Abstract
Abstract Biologics targeting the tumour necrosis factor (TNF) and interleukin (IL)-17/23 axis are effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, a phenotype resembling atopic eczema occurring after biologic initiation for psoriasis, is unknown. This study aimed to explore the systemic disease signature of paradoxical eczema occurring in psoriasis patients treated with biologics. Peripheral blood mononuclear cells (PBMCs) from three patients with paradoxical eczema (two on adalimumab, one on guselkumab), six matched psoriasis controls receiving biologics and five healthy volunteers were subjected to staining for surface markers and eight intracellular cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon alpha (IFNa), interferon gamma (IFNg), IL-4, IL-10, IL-13, IL-17a, TNF. Prior to staining, PBMCs from each donor were either stimulated with phorbol 12-myristate 13-acetate/ionomycin or left unstimulated. Mass cytometry was used to compare cell-type abundance and cell-type (cluster)-specific cytokine expression. After data cleaning, there were 8 613 686 live singlets which were clustered using FlowSOM and manually annotated based on canonical marker expression. There was lower abundance (false discovery rate adjusted P < 0.1) of the CD4 natural killer T (NKT) (logFC −5.17), CD8 NKT (logFC −4.16) and CD8 mucosal-associated invariant T (MAIT)/NKT (logFC −2.76) clusters in paradoxical eczema cases relative to psoriasis controls; the findings were similar for stimulated cells. Compared with healthy controls, cases had a lower abundance (adjusted P < 0.1) of the CD8 MAIT/NKT (logFC −4.17) and CD56dim NK (logFC −2.64) clusters. TNF expression was higher across most unstimulated cell clusters in cases than controls (36 out of 41 clusters), with 18 reaching statistical significance (adjusted P < 0.1) including CD4 T cells, CD8 T cells, gdT cells, B cells and NK cells. IFN-γ was more highly expressed in 21 case clusters encompassing CD4 T cells, CD8 T cells, gdT cells, B cells, monocytes and NK cells. In cases relative to controls, IFN-α was more highly expressed in the double-negative B (IgD− CD27−), Naive B, CD4 Naive, CD8 Naive and CD4+CD8+ Naive T-cell clusters; there was a lower expression in CD14 (classical) monocytes. There were few differences in GM-CSF, IL-4, IL-10, IL-13 and IL-17A expression between group clusters. On stimulation, there were no differences between case and control cytokine expression. These findings suggest that the systemic signature of paradoxical eczema is characterized by Type 1 inflammation and a reduced systemic cytolytic/NKT signature. Further work is required to establish the disease signature in skin and identify if Type 1 inflammation is the primary pathophysiological process in paradoxical eczema or a reactive phenomenon.
Published Version
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