酪氨酸激酶抑制剂伊马替尼对重度难治性哮喘患者的作用
2017/07/12
摘要
背景：激素难治性重症哮喘患者的气道中存在肥大细胞。这些细胞与包括低生活质量、不理想的症状控制在内的哮喘疾病特点相关。干细胞因子及其受体酪氨酸激酶是肥大细胞保持稳态的关键。
目的：本研究的目的是评估酪氨酸激酶受体抑制剂伊马替尼对重度哮喘患者气道高反应性及其气道内肥大细胞的计数及活化程度的效应。
方法：本随机双盲安慰剂对照研究持续24周，研究包括了62例18-65岁的、在持续最大用药剂量治疗下仍存在气道高反应的重度难治性哮喘患者。通过支气管激发试验及支气管镜下肺泡灌洗了解治疗前后气道反应性、肥大细胞计数及活化程度变化。试验的主要终点是气道高反应性的变化，主要通过使FEV1下降20%的乙酰甲胆碱浓度（简称PC20，下同）的变化来衡量。
结果：与安慰剂组相比，使用伊马替尼治疗能更大程度地降低气道高反应性。在研究结束时，伊马替尼组PC20倍增剂量平均提高1.73±0.60，安慰剂组PC20倍增剂量提高 1.07±0.60 。(P = 0.048)。伊马替尼较安慰剂能更大程度地降低血清内肥大细胞活化标记物--类胰蛋白酶的水平(伊马替尼降低 2.02±2.32，安慰剂降低 0.56±1.39 ng/ ml, P = 0.02)。两组气道肥大细胞计数均有下降。伊马替尼更易诱发气道痉挛和低磷血症。
结论：对于重症哮喘患者来说，伊马替尼能降低气道高反应性、肥大细胞计数及类胰蛋白酶释放。本研究表明，酪氨酸激酶依赖途径参与组成重症哮喘的病理基础。
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma
Katherine N. Cahill, M.D., Howard R. Katz, Ph.D., Jing Cui, M.D., Ph.D., Juying Lai, M.D., Shamsah Kazani, M.D.,Allison Crosby-Thompson, M.S., Denise Garofalo, B.A., Mario Castro, M.D., Nizar Jarjour, M.D., Emily DiMango, M.D.,Serpil Erzurum, M.D., Jennifer L. Trevor, M.D., Kartik Shenoy, M.D., Vernon M. Chinchilli, Ph.D.,Michael E. Wechsler, M.D., Tanya M. Laidlaw, M.D., Joshua A. Boyce, M.D., and Elliot Israel, M.D
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.
OBJECTIVE:The aim of this study was 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% (PC 20 ). 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 PC 20 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.
背景：激素难治性重症哮喘患者的气道中存在肥大细胞。这些细胞与包括低生活质量、不理想的症状控制在内的哮喘疾病特点相关。干细胞因子及其受体酪氨酸激酶是肥大细胞保持稳态的关键。
目的：本研究的目的是评估酪氨酸激酶受体抑制剂伊马替尼对重度哮喘患者气道高反应性及其气道内肥大细胞的计数及活化程度的效应。
方法：本随机双盲安慰剂对照研究持续24周，研究包括了62例18-65岁的、在持续最大用药剂量治疗下仍存在气道高反应的重度难治性哮喘患者。通过支气管激发试验及支气管镜下肺泡灌洗了解治疗前后气道反应性、肥大细胞计数及活化程度变化。试验的主要终点是气道高反应性的变化，主要通过使FEV1下降20%的乙酰甲胆碱浓度（简称PC20，下同）的变化来衡量。
结果：与安慰剂组相比，使用伊马替尼治疗能更大程度地降低气道高反应性。在研究结束时，伊马替尼组PC20倍增剂量平均提高1.73±0.60，安慰剂组PC20倍增剂量提高 1.07±0.60 。(P = 0.048)。伊马替尼较安慰剂能更大程度地降低血清内肥大细胞活化标记物--类胰蛋白酶的水平(伊马替尼降低 2.02±2.32，安慰剂降低 0.56±1.39 ng/ ml, P = 0.02)。两组气道肥大细胞计数均有下降。伊马替尼更易诱发气道痉挛和低磷血症。
结论：对于重症哮喘患者来说，伊马替尼能降低气道高反应性、肥大细胞计数及类胰蛋白酶释放。本研究表明，酪氨酸激酶依赖途径参与组成重症哮喘的病理基础。
(中日友好医院医院呼吸与危重症医学科 张科文摘译 林江涛审校)
（N Engl J Med 2017;376:1911-20）
（N Engl J Med 2017;376:1911-20）
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma
Katherine N. Cahill, M.D., Howard R. Katz, Ph.D., Jing Cui, M.D., Ph.D., Juying Lai, M.D., Shamsah Kazani, M.D.,Allison Crosby-Thompson, M.S., Denise Garofalo, B.A., Mario Castro, M.D., Nizar Jarjour, M.D., Emily DiMango, M.D.,Serpil Erzurum, M.D., Jennifer L. Trevor, M.D., Kartik Shenoy, M.D., Vernon M. Chinchilli, Ph.D.,Michael E. Wechsler, M.D., Tanya M. Laidlaw, M.D., Joshua A. Boyce, M.D., and Elliot Israel, M.D
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.
OBJECTIVE:The aim of this study was 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% (PC 20 ). 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 PC 20 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.
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少数民族青年感知的歧视与哮喘及其相关结局具有相关性 GALA II 和SAGE II研究
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在轻度持续性哮喘的儿童中使用对乙酰氨基酚和布洛芬的对比
