Kacsándi Dorottya, Fagyas Miklós, Horváth Ágnes, Végh Edit, Pusztai Anita, Czókolyová Monika, Soós Boglárka, Szabó Attila Ádám, Hamar Attila, Pethő Zsófia, Bodnár Nóra, Kerekes György, Hodosi Katalin, Szamosi Szilvia, Szűcs Gabriella, Papp Zoltán, Szekanecz Zoltán
Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Front Med (Lausanne). 2023 Oct 9;10:1226760. doi: 10.3389/fmed.2023.1226760. eCollection 2023.
The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers.
Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment.
After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy ( < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) ( < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively ( < 0.05).
JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.
肾素-血管紧张素-醛固酮系统（RAAS）与心血管系统的调节有关，并与类风湿关节炎（RA）相关。关于Janus激酶（JAK）抑制对RAAS的影响，目前可用信息较少。在此，我们研究了托法替布治疗12个月对RA患者血管紧张素转换酶（ACE）、ACE2生成及ACE/ACE2比值的影响，同时还研究了许多其他生物标志物。
在这项前瞻性研究中，30例RA患者接受了托法替布治疗。采用酶联免疫吸附测定法（ELISA）评估血清ACE浓度。通过一种特异性淬灭荧光底物测定ACE2活性。计算ACE/ACE2比值。我们还通过超声测定了颈总动脉内膜中层厚度（ccIMT）、肱动脉血流介导的血管舒张功能（FMD）和颈股脉搏波速度（cfPWV）。还测定了C反应蛋白（CRP）、类风湿因子（RF）和抗瓜氨酸化蛋白自身抗体（ACPA）。所有测量均在基线时以及托法替布治疗6个月和12个月后进行。
4例患者退出研究后，26例完成了研究。托法替布治疗6个月和12个月后ACE水平升高，而ACE2活性仅在6个月时短暂升高。治疗1年后ACE/ACE2比值升高（<0.05）。逻辑回归分析确定了不同时间点ACE、ACE2或ACE/ACE2比值与RF之间的相关性。基线病程也与红细胞沉降率（ESR）相关（<0.05）。托法替布治疗加ACPA或RF分别决定了ACE或ACE2的一年变化（<0.05）。
JAK抑制可增加RA患者血清ACE及ACE/ACE2比值。基线炎症（ESR）、病程以及不同时间点的ACPA和RF水平可与ACE/ACE2比值的调节相关联。托法替布对RAAS的影响为JAK抑制在RA中的心血管效应提供了一个合理的解释。
