From Niigata University Medical and Dental Hospital, Niigata (R.T., T.U., K.A., T.S., A.H., Takahiro Tanaka, T. Takada, N.K., K.N.), the Department of Respirology, Graduate School of Medicine, Chiba University, Chiba (M.A., K. Tatsumi), Kurashiki Municipal Hospital, Kurashiki (R.E., S. Kondoh), the Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki (K.M., Takeshi Tanaka), the Division of Respiratory Medicine and Allergology, Department of Medicine, Aichi Medical University School of Medicine, Aichi (E.Y., A.T.), the Department of Respiratory Medicine, Kyorin University School of Medicine (M.O., H.I.), and the Center Hospital of the National Center for Global Health and Medicine (S.I., H.S., A.M.), Tokyo, Kobe City Medical Center General Hospital, Kobe (A.N., K. Tomii), the Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo (M.S., S. Konno), the Department of Respiratory Medicine and Department of Occupational Health, Tohoku University Graduate School of Medicine, Sendai (S.O., N.T.), the Departments of Advanced Medicine for Respiratory Failure (T. Handa) and Respiratory Medicine (T. Handa, T. Hirai), Graduate School of Medicine, Kyoto University, Kyoto, and the National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka (Y.I., T.A.) - all in Japan.
N Engl J Med. 2019 Sep 5;381(10):923-932. doi: 10.1056/NEJMoa1816216.
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.
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 (Pao) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao <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.
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.
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; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).
肺泡蛋白沉积症是一种以肺泡表面活性物质异常积聚为特征的疾病。大多数病例为自身免疫性疾病，与粒细胞-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、2 期研究表明，吸入重组人 GM-CSF 对严重肺泡蛋白沉积症患者具有一定的治疗效果；然而，对于轻度至中度疾病患者的疗效尚不清楚。
我们对 64 例自身免疫性肺泡蛋白沉积症患者进行了一项双盲、安慰剂对照试验，患者在 24 周内每两周接受一次 125μg 重组人 GM-CSF（沙格司亭），每日两次，每次 7 天，或安慰剂。所有患者在呼吸空气时的动脉血氧分压（PaO2）均低于 70mmHg（症状性患者为<75mmHg）。排除严重的肺泡蛋白沉积症（PaO2 <50mmHg）患者，以避免可能加重疾病。主要终点是从基线到第 25 周肺泡-动脉血氧梯度的变化。
GM-CSF 组（33 例）的平均（±SD）肺泡-动脉血氧梯度变化明显优于安慰剂组（30 例）（从基线的平均变化，-4.50±9.03mmHg 比 0.17±10.50mmHg；P=0.02）。GM-CSF 组的肺部 CT 密度变化也优于安慰剂组（组间差异，-36.08 亨氏单位；95%置信区间，-61.58 至-6.99，采用 Mann-Whitney U 检验和 Hodges-Lehmann 置信区间估计假中位数计算）。GM-CSF 组有 6 例患者和安慰剂组有 3 例患者发生严重不良事件。
在这项随机对照试验中，吸入重组人 GM-CSF 对动脉血氧分压的实验室结果有适度的有益影响，但未观察到临床获益。（由日本医疗研究与发展机构和日本卫生、劳动和福利部资助；PAGE ClinicalTrials.gov 编号，NCT02835742；日本医学会临床试验中心编号，JMA-IIA00205。）
