结缔组织病相关肺动脉高压的临床特点及预后危险因素分析

Clinical characteristics and prognostic risk factors of connective tissue disorders associated pulmonary arterial hypertension

摘要:

目的： 探讨结缔组织病相关肺动脉高压（connective tissue disorders associated pulmonary arterial hypertension，CTD-PAH）患者的临床特点及预后的临床危险因素。方法： 以2011年1月至2018年12月河北北方学院附属第一医院风湿免疫科和皮肤科住院及门诊收治的81例CTD-PAH患者为研究对象，其中系统性红斑狼疮相关肺动脉高压（systemic lupus erythematosus associated pulmonary arterial hypertension，SLE-PAH）36例，系统性硬化症相关肺动脉高压（systemic sclerosis associated pulmonary arterial hypertension，SSc-PAH）24例，原发性干燥综合征相关肺动脉高压（primary Sj?gren syndrome associated pulmonary arterial hypertension，pSS-PAH）21例。收集并分析这81例CTD-PAH患者的基线人口学资料、临床特征、经胸超声心动图相关指标和实验室检查结果。采用单因素和多因素Cox回归模型分析影响CTD-PAH患者生存预后的相关危险因素。结果： 81例CTD-PAH患者的平均年龄为（38.54±9.76）岁，57例（70.4%）伴有雷诺现象，女性77例（95.1%）。SLE-PAH（44.4%）是最常见的CTD-PAH，其次是SSc-PAH（29.6%）、pSS-PAH（25.9%）。自身抗体以抗U1核糖核蛋白（U1 ribonucleoprotein，U1RNP）抗体为主（56.8%）。SLE-PAH患者的发病年龄明显早于pSS-PAH和SSc-PAH患者（P<0.05）。81例CTD-PAH患者均完成随访，无一人失访。1、3、5年总体生存率分别为86.2%、77.9%、65.7%。其中SLE-PAH患者的1、3、5年总体生存率分别为94.4%、88.5%、78.5%，SSc-PAH患者依次为74.1%、63.9%、47.3%，pSS-PAH患者分别为85.7%、74.6%、62.6%。单因素Cox分析显示，CTD类型、心脏指数（cardiac index，CI）<2.0 L/（mL·m²）、合并轻度间质性肺病（interstitial lung disease，ILD）、6分钟步行距离（6-minute walking distance，6MWD）<440 m、红细胞分布宽度变异系数（red blood cell distribution width-coefficient of variation，RDW-CV）>15.0%、合并高尿酸血症（hyperuricemia，HUA）、世界卫生组织（World Health Organization，WHO）心功能分级为Ⅲ~Ⅳ级、合并雷诺现象、N末端B型利钠肽原（N-terminal pro-B-type natriuretic peptide，NT-proBNP）>1 400 ng/L及内皮素-1（endothelin-1，ET-1）>0.55 ng/L是影响CTD-PAH患者生存预后的相关因素（P<0.05）。经校正年龄、右心房压力（right atrial pressure，RAP）及平均肺动脉压（mean pulmonary artery pressure，mPAP）后，多因素Cox分析显示，SSc-PAH患者的死亡风险是SLE-PAH患者的3.728倍（P<0.05），6MWD<440 m的CTD-PAH患者的死亡风险是6MWD≥440 m者的5.629倍（P<0.05），RDW-CV>15.0%的CTD-PAH患者死亡风险是RDW-CV≤15%者的2.785倍（P<0.05），合并HUA的CTD-PAH患者死亡风险是未合并HUA者的3.978倍（P<0.05），血清ET-1浓度>0.55 ng/L的CTD-PAH患者死亡风险是血清ET-1浓度≤0.55 ng/L者的3.186倍（P<0.05）。结论： CTD-PAH患者以女性居多，主要临床表现为雷诺现象，过半数的患者抗U1RNP抗体阳性，SLE-PAH是最常见的CTD-PAH，SSc-PAH患者的预后最差。CTD类型、6MWD<440 m、RDW-CV>15.0%、合并HUA和血清ET-1水平>0.55 ng/L是CTD-PAH患者不良预后的独立危险因素。尽早识别存在预后不良因素的CTD-PAH患者，加强早期干预并积极有效随访，有助于改善患者长期预后。

Abstract:

Objective: To investigate the clinical characteristics and prognostic risk factors of patients with connective tissue disorders associated pulmonary arterial hypertension (CTD-PAH). Methods: In this study, 81 patients with CTD-PAH admitted to the Department of Rheumatology and Immunology and the Department of Dermatology in the First Affiliated Hospital of Hebei North University from January 2011 to December 2018 were selected as the research objects, among which, there were 36 cases of systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-PAH), 24 cases of systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH), and 21 cases of primary Sj?gren syndrome associated pulmonary arterial hypertension (pSS-PAH). Baseline demographic data, clinical features, transthoracic echocardiography related parameters and laboratory findings of these 81 CTD-PAH patients were collected and analyzed. Univariate and multivariate Cox regression models were used to analyze the related risk factors for survival and prognosis in patients with CTD-PAH. Results: The mean age of 81 CTD-PAH patients was (38.54±9.76) years old, 57 cases (70.4%) with Raynaud’s phenomenon, and 77 cases (95.1%) of females. SLE-PAH was the most common type of CTD-PAH (44.4%), followed by SSc-PAH (29.6%) and pSS-PAH (25.9%). Autoantibodies were mainly anti-U1 ribonucleoprotein (U1RNP) (56.8%). The onset age of SLE-PAH patients was significantly earlier than that of pSS-PAH and SSc-PAH patients (P<0.05). All the 81 patients with CTD-PAH were followed up, and no one was lost. The overall 1-, 3-and 5-year survival rates were 86.2%, 77.9% and 65.7%, respectively. The 1-, 3-and 5-year overall survival rates of SLE-PAH patients were 94.4%, 88.5% and 78.5%, those of SSc-PAH patients were 74.1%, 63.9% and 47.3% respectively, and those of pSS-PAH patients were 85.7%, 74.6% and 62.6% respectively. Univariate Cox analysis showed: CTD type, cardiac index (CI) <2.0 L/ (mL·m²), combined with mild interstitial lung disease (ILD), 6-minute walking distance (6MWD) <440 m, red blood cell distribution width-coefficient of variation (RDW-CV) >15.0%, combined with hyperuricemia (HUA), World Health Organization (WHO) cardiac function classification ofⅢtoⅣ, combined with Raynaud’s phenomenon, N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1 400 ng/L and endothelin-1 (ET-1) >0.55 ng/L were related factors affecting survival and prognosis of patients with CTD-PAH (P<0.05). After adjusting for age, right atrial pressure (RAP) and mean pulmonary artery pressure (mPAP), multivariate Cox analysis showed that the mortality in SSc-PAH patients was 3.728 times higher than that in SLE-PAH patients (P<0.05), that of 6 MWD<440 m CTD-PAH patients was 5.629 times than that of 6MWD≥440 m patients (P<0.05), that of RDW-CV>15.0% CTD-PAH patients was 2.785 times than that of RDW-CV≤15% patients (P<0.05), that of patients combined with HUA was 3.978 times higher than that of non-HUA patients (P<0.05), that of the CTD-PAH patients with ET-1 concentration>0.55 ng/L was 3.186 times higher than that of CTD-PAH patients with ET-1 concentration≤0.55 ng/L (P<0.05). Conclusion: The majority of CTD-PAH patients are female, and the main clinical manifestations are combination of Raynaud’s phenomenon, and more than half of the patients with present anti-U1RNP antibody. SLE-PAH is the most common type of CTD-PAH and SSc-PAH has the worst prognosis. CTD type, 6 MWD<440 m, RDW-CV>15.0%, combined HUA and serum ET-1 level>0.55 ng/L are independent risk factors for poor prognosis in patients with CTD-PAH. Early identification of CTD-PAH patients with poor prognosis, early intervention and active and effective follow-up are helpful to improve the long-term prognosis of patients.