University of Cincinnati, Cincinnati, OH, USA.
University of South Florida, Tampa, FL, USA.
Eur Respir J. 2019 Apr 4;53(4). doi: 10.1183/13993003.02066-2018. Print 2019 Apr.
The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical and physiological patient characteristics on disease progression and treatment response in LAM.
MILES subjects were stratified on the basis of menopausal status (pre-menopausal/post-menopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial forced expiratory volume in 1 s (FEV; 51-70% ≤50% predicted) and tuberous sclerosis complex (TSC) association (yes/no). A linear mixed effects model was used to compare slope differences, and nonparametric tests were used to compare medians and proportions between treatment groups in each stratum.
In the MILES placebo group, pre-menopausal patients declined 5-fold faster than post-menopausal patients (mean±se FEV slope -17±3 -3±3 mL·month; p=0.003). Upon treatment with sirolimus, both the pre-menopausal (-17±3 -1±2 mL·month; p<0.0001) and post-menopausal patients (-3±3 6±3 mL·month; p=0.04) exhibited a beneficial response in mean±se FEV slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness or baseline FEV did not impact the rate of disease progression in the placebo group or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum vascular endothelial growth factor (VEGF)-D >600 pg·mL identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus.
In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV or TSC association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.
多中心国际淋巴管平滑肌瘤病（LAM）雷帕霉素疗效（MILES）试验表明，雷帕霉素稳定了中重度 LAM 患者的肺功能。本研究的目的是进一步检查 MILES 队列中种族、人口统计学、临床和生理患者特征对 LAM 疾病进展和治疗反应的影响。
根据绝经状态（绝经前/绝经后）、种族（亚洲/高加索人）、支气管扩张剂反应性（存在/不存在）、初始用力呼气量（FEV；51-70%≤50%预计值）和结节性硬化症复合物（TSC）关联（是/否）对 MILES 受试者进行分层。使用线性混合效应模型比较斜率差异，非参数检验用于比较每个分层中治疗组之间的中位数和比例。
在 MILES 安慰剂组中，绝经前患者的 FEV 下降速度比绝经后患者快 5 倍（平均±se FEV 斜率-17±3-3±3mL·月；p=0.003）。接受雷帕霉素治疗后，绝经前（-17±3-1±2mL·月；p<0.0001）和绝经后患者（-3±3 6±3mL·月；p=0.04）的 FEV 平均斜率均较安慰剂组有获益。种族、LAM 亚型、支气管扩张剂反应性或基线 FEV 均未影响安慰剂组的疾病进展速度或雷帕霉素组的治疗反应。绝经状态和种族对雷帕霉素的不良事件谱有不同的影响。基线血清血管内皮生长因子（VEGF）-D>600pg·mL 确定了更有可能在安慰剂中下降并对雷帕霉素治疗有反应的患者亚组。
在 LAM 患者中，无论绝经状态、种族、支气管扩张剂反应性、基线 FEV 或 TSC 关联如何，雷帕霉素治疗均有益。血清 VEGF-D 和绝经状态可帮助确定治疗决策。
