Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis - 04/08/22
and
Biomap and the TREATgermany study group
Abstract |
Background |
Few studies have analyzed the blood transcriptome in atopic dermatitis (AD).
Objective |
We explored blood transcriptomic features of moderate to severe AD.
Methods |
Blood messenger RNA sequencing on 60 adults from the TREATgermany registry including 49 patients before and after dupilumab treatment, as well as from an independent cohort of 31 patients and 43 controls was performed. Patient clustering, differential expression, correlation and coexpression network analysis, and unsupervised learning were conducted.
Results |
AD patients showed pronounced inflammatory expression signatures with increased myeloid and IL-5–related patterns, and clearly segregated into 2 distinct clusters, with striking differences in particular for transcripts involved in eosinophil signaling. The eosinophil-high endotype showed a more pronounced global dysregulation, a positive correlation between disease activity and signatures related to IL-5 signaling, and strong correlations with several target proteins of antibodies or small molecules under development for AD. In contrast, the eosinophil-low endotype showed little transcriptomic dysregulation and no association between disease activity and gene expression. Clinical improvement with receipt of dupilumab was accompanied by a decrease of innate immune responses and an increase of lymphocyte signatures including B-cell activation and natural killer cell composition and/or function. The proportion of super responders was higher in the eosinophil-low endotype (32% vs 11%). Continued downregulation of IL18RAP, IFNG, and granzyme A in the eosinophil-high endotype suggests a residual disturbance of natural killer cell function despite clinical improvement.
Conclusion |
AD can be stratified into eosinophilic and noneosinophilic endotypes; such stratification may be useful when assessing stratified trial designs and treatment strategies.
Il testo completo di questo articolo è disponibile in PDF.Key words : Atopic dermatitis, blood transcriptome, RNA-Seq, gene expression, dupilumab, endotypes, eosinophil signatures
Abbreviations used : AD, BIT, DEG, EASI, GO, LFC, m0, m3, NK, NRS, oSCORAD, RNA-Seq, TSLP
Mappa
| The TREATgermany registry currently receives independent research grants from AbbVie, LEO Pharma, Galderma, Eli Lilly, Pfizer, and Sanofi-Aventis Deutschland GmbH. Molecular profiling of an initial subgroup of TREATgermany patients was supported by a research grant of Sanofi-Aventis Deutschland GmbH. This work also received support through Biomap (Biomarkers in Atopic Dermatitis and Psoriasis), a project funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 821511 and in-kind contributions of the participating pharma companies. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Infrastructure support was provided through the DFG Cluster of Excellence “Precision Medicine in Inflammation” (grant EXC2167). |
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| Disclosure of potential conflict of interest: M. Hübenthal received project funding from LEO Pharma A/S. S. Abraham received lecture and/or consultancy fees from Novartis, LEO Pharma, Lilly, Sanofi, Beiersdorf and AbbVie. E. Haufe is an employee at the Centre for Evidence-Based Health Care at TU Dresden that received institutional support for self-designed scientific studies from ALK, Novartis, Pfizer and Sanofi. A. Heratizadeh received lecture and/or consultancy fees from LEO Pharma, Novartis, Pierre Fabre, Sanofi, Beiersdorf, Hans Karrer, Nutricia and Meda. S. Gerdes has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials of the following companies: Abbott/AbbVie, Affibody AB, Akari Therapeutics Plc, Almirall-Hermal, Amgen, Anaptys Bio, Baxalta, Bayer Health Care, Biogen Idec, Bioskin, Boehringer-Ingelheim, Celgene, Centocor, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Incyte Inc, Isotechnika, Janssen-Cilag, Johnson & Johnson, Kymab, LEO Pharma, Medac, Merck Serono, Mitsubishi Tanabe, MSD, Novartis, Pfizer, Polichem SA, Regeneron Pharmaceutical, Sandoz Biopharmaceuticals, Sanofi-Aventis, Schering-Plough, Sienna Biopharmaceuticals, Takeda, Teva, UCB Pharma, VBL therapeutics, Wyeth Pharma. T. Werfel is co–principal investigator of the German Atopic Eczema Registry TREATgermany. He has received institutional research grants from LEO Pharma and Novartis, has performed consultancies for AbbVie, Janssen, Galderma, LEO, Sanofi-Genzyme, and Novartis. He has also lectured at educational events sponsored by AbbVie, Janssen, Celgene, Galderma, LEO Pharma, Sanofi, and Novartis, and is involved in performing clinical trials various pharmaceutical industries that manufacture drugs used for the treatment of atopic dermatitis. J. Schmitt is co–principal investigator of the German Atopic Eczema Registry TREATgermany. He has received institutional research grants for IITs from Sanofi, ALK, Novartis, and Pfizer, and has performed consultancies for Lilly, Sanofi, ALK, and Novartis. S. Weidinger is co–principal investigator of the German Atopic Eczema Registry TREATgermany. He has received institutional research grants from Sanofi Deutschland GmbH, Leo Pharma, and La Roche Posay; has performed consultancies and lectures for AbbVie, Almirall, Eli Lilly, GSK, Kymab, Leo Pharma, Pfizer, Sanofi-Genzyme, and Regeneron; and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic eczema. The other authors declare that they have no relevant conflicts of interest. |
Vol 150 - N° 2
P. 385-395 - Agosto 2022 Ritorno al numero
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