Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease
Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease
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DOI：
10.1056/nejmoa1903076
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发表时间：
2019-06-27
影响因子：
158.5
通讯作者：
Maher, Toby M.
中科院分区：
文献类型：
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作者：
Distler, Oliver;Highland, Kristin B.;Maher, Toby M.
间质性肺病（ILD）是系统性硬化症的常见表现，也是系统性硬化症相关死亡的主要原因。Nintedanib是一种酪氨酸激酶抑制剂，已被证明在系统性硬化症和ILD.MethodsWe的临床前模型中具有抗纤维化和抗纤维化作用，我们进行了一项随机、双盲、安慰剂对照试验，以研究尼达尼布在系统性硬化症相关ILD患者中的疗效和安全性。在过去7年内首次出现非雷诺症状的系统性硬化症患者，高分辨率计算机断层扫描显示纤维化累及至少10%的肺部，以1：1的比例随机分配接受150 mg尼达尼布（每日两次口服给药）或安慰剂。主要终点是在52周内评估用力肺活量（FVC）的年下降率。关键次要终点为第52周时改良Rodnan皮肤评分和圣乔治呼吸问卷（SGRQ）总分较基线的绝对变化。结果共有576例患者接受至少一剂尼达尼布或安慰剂治疗; 51.9%的患者患有弥漫性皮肤系统性硬化症，48.4%的患者在基线时接受麦考酚酯治疗。在主要终点分析中，尼达尼布组FVC的校正年变化率为-52.4 ml/年，安慰剂组为-93.3 ml/年（差异为41.0 ml/年; 95%置信区间[CI]为2.9 - 79.0; P=0.04）。基于缺失数据多重插补的敏感性分析得出主要终点的P值范围为0.06 - 0.10。第52周时改良Rodnan皮肤评分和SGRQ总分较基线的变化在试验组间无显著差异，差异分别为-0.21（95% CI，-0.94至0.53; P=0.58）和1.69（95% CI，-0.73至4.12 [未调整多重比较]）。腹泻是最常见的不良事件，尼达尼布组75.7%的患者和安慰剂组31.6%的患者报告了这一事件。结论在系统性硬化症相关ILD患者中，尼达尼布组FVC年下降率低于安慰剂组;尼达尼布对系统性硬化症的其他表现没有临床获益。在本试验中观察到的尼达尼布不良事件特征与在特发性肺纤维化患者中观察到的相似;尼达尼布组胃肠道不良事件（包括腹泻）比安慰剂组更常见。
BackgroundInterstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD.MethodsWe conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52.ResultsA total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P=0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.ConclusionsAmong patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo.