Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. Guttman-Yassky Emma,Bissonnette Robert,Ungar Benjamin,Suárez-Fariñas Mayte,Ardeleanu Marius,Esaki Hitokazu,Suprun Maria,Estrada Yeriel,Xu Hui,Peng Xiangyu,Silverberg Jonathan I,Menter Alan,Krueger James G,Zhang Rick,Chaudhry Usman,Swanson Brian,Graham Neil M H,Pirozzi Gianluca,Yancopoulos George D,D Hamilton Jennifer D The Journal of allergy and clinical immunology 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. 10.1016/j.jaci.2018.08.022

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. Pavel Ana B,Song Teresa,Kim Hyun-Je,Del Duca Ester,Krueger James G,Dubin Celina,Peng Xiangyu,Xu Hui,Zhang Ning,Estrada Yeriel D,Denis Louis,Rao Niranjan,Gupta Sandeep,Zammit David J,Bissonnette Robert,Guttman-Yassky Emma The Journal of allergy and clinical immunology 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. 10.1016/j.jaci.2019.07.013

Atopic dermatitis displays stable and dynamic skin transcriptome signatures. Möbus Lena,Rodriguez Elke,Harder Inken,Stölzl Dora,Boraczynski Nicole,Gerdes Sascha,Kleinheinz Andreas,Abraham Susanne,Heratizadeh Annice,Handrick Christiane,Haufe Eva,Werfel Thomas,Schmitt Jochen,Weidinger Stephan, The Journal of allergy and clinical immunology BACKGROUND:Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as "improvement" under therapy. These observations were mainly made in trials and based on microarray data. OBJECTIVES:Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry. METHODS:Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted. RESULTS:Both lesional and nonlesional skin showed a stable "core" signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, T17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized T17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab. CONCLUSION:The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of T17 and natural killer cell signaling. 10.1016/j.jaci.2020.06.012

Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities. He Helen,Del Duca Ester,Diaz Aisleen,Kim Hyun Je,Gay-Mimbrera Jesús,Zhang Ning,Wu Jianni,Beaziz Jessica,Estrada Yeriel,Krueger James G,Pavel Ana B,Ruano Juan,Guttman-Yassky Emma The Journal of allergy and clinical immunology 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. 10.1016/j.jaci.2020.08.041