Publications by authors named "Yeriel Estrada"

60 Publications

The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults.

J Allergy Clin Immunol 2021 Jan 13. Epub 2021 Jan 13.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill. Electronic address:

Background: Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking.

Objective: We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls.

Methods: We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry.

Results: T2/T22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. T17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. T1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with T2/T22-related markers in all pediatric age groups.

Conclusions: The shared signature of AD across ages is T2/T22-skewed, yet differential expression of specific T2/T22-related genes, other T pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints.
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http://dx.doi.org/10.1016/j.jaci.2021.01.001DOI Listing
January 2021

RNA Sequencing Keloid Transcriptome Associates Keloids With Th2, Th1, Th17/Th22, and JAK3-Skewing.

Front Immunol 2020 23;11:597741. Epub 2020 Nov 23.

Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Keloids are disfiguring, fibroproliferative growths and their pathogenesis remains unclear, inhibiting therapeutic development. Available treatment options have limited efficacy and harbor safety concerns. Thus, there is a great need to clarify keloid pathomechanisms that may lead to novel treatments. In this study, we aimed to elucidate the profile of lesional and non-lesional keloid skin compared to normal skin. We performed gene (RNAseq, qRT-PCR) and protein (immunohistochemistry) expression analyses on biopsy specimens obtained from lesional and non-lesional skin of African American (AA) keloid patients compared to healthy skin from AA controls. Fold-change≥2 and false-discovery rate (FDR)<0.05 was used to define significance. We found that lesional versus normal skin showed significant up-regulation of markers of T-cell activation/migration (ICOS, CCR7), Th2- (IL-4R, CCL11, TNFSF4/OX40L), Th1- (CXCL9/CXCL10/CXCL11), Th17/Th22- (CCL20, S100As) pathways, and JAK/STAT-signaling (JAK3) (false-discovery rate [FDR]<0.05). Non-lesional skin also exhibited similar trends. We observed increased cellular infiltrates in keloid tissues, including T-cells, dendritic cells, mast cells, as well as greater IL-4rα, CCR9, and periostin immunostaining. In sum, comprehensive molecular profiling demonstrated that both lesional and non-lesional skin show significant immune alternations, and particularly Th2 and JAK3 expression. This advocates for the investigation of novel treatments targeting the Th2 axis and/or JAK/STAT-signaling in keloid patients.
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http://dx.doi.org/10.3389/fimmu.2020.597741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719808PMC
November 2020

Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities.

J Allergy Clin Immunol 2020 Oct 1. Epub 2020 Oct 1.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease.

Objective: Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD.

Methods: Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay.

Results: Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream T2 cell-, T22 cell-, T1 cell-, and T17 cell-related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the T2 (IL13, CCL17, and CCL26) and T22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of T1 cell (IFNG, CXCL9, and CXCL10) and T17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell-related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of T1 cell-, T2 cell-, and T17 cell-related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls.

Conclusion: Mild and limited AD show high levels of T2/T22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease.
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http://dx.doi.org/10.1016/j.jaci.2020.08.041DOI Listing
October 2020

Tape-strips provide a minimally invasive approach to track therapeutic response to topical corticosteroids in atopic dermatitis patients.

J Allergy Clin Immunol Pract 2021 Jan 2;9(1):576-579.e3. Epub 2020 Sep 2.

Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2020.08.037DOI Listing
January 2021

Tape-Strip Proteomic Profiling of Atopic Dermatitis on Dupilumab Identifies Minimally Invasive Biomarkers.

Front Immunol 2020 6;11:1768. Epub 2020 Aug 6.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Tape-stripping is a minimally invasive approach for skin sampling that captures the cutaneous immune/barrier abnormalities in atopic dermatitis (AD). However, tape-strips have not been used to evaluate molecular changes with therapeutic targeting. In this study, we sought to characterize the proteomic signature of tape-strips from AD patients, before and after dupilumab therapy. Twenty-six AD patients were treated with every-other-week dupilumab 300 mg for 16 weeks. Tape-strips from lesional and non-lesional skin were collected before and after treatment, and analyzed with the Olink proteomic assay. Using criteria of fold-change>1.5 and FDR < 0.05, 136 proteins significantly decreased after dupilumab treatment, corresponding to an overall mean improvement of 66.2% in the lesional vs. non-lesional AD proteome. Significant decreases after dupilumab were observed in immune markers related to general inflammation (MMP12), Th2 (CCL13/CCL17), Th17/Th22 (IL-12B, CXCL1, S100A12), and innate immunity (IL-6, IL-8, IL-17C), while the Th1 chemokines CXCL9/CXCL10 remained elevated. Proteins related to atherosclerosis/cardiovascular risk (e.g., SELE/E-selectin, IGFBP7, CHIT1/ chitotriosidase-1, AXL) also significantly decreased after treatment. Dupilumab therapy suppressed AD-related immune biomarkers and atherosclerosis/cardiovascular risk proteins. Tape-strip proteomics may be useful for monitoring therapeutic response in real-life settings, clinical trials, and longitudinal studies for AD and beyond.
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http://dx.doi.org/10.3389/fimmu.2020.01768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423990PMC
August 2020

Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.

J Allergy Clin Immunol 2021 Jan 21;147(1):199-212. Epub 2020 Jul 21.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory of Investigative Dermatology, The Rockefeller University, New York, NY. Electronic address:

Background: Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable.

Objective: Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis.

Methods: A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers.

Results: We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential T2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of T17-related (IL-17A/F and IL-36A/IL-36G), T1-related (IFN-γ and CXCL9/CXCL10), and innate immunity-related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy.

Conclusion: RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers.
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http://dx.doi.org/10.1016/j.jaci.2020.05.048DOI Listing
January 2021

Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis.

J Allergy Clin Immunol 2021 Jan 16;147(1):394-397. Epub 2020 May 16.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.055DOI Listing
January 2021

Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.

J Am Acad Dermatol 2021 Feb 4;84(2):370-380. Epub 2020 May 4.

Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile.

Objective: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity.

Methods: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49).

Results: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy.

Limitations: Our analysis was limited to 350 proteins.

Conclusion: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.
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http://dx.doi.org/10.1016/j.jaad.2020.04.138DOI Listing
February 2021

Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis.

J Allergy Clin Immunol 2020 06 7;145(6):1615-1628. Epub 2020 Feb 7.

Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell-based molecular alterations are largely unknown.

Objective: Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls.

Methods: We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics.

Results: We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5COL18A1 subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3 dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1AFCER1A) and tissue-resident memory T cells (CD69CD103). The frequencies of type 2 (IL13)/type 22 (IL22) T cells were higher than those of type 1 (IFNG) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls.

Conclusion: AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation.
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http://dx.doi.org/10.1016/j.jaci.2020.01.042DOI Listing
June 2020

The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.

J Am Acad Dermatol 2020 Mar 25;82(3):690-699. Epub 2019 Oct 25.

Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues.

Objective: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals.

Methods: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 μg/10 μL for skin and blood and RNA sequencing of the skin.

Results: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin.

Limitations: Our analysis was limited to 354 proteins.

Conclusions: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring.
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http://dx.doi.org/10.1016/j.jaad.2019.10.039DOI Listing
March 2020

Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood.

J Allergy Clin Immunol 2020 01 15;145(1):215-228. Epub 2019 Oct 15.

Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored.

Objective: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects.

Methods: Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4/CD8 T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA) versus systemic/CLA T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies.

Results: Although CLA T1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA T2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA T2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22).

Conclusions: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance.
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http://dx.doi.org/10.1016/j.jaci.2019.09.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957229PMC
January 2020

Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.

Ann Allergy Asthma Immunol 2020 01 14;124(1):70-78. Epub 2019 Oct 14.

Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Atopic dermatitis (AD) is associated with increased systemic inflammation and cardiovascular risk. Although previous studies have found increased inflammatory proteins in the blood of patients with AD, detailed comparison among patients with AD of different ages is unavailable.

Objective: To characterize the blood proteomic signature of patients with AD as a function of age.

Methods: We used the OLINK high-throughput proteomic assay to measure serum inflammatory and cardiovascular risk proteins in 71 patients with moderate to severe AD from 3 age groups (18-40 years old [n = 26], 41-60 years old [n = 24], and >60 years old [n = 21]) compared with 37 age-matched controls. Total and allergen-specific serum IgEs were also measured.

Results: When we compared patients with AD from 3 different age groups with their respective controls, we identified a total of 172 differentially expressed proteins. T2 chemokines (CCL13, CCL17) were consistently elevated in patients with AD across all ages (P < .05), whereas T1 (CXCL10) and T17 (KYNU, CCL20) markers incrementally increased with age in both patients with AD and healthy subjects. Elderly patients with AD (>60 years old) exhibited striking upregulation of key proinflammatory proteins, including markers of atherosclerosis (CCL4, CCL7, SORT1), cardiovascular risk (GDF15, MPO, ST2), cell adhesion (CDH3), and apoptosis (FAS; all P < .05) compared with younger patients with AD and age-matched controls. We also found that total and allergen-specific serum IgEs decreased significantly with age in patients with AD (P < .05).

Conclusion: Elderly patients with AD had increased levels of systemic inflammatory markers, including those associated with cardiovascular and atherosclerosis risk, which may explain their increased incidence of cardiovascular disease. This finding suggests that older patients with AD may benefit from cardiovascular disease screening and prevention.
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http://dx.doi.org/10.1016/j.anai.2019.10.013DOI Listing
January 2020

Use of Tape Strips to Detect Immune and Barrier Abnormalities in the Skin of Children With Early-Onset Atopic Dermatitis.

JAMA Dermatol 2019 Oct 9. Epub 2019 Oct 9.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Importance: Molecular profiling of skin biopsies is the criterion standard for evaluating the cutaneous atopic dermatitis (AD) phenotype. However, skin biopsies are not always feasible in children. A reproducible minimally invasive approach that can track cutaneous disease in pediatric longitudinal studies or clinical trials is lacking.

Objective: To assess a minimally invasive approach using tape strips to identify skin biomarkers that may serve as a surrogate to biomarkers identified using whole-tissue biopsies.

Design, Setting, And Participants: This cross-sectional study of 51 children younger than 5 years recruited children with moderate to severe AD and children without AD from the dermatology outpatient clinics at a children's hospital. Sixteen tape strips were serially collected from the nonlesional and lesional skin of 21 children who had AD and were less than 6 months from disease initiation and from the normal skin of 30 children who did not have AD between January 22, 2016, and April 20, 2018.

Main Outcomes And Measures: Gene and protein expression were evaluated using quantitative real-time polymerase chain reaction and immunohistochemistry.

Results: A total of 51 children younger than 5 years were included in the study; 21 children had moderate to severe AD with less than 6 months of disease duration, and 30 children did not have AD. Of the 21 children with AD, the mean (SD) age was 1.7 (1.7) years, and most were male (15 [71.4%] and white (15 [71.4%]). Of the 30 children without AD, the mean (SD) age was 1.8 (2.0) years, and most were female (20 [66.7%]) and white (22 [73.3%]). Seventy-seven of 79 evaluated immune and barrier gene products were detected (gene detection rate, 97%) in 70 of 71 tape strips (sample detection rate, 99%), with 53 of 79 markers differentiating between children with lesional and/or nonlesional AD from children without AD. Many cellular markers of T cells (CD3), AD-related dendritic cells (Fc ε RI and OX40 ligand receptors), and key inflammatory (matrix metallopeptidase 12), innate (interleukin 8 [IL-8] and IL-6), helper T cell 2 (TH2; IL-4, IL-13, and chemokines CCL17 and CCL26), and TH17/TH22 (IL-19, IL-36G, and S100A proteins) genes were significantlyincreased in lesional and nonlesional AD compared with tape strips from normal skin. For example, IL-4 mean (SE) for lesional was -15.2 (0.91) and normal was -19.5 (0.48); P < .001. Parallel decreases occurred in epidermal barrier gene products (FLG, CLDN23, and FA2H) and negative immune regulators (IL-34 and IL-37). For example, the decrease for FLG lesional was mean (SE) -2.9 (0.42) and for normal was 2.2 (0.45); P < .001. Associations were found between disease severity or transepidermal water loss and TH2 (IL-33 and IL-4R) and TH17/TH22 (IL-36G and S100As) products in lesional and nonlesional AD skin (evaluated using the SCORing Atopic Dermatitis, Eczema Area and Severity Index, and Pruritus Atopic Dermatitis Quickscore tools).

Conclusions And Relevance: In this study, tape strips provide a minimally invasive alternative for serially evaluating AD-associated cutaneous biomarkers and may prove useful for tracking pediatric AD therapeutic response and predicting future course and comorbidities.
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http://dx.doi.org/10.1001/jamadermatol.2019.2983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802262PMC
October 2019

Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation.

J Allergy Clin Immunol Pract 2020 01 17;8(1):236-247.e3. Epub 2019 Aug 17.

MedImmune, LLC, Gaithersburg, Md. Electronic address:

Background: Atopic dermatitis (AD) is a chronic inflammatory disease with significant local and systemic inflammation and barrier disruption. AD is associated with increased risk of allergen sensitization and skin colonization by Staphylococcus aureus. The heterogeneity of AD is unknown, and its complexity suggests its subdivision into several endotypes.

Objective: To evaluate allergy-driven endotypic differences in patients with AD and identify proteomic signatures to distinguish between inflammatory responses. To perform proteomic profiling of allergen sensitivity, antibody levels to S aureus antigens, and circulating inflammatory mediators to characterize AD subsets in 76 subjects with moderate to severe AD and 39 healthy controls (HCs).

Methods: Sera were collected from 76 subjects with moderate to severe AD and 39 HCs with no history of skin disease. Serum was tested for levels of total serum immunoglobulin E (IgE) and allergen-specific IgE using a panel of 119 allergens as well as IgE antibodies against S aureus antigens, and was profiled for more than 1100 proteins by SOMAscan to detect differential expression of inflammatory mediators.

Results: Total serum IgE levels were significantly (P < .001) elevated in subjects with AD versus controls. A greater percentage of subjects with AD were allergic compared with HCs, and patients with AD tested positive to a greater number of allergens than did HCs. IgE was upregulated across 4 allergen subsets (food, perennial, seasonal, and mixed), and each allergen subset was associated with a distinct inflammatory signature marked by a specific suite of upregulated proteins. Finally, IgE antibodies against S aureus toxic shock syndrome toxin-1 were significantly upregulated in subjects with seasonal allergy (P = .0430) and perennial allergy (P = .00032).

Conclusions: Overall, this study addresses the heterogeneity of AD by characterizing subsets of AD on the basis of allergen sensitization. It also demonstrates the differential systemic inflammation and S aureus-specific antibody responses associated with the allergenic endotypes. These unique proteomic signatures may be valuable for precise disease characterization and subsequent personalized treatment.
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http://dx.doi.org/10.1016/j.jaip.2019.08.013DOI Listing
January 2020

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial.

J Allergy Clin Immunol 2019 11 13;144(5):1274-1289. Epub 2019 Aug 13.

Department of Dermatology and Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined.

Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD.

Methods: Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.

Results: Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10) that was sustained until day 15 (92.90% vs 49.59%, P < 10). Crisaborole significantly modulated key AD biomarkers versus vehicle, including T2 and T17/T22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function.

Conclusion: Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.
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http://dx.doi.org/10.1016/j.jaci.2019.06.047DOI Listing
November 2019

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.

J Allergy Clin Immunol 2019 10 26;144(4):1011-1024. Epub 2019 Jul 26.

Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (T2/T22/T17/T1) and epidermal differentiation.

Objective: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus.

Methods: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry.

Results: ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including T2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), T17/T22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and T1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups.

Conclusion: The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.
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http://dx.doi.org/10.1016/j.jaci.2019.07.013DOI Listing
October 2019

Major Differences in Expression of Inflammatory Pathways in Skin from Different Body Sites of Healthy Individuals.

J Invest Dermatol 2019 10 3;139(10):2228-2232.e10. Epub 2019 May 3.

Department of Dermatology and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.04.008DOI Listing
October 2019

The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.

J Am Acad Dermatol 2019 Aug 19;81(2):510-519. Epub 2019 Apr 19.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Background: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.

Objective: To analyze blood inflammatory proteins of early pediatric AD.

Methods: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD.

Results: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11).

Limitations: Different baseline expression levels in healthy pediatric vs adult samples.

Conclusions: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.
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http://dx.doi.org/10.1016/j.jaad.2019.04.036DOI Listing
August 2019

GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis.

J Allergy Clin Immunol 2019 08 6;144(2):482-493.e7. Epub 2019 Feb 6.

Glenmark Pharmaceuticals, Inc, Paramus, NJ.

Background: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD).

Objective: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.

Methods: Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71.

Results: GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in T1 (IFN-γ/CXCL10), T2 (IL-31/CCL11/CCL17), and T17/T22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40 T cells and OX40L dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001).

Conclusions: Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.
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http://dx.doi.org/10.1016/j.jaci.2018.11.053DOI Listing
August 2019

Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.

J Allergy Clin Immunol 2019 07 24;144(1):144-156. Epub 2019 Jan 24.

Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown.

Objective: We sought to characterize age-related changes in the AD profile.

Methods: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years).

Results: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b and FcεRI, P < .05) decreased with age. T2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). T22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of T1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and T17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T2 downregulation (CCL26; r = -0.32, P < .1) and T1 upregulation (IFN-γ; r = 0.48, P < .01) with age.

Conclusion: The adult AD profile varies with age. Although T1/T17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T2/T22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.
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http://dx.doi.org/10.1016/j.jaci.2019.01.015DOI Listing
July 2019

Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases.

J Allergy Clin Immunol 2019 06 18;143(6):2095-2107. Epub 2018 Dec 18.

Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA) T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo.

Objective: We sought to measure cytokine production by circulating skin-homing (CLA) versus systemic (CLA) "polar" CD4/CD8 ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects.

Methods: Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4/CD8 T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies.

Results: Patients with Vitiligo showed the highest CLA/CLA T1/type 1 cytotoxic T-cell polarization, with parallel T2/T9/T17/T22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P < .05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P < .001). Vitiligo severity correlated with levels of multiple cytokines (P < .1), whereas duration was linked with IFN-γ and IL-17 levels (P < .04). Patients and control subjects grouped into separate clusters based on blood biomarkers.

Conclusions: Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation.
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http://dx.doi.org/10.1016/j.jaci.2018.11.031DOI Listing
June 2019

A Phase 2 Randomized Trial of Apremilast in Patients with Atopic Dermatitis.

J Invest Dermatol 2019 05 5;139(5):1063-1072. Epub 2018 Dec 5.

Icahn School of Medicine at the Mount Sinai Medical Center, New York, New York, USA.

A phase 2, double-blind, placebo-controlled trial evaluated apremilast efficacy, safety, and pharmacodynamics in adults with moderate to severe atopic dermatitis. Patients were randomly assigned to receive placebo, apremilast 30 mg twice daily (APR30), or apremilast 40 mg twice daily (APR40) for 12 weeks. During weeks 12-24, all patients received APR30 or APR40. A biopsy substudy evaluated atopic dermatitis-related biomarkers. Among 185 randomly assigned intent-to-treat patients at week 12, a dose-response relationship was observed; APR40 (n = 63), but not APR30 (n = 58), led to statistically significant improvements (vs. placebo, n = 64) in Eczema Area and Severity Index (mean [standard deviation] percent change from baseline = -31.6% [44.6] vs. -11.0% [71.2], P < 0.04; primary endpoint). mRNA expression of T helper type 17/T helper type 22-related markers (IL-17A, IL-22, and S100A7/A8; P < 0.05) showed the highest reductions with APR40, with minimal changes in other immune axes. Safety with APR30 was largely consistent with apremilast's known profile (common adverse events: nausea, diarrhea, headache, and nasopharyngitis). With APR40, adverse events were more frequent, and cellulitis occurred (n = 6). An independent safety monitoring committee discontinued the APR40 dosage. APR40 showed modest efficacy and decreased atopic dermatitis-related biomarkers in moderate to severe atopic dermatitis patients. Adverse events, including cellulitis, were more frequent with APR40, which was discontinued during the trial. Clinical Trial Registration Number: NCT02087943 (clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.jid.2018.10.043DOI Listing
May 2019

Distinct transcriptomic profiles of early-onset atopic dermatitis in blood and skin of pediatric patients.

Ann Allergy Asthma Immunol 2019 03 1;122(3):318-330.e3. Epub 2018 Dec 1.

The Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York; Department of Dermatology, the Laboratory for Inflammatory Skin Diseases, and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from long-standing adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Because obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature.

Objective: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD.

Methods: We compared microarrays and reverse transcription polymerase chain reaction (RT-PCR) of blood cells from 28 AD children (<5 years and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes (DEGs) in blood (fold change [FCH] > 1.2 and false discovery rate [FDR] < 0.05) were then compared with skin DEGs.

Results: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were up-regulated in early pediatric AD blood, whereas IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss [TEWL]), whereas Th2/Th17-induced interleukin (IL)-19 was positively correlated with SCORAD. Although a few RT-PCR-defined immune markers (IL-13/CCL22) were increased in blood, as previously also reported for skin, minimal overlap based on gene array DEGs was seen.

Conclusion: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile; however, markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course, allergic comorbidity development, and response to systemic medications.
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http://dx.doi.org/10.1016/j.anai.2018.11.025DOI Listing
March 2019

Atopic dermatitis in African American patients is T2/T22-skewed with T1/T17 attenuation.

Ann Allergy Asthma Immunol 2019 01 14;122(1):99-110.e6. Epub 2018 Sep 14.

Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: African Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population.

Objective: We sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls.

Methods: We performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls.

Results: African American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA.

Conclusion: The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.
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http://dx.doi.org/10.1016/j.anai.2018.08.024DOI Listing
January 2019

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.

J Allergy Clin Immunol 2019 01 5;143(1):155-172. Epub 2018 Sep 5.

Regeneron Pharmaceuticals, Tarrytown, NY.

Background: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases.

Objective: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD).

Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks.

Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and T17/T22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs.

Conclusion: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.
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http://dx.doi.org/10.1016/j.jaci.2018.08.022DOI Listing
January 2019

Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab.

J Allergy Clin Immunol 2019 01 17;143(1):142-154. Epub 2018 Aug 17.

Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects.

Objective: We sought to evaluate the cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD.

Methods: We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti-IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses.

Results: Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22-high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22-high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22-low groups. Significant downregulations of multiple immune pathways, including T1/CXCL9, T2/CCL18/CCL22, T17/CCL20/DEFB4A, and T22/IL22/S100A's, were restricted to the IL-22-high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation.

Conclusions: This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.
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http://dx.doi.org/10.1016/j.jaci.2018.07.028DOI Listing
January 2019

An integrated model of alopecia areata biomarkers highlights both T1 and T2 upregulation.

J Allergy Clin Immunol 2018 11 5;142(5):1631-1634.e13. Epub 2018 Jul 5.

Department of Dermatology, Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.06.029DOI Listing
November 2018

Author Correction: The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins.

Sci Rep 2018 May 29;8(1):8439. Epub 2018 May 29.

The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-26378-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974294PMC
May 2018

Ichthyosis molecular fingerprinting shows profound T17 skewing and a unique barrier genomic signature.

J Allergy Clin Immunol 2019 02 24;143(2):604-618. Epub 2018 May 24.

Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Laboratory for Investigative Dermatology, Rockefeller University, New York, NY. Electronic address:

Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy.

Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses.

Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16).

Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with T1/IFN-γ, OASL, and T2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G).

Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.
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http://dx.doi.org/10.1016/j.jaci.2018.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195861PMC
February 2019

Early-onset pediatric atopic dermatitis is characterized by T2/T17/T22-centered inflammation and lipid alterations.

J Allergy Clin Immunol 2018 06 3;141(6):2094-2106. Epub 2018 May 3.

Laboratory for Investigative Dermatology, Rockefeller University, New York, NY; Department of Dermatology and the Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments.

Objective: We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects.

Methods: We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early-onset AD (<6 months disease duration) compared with age-matched control subjects and adults with longstanding AD.

Results: Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored T2-centered inflammation, pediatric AD also showed significant T17/T22 skewing but lacked the T1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier.

Conclusions: Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.
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http://dx.doi.org/10.1016/j.jaci.2018.02.040DOI Listing
June 2018