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研究分析吸入GM-CSF治疗肺泡蛋白沉积症的临床效果
作者:小柯机器人 发布时间:2019/9/6 12:33:34

日本新潟大学Koh Nakata与合作团队研究了吸入重组人GM-CSF治疗肺泡蛋白沉积症的临床效果。相关论文2019年9月5日发表在《新英格兰医学杂志》上。

肺泡蛋白沉积症是一种肺泡表面活性剂异常积聚的疾病。大多数病例是自身免疫性的,与抗粒细胞-巨噬细胞集落刺激因子(GM-CSF)的自身抗体有关,该抗体可阻止肺泡巨噬细胞清除肺表面活性物质。一项开放标签的临床2期研究显示,吸入重组人GM-CSF对重度肺泡蛋白沉积症患者有一定疗效,但对轻中度患者的疗效尚不清楚。

研究组对64例自身免疫性肺泡蛋白沉积症患者进行了一项双盲、安慰剂对照的试验,这些患者在呼吸室内空气条件下的动脉血氧分压(PaO2)低于70 mm Hg,或有症状时低于75 mm Hg。33例患者每日吸入重组人GM-CSF(沙格司亭),每次125 μg,每日两次,持续7天,隔周治疗,共治疗24周,30例患者接受安慰剂治疗。排除严重肺泡蛋白沉积症(PaO2 < 50 mm hg)的患者,以避免安慰剂组患者病情恶化。

GM-CSF组的肺泡-动脉氧梯度的平均值变化明显优于安慰剂组。从基线检查到第25周,GM-CSF组的CT肺野密度变化也好于安慰剂组。GM-CSF组有6名患者出现严重不良反应,安慰剂组有3名。

综上,在这项随机、对照试验中,吸入重组人GM-CSF对PaO2的实验室结果有一定效果,但未发现明显的临床获益。

附:英文原文

Title: Inhaled GM-CSF for Pulmonary Alveolar Proteinosis

Author: Ryushi Tazawa, M.D., Ph.D., Takahiro Ueda, M.D., Ph.D., Mitsuhiro Abe, M.D., Ph.D., Koichiro Tatsumi, M.D., Ph.D., Ryosuke Eda, M.D., Ph.D., Shotaro Kondoh, M.D., Konosuke Morimoto, M.D., Ph.D., Takeshi Tanaka, M.D., Ph.D., Etsuro Yamaguchi, M.D., Ph.D., Ayumu Takahashi, M.D., Miku Oda, M.D., Haruyuki Ishii, M.D., Ph.D., Shinyu Izumi, M.D., Ph.D., Haruhito Sugiyama, M.D., Ph.D., Atsushi Nakagawa, M.D., Keisuke Tomii, M.D., Ph.D., Masaru Suzuki, M.D., Ph.D., Satoshi Konno, M.D., Ph.D., Shinya Ohkouchi, M.D., Ph.D., Naoki Tode, M.D., Ph.D., Tomohiro Handa, M.D., Ph.D., Toyohiro Hirai, M.D., Ph.D., Yoshikazu Inoue, M.D., Ph.D., Toru Arai, M.D., Ph.D., Katsuaki Asakawa, M.D., Takuro Sakagami, M.D., Ph.D., Atsushi Hashimoto, M.S., Takahiro Tanaka, Ph.D., Toshinori Takada, M.D., Ph.D., Ayako Mikami, M.D., Ph.D., Nobutaka Kitamura, D.D.S., Ph.D., and Koh Nakata, M.D., Ph.D.

Issue&Volume: Vol 381 No 10

Abstract: 

BACKGROUND
Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte–macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear.

METHODS
We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar–arterial oxygen gradient between baseline and week 25.

RESULTS
The change in the mean (±SD) alveolar–arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, −4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P=0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, −36.08 Hounsfield units; 95% confidence interval, −61.58 to −6.99, calculated with the use of the Mann–Whitney U test and the Hodges–Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group.

CONCLUSIONS
In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742. opens in new tab; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.)

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home