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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

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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Page 1: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 2: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 3: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 4: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 5: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 6: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 7: 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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Not for Distribution

Page 8: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 9: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 10: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

A paradigm shift in pathogenesis of AD

Gittler J….Guttman-Yassky E Allergy Clin Immunol 2012

Staph

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Page 11: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 12: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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.

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Page 13: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 14: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

…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

Page 15: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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.

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Page 16: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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Page 17: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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-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

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Page 18: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

Through Clinical Trials with Targeted

Treatments in AD Patients

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Page 19: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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Page 20: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

18.8

0

37.527.3

54.552.4

71.4

0

10

20

30

40

50

60

70

80

90

100

% R

esp

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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

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Page 21: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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.

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Page 22: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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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mal

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mal

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A..N

8.N

orm

al.

NA

..N9.

Nor

mal

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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

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

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NL.

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440

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167.

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8.B

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LS.W

163.

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LS.W

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1.B

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LS.W

162.

4.B

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LS.W

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1.B

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161.

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LS.W

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2.B

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7.B

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NL.

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NL.

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NL.

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L.W

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W0

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W0

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L.W

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2.B

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B.5

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L.W

166.

3.B

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NL.

W16

5.9.

B.1

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L.W

164.

8.B

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NL.

W16

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B.5

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L.W

163.

8.B

.43.

NL.

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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

Page 23: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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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

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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.

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Page 27: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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Page 28: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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Page 29: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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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

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Page 31: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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.

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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

●●

●●

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

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Page 36: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

Page 37: The Atopic Dermatitis Pathogenesis, and Implications for ... · Atopic dermatitis • AD, atopic dermatitis; H&E, hematoxylin and eosin; K16, keratin 16. • 1. Guttman-Yassky E

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

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