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

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*PSORT COnsortium

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)
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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.

Original languageEnglish
Article number4741
Pages (from-to)4741
Number of pages1
JournalNature Communications
Volume12
Issue number1
Early online date6 Aug 2021
DOIs
Publication statusPublished - Dec 2021

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