Determinants of Progression and Mortality in Lymphangioleiomyomatosis
Determinants of Progression and Mortality in Lymphangioleiomyomatosis
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DOI：
10.1016/j.chest.2023.02.026
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发表时间：
2023-07-07
期刊：
影响因子：
9.6
通讯作者：
Xu, Kai -Feng
中科院分区：
文献类型：
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作者：
Xu, Wenshuai;Yang, Chenlu;Xu, Kai -Feng
背景：淋巴管平滑肌瘤病是一种进行性弥漫性囊性肺疾病，10年生存率约为85%。在引入西罗莫司治疗和血管内皮生长因子D（VEGF-D）作为生物标志物后，疾病进展和死亡的决定因素尚未得到很好的定义。研究问题：哪些因素，包括VEGF-D和西罗莫司治疗，影响淋巴管平滑肌瘤病患者的疾病进展和生存预后？研究设计和方法：进展数据集和生存数据集分别包括来自中国北京协和医院的282例和574例患者。采用混合效应模型计算FEV 1下降率，采用广义线性模型确定影响FEV 1下降的变量。采用考克斯比例风险模型分析淋巴管平滑肌瘤病患者的临床变量与死亡或肺移植结局之间的关系。结果：VEGF-D水平和西罗莫司治疗与FEV 1变化和生存预后相关。与基线时VEGF-D < 800 pg/mL的患者相比，VEGF-D <800 pg/mL的患者FEV 1损失更快（SE，-38.86 mL/y; 95% CI，-73.90至-3.82 mL/ y; P = 0.031）。VEGF-D > 2,000 pg/mL和< 2,000 pg/mL患者的8年累积生存率分别为82.9%和95.1%（P = 0.014）。广义线性回归模型也显示，与未使用西罗莫司的患者相比，使用西罗莫司的患者FEV 1下降延迟65.56 mL/y（95% CI，29.06-102.06 mL/y）（P < .001）。西罗莫司治疗后，8年死亡风险降低85.1%（风险比，0.149; 95% CI，0.075-0.299）。经过逆治疗概率加权后，西罗莫司组的死亡风险降低了85.6%。与I级或II级严重程度的结果相比，III级严重程度的CT扫描结果与更差的进展相关。基线FEV 1为70%预测值或圣乔治呼吸问卷症状域50或更高的患者预测较差survival.Interpretation：血清VEGF-D水平，淋巴管平滑肌瘤病的生物标志物，与疾病进展和生存率相关。西罗莫司治疗与淋巴管平滑肌瘤病患者的疾病进展较慢和生存期较好相关。试验注册：ClinicalTrials.gov;编号：NCT03193892; URL：www.clinicaltrials.gov
BACKGROUND: Lymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mor-tality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined. RESEARCH QUESTION: Which factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?STUDY DESIGN AND METHODS: The progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the out-comes of death or lung transplantation in patients with lymphangioleiomyomatosis.RESULTS: VEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of & GE; 800 pg/mL lost FEV1 faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/ y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of & GE; 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival.INTERPRETATION: Serum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis.TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03193892; URL: www.clinicaltrials.gov