molecular signatures order the potency of topically applied anti inflammatory drugs in atopic dermatitis patients

Accepted Manuscript Molecular signatures order the potency of topically applied anti-inflammatory drugs in atopic dermatitis patients Emma Guttman-Yassky, MD PhD, Benjamin Ungar, BA, Kunal Malik, BA, Daniel Dickstein, BA, Maria Suprun, MPH, Yeriel D Estrada, BS, Hui Xu, MSc, Xiangyu Peng, MSc, Margeaux Oliva, BA, Dan Todd, MSc, Tord Labuda, PhD, Mayte SuarezFarinas, PhD, Robert Bissonnette, MD PII: S0091-6749(17)30320-2 DOI: 10.1016/j.jaci.2017.01.027 Reference: YMAI 12660 To appear in: Journal of Allergy and Clinical Immunology Received Date: 20 September 2016 Revised Date: 21 December 2016 Accepted Date: January 2017 Please cite this article as: Guttman-Yassky E, Ungar B, Malik K, Dickstein D, Suprun M, Estrada YD, Xu H, Peng X, Oliva M, Todd D, Labuda T, Suarez-Farinas M, Bissonnette R, Molecular signatures order the potency of topically applied anti-inflammatory drugs in atopic dermatitis patients, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/j.jaci.2017.01.027 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Molecular signatures order the potency of topically applied anti-inflammatory drugs in atopic dermatitis patients Emma Guttman-Yassky MD PhD1,2,3, Benjamin Ungar BA1, Kunal Malik BA1, Daniel Dickstein BA1, Maria Suprun MPH4, Yeriel D Estrada BS1,3, Hui Xu MSc1,3, Xiangyu Peng MSc1,3, Margeaux Oliva BA1, Dan Todd MSc5, Tord Labuda PhD5, Mayte Suarez-Farinas PhD4,6,7, Robert Bissonnette MD8 SC RI PT Department of Dermatology, Icahn School of Medicine at Mount Sinai, NY, USA 10 Laboratory for Investigative Dermatology, The Rockefeller University, NY, USA 11 The Immunology Institute, Icahn School of Medicine at Mount Sinai, NY, USA 12 Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, 13 NY, USA 14 LEO Pharma A/S 15 Department of Genetics and Genomics Science, Icahn School of Medicine at Mount Sinai, NY, 16 USA 17 18 NY, USA 19 TE D EP Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, AC C 20 M AN U Innovaderm Research, Montreal, Canada 21 Corresponding Author: 22 Emma Guttman-Yassky, MD PhD 23 Department of Dermatology, Icahn School of Medicine at Mount Sinai, E 98th Street, New 24 York, NY 10029 ACCEPTED MANUSCRIPT Email: Emma.Guttman@mountsinai.org 26 Telephone: 212-241-9728/3288; Fax: 212-876-8961 27 Word Count: Abstract: 244; Manuscript: 3457 28 29 30 Funding: This work was funded by a research grant from LEO Pharma A/S 31 Disclosures: 32 EGY is on the advisory board for Sanofi Aventis, Regeneron, Stiefel/GlaxoSmithKline, 33 MedImmune, Celgene, Anacor, AnaptysBio, Celsus, Dermira, Galderma, Glenmark, Novartis, 34 Pfizer, Vitae and Leo Pharma; has received consultancy fees from Regeneron, Sanofi, 35 MedImmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, Drais, AbbVie, Anacor, 36 AnaptysBio, Dermira, Galderma, Glenmark, LEO Pharma, Novartis, Pfizer, Vitae, Mitsubishi 37 Tanabe and Eli Lilly; and has received research support from Janssen, Regeneron, Celgene, 38 BMS, Novartis, Merck, LEO Pharma and Dermira MSF has received research support from 39 Pfizer and Quorum Consulting 40 RB was an advisory board member and has received honoraria from AbbVie, Amgen, Janssen, 41 and Merck He was a consultant and received honoraria from AbbVie, Amgen, Celgene, Eli Lilly 42 and Company, Galderma, Incyte, Janssen, LEO Pharma, Merck, and Novartis He has been a 43 speaker for and received honoraria from AbbVie, Amgen, Galderma, Janssen, LEO Pharma and 44 Merck He was an investigator for and his institution received grant support from AbbVie, 45 Amgen, Aquinox, Celgene, Eli Lilly and Company, Galderma, Glenmark, Merck, Novartis, 46 Pfizer, Kineta, Incyte, Janssen, LEO Pharma and Vitae 47 DT and TL are LEO employees The rest of the authors declare that they have no relevant 48 conflicts of interest AC C EP TE D M AN U SC RI PT 25 Abbreviations: 50 AD: atopic dermatitis 51 DCs: dendritic cells 52 FLG: filaggrin 53 hARP: human acidified ribosomal protein 54 IGA: Investigators Global Assessments 55 IHC: immunohistochemistry 56 LCs: langerhans cells 57 LOR: loricrin 58 LRT: likelihood ratio test 59 OR: online repository 60 PPL: periplakin 61 RT-PCR: real time PCR 62 TAA: Target Area Assessment 63 TCI: topical calcineurin inhibitor 64 TEWL: Trans-epidermal Water Loss 65 TSS: Total Sign Score 67 68 M AN U TE D EP AC C 66 SC 49 RI PT ACCEPTED MANUSCRIPT 69 70 71 ACCEPTED MANUSCRIPT Abstract 73 Background: Atopic Dermatitis (AD) presents a large unmet need for treatments with better 74 safety and efficacy To facilitate development of topical therapeutics, we need an efficient model 75 for assessing different formulations and concentrations The “plaque model” has been 76 successfully implemented in psoriasis, another common inflammatory disease, to assess efficacy 77 of topical treatments This model has not been validated for AD, which has higher placebo 78 responses and less stable lesions than psoriasis 79 Objective: We aimed to assess changes in molecular signatures of intra-patient target lesions 80 treated with topical therapeutics 81 Methods: We enrolled 30 mild-to-moderate AD patients in a randomized, double-blinded, intra- 82 individual comparison of approved agents applied blindly at the investigator site daily for 14d: 83 pimecrolimus, betamethasone diproprionate, clobetasol proprionate, and a vehicle/emollient 84 control Changes in total sign scores (TSS), trans-epidermal water loss (TEWL), and tissue 85 biomarkers (using RT-PCR and immunohistochemistry) were evaluated 86 Results: TSS showed improvements of 30%, 40%, 68%, and 76% at 2wks with vehicle, 87 pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in TEWL 88 (p