Odler Balazs, Foris Vasile, Gungl Anna, Müller Veronika, Hassoun Paul M, Kwapiszewska Grazyna, Olschewski Horst, Kovacs Gabor
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.
Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Front Physiol. 2018 Jun 19;9:587. doi: 10.3389/fphys.2018.00587. eCollection 2018.
Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT-proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH.
肺动脉高压（PAH）是系统性硬化症（SSc）的一种严重并发症，具有高发病率和死亡率。SSc-PAH有多种生物标志物，反映内皮生理、炎症、免疫激活、细胞外基质、代谢变化或心脏受累情况。已确定了与诊断、疾病严重程度和进展相关的生物标志物，然而，很少有在前瞻性研究中进行测试的。一些抗核抗体，如核小体抗体（NUC）、抗着丝粒抗体（CENP-A/B）和抗U3核糖核蛋白（抗U3-RNP）与PAH相关，而抗U1核糖核蛋白（抗U1-RNP）与PAH风险降低相关。抗内皮素受体和血管紧张素-1受体抗体可能是SSc-PAH和肺血管病变进展的良好标志物。关于反映免疫激活和炎症的标志物，有许多不一致的结果。CXCL-4与SSc进展相关，包括PAH和肺纤维化。生长分化因子（GDF）-15与PAH和死亡率相关，但并非SSc所特有。在代谢产物中，犬尿氨酸被确定为PAH的诊断标志物，然而，其在疾病中的病理作用尚不清楚。内皮抑素是一种血管生成抑制因子，与心力衰竭和预后不良相关。已确立的心脏相关标志物，如A型利钠肽/脑利钠肽的N末端片段（NT-proANP、NT-proBNP）或肌钙蛋白I/T在SSc-PAH中升高，但并非右心室所特有，在左心疾病中可能会升高到相同程度。综上所述，SSc-PAH没有通用的特异性生物标志物，然而，有一组标志物与SSc患者血管并发症风险密切相关。有必要进行进一步全面、多中心和前瞻性研究，以开发用于检测和预测SSc-PAH的可靠算法。
