Department of Rheumatology, University of Debrecen, 4032 Debrecen, Hungary.
Department of Biophysics and Cell Biology, University of Debrecen, 4032 Debrecen, Hungary.
Biomolecules. 2022 Oct 14;12(10):1483. doi: 10.3390/biom12101483.
Background: Cardiovascular (CV) morbidity, mortality and metabolic syndrome are associated with rheumatoid arthritis (RA). A recent trial has suggested increased risk of major CV events (MACE) upon the Janus kinase (JAK) inhibitor tofacitinib compared with anti-tumor necrosis factor α (TNF-α) therapy. In our study, we evaluated lipids and other metabolic markers in relation to vascular function and clinical markers in RA patients undergoing one-year tofacitinib therapy. Patients and methods: Thirty RA patients treated with either 5 mg or 10 mg bid tofacitinib were included in a 12-month follow-up study. Various lipids, paraoxonase (PON1), myeloperoxidase (MPO), thrombospondin-1 (TSP-1) and adipokine levels, such as adiponectin, leptin, resistin, adipsin and chemerin were determined. In order to assess flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and arterial pulse-wave velocity (PWV) ultrasonography were performed. Assessments were carried out at baseline, and 6 and 12 months after initiating treatment. Results: One-year tofacitinib therapy significantly increased TC, HDL, LDL, APOA, APOB, leptin, adipsin and TSP-1, while significantly decreasing Lp(a), chemerin, PON1 and MPO levels. TG, lipid indices (TC/HDL and LDL/HDL), adiponectin and resistin showed no significant changes. Numerous associations were found between lipids, adipokines, clinical markers and IMT, FMD and PWV (p < 0.05). Regression analysis suggested, among others, association of BMI with CRP and PWV (p < 0.05). Adipokines variably correlated with age, BMI, CRP, CCP, FMD, IMT and PWV, while MPO, PON1 and TSP-1 variably correlated with age, disease duration, BMI, RF and PWV (p < 0.05). Conclusions: JAK inhibition by tofacitinib exerts balanced effects on lipids and other metabolic markers in RA. Various correlations may exist between metabolic, clinical parameters and vascular pathophysiology during tofacitinib treatment. Complex assessment of lipids, metabolic factors together with clinical parameters and vascular pathophysiology may be utilized in clinical practice to determine and monitor the CV status of patients in relation with clinical response to JAK inhibition.
心血管（CV）发病率、死亡率和代谢综合征与类风湿关节炎（RA）有关。最近的一项试验表明，与抗肿瘤坏死因子-α（TNF-α）治疗相比，Janus 激酶（JAK）抑制剂托法替布增加了主要心血管事件（MACE）的风险。在我们的研究中，我们评估了接受托法替布治疗一年的 RA 患者的血管功能和临床标志物与血脂和其他代谢标志物的关系。
30 名接受托法替布 5mg 或 10mg 每日两次治疗的 RA 患者纳入为期 12 个月的随访研究。测定了各种血脂、对氧磷酶（PON1）、髓过氧化物酶（MPO）、血栓调节蛋白-1（TSP-1）和脂联素、瘦素、抵抗素、阿狄森素和 chemerin 等脂肪因子水平。为了评估血流介导的血管扩张（FMD），进行了颈总动脉内膜中层厚度（IMT）和动脉脉搏波速度（PWV）超声检查。在开始治疗前、治疗后 6 个月和 12 个月进行评估。
托法替布治疗 1 年显著增加了 TC、HDL、LDL、APOA、APOB、瘦素、阿狄森素和 TSP-1，而显著降低了 Lp(a)、chemerin、PON1 和 MPO 水平。TG、血脂指数（TC/HDL 和 LDL/HDL）、脂联素和抵抗素无显著变化。在血脂、脂肪因子、临床标志物和 IMT、FMD 和 PWV 之间发现了许多关联（p<0.05）。回归分析表明，BMI 与 CRP 和 PWV 相关（p<0.05）。脂肪因子与年龄、BMI、CRP、抗环瓜氨酸肽（CCP）、FMD、IMT 和 PWV 呈不同程度相关，而 MPO、PON1 和 TSP-1 与年龄、疾病持续时间、BMI、RF 和 PWV 呈不同程度相关（p<0.05）。
托法替布抑制 JAK 对 RA 患者的血脂和其他代谢标志物产生平衡作用。在托法替布治疗期间，可能存在代谢、临床参数和血管病理生理学之间的各种关联。在临床实践中，对血脂、代谢因素以及临床参数和血管病理生理学进行综合评估，可能有助于确定和监测与 JAK 抑制的临床反应相关的患者的心血管状态。
