title: Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis.
abstract: BACKGROUND
  Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The "plaque model" has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis.
  
  
  OBJECTIVE
  We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics.
  
  
  METHODS
  We enrolled 30 patients with mild-to-moderate AD in a randomized, double-blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT-PCR and immunohistochemistry) were evaluated.
  
  
  RESULTS
  TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL-13, IL-22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers.
  
  
  CONCLUSIONS
  We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: Emma.Guttman@mountsinai.org.
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ungar
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Kunal
authors.initials: K
authors.lastname: Malik
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dickstein
authors.affiliation: Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Maria
authors.initials: M
authors.lastname: Suprun
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Yeriel D
authors.initials: YD
authors.lastname: Estrada
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Margeaux
authors.initials: M
authors.lastname: Oliva
authors.affiliation: LEO Pharma A/S, Ballerup, Denmark.
authors.forename: Dan
authors.initials: D
authors.lastname: Todd
authors.affiliation: LEO Pharma A/S, Ballerup, Denmark.
authors.forename: Tord
authors.initials: T
authors.lastname: Labuda
authors.affiliation: Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Genetics and Genomics Science, Icahn School of Medicine at Mount Sinai, New York, NY; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suarez-Farinas
authors.affiliation: Innovaderm Research, Montreal, Quebec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Bissonnette
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001623:Betamethasone / Q000031:analogs & derivatives / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002990:Clobetasol / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011565:Psoriasis / Q000188:drug therapy; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; C117268:pimecrolimus; C011175:betamethasone-17,21-dipropionate; D001623:Betamethasone; D002990:Clobetasol; D016559:Tacrolimus
keywords: Atopic dermatitis; biomarkers; emollients; plaque model; psoriasis; topical calcineurin inhibitor; topical steroids; topical treatments