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Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis

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Rosa Andres Ejarque, Hira Bahadur Ale Ale, Katarzyna Grys, Isabella Tosi, Shane Solanky, Chrysanthi Ainali, Zeynep Catak, Hemawtee Sreeneebus, Jake Saklatvala, Nick Dand, Emanuele de Rinaldis, Anna Chapman, Frank Nestle, Michael R. Barnes, Warren Richard, Nick J. Reynolds, Christopher Griffiths, Jonathan Barker, Catherine Smith, Paola Di Meglio & 1 more PSORT COnsortium

Original languageEnglish
Article number4741
Pages (from-to)4741
Number of pages1
JournalNature Communications
Volume12
Issue number1
Early online date6 Aug 2021
DOIs
E-pub ahead of print6 Aug 2021
PublishedDec 2021

Bibliographical note

Funding Information: The authors declare the following competing interests: C.A. is an employee of DIGNOSIS Ltd. E.d.R. and F.O.N. are currently employees of Sanofi. M.R.B. has received honoraria and/or research grants from Janssen, Servier and Lilly. R.B.W. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo, Lilly, Novartis, Pfizer, Sanofi, Xenoport, and UCB. N.J.R. has received research grants from GSK-Stiefel and Novartis; and other income to Newcastle University from Almirall, Amgen, Janssen, Novartis, Sanofi Genzyme Regeneron and UCB Pharma Ltd for lectures/attendance at advisory boards. C.E.M.G. reports grants and/or personal fees from AbbVie, Almirall, Amgen, BMS, Celgene, Galderma, Janssen, Leo Pharma, Lilly, Novartis, Sandoz and UCB Pharma. J.N.B. has received honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Janssen, Leo, Lilly, Novartis, Samsung, Sun Pharma. C.H.S. has received departmental research funding from AbbVie, GSK, Pfizer, Novartis, Regeneron, and Roche. P.D.M. reports grants and/or personal fees from Janssen, Novartis, and UCB Pharma. All the other authors declare no competing interests. Funding Information: Supported by the PSORT Consortium, which is in turn funded by a Medical Research Council (MRC) Stratified Medicine award (MR/L011808/1). Partners of the PSORT consortium are AbbVie, the British Association of Dermatologists, Becton Dickinson and Company, Celgene Limited, GlaxoSmithKline, Guy’s and St Thomas’ NHS Foundation Trust, Eli Lilly, Janssen Research & Development, King’s College London, LEO Pharma, MedImmune, Novartis Pharmaceuticals UK, Pfizer Italy, the Psoriasis Association, Qiagen Manchester, Queen Mary University of London, the Royal College of Physicians, Sanquin Blood Supply Foundation, the University of Liverpool, the University of Manchester, and Newcastle University. We particularly acknowledge generous in-kind support from the PSORT industrial partner Becton Dickson. All decisions concerning analysis, interpretation, and publication are made independently of any industrial contribution. This research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, the Newcastle NIHR Biomedical Research Centre, and the NIHR Manchester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. ND is supported by Health Data Research UK (MR/S003126/1). NJR is supported by the Newcastle NIHR Biomedical Research Centre and the Newcastle NIHR Medtech and In vitro diagnostics Co‐operative. CEMG and NJR are NIHR Senior Investigators. We are grateful to psoriasis patients and healthy volunteers for their participation. We acknowledge the enthusiastic collaboration of the dermatologists and specialist nurses in the UK who recruited to this study, in particular, Prof. David Burden (Western Infirmary, Glasgow), Dr Evmorfia Ladoyanni (Russells Hall Hospital, The Dudley Group NHS Foundation Trust, Dudley), Dr Richard Parslew (Royal Liverpool& Broadgreen University Hospital NHS Trust), and Dr Gayathri Perera (West Middlesex University Hospital, Chelsea and Westminster Hospital NHS Foundation Trust). We thank Theo Rispens and Annick de Vries at Sanquin, for measuring adalimumab drug levels. We thank Alice Russel, Michael Duckworth, Tejus Dasandi, Nadya Dinev, Freya Meynell (London), Tom Ewen, and Dhanisha Lukka (Newcastle) for sample and data management, and Federica Villanova (London) for her contribution to obtain ethical approval. We thank Esme Nichols (Newcastle) for skin sectioning, Susanne Heck, Anna Rose and PJ Chana at the BRC Flow Cytometry Platform at NIHR Guy’s and St Thomas’ Biomedical Research Centre and Virginia Silio and Isma Ali at the Nikon Imaging Centre at Kings College London for technical assistance. We thank Ruth Williams at Novartis for help with clinical data of patients recruited into the Signature study. We thank Dr Brigitta Stockinger for her critical reading of the manuscript. Publisher Copyright: © 2021, The Author(s).

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Abstract

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.

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