O05 Single-cell transcriptomic signature of paradoxical eczema in patients with psoriasis treated with biologics

Abstract

Abstract Introduction and aims Biologics targeting the tumour necrosis factor (TNF) and the interleukin (IL)-17/23 axis are highly effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, an atopic dermatitis (AD) phenotype occurring after biologic initiation in people with psoriasis, is unknown. This study explored the systemic disease signature of paradoxical eczema. Methods We used single-cell RNA-Seq on peripheral blood mononuclear cells (PBMCs) from three patients with psoriasis with paradoxical eczema, and three matched, biologic-treated controls who had psoriasis. Differential gene expression, gene network expression and cell–cell interaction (using MultiNicheNet) analyses allowed comparison of cases and controls. We assessed overlap between paradoxical eczema and AD using six AD transcriptome datasets. Results Overall, 32 827 PBMCs (14 521 from cases, 18 306 from controls) were included and categorized into 27 clusters. Between cases and controls, there were 727 differentially expressed genes (DEGs) (log fold-change > 0.25, adjusted P < 0.05). A total of 94 of the top 100 DEGs were from monocytes. Significant DEG networks (P < 0.05) mostly mapped to T-cell and monocyte clusters, with commonly enriched pathways in cases including interferon (IFN)-γ, IFN-α, TNF, IL-2/signal transducer and activator of transcription 5 and T-cell differentiation pathways. Cell–cell interaction analysis revealed that the most prioritized interactions in controls, based on differential expression data and known ligand-receptor interactions, included immune regulatory interactions (including ligands such as transforming growth factor β1 and lymphocyte-activation gene 3). In cases, functions of prioritized interactions included chemotaxis, leucocyte activation, T-cell priming and IFN-γ signalling. There was significant enrichment of concordance in the direction of effect of DEGs (65%, P = 5.39 × 10−6) and enriched pathways (85%, P = 3.62 × 10−13) between AD and paradoxical eczema. Conclusions Patients with paradoxical eczema have reduced immune regulatory mechanisms and evidence of monocyte and T-cell activation systemically, with increased production IFN-γ, IFN-α and TNF. There is a significant overlap with the AD transcriptome.