Journal Article

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

Chapman, Anna, Grys, Katarzyna, Ale, Hira Bahadur, Nestle, Frank O., Warren, Richard B., Di Meglio, Paola, Barker, Jonathan N., Barnes, Michael R., Andres-Ejarque, Rosa, Saklatvala, Jake, Reynolds, Nick J., Tosi, Isabella, Sreeneebus, Hemawtee, Ainali, Chrysanthi, Dand, Nick, Griffiths, Christopher E. M., de Rinaldis, Emanuele, Solanky, Shane, Catak, Zeynep, Smith, Catherine H.

2021

Overview

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. Biomarkers to indicate potential response to biologic therapeutics are needed for patients with psoriasis. Here the authors show that phosphorylation of NFκBp65 in cDC2 before therapy is an indication of non-response to the anti-TNF therapy adalimumab in patients with psoriasis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250/1619/554 / 631/250/2504/133/2505 / 692/308/53/2423 / 96/1 / 96/106 / 96/21 / 96/31 / 96/63 / Adalimumab - therapeutic use / B7-H1 Antigen / Biological Therapy / Biomarkers / Biomarkers - blood / Blood / CD83 antigen / Cdc2 protein / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - metabolism / Humanities and Social Sciences / Humans / Immune system / Interleukin 17 / Interleukin 23 / Lipopolysaccharides / Lipopolysaccharides - adverse effects / Lymphocytes / Lymphocytes T / Maturation / Monoclonal antibodies / multidisciplinary / NF-kappa B - metabolism / NF-κB protein / Patients / Phosphorylation / Psoriasis / Psoriasis - immunology / Science / Science (multidisciplinary) / Sensitivity and Specificity / Signal Transduction / Skin diseases / Therapy / TNF inhibitors / Tumor necrosis factor / Tumor Necrosis Factor Inhibitors / Tumor Necrosis Factor-alpha