在严重未控制的嗜酸性粒细胞性哮喘患者中，使用贝那利珠单抗后嗜酸性粒细胞耗竭与甘露醇诱导的气道高反应性减弱相关
2023/02/01
摘要
背景：气道高反应性（AHR）和嗜酸性粒细胞增多是持续性哮喘的特征。
目的：我们采用一种实用的开放标签设计，研究了在严重未控制的哮喘患者中使用贝那利珠单抗后嗜酸性粒细胞耗竭是否可以间接减轻甘露醇诱发的AHR。
方法：在提供常规吸入性皮质类固醇和/或长效β激动剂（基线）的4周预处理后，甘露醇反应性未控制的重度嗜酸性粒细胞性哮喘成人每4周接受 3 剂开放标签贝那利珠单抗 30 mg，然后在最后一次给药后16周洗脱。主要终点是12周后将FEV降低10%（PD）所需的激发剂量甘露醇的差异加倍（DD），功率为90%，需要18名患者检测1DD。次要结局包括通过哮喘控制问卷和迷你哮喘生活质量问卷评估的测量。
结果：21例患者在第12周结束时完成了12周的贝那利珠单抗治疗。平均（SEM）年龄为53（4）岁，FEV 80.2%（4.1%）吸入皮质类固醇剂量为1895（59）ug，其中12人接受长效毒蕈碱拮抗剂，13人接受白三烯受体拮抗剂。AHR 在8周后显著改善，第12周时PD的平均变化为2.1 DD（95% 可信区间 1.0，3.3;P < 0.01），而哮喘控制问卷和迷你哮喘生活质量问卷的平均变化在第2周时是显着的，并持续了12周，均超过最小重要差异。外周血嗜酸性粒细胞在2周内耗尽（439至6个细胞/μL）。12周后肺功能无明显改善。贝那利珠单抗组的家庭峰值流量和症状也有所改善。
结论：在严重未控制的哮喘患者中，嗜酸性粒细胞耗竭可导致有临床意义的AHR降低。
Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma.
Chan R, RuiWen Kuo C, Jabbal S, Lipworth BJ,
Abstrast
Background: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma.
Objective: We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design.
Methods: After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV by 10% (PD) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire.
Results: Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab.
Conclusions: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.
背景：气道高反应性（AHR）和嗜酸性粒细胞增多是持续性哮喘的特征。
目的：我们采用一种实用的开放标签设计，研究了在严重未控制的哮喘患者中使用贝那利珠单抗后嗜酸性粒细胞耗竭是否可以间接减轻甘露醇诱发的AHR。
方法：在提供常规吸入性皮质类固醇和/或长效β激动剂（基线）的4周预处理后，甘露醇反应性未控制的重度嗜酸性粒细胞性哮喘成人每4周接受 3 剂开放标签贝那利珠单抗 30 mg，然后在最后一次给药后16周洗脱。主要终点是12周后将FEV降低10%（PD）所需的激发剂量甘露醇的差异加倍（DD），功率为90%，需要18名患者检测1DD。次要结局包括通过哮喘控制问卷和迷你哮喘生活质量问卷评估的测量。
结果：21例患者在第12周结束时完成了12周的贝那利珠单抗治疗。平均（SEM）年龄为53（4）岁，FEV 80.2%（4.1%）吸入皮质类固醇剂量为1895（59）ug，其中12人接受长效毒蕈碱拮抗剂，13人接受白三烯受体拮抗剂。AHR 在8周后显著改善，第12周时PD的平均变化为2.1 DD（95% 可信区间 1.0，3.3;P < 0.01），而哮喘控制问卷和迷你哮喘生活质量问卷的平均变化在第2周时是显着的，并持续了12周，均超过最小重要差异。外周血嗜酸性粒细胞在2周内耗尽（439至6个细胞/μL）。12周后肺功能无明显改善。贝那利珠单抗组的家庭峰值流量和症状也有所改善。
结论：在严重未控制的哮喘患者中，嗜酸性粒细胞耗竭可导致有临床意义的AHR降低。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Allergy Clin Immunol. 2022 Nov 16; doi: 10.1016/j.jaci.2022.10.028.IF: 10.228)
(Allergy Clin Immunol. 2022 Nov 16; doi: 10.1016/j.jaci.2022.10.028.IF: 10.228)
Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma.
Chan R, RuiWen Kuo C, Jabbal S, Lipworth BJ,
Abstrast
Background: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma.
Objective: We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design.
Methods: After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV by 10% (PD) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire.
Results: Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab.
Conclusions: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.
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奥马珠单抗、美泊利珠单抗和度普利尤单抗治疗哮喘有效性比较：靶向试验模拟
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