Zavoriti Aliki, Miossec Pierre
Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
ACR Open Rheumatol. 2025 Jan;7(1):e11790. doi: 10.1002/acr2.11790.
Inflammation drives cardiovascular disease in rheumatoid arthritis (RA). Treatment with tofacitinib, a JAK1/JAK3 inhibitor, is associated with increased cardiovascular events in patients with RA. Here, we determined its effects on cytokine production during interactions between immune cells at the synovial and vascular levels and its impact on endothelial activation and coagulation during inflammation.
Activated human peripheral blood mononuclear cells (PBMCs) were cocultured with RA synoviocytes or endothelial cells (ECs) mimicking the cellular interactions in synovium and vessels responsible for cytokine production. A dose-response of tofacitinib was tested on interferon γ, interleukin (IL) 17A, IL-10, IL-6, and IL-1β, and cytokine production was measured by enzyme-linked immunosorbent assay at 48 hours. Endothelial activation was induced with IL-17A and tumor necrosis factor (TNF) or on contact with PBMCs. Shortly after tofacitinib treatment, the expression of EC activation markers, specifically IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, and of coagulation, including tissue factor and thrombomodulin, was assessed by real-time polymerase chain reaction.
Tofacitinib differentially inhibited production of IFNɣ, IL-17A, and IL-10 from PBMC cocultures with RA synoviocytes or ECs (all P < 0.001). In cocultures with ECs, tofacitinib reduced further IL-6 and IL-8 production (both P < 0.001). In ECs activated by TNF/IL-17A or indirectly via contact with activated PBMCs, tofacitinib decreased IL-6 upregulation but not that of IL-8, E-selectin, or tissue factor. Thrombomodulin was significantly decreased. VCAM-1 was greatly induced with a higher dose of tofacitinib in ECs incubated directly with added inflammatory cytokines (P < 0.05) or released by interaction with activated PBMCs (P < 0.001).
Tofacitinib inhibits synovium and vascular inflammation but fails to prevent the prothrombotic effects of inflammatory cytokines on ECs.
炎症驱动类风湿关节炎（RA）患者发生心血管疾病。JAK1/JAK3抑制剂托法替布治疗与RA患者心血管事件增加相关。在此，我们确定了其在滑膜和血管水平免疫细胞相互作用期间对细胞因子产生的影响，以及其在炎症期间对内皮细胞活化和凝血的影响。
将活化的人外周血单个核细胞（PBMC）与RA滑膜细胞或内皮细胞（EC）共培养，模拟滑膜和血管中负责细胞因子产生的细胞间相互作用。对托法替布进行剂量反应测试，观察其对干扰素γ、白细胞介素（IL）-17A、IL-10、IL-6和IL-1β的影响，并在48小时时通过酶联免疫吸附测定法测量细胞因子的产生。用IL-17A和肿瘤坏死因子（TNF）诱导内皮细胞活化，或使其与PBMC接触诱导活化。在托法替布治疗后不久，通过实时聚合酶链反应评估EC活化标志物的表达，特别是IL-6、IL-8、血管细胞黏附分子1（VCAM-1）和E-选择素，以及凝血相关标志物，包括组织因子和血栓调节蛋白。
托法替布不同程度地抑制PBMC与RA滑膜细胞或EC共培养时IFNɣ、IL-17A和IL-10的产生（所有P<0.001）。在与EC的共培养中，托法替布进一步降低IL-6和IL-8的产生（均P<0.001）。在由TNF/IL-17A或通过与活化PBMC接触间接激活的EC中，托法替布降低IL-6上调，但不降低IL-8、E-选择素或组织因子的上调。血栓调节蛋白显著降低。在直接与添加的炎性细胞因子孵育的EC中，较高剂量的托法替布可显著诱导VCAM-1表达（P<0.05），或通过与活化PBMC相互作用释放VCAM-1（P<0.001）。
托法替布可抑制滑膜和血管炎症，但未能预防炎性细胞因子对EC的促血栓形成作用。
