Lena Möbus1, Elke Rodriguez1, Inken Harder1, Dora Stölzl1, Nicole Boraczynski1, Sascha Gerdes1, Andreas Kleinheinz2, Susanne Abraham3, Annice Heratizadeh4, Christiane Handrick5, Eva Haufe6, Thomas Werfel4, Jochen Schmitt6, Stephan Weidinger7. 1. Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 2. Department of Dermatology, Elbe Medical Centre, Buxtehude, Germany. 3. University Allergy Centre, Carl Gustav Carus University Medical Centre, TU Dresden, Dresden, Germany. 4. Division of Immunodermatology and Allergy Research, Department of Dermatology, Allergy, and Venereology, Hannover Medical School, Hannover, Germany. 5. Practice for Dermatology and Venereology, Christiane Handrick, MD, Berlin, Germany. 6. Center for Evidence-Based Health Care, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany. 7. Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address: sweidinger@dermatology.uni-kiel.de.
Abstract
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, TH17 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 TH17 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 TH17 and natural killer cell signaling.
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, TH17 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 TH17 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 TH17 and natural killer cell signaling.
Authors: El-Bdaoui Haddad; Sonya L Cyr; Kazuhiko Arima; Robert A McDonald; Noah A Levit; Frank O Nestle Journal: Dermatol Ther (Heidelb) Date: 2022-05-21
Authors: Maxim A X Tollenaere; Thomas Litman; Lena Moebus; Elke Rodriguez; Dora Stölzl; Katharina Drerup; Thomas Werfel; Jochen Schmitt; Hanne Norsgaard; Stephan Weidinger Journal: Acta Derm Venereol Date: 2021-04-29 Impact factor: 3.875