重度难治性哮喘患者中伊马替尼抑制KIT作用
2017/07/24
摘要
背景：经糖皮质激素治疗后的重度哮喘患者，其气道中存在肥大细胞，后者与患者生活质量差、哮喘控制不佳等疾病特征有关。干细胞因子及其受体KIT对肥大细胞稳态具有关键作用。我们通过一项原理验证性试验来评估KIT抑制剂伊马替尼对重度哮喘患者的生理学标志——气道高反应性，和气道肥大细胞数量及其活化的影响。
方法：我们进行了为期24周的伊马替尼随机、双盲、安慰剂对照试验，以控制不佳的重度哮喘患者为研究对象，这些患者接受最大限度的药物治疗后仍存在气道高反应性。通过第1秒用力呼气容积（FEV1）下降≥20%时需吸入的乙酰甲胆碱的浓度（PC20）衡量气道的高反应性,以气道高反应性的改变作为主要终点。患者同时接受支气管镜检查。
结果：在62位随机分组的患者中，伊马替尼治疗较安慰剂能更大程度减少气道高反应性。用药6个月后，安慰剂组乙酰甲胆碱PC20增加1.07±0.60（均数±标准差）倍剂量，伊马替尼组乙酰甲胆碱PC20增加1.73±0.60倍剂量（P=0.048）。血清类胰蛋白酶为肥大细胞活化的标志，伊马替尼较安慰剂能更大程度降低血清类胰蛋白酶水平（降低量2.02±2.32 vs 0.56±1.39 ng/毫升，P=0.02）。两组患者的气道肥大细胞计数均有降低。伊马替尼组发生肌痉挛和低磷酸盐血症多于安慰剂组。
结论：在重度哮喘患者中，伊马替尼能降低患者的气道高反应性、肥大细胞计数和类胰蛋白酶释放。这些结果表明KIT依赖的过程和肥大细胞参与重度哮喘发生的病理生理机制。
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.
Cahill KN, Katz HR, Cui J, et al
Abstract
BACKGROUND:Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.
METHODS:We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy.
RESULTS:Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.
CONCLUSIONS:In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .)
N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 1056/NEJMoa1613125.
背景：经糖皮质激素治疗后的重度哮喘患者，其气道中存在肥大细胞，后者与患者生活质量差、哮喘控制不佳等疾病特征有关。干细胞因子及其受体KIT对肥大细胞稳态具有关键作用。我们通过一项原理验证性试验来评估KIT抑制剂伊马替尼对重度哮喘患者的生理学标志——气道高反应性，和气道肥大细胞数量及其活化的影响。
方法：我们进行了为期24周的伊马替尼随机、双盲、安慰剂对照试验，以控制不佳的重度哮喘患者为研究对象，这些患者接受最大限度的药物治疗后仍存在气道高反应性。通过第1秒用力呼气容积（FEV1）下降≥20%时需吸入的乙酰甲胆碱的浓度（PC20）衡量气道的高反应性,以气道高反应性的改变作为主要终点。患者同时接受支气管镜检查。
结果：在62位随机分组的患者中，伊马替尼治疗较安慰剂能更大程度减少气道高反应性。用药6个月后，安慰剂组乙酰甲胆碱PC20增加1.07±0.60（均数±标准差）倍剂量，伊马替尼组乙酰甲胆碱PC20增加1.73±0.60倍剂量（P=0.048）。血清类胰蛋白酶为肥大细胞活化的标志，伊马替尼较安慰剂能更大程度降低血清类胰蛋白酶水平（降低量2.02±2.32 vs 0.56±1.39 ng/毫升，P=0.02）。两组患者的气道肥大细胞计数均有降低。伊马替尼组发生肌痉挛和低磷酸盐血症多于安慰剂组。
结论：在重度哮喘患者中，伊马替尼能降低患者的气道高反应性、肥大细胞计数和类胰蛋白酶释放。这些结果表明KIT依赖的过程和肥大细胞参与重度哮喘发生的病理生理机制。
(复旦大学附属中山医院呼吸科 胡湘麟摘译 杨冬审校)
（N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 1056/NEJMoa1613125.）
（N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 1056/NEJMoa1613125.）
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.
Cahill KN, Katz HR, Cui J, et al
Abstract
BACKGROUND:Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.
METHODS:We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy.
RESULTS:Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.
CONCLUSIONS:In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .)
N Engl J Med. 2017 May 18;376(20):1911-1920. doi: 1056/NEJMoa1613125.
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儿童重症哮喘全身糖皮质激素的反应：表型和亚型特征
