系统性硬化症和混合性结缔组织病中循环内皮抑素水平与血管器官损伤的关联：一项观察性研究。
Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study.
作者信息
Reiseter Silje, Molberg Øyvind, Gunnarsson Ragnar, Lund May Brit, Aalokken Trond Mogens, Aukrust Pål, Ueland Thor, Garen Torhild, Brunborg Cathrine, Michelsen Annika, Abraityte Aurelija, Hoffmann-Vold Anna-Maria
机构信息
Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway.
Department of Rheumatology, Oslo University Hospital Rikshospitalet, 0424, Oslo, Norway.
出版信息
Arthritis Res Ther. 2015 Aug 28;17(1):231. doi: 10.1186/s13075-015-0756-5.
INTRODUCTION
Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD.
METHODS
Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay.
RESULTS
Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2-29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3-100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2-17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2-2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0-2.4, P = .041) in the MCTD cohort after adjustments to known risk factors.
CONCLUSIONS
Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.
引言
系统性硬化症（SSc）和混合性结缔组织病（MCTD）是慢性免疫介导的疾病，常伴有血管器官损伤。本研究旨在检测未经选择的SSc和MCTD队列中血清新生血管生成标志物内皮抑素和血管内皮生长因子（VEGF）的水平。
方法
纳入来自挪威两个纵向队列的SSc患者（N = 298）和MCTD患者（N = 162）的血清。将献血者作为对照（N = 100）。采用酶免疫测定法分析循环中的VEGF和内皮抑素。
结果
与对照组65.1（12）ng/ml相比，SSc患者的平均内皮抑素水平升高至93.7（37）ng/ml（P <.001），MCTD患者升高至83.2（25）ng/ml（P <.001）。SSc患者的VEGF中位数水平为209.0（202）pg/ml，高于MCTD患者的181.3（175）pg/ml（P =.017）和对照组的150.0（145）pg/ml（P <.001）。对SSc亚组的多变量分析显示，肺动脉高压（系数15.7，95%CI：2.2 - 29.2，P =.023）和硬皮病肾危象（系数77.6，95%CI：59.3 - 100.0，P <.001）与内皮抑素水平升高相关。对MCTD亚组的多变量分析显示，指端溃疡与内皮抑素水平升高相关（系数10.5，95%CI：3.2 - 17.8，P =.005）。在对已知风险因素进行调整后，SSc队列中内皮抑素每增加1个标准差，死亡风险增加1.6（95%CI：1.2 - 2.1，P =.001）；MCTD队列中内皮抑素每增加1个标准差，死亡风险增加1.6（95%CI：1.0 - 2.4，P =.041）。
结论
SSc和MCTD患者的内皮抑素水平升高，特别是合并肺动脉高压和硬皮病肾危象的SSc患者以及有指端溃疡的MCTD患者。在两组患者的随访期间，内皮抑素水平升高还与全因死亡率增加相关。我们认为内皮抑素可能提示SSc和MCTD患者的血管损伤程度。
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