SCI
6 July 2019
Nintedanib for Systemic Sclerosis– Associated Interstitial Lung Disease
Distler O, Highland KB, Gahlemann M, et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med 2019.
Address reprint requests to Dr. Distler at the University Hospital Zurich, Department of Rheumatology, Gloriastr. 25, Zurich 8091, Switzerland, or at oliver.distler@usz.ch.
BACKGROUND 背景
Interstitial 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.
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的临床前模型中具有抗纤维化和抗炎作用。
METHODS 方法
We 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.
我们进行了一项随机、双盲、安慰剂对照试验，以研究nintedanib对ILD合并系统性硬化症患者的疗效和安全性。患有系统性硬化症且在过去7年内出现第一次非雷诺氏症状的患者和高分辨率计算机断层扫描显示，纤维化影响至少10％的肺部的患者被随机分配，比例为1：1，接受150毫克的nintedanib，每日口服两次，或安慰剂。主要终点是在52周内评估强迫肺活量（FVC）的年下降率。关键的次要终点是第52周改良的Rodnan皮肤评分和圣乔治呼吸问卷（SGRQ）总分与基线相比的绝对变化。
RESULTS 结果
A 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.
共有576名患者接受了至少一剂nintedanib或安慰剂; 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了霉酚酸酯治疗。在主要终点分析中，nintedanib组的FVC调整后年变化率为-52.4 ml /年，安慰剂组为-93.3 ml（差异，每年41.0 ml; 95％置信区间[CI] ]，2.9至79.0; P = 0.04）。基于对缺失数据的多重插补的灵敏度分析产生主要终点的P值范围在0.06到0.10质检。在第52周时，改良Rodnan皮肤评分与基线的变化以及SGRQ的总评分在试验组之间没有显著差异，差异为-0.21（95％CI，-0.94至0.53; P = 0.58）和1.69 （95％CI，-0.73至4.12 [未进行多重比较调整]）。在nintedanib组中75.7％的患者和安慰剂组中31.6％的患者报告了腹泻，这是最常见的不良事件。
CONCLUSIONS 结论
Among 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.
在ILD伴系统性硬化症患者中，使用nintedanib的FVC年降低率低于安慰剂组; 对于系统性硬化症的其他表现，没有观察到nintedanib的临床益处。在本试验中观察到的nintedanib的不良事件特征与在特发性肺纤维化患者中相似; 包括腹泻在内的胃肠道不良事件nintedanib比安慰剂更常见。
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