Rheumatoid arthritis (RA) is a disease associated with circadian disorders of steroid hormones or cytokine secretion which induce inflammatory, destructive and proliferative processes in the synovial joints. Angiogenesis plays an important role in RA, but circadian rhythms of the angiogenic mediator production, especially endothelial nitric oxide synthase (NOS3), are still unclear. NOS3 takes part in regulation of endothelial functions, inflammation, and bone remodeling process. Studying circadian rhythms of NOS3 production in RA patients will make an improvement in understanding the angiogenic-inflammatory pathways relevant to rheumatic diseases. The aim of the study was to test the hypothesis of a diurnal variation in circulating levels of NOS3 in RA patients. A cross-sectional monocentric pilot study of circadian variability of endothelial nitric oxide synthase in a Ukrainian population was conducted between March and July 2017. We examined 36 RA patients (100% women) and 34 age-matched healthy women without joint diseases and autoimmune diseases (control). Blood samples were collected four times per day (at 08:00; 14:00; 20:00 and 02:00) for two consecutive days. Serum NOS3 concentration was measured by ELISA (Cloud-Clone Corp kit). The study was conducted in compliance with bioethical standards. The SPSS22 software package was used for statistical processing of the results. A diurnal variation in circulating levels of NOS3 in healthy women was established, with peak values appearing in the evening and acrophase at 20:00, and low values in the morning, with batiphase at 08:00. In patients with RA serum, NOS3 levels were substantially decreased throughout the day compared to the control. In RA patients, a diurnal variation in circulating levels of NOS3 was also established. However, the variability of NOS3 production was higher in RA patients than in the control group. For example, in RA patients the difference between morning/evening values of NOS3 was 1.3 times higher (p < 0.05) than in the control. Negative correlations were found between the morning NOS3 levels and RA activity markers such as DAS28 and the number of tender and swollen joints. The diurnal variation in circulating levels of NOS3 in women with RA as well as in healthy women was found. However, in RA patients, a decrease in NOS3 production was observed, especially in the morning, which was associated with an increase in the disease activity. Thus, the circadian rhythm of circulating NOS3 can be opposite to the circadian rhythm of secretion of main inflammatory regulators in RA.

中文翻译：

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类风湿关节炎女性的内皮型一氧化氮合酶活性的昼夜节律波动：一项前瞻性研究。

类风湿关节炎（RA）是一种与类固醇激素或细胞因子分泌的昼夜节律紊乱有关的疾病，会引起滑膜关节的炎症，破坏性和增生过程。血管生成在RA中起重要作用，但是尚不清楚血管生成介质产生的昼夜节律，尤其是内皮型一氧化氮合酶（NOS3）。NOS3参与调节内皮功能，炎症和骨骼重塑过程。研究RA患者的NOS3昼夜节律将改善对与风湿性疾病相关的血管生成-炎症途径的了解。该研究的目的是检验RA患者NOS3循环水平昼夜变化的假说。2017年3月至2017年7月间，对乌克兰人群中内皮一氧化氮合酶的昼夜节律变异性进行了横断面单中心先导研究。我们检查了36例RA患者（100％为女性）和34例年龄相匹配的健康女性，无关节病和自身免疫性疾病（控制）。连续两天每天（在08：00、14：00、20：00和02:00）每天采集四次血样。通过ELISA（Cloud-Clone Corp试剂盒）测量血清NOS 3浓度。该研究是按照生物伦理标准进行的。SPSS22软件包用于结果的统计处理。建立了健康女性中NOS3循环水平的昼夜变化，峰值出现在傍晚和顶峰20:00，早晨出现低峰值，batiphase在08:00。与对照组相比，RA血清患者全天NOS3水平显着下降。在RA患者中，还确定了NOS3循环水平的昼夜变化。但是，RA患者中NOS3产生的变异性高于对照组。例如，在RA患者中，NOS3早/晚值之间的差异是对照组的1.3倍（p <0.05）。早晨的NOS3水平和RA活动标志物（例如DAS28）与关节的柔软和肿胀数目之间存在负相关。发现RA妇女以及健康妇女的NOS3循环水平存在昼夜变化。但是，在RA患者中，观察到NOS3产生减少，尤其是在早晨，这与疾病活动增加有关。从而，