Whole blood transcriptome profiling in patients treated with deucravacitinib and novel mechanistic insights into TYK2 inhibition in lupus: results from a post hoc analysis of the PAISLEY SLE phase 2 trial.

Methods

RNA sequencing (RNA-seq) was performed on samples collected from baseline to week 32 in 363 patients and 56 healthy volunteers.

在363名患者和56名健康志愿者中，从基线到第32周收集的样本进行了RNA测序（RNA-seq）。

Pharmacodynamics of differentially expressed genes (DEGs) were analysed with linear mixed-effects models using the statistical software package DREAM (differential expression for repeated measures).

使用统计软件包DREAM（重复测量的差异表达）通过线性混合效应模型分析了差异表达基因（DEGs）的药效学。

Single-sample gene set enrichment analysis (ssGSEA) was performed using MSigDB Hallmark and BloodGen3 gene modules.

使用MSigDB标志和BloodGen3基因模块进行了单样本基因集富集分析（ssGSEA）。

The xCell R package was used to digitally portray the blood cellular heterogeneity landscape.

使用了xCell R包来数字化描绘血液细胞异质性的景观。

Results

At baseline, 527 DEGs were identified in patients with SLE vs healthy volunteers (log2 fold change >1; adjusted P < .05).

在基线时，与健康志愿者相比，在系统性红斑狼疮患者中识别出527个差异表达基因（log2倍数变化>1；调整后的P<.05）。

Deucravacitinib modulated up to 2529 genes and SLE-relevant gene sets, including interferon-regulated genes. ssGSEA showed that plasma cell gene sets decreased and myeloid cell gene sets reverted towards normal levels with deucravacitinib; xCell deconvolution revealed significant enrichment of dendritic cell populations with deucravacitinib vs placebo.

Deucravacitinib 调控了多达 2529 个基因和与系统性红斑狼疮（SLE）相关的基因集，包括干扰素调节的基因。单样本基因集富集分析（ssGSEA）显示，浆细胞基因集随着 deucravacitinib 的使用而减少，髓系细胞基因集趋向于正常水平；xCell 解卷积揭示了与安慰剂相比，deucravacitinib 显著富集了树突状细胞群体。

At baseline, regulatory T-cell gene sets were increased in patients with SLE vs healthy volunteers and further increased with deucravacitinib.

在基线时，与健康志愿者相比，系统性红斑狼疮（SLE）患者的调节性 T 细胞基因集增加，并且随着 deucravacitinib 的使用而进一步增加。

There were some variable, dose-dependent increases in naïve and memory B lymphocytes.

在未成熟和记忆B淋巴细胞中观察到一些剂量依赖性的变化。

Conclusions

Whole blood transcriptome profiling via RNA-seq revealed both expected and novel gene expression changes with deucravacitinib across multiple pathogenic pathways.

通过RNA测序的全血转录组分析揭示了deucravacitinib在多个病理途径上预期和新颖的基因表达变化。

These data demonstrate successful targeting of pathophysiologic immune mechanisms that should be validated in future studies and support continued evaluation of deucravacitinib in the phase 3 POETYK SLE trials.

这些数据展示了成功靶向病理生理免疫机制，这应在未来的试验中得到验证，并支持在第三阶段POETYK SLE试验中继续评估deucravacitinib。