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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.
Not for Distribution
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)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
N NL LS
N NL LS
De Benedetto A et al JACI 2011; 127: 773-786
Not for Distribution
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Not for Distribution
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
Not for Distribution
A paradigm shift in pathogenesis of AD
Gittler J….Guttman-Yassky E Allergy Clin Immunol 2012
Staph
Not for Distribution
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
Not for Distribution
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.
Not for Distribution
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 CCL17
IL-13 CCL22 CCL13
CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3
FCH
(lo
g 2)
-3
-2
-1
0
1
2
3
4
5
Not for Distribution
…post CsA treatment …
Modifiable risk factors?
Ungar B…Guttman-Yassky E. J Invest Dermatol Nov 2016
IL-22 CCL17
IL-13 CCL22 CCL13
CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3
-4.0-3.5-3.0
-2.5-2.0-1.5-1.0
-0.50.00.5
FCH
(lo
g 2)
Not for Distribution
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.
Not for Distribution
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
Not for Distribution
LS NL LS + NL + Blood
-60 -50 -40 -30μScore
-70 -60 -50 -40 -30μScore
-60 -50 -40 -30μScore
SCO
RA
D im
pro
vem
ent
-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
-80SC
OR
AD
imp
rove
men
t
SCO
RA
D im
pro
vem
ent
Not for Distribution
Through Clinical Trials with Targeted
Treatments in AD Patients
Not for Distribution
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
Not for Distribution
18.8
0
37.527.3
54.552.4
71.4
0
10
20
30
40
50
60
70
80
90
100
% R
esp
on
ders
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
†
Not for Distribution
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.
Not for Distribution
Patients with lower EASI improved faster (already resolved by
Week 4)
In a larger 16wk study Dupilumab progressively reversed the AD transcriptome
Time
EASI.LOCF
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.B.1
1.LS
.W0
54.8
.B.1
7.LS
.W0
54.1
.B.3
0.LS
.W0
54.B
.14.
LS.W
052
.2.B
.21.
LS.W
049
.2.B
.2.L
S.W
049
.2.B
.3.L
S.W
048
.1.B
.45.
LS.W
047
.6.B
.36.
LS.W
041
.4.B
.16.
LS.W
035
.2.B
.38.
LS.W
031
.2.B
.33.
LS.W
030
.3.B
.8.L
S.W
026
.9.B
.60.
LS.W
024
.2.B
.51.
LS.W
020
.7.B
.40.
LS.W
020
.2.B
.19.
LS.W
018
.9.B
.25.
LS.W
018
.8.B
.24.
LS.W
018
.4.B
.42.
LS.W
018
.4.B
.57.
LS.W
018
.3.B
.53.
LS.W
017
.8.B
.1.L
S.W
017
.8.B
.59.
LS.W
016
.4.B
.43.
LS.W
016
.3.B
.31.
LS.W
046
.2.B
.14.
LS.W
440
.6.B
.38.
LS.W
437
.8.B
.21.
LS.W
420
.8.B
.19.
LS.W
418
.8.B
.17.
LS.W
418
.3.B
.28.
LS.W
417
.9.B
.3.L
S.W
416
.8.B
.11.
LS.W
415
.B.2
.LS
.W4
13.9
.B.4
5.LS
.W4
12.5
.B.5
1.LS
.W4
8.5.
B.3
3.LS
.W4
7.7.
B.5
3.LS
.W4
7.1.
B.2
4.LS
.W4
6.B
.57.
LS.W
45.
5.B
.43.
LS.W
43.
9.B
.31.
LS.W
42.
6.B
.40.
LS.W
42.
4.B
.59.
LS.W
41.
8.B
.16.
LS.W
41.
8.B
.42.
LS.W
41.
6.B
.25.
LS.W
40.
9.B
.1.L
S.W
40.
2.B
.8.L
S.W
429
.2.B
.14.
LS.W
168.
2.B
.30.
LS.W
167.
6.B
.59.
LS.W
166.
3.B
.28.
LS.W
165.
9.B
.16.
LS.W
165.
6.B
.11.
LS.W
164.
8.B
.24.
LS.W
164.
8.B
.57.
LS.W
163.
8.B
.43.
LS.W
163.
6.B
.51.
LS.W
163.
1.B
.21.
LS.W
162.
4.B
.25.
LS.W
162.
1.B
.19.
LS.W
161.
6.B
.40.
LS.W
161.
2.B
.17.
LS.W
160.
7.B
.8.L
S.W
160.
B.1
.LS
.W16
0.B
.2.L
S.W
1654
.8.B
.17.
NL.
W0
54.1
.B.3
0.N
L.W
052
.2.B
.21.
NL.
W0
48.1
.B.4
5.N
L.W
047
.6.B
.36.
NL.
W0
41.4
.B.1
6.N
L.W
035
.2.B
.38.
NL.
W0
31.2
.B.3
3.N
L.W
030
.3.B
.8.N
L.W
026
.9.B
.60.
NL.
W0
24.2
.B.5
1.N
L.W
020
.7.B
.40.
NL.
W0
20.2
.B.1
9.N
L.W
018
.9.B
.25.
NL.
W0
18.8
.B.2
4.N
L.W
018
.4.B
.42.
NL.
W0
18.4
.B.5
7.N
L.W
018
.3.B
.53.
NL.
W0
17.8
.B.1
.NL.
W0
17.8
.B.5
9.N
L.W
016
.4.B
.43.
NL.
W0
16.3
.B.3
1.N
L.W
08.
2.B
.30.
NL.
W16
7.6.
B.5
9.N
L.W
166.
3.B
.28.
NL.
W16
5.9.
B.1
6.N
L.W
164.
8.B
.24.
NL.
W16
4.8.
B.5
7.N
L.W
163.
8.B
.43.
NL.
W16
3.6.
B.5
1.N
L.W
163.
1.B
.21.
NL.
W16
2.4.
B.2
5.N
L.W
162.
1.B
.19.
NL.
W16
1.6.
B.4
0.N
L.W
161.
2.B
.17.
NL.
W16
0.7.
B.8
.NL.
W16
0.B
.1.N
L.W
16
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_at205229_s_at1560131_at241506_at210002_at239752_at236264_at209866_s_at209867_s_at229309_at205208_at229125_at1560697_at1560698_a_at203400_s_at214063_s_at229477_at229476_s_at208510_s_at1565162_s_at231736_x_at228821_at219616_at205364_at210247_at232206_at213695_at208367_x_at205999_x_at220675_s_at233030_at205404_at205029_s_at205030_at206002_at1553605_a_at206392_s_at221872_at221295_at223605_at221142_s_at1553583_a_at220431_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_at206930_at222083_at210963_s_at238003_at1563182_at225420_at243879_at208383_s_at206955_at223727_at230463_at206243_at218865_at228409_at1555740_a_at1554044_a_at204997_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_at222124_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_at219194_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_at238763_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_at1559950_at230187_s_at236888_at207757_at1561306_s_at240014_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_at224189_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_at211519_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_at1555756_a_at204465_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−HUMISGF3A/M97935_MA_at204415_at205483_s_at205552_s_at227609_at204972_at237314_at220745_at203184_at1556409_a_at219669_at239452_at228038_at235549_at221111_at222974_at236198_at1552807_a_at202018_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_at220330_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_at229947_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_at204118_at219045_at210140_at209083_at232234_at203828_s_at204116_at211796_s_at210915_x_at213193_x_at206025_s_at224358_s_at223344_s_at1555229_a_at1555745_a_at223809_at214467_at207238_s_at229152_at1569344_a_at214602_at229779_at1560916_a_at224399_at225647_s_at242943_at206420_at214560_at230422_at240536_at207328_at223710_at209924_at32128_at204580_at1553834_at1553835_a_at240997_at242641_at230867_at228658_at1563509_at205039_s_at205285_s_at239237_at207861_at206749_at215784_at227677_at204563_at210164_at240232_at227458_at209765_at210643_at207651_at206545_at1558972_s_at1552497_a_at227344_at231794_at206181_at239427_at210439_at236341_at211339_s_at226218_at210116_at236280_at1555687_a_at228056_s_at210313_at1556698_a_at205307_s_at206914_at1552552_s_at1554519_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_at213475_s_at204890_s_at230489_at202524_s_at206804_at213958_at204891_s_at205456_at
All Patients: R668 AD genes
−2 −1 0 1 2
Row Z−Score
Color Key
W0W4
W16(0,7.6](7.6,18.9]
(18.9,35.2](35.2,72]
Time
EASI.LOCF
NA
..N1.
Nor
mal
.N
A..N
10.N
orm
al.
NA
..N11
.Nor
mal
.N
A..N
124.
Nor
mal
.N
A..N
126.
Nor
mal
.N
A..N
127.
Nor
mal
.N
A..N
129.
Nor
mal
.N
A..N
130.
Nor
mal
.N
A..N
131.
Nor
mal
.N
A..N
132.
Nor
mal
.N
A..N
133.
Nor
mal
.N
A..N
134.
Nor
mal
.N
A..N
2.N
orm
al.
NA
..N3.
Nor
mal
.N
A..N
4.N
orm
al.
NA
..N5.
Nor
mal
.N
A..N
7.N
orm
al.
NA
..N70
.Nor
mal
.N
A..N
8.N
orm
al.
NA
..N9.
Nor
mal
.62
.6.A
.23.
LS.W
062
.A.1
5.LS
.W0
60.6
.A.5
.LS
.W0
51.8
.A.1
2.LS
.W0
45.6
.A.7
.LS
.W0
44.2
.A.1
0.LS
.W0
43.9
.A.2
0.LS
.W0
38.9
.A.6
1.LS
.W0
38.5
.A.3
7.LS
.W0
37.6
.A.5
2.LS
.W0
37.5
.A.5
8.LS
.W0
35.2
.A.2
7.LS
.W0
33.9
.A.3
9.LS
.W0
33.4
.A.4
1.LS
.W0
31.4
.A.3
2.LS
.W0
28.6
.A.4
6.LS
.W0
26.3
.A.5
6.LS
.W0
21.4
.A.4
9.LS
.W0
21.3
.A.2
6.LS
.W0
19.2
.A.1
3.LS
.W0
18.8
.A.4
7.LS
.W0
17.2
.A.4
4.LS
.W0
17.A
.48.
LS.W
016
.7.A
.35.
LS.W
016
.2.A
.4.L
S.W
072
.A.5
.LS
.W4
53.6
.A.1
2.LS
.W4
50.A
.49.
LS.W
442
.4.A
.7.L
S.W
440
.3.A
.23.
LS.W
436
.9.A
.44.
LS.W
434
.4.A
.37.
LS.W
433
.A.5
8.LS
.W4
32.2
.A.3
2.LS
.W4
31.2
.A.5
6.LS
.W4
29.8
.A.3
5.LS
.W4
25.A
.46.
LS.W
423
.4.A
.41.
LS.W
420
.6.A
.39.
LS.W
419
.8.A
.20.
LS.W
418
.8.A
.13.
LS.W
413
.8.A
.47.
LS.W
411
.4.A
.26.
LS.W
410
.6.A
.48.
LS.W
47.
A.4
.LS
.W4
43.8
.A.1
2.LS
.W16
39.8
.A.5
8.LS
.W16
29.4
.A.3
7.LS
.W16
24.A
.27.
LS.W
1622
.8.A
.23.
LS.W
1613
.4.A
.26.
LS.W
1610
.7.A
.48.
LS.W
166.
2.A
.7.L
S.W
166.
A.2
0.LS
.W16
5.A
.4.L
S.W
162.
9.A
.47.
LS.W
1644
.2.A
.10.
NL.
W0
43.9
.A.2
0.N
L.W
038
.9.A
.61.
NL.
W0
38.5
.A.3
7.N
L.W
037
.6.A
.52.
NL.
W0
37.5
.A.5
8.N
L.W
035
.2.A
.27.
NL.
W0
33.9
.A.3
9.N
L.W
033
.4.A
.41.
NL.
W0
31.4
.A.3
2.N
L.W
028
.6.A
.46.
NL.
W0
26.3
.A.5
6.N
L.W
021
.4.A
.49.
NL.
W0
21.3
.A.2
6.N
L.W
019
.2.A
.13.
NL.
W0
18.8
.A.4
7.N
L.W
017
.2.A
.44.
NL.
W0
17.A
.48.
NL.
W0
16.7
.A.3
5.N
L.W
016
.2.A
.4.N
L.W
039
.8.A
.58.
NL.
W16
29.4
.A.3
7.N
L.W
1624
.A.2
7.N
L.W
1613
.4.A
.26.
NL.
W16
10.7
.A.4
8.N
L.W
166.
A.2
0.N
L.W
162.
9.A
.47.
NL.
W16
62.4
.B.1
1.LS
.W0
54.8
.B.1
7.LS
.W0
54.1
.B.3
0.LS
.W0
54.B
.14.
LS.W
052
.2.B
.21.
LS.W
049
.2.B
.2.L
S.W
049
.2.B
.3.L
S.W
048
.1.B
.45.
LS.W
047
.6.B
.36.
LS.W
041
.4.B
.16.
LS.W
035
.2.B
.38.
LS.W
031
.2.B
.33.
LS.W
030
.3.B
.8.L
S.W
026
.9.B
.60.
LS.W
024
.2.B
.51.
LS.W
020
.7.B
.40.
LS.W
020
.2.B
.19.
LS.W
018
.9.B
.25.
LS.W
018
.8.B
.24.
LS.W
018
.4.B
.42.
LS.W
018
.4.B
.57.
LS.W
018
.3.B
.53.
LS.W
017
.8.B
.1.L
S.W
017
.8.B
.59.
LS.W
016
.4.B
.43.
LS.W
016
.3.B
.31.
LS.W
046
.2.B
.14.
LS.W
440
.6.B
.38.
LS.W
437
.8.B
.21.
LS.W
420
.8.B
.19.
LS.W
418
.8.B
.17.
LS.W
418
.3.B
.28.
LS.W
417
.9.B
.3.L
S.W
416
.8.B
.11.
LS.W
415
.B.2
.LS
.W4
13.9
.B.4
5.LS
.W4
12.5
.B.5
1.LS
.W4
8.5.
B.3
3.LS
.W4
7.7.
B.5
3.LS
.W4
7.1.
B.2
4.LS
.W4
6.B
.57.
LS.W
45.
5.B
.43.
LS.W
43.
9.B
.31.
LS.W
42.
6.B
.40.
LS.W
42.
4.B
.59.
LS.W
41.
8.B
.16.
LS.W
41.
8.B
.42.
LS.W
41.
6.B
.25.
LS.W
40.
9.B
.1.L
S.W
40.
2.B
.8.L
S.W
429
.2.B
.14.
LS.W
168.
2.B
.30.
LS.W
167.
6.B
.59.
LS.W
166.
3.B
.28.
LS.W
165.
9.B
.16.
LS.W
165.
6.B
.11.
LS.W
164.
8.B
.24.
LS.W
164.
8.B
.57.
LS.W
163.
8.B
.43.
LS.W
163.
6.B
.51.
LS.W
163.
1.B
.21.
LS.W
162.
4.B
.25.
LS.W
162.
1.B
.19.
LS.W
161.
6.B
.40.
LS.W
161.
2.B
.17.
LS.W
160.
7.B
.8.L
S.W
160.
B.1
.LS
.W16
0.B
.2.L
S.W
1654
.8.B
.17.
NL.
W0
54.1
.B.3
0.N
L.W
052
.2.B
.21.
NL.
W0
48.1
.B.4
5.N
L.W
047
.6.B
.36.
NL.
W0
41.4
.B.1
6.N
L.W
035
.2.B
.38.
NL.
W0
31.2
.B.3
3.N
L.W
030
.3.B
.8.N
L.W
026
.9.B
.60.
NL.
W0
24.2
.B.5
1.N
L.W
020
.7.B
.40.
NL.
W0
20.2
.B.1
9.N
L.W
018
.9.B
.25.
NL.
W0
18.8
.B.2
4.N
L.W
018
.4.B
.42.
NL.
W0
18.4
.B.5
7.N
L.W
018
.3.B
.53.
NL.
W0
17.8
.B.1
.NL.
W0
17.8
.B.5
9.N
L.W
016
.4.B
.43.
NL.
W0
16.3
.B.3
1.N
L.W
08.
2.B
.30.
NL.
W16
7.6.
B.5
9.N
L.W
166.
3.B
.28.
NL.
W16
5.9.
B.1
6.N
L.W
164.
8.B
.24.
NL.
W16
4.8.
B.5
7.N
L.W
163.
8.B
.43.
NL.
W16
3.6.
B.5
1.N
L.W
163.
1.B
.21.
NL.
W16
2.4.
B.2
5.N
L.W
162.
1.B
.19.
NL.
W16
1.6.
B.4
0.N
L.W
161.
2.B
.17.
NL.
W16
0.7.
B.8
.NL.
W16
0.B
.1.N
L.W
16
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All Patients: R668 AD genes
−2 −1 0 1 2
Row Z−Score
Color Key
W0W4
W16(0,7.6](7.6,18.9]
(18.9,35.2](35.2,72]
Baseline Baseline Baseline BaselineW4 W16 W4 W16 W16Lesional LesionalNon-lesional Non-lesionalNormal
Placebo Dupilumab
EASI
No major change at Week 4Some change at Week 16
W16
Z-score = no. of SD’s removed from the mean.
Shift toward NL profile at Week 4Further 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
Not for Distribution
Me
an
lo
g2(F
CH
)
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
Not for Distribution
Epidermal thicknessBaseline NLBaseline Week 16Week 4
Pla
ceb
oD
up
ilu
ma
b
H&E
H&E
Lesional
Pla
ceb
oD
up
ilu
ma
b
BaselineBaseline Week 16Week 4
Lesional Non-lesional
K16
K16
Baseline LS Week 4 LS Week 16 LS
Pla
ceb
oD
up
ilu
ma
b
Baseline LS Week 4 LS Week 16 LS
-60
-40
-20
0
20
40
60
4 16
Study week
Placebo200 mg dpl
**
***
***§
Epidermal Thickness
FLG
FLG
Guttman-Yassky E, et al. J Allergy Clin Immunol. 2018. doi: 10.1016/j.jaci.2018.8.022
Not for Distribution
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.
Not for Distribution
Not for Distribution
p-value for the Time x Treatment x Severity interaction Multivariate Binary Regression
modelp-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 up6 IV doses until week 10
Not for Distribution
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
Not for Distribution
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
Not for Distribution
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
Not for Distribution
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.
Not for Distribution
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
Not for Distribution
An Integrated Model of Alopecia Areata Scalp and Serum Biomarkers Highlights Th1 and Th2 Biomarkers
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r=0.79 p<0.01
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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
Not for Distribution
**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
Not for Distribution
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
Not for Distribution