Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.
Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis.
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DOI：
10.1056/nejmoa1913590
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发表时间：
2020-10-22
期刊：
影响因子：
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通讯作者：
IMPALA Trial Investigators
中科院分区：
文献类型：
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作者：
Trapnell BC;Inoue Y;Bonella F;Morgan C;Jouneau S;Bendstrup E;Campo I;Papiris SA;Yamaguchi E;Cetinkaya E;Ilkovich MM;Kramer MR;Veltkamp M;Kreuter M;Baba T;Ganslandt C;Tarnow I;Waterer G;Jouhikainen T;IMPALA Trial Investigators
自身免疫性肺泡蛋白沉积症 (aPAP) 是一种罕见疾病，其特征是进行性表面活性剂积聚和低氧血症，这是由于粒细胞/巨噬细胞集落刺激因子 (GM-CSF) 信号中断引起的，而肺泡巨噬细胞需要清除表面活性剂。最近，吸入 GM-CSF 被证明可以改善 aPAP 患者的动脉氧张力。我们对 138 名 aPAP 患者进行了一项双盲、安慰剂对照、3 组研究，随机接受莫格莫司亭（300 μg/天）连续治疗（n=46）或每隔一周间歇性治疗（n=45），或每天吸入一次安慰剂（n=47），持续 24 周，然后是开放标签治疗延长期。在排除动脉血气测量期间接受鼻氧治疗的 4 名患者（每个 molgramostim 组 1 例，安慰剂组 2 例）的无效 A-aDO2 数据后，主要终点（A-aDO2 从基线到 24 周的变化）的改善，接受连续 molgramostim 的患者比安慰剂组更大（估计治疗差异（ETD）-6.2 mmHg，P=0.025，最小二乘均值（LSMean）比较）。与安慰剂相比，接受连续莫格司亭治疗的患者的次要终点也有所改善，包括圣乔治呼吸问卷总分（ETD -7.4，P=0.012，LS均值）。连续给药比间歇性莫格司亭给药在多个终点上的改善更大。各组间不良事件和严重不良事件的发生率相似。每日服用莫格司亭可改善 aPAP 患者的临床、生理、生化和放射学结果指标，并且是安全的。吸入莫格司亭可能可用于治疗 aPAP。
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by disruption of signaling by granulocyte/macrophage-colony stimulating factor (GM-CSF), which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve arterial oxygen tension in aPAP patients. We conducted a double-blind, placebo-controlled, 3-group study in 138 aPAP patients randomized to receive molgramostim (300 μg/day) continuously (n=46) or intermittently every other week (n=45), or matching placebo (n=47) by once-daily inhalation for 24-weeks, followed by an open-label treatment-extension period. After excluding invalid A-aDO2 data for four patients who received nasal oxygen therapy during arterial blood gas measurement (1 in each molgramostim group and 2 in placebo), improvement in the primary endpoint – change in A-aDO2 from baseline to 24 weeks – was greater in patients receiving continuous molgramostim than placebo (estimated treatment difference (ETD) −6.2 mmHg, P=0.025, least square mean (LSMean) comparison). Patients receiving continuous molgramostim also had an improvement in secondary endpoints compared to placebo including Saint George’s Respiratory Questionnaire total score (ETD −7.4, P=0.012, LSMean). Improvement in multiple endpoints was greater for continuous than intermittent molgramostim administration. Rates of adverse events and serious adverse events were similar among groups. Daily molgramostim administration improved clinical, physiological, biochemical, and radiologic outcome measures and was safe in patients with aPAP. Inhaled molgramostim may be useful as therapy of aPAP.