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The atopic dermatitis pathogenesis and implications for alopecia areata

Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.

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The atopic dermatitis pathogenesis and implications for alopecia areata

  1. 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. 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. 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. 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. 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. 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. 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 64 256 1024 TSLPR OX40L IL−9 IL−22 S100A7 S100A8 S100A9 S100A12 IL−32 IFNg IL−8 IL−1b IFNa1 * * ** * * * *** ** ** ** * * * 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 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 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 Th1
  8. 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. 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. 10. A paradigm shift in pathogenesis of AD Gittler J….Guttman-Yassky E Allergy Clin Immunol 2012 Staph
  11. 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. 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. 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. 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. 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. 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. 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. 18. Through Clinical Trials with Targeted Treatments in AD Patients
  19. 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. 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. 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. 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 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 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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 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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. 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. 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. 25. Dupilumab impacts both the inflammation and the barrier dysfunction of AD Type 2 Immune Response Chronic StageAcute StageInitiation Skin Barrier DysfunctionEnvironmental Factors/Allergens Innate Immune Response Dupilumab Dupilumab This establishes the Th2 axis and IL-4 and IL-13 cytokines as pathogenic in AD and cements AD as a reversible, immune-driven disease, like psoriasis Noda S et al. J Allergy Clin Immunol 2015;135:324–336.
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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.
  31. 31. 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
  32. 32. 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
  33. 33. **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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  • ZahidullahAhmadi

    Jan. 4, 2021
  • JeanLucTran

    Jul. 23, 2020

Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.

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