_at201249_at216202_s_at222385_x_at228066_at204638_at206008_at205724_at230859_at243955_at216670_at217315_s_at224051_at217192_s_at237296_at206877_at1554914_at226698_at232074_at214088_s_at233687_s_at219403_s_at1562098_at219159_s_at222838_at205681_at210663_s_at204385_at217388_s_at229635_at1554406_a_a1555756_a_a204465_s_at210138_at224204_x_at220658_s_at206561_s_at227735_s_at227736_at204420_at219985_at239430_at243754_at210797_s_at205660_at212942_s_at238542_at203779_s_at209772_s_at220322_at223906_s_at221627_at224239_at205513_at220664_at205863_at232220_at41469_at203691_at211906_s_at209720_s_at210413_x_at209719_x_at232082_x_at203535_at232170_at207356_at217430_x_at227860_at206134_at206039_at242809_at232224_at203936_s_at230025_at221601_s_at244057_s_at213869_x_at208850_s_at208851_s_at205119_s_at214511_x_at216950_s_at206207_at219014_at230983_at203649_s_at202637_s_at203052_at202953_at207277_at203922_s_at206206_at210152_at205098_at207697_x_at211133_x_at211135_x_at210225_x_at210784_x_at207533_at207094_at206999_at234296_s_at212909_at208600_s_at211668_s_at205479_s_at224507_s_at200951_s_at211013_x_at242624_at209652_s_at229373_at205242_at203915_at204533_at220445_s_at219684_at228230_at219716_at236285_at217497_atAFFX−HUMIS204415_at205483_s_at205552_s_at227609_at204972_at237314_at220745_at203184_at1556409_a_a219669_at239452_at228038_at235549_at221111_at222974_at236198_at1552807_a_a202018_s_at207900_at206632_s_at244748_at218960_at223541_at227975_at214226_at203256_at220468_at1560396_at228367_at226804_at203234_at231880_at205733_at220651_s_at204695_at226661_at212021_s_at209408_at207072_at227168_at206513_at206715_at229937_x_at210146_x_at229437_at216834_at202988_s_at1555638_a_a220330_s_at205680_at205943_at206343_s_at220153_at205676_at207526_s_at230973_at207351_s_at206569_at202859_x_at204475_at210873_x_at214866_at211924_s_at210845_s_at205825_at218990_s_at207602_at1559280_a_a229947_at206211_at207850_at209774_x_at209959_at220187_at204470_at206932_at202628_s_at203413_at206172_at237169_at241272_at216005_at52837_at221901_at244561_at206785_s_at205495_s_at37145_at210321_at1405_i_at204655_at211144_x_at215806_x_at205488_at206366_x_at214567_s_at205639_at202833_s_at211429_s_at214450_at1555349_a_a204118_at219045_at210140_at209083_at232234_at203828_s_at204116_at211796_s_at210915_x_at213193_x_at206025_s_at224358_s_at223344_s_at1555229_a_a1555745_a_a223809_at214467_at207238_s_at229152_at1569344_a_a214602_at229779_at1560916_a_a224399_at225647_s_at242943_at206420_at214560_at230422_at240536_at207328_at223710_at209924_at32128_at204580_at1553834_at1553835_a_a240997_at242641_at230867_at228658_at1563509_at205039_s_at205285_s_at239237_at207861_at206749_at215784_at227677_at204563_at210164_at240232_at227458_at209765_at210643_at207651_at206545_at1558972_s_a1552497_a_a227344_at231794_at206181_at239427_at210439_at236341_at211339_s_at226218_at210116_at236280_at1555687_a_a228056_s_at210313_at1556698_a_a205307_s_at206914_at1552552_s_a1554519_at207315_at204103_at205306_x_at211138_s_at205798_at206341_at240070_at209201_x_at211919_s_at235229_at205890_s_at223820_at210072_at229560_at206978_at235735_at210895_s_at205686_s_at206991_s_at210184_at205180_s_at220358_at204575_s_at221581_s_at243099_at219385_at206682_at233510_s_at1552584_at214054_at204789_at204265_s_at204923_at209879_at241819_at236787_at207085_x_at210340_s_at211286_x_at210038_at222062_at206761_at220485_s_at229597_s_at239529_at204852_s_at214219_x_at206296_x_at228055_at208450_at213539_at205831_at228869_at207339_s_at236673_at206974_at237753_at206337_at229686_at1554240_a_a213475_s_at204890_s_at230489_at202524_s_at206804_at213958_at204891_s_at205456_at
All Patients: R668 AD genes
2
W0
W4
W16
(0,7.6]
(7.6,18.9]
(18.9,35.2]
(35.2,72]
Baseline Baseline Baseline BaselineW4 W16 W4 W16 W16
Lesional LesionalNon-lesional Non-lesionalNormal
Placebo Dupilumab
EASI
No major change at Week 4
Some change at Week 16
W16
Z-score = no. of SD’s removed from the mean.
Shift toward NL profile at Week 4
Further shift at Week 16
At Week 16 the LS phenotype
simulates the NL molecular
phenotype
Guttman-Yassky E, et al. J Allergy Clin Immunol. 2018. doi: 10.1016/j.jaci.2018.8.022

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.

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