度普利尤单抗对不可控重症哮喘患者甘露醇气道高反应性的影响
2025/01/26
摘要
背景：气道高反应性（AHR）是持续性哮喘的标志。然而，度普利尤单抗阻断IL-4/13对AHR的影响尚不清楚。
目的：探讨度普利尤单抗12周对急性呼吸衰竭、哮喘控制和生活质量的影响。
方法：在连续4周服用倍氯米松/福莫特罗（BDP/FM）MART（基线）后，患有不受控制的2型重度哮喘的受试者接受了开放标签的Dupi 300mg，每周2次，持续12周。甘露醇激发在基线、2、4和12周以及12周洗脱后进行。在第12周检测甘露醇PD10-FEV1阈值的1倍差异（dd）的研究功率为90%。
结果：24名入选患者中有23名在12周时按照方案完成了甘露醇AHR。平均基线值为：年龄52岁；FEV1 82%；ACQ 2.53，最小AQLQ 3.84；ICS剂量1300μg；FeNO 50ppb；Eos 552个细胞/μl。甘露醇敏感性作为PD10在第4周显著减弱，反应性作为反应剂量比（RDR）在第2周显著减弱。Dupi治疗12周后，PD10的平均（95%CI）dd为1.78（1.23,2.33）p<0.001，RDR为3.40（2.25,4.55）p<0.001。在第12周，ACQ改善了1.73，（1.11,2.36）p<0.001，迷你AQLQ改善了2.31（1.57,3.05）p<0.001，FEV1改善了0.39L（0.11,0.67）p<0.01，PEF改善了61L/min（24,98）p<0.001。与基线相比，12周时BDP/FM MART需求量减少了1.7次/天（0.7、2.7），p<0.01。在第24周冲洗后，dd变化为0.96（0.02，1.91），p<0.05。
结论：尽管伴随ICS降低，度普利尤单抗仍将甘露醇AHR降至临床相关程度，并改善了肺功能、哮喘控制和生活质量。
Effects of dupilumab on mannitol airway hyperresponsiveness in uncontrolled severe asthma
Kirsten E Stewart, Chris RuiWen Kuo, Rory Chan, Brian J Lipworth
Abstract
Background: Airway hyper-responsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown.
Objective: To investigate the effect of 12 weeks of Dupi on AHR, asthma control and quality of life.
Methods: After a 4-week run-in on beclomethasone/formoterol(BDP/FM) MART (baseline), participants with uncontrolled type-2 high severe asthma received open-label Dupi 300mg 2-weekly, for 12 weeks. Mannitol challenges were done at baseline, 2, 4 and 12 weeks and following a 12-week washout. Study power was 90% to detect 1 doubling difference (dd) in mannitol PD10 FEV1 threshold at week 12.
Results: 23 out of 24 enrolled patients completed per protocol mannitol AHR at 12 weeks. Mean baseline values were: age 52 years; FEV1 82%; ACQ 2.53, mini-AQLQ 3.84; ICS dose 1300μg; FeNO 50ppb; Eos 552cells/μl. Mannitol sensitivity as PD10 was significantly attenuated by week 4, and reactivity as response dose ratio (RDR) by week 2. After 12 weeks of Dupi, mean (95%CI) dd for PD10 was 1.78 (1.23,2.33) p<0.001 and for RDR was 3.40 (2.25,4.55) p<0.001. At week 12, ACQ improved by 1.73, (1.11,2.36) p<0.001, mini-AQLQ by 2.31 (1.57,3.05) p<0.001, FEV1 by 0.39L (0.11,0.67) p<0.01 and PEF by 61L/min (24,98) p<0.001. BDP/FM MART requirement was reduced at 12 weeks vs baseline by 1.7 puffs/day (0.7,2.7) p<0.01. After washout at week 24 the dd change was 0.96 (0.02,1.91) p<0.05.
Conclusion: Dupilumab attenuated mannitol AHR to a clinically relevant degree despite concomitant ICS reduction, combined with improvements in lung function, asthma control and quality of life.
背景：气道高反应性（AHR）是持续性哮喘的标志。然而，度普利尤单抗阻断IL-4/13对AHR的影响尚不清楚。
目的：探讨度普利尤单抗12周对急性呼吸衰竭、哮喘控制和生活质量的影响。
方法：在连续4周服用倍氯米松/福莫特罗（BDP/FM）MART（基线）后，患有不受控制的2型重度哮喘的受试者接受了开放标签的Dupi 300mg，每周2次，持续12周。甘露醇激发在基线、2、4和12周以及12周洗脱后进行。在第12周检测甘露醇PD10-FEV1阈值的1倍差异（dd）的研究功率为90%。
结果：24名入选患者中有23名在12周时按照方案完成了甘露醇AHR。平均基线值为：年龄52岁；FEV1 82%；ACQ 2.53，最小AQLQ 3.84；ICS剂量1300μg；FeNO 50ppb；Eos 552个细胞/μl。甘露醇敏感性作为PD10在第4周显著减弱，反应性作为反应剂量比（RDR）在第2周显著减弱。Dupi治疗12周后，PD10的平均（95%CI）dd为1.78（1.23,2.33）p<0.001，RDR为3.40（2.25,4.55）p<0.001。在第12周，ACQ改善了1.73，（1.11,2.36）p<0.001，迷你AQLQ改善了2.31（1.57,3.05）p<0.001，FEV1改善了0.39L（0.11,0.67）p<0.01，PEF改善了61L/min（24,98）p<0.001。与基线相比，12周时BDP/FM MART需求量减少了1.7次/天（0.7、2.7），p<0.01。在第24周冲洗后，dd变化为0.96（0.02，1.91），p<0.05。
结论：尽管伴随ICS降低，度普利尤单抗仍将甘露醇AHR降至临床相关程度，并改善了肺功能、哮喘控制和生活质量。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2024 Nov 26:S0091-6749(24)01275-2.)
(J Allergy Clin Immunol. 2024 Nov 26:S0091-6749(24)01275-2.)
Effects of dupilumab on mannitol airway hyperresponsiveness in uncontrolled severe asthma
Kirsten E Stewart, Chris RuiWen Kuo, Rory Chan, Brian J Lipworth
Abstract
Background: Airway hyper-responsiveness (AHR) is a hallmark of persistent asthma. However, effects of IL-4/13 blockade with dupilumab (Dupi) on AHR are unknown.
Objective: To investigate the effect of 12 weeks of Dupi on AHR, asthma control and quality of life.
Methods: After a 4-week run-in on beclomethasone/formoterol(BDP/FM) MART (baseline), participants with uncontrolled type-2 high severe asthma received open-label Dupi 300mg 2-weekly, for 12 weeks. Mannitol challenges were done at baseline, 2, 4 and 12 weeks and following a 12-week washout. Study power was 90% to detect 1 doubling difference (dd) in mannitol PD10 FEV1 threshold at week 12.
Results: 23 out of 24 enrolled patients completed per protocol mannitol AHR at 12 weeks. Mean baseline values were: age 52 years; FEV1 82%; ACQ 2.53, mini-AQLQ 3.84; ICS dose 1300μg; FeNO 50ppb; Eos 552cells/μl. Mannitol sensitivity as PD10 was significantly attenuated by week 4, and reactivity as response dose ratio (RDR) by week 2. After 12 weeks of Dupi, mean (95%CI) dd for PD10 was 1.78 (1.23,2.33) p<0.001 and for RDR was 3.40 (2.25,4.55) p<0.001. At week 12, ACQ improved by 1.73, (1.11,2.36) p<0.001, mini-AQLQ by 2.31 (1.57,3.05) p<0.001, FEV1 by 0.39L (0.11,0.67) p<0.01 and PEF by 61L/min (24,98) p<0.001. BDP/FM MART requirement was reduced at 12 weeks vs baseline by 1.7 puffs/day (0.7,2.7) p<0.01. After washout at week 24 the dd change was 0.96 (0.02,1.91) p<0.05.
Conclusion: Dupilumab attenuated mannitol AHR to a clinically relevant degree despite concomitant ICS reduction, combined with improvements in lung function, asthma control and quality of life.
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贝纳利珠单抗（ABRA）治疗哮喘和COPD的嗜酸性粒细胞加重：一项双盲、双模拟、有效安慰剂对照随机试验
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