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

Rosa Andres-Ejarque, Hira Bahadur Ale, Katarzyna Grys, Isabella Tosi, Shane Solanky, Chrysanthi Ainali, Zeynep Catak, Hemawtee Sreeneebus, Jake Saklatvala, Nick Dand, Emanuele de Rinaldis, Anna Chapman, Frank O. Nestle, Michael R. Barnes, Richard B. Warren, Nick J. Reynolds, Christopher E. M. Griffiths, Jonathan N. Barker, Catherine H. Smith and Paola Di Meglio ()
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Rosa Andres-Ejarque: Kings College London
Hira Bahadur Ale: Kings College London
Katarzyna Grys: Kings College London
Isabella Tosi: Kings College London
Shane Solanky: Kings College London
Chrysanthi Ainali: Kings College London
Zeynep Catak: Kings College London
Hemawtee Sreeneebus: Kings College London
Jake Saklatvala: Kings College London
Nick Dand: Kings College London
Emanuele de Rinaldis: Guys & St Thomas NHS Foundation Trust & King’s College London
Anna Chapman: Lewisham and Greenwich NHS Trust
Frank O. Nestle: Kings College London
Michael R. Barnes: Queen Mary University of London, Charterhouse Square
Richard B. Warren: Manchester Academic Health Science Centre
Nick J. Reynolds: Institute of Translational and Clinical Medicine, Newcastle University Medical School and Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust
Christopher E. M. Griffiths: Manchester Academic Health Science Centre
Jonathan N. Barker: Kings College London
Catherine H. Smith: Kings College London
Paola Di Meglio: Kings College London

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25066-9

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