Current knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.

Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.

Tofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.

Tofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

目前关于托法替尼对类风湿性关节炎 (RA) 细胞因子信号通路作用的认识是基于 体外学习。我们的研究是第一个检查托法替尼治疗对 Janus 激酶 (JAK) - 信号转导和转录激活剂 (STAT) 通路的影响的研究体内 在 RA 患者中。

16 名活动性 RA 患者，尽管接受了传统的合成疾病缓解抗风湿药物 (csDMARDs) 治疗，但仍接受了托法替尼 5 mg，每天两次，持续三个月。在基线和三个月访问时，通过流式细胞术测量外周血单核细胞、T 细胞和 B 细胞中组成型和细胞因子诱导的磷酸化 STAT 的水平。通过定量 PCR 从外周血单核细胞 (PBMC) 测量 JAK、STAT 和细胞因子信号抑制因子 (SOCS) 的 mRNA 表达。还研究了基线信号特征与治疗反应的关联。

在 csDMARDs 背景下，托法替尼将疾病活动性评分中位数 (DAS28) 从 4.4 降低至 2.6（p < 0.001）。托法替尼治疗显着降低了所有研究的 JAK-STAT 通路的细胞因子诱导的磷酸化。然而，抑制作用的大小取决于所研究的细胞因子和细胞类型，在用托法替尼治疗 3 个月后，抑制作用从 10% 到 73% 不等。一般而言，通过 T 细胞中的共同 γ 链细胞因子受体通过细胞因子信号传导诱导 STAT 磷酸化，观察到托法替尼的最强抑制作用，而对单核细胞中 IL-10 诱导的 STAT3 磷酸化显示出最低的抑制作用。单核细胞和/或 T 细胞中的组成型 STAT1、STAT3、STAT4 和 STAT5 磷酸化也被托法替尼下调。托法替尼治疗下调了 PBMC 中几种 JAK-STAT 通路成分的表达，SOCS 显示出最强的下调。T 细胞和单核细胞中的基线 STAT 磷酸化水平以及 PBMC 中的 SOCS3 表达与治疗反应相关。

Tofacitinib 在 RA 患者中以细胞因子和细胞群特异性方式抑制多个 JAK-STAT 通路 体内. 除了直接抑制 JAK 激活外，托法替尼还能下调 JAK-STAT 通路成分的表达。这可能会调节托法替尼对 JAK-STAT 通路激活的影响体内 并解释当前研究与先前研究之间的一些不同发现 体外学习。最后，基线免疫标志物与对托法替尼的治疗反应相关。