Mepolizumab在重症哮喘中消除炎症但保留稳态嗜酸性粒细胞
2024/08/28
摘要
背景：嗜酸性粒细胞是重症哮喘的关键治疗靶点，可被IL5（美泊利珠单抗）和IL5受体（贝那利珠单抗）拮抗剂抑制。IL5途径生物制剂对最近描述的稳态（hEO）和炎性（iEOs）嗜酸性粒细胞亚群的影响尚不清楚。我们的目的是确定美泊利珠单抗和贝那利珠单抗治疗对嗜酸性粒细胞亚群和表型的相对影响，并探讨嗜酸性粒细胞亚群与重症哮喘特征和治疗反应的临床关联。
方法：我们对重症哮喘（嗜酸性粒细胞性n=32，非嗜酸性粒蛋白性n=23，美泊利珠单抗治疗n=25）进行了横断面观察研究，并在美泊利单抗（n=20）或贝那利珠单抗（n=10）开始治疗后的两个时间点（4-24周，>24周）对这30名嗜酸性参与者进行了纵向随访。通过流式细胞术评估表面CD62L蛋白来测量血液hEO和iEOs。
结果：在横断面和纵向研究中，美泊珠单抗治疗的参与者iEO比例显著降低。美泊利珠单抗和贝那利珠单抗在相似程度上耗尽了iEO，但在随访时，美泊利珠单抗受试者体内仍有更多的hEO。在嗜酸性粒细胞性哮喘中，iEO比例越大，哮喘控制越差，但与非嗜酸性粒细胞性哮喘无关。美泊利珠单抗治疗个体中，较高的残留iEO比例与较差的哮喘控制相关。在大约一半接受美泊珠单抗治疗的参与者中观察到血液嗜酸性粒细胞存活率降低，这与哮喘控制和肺活量测定明显改善有关。
结论：美泊利珠单抗可耗尽重症哮喘患者的iEOs并降低循环嗜酸性粒细胞的存活率，但保留了循环hEO的残留种群。相比之下，贝那利珠单抗会耗尽iEOs和hEOs。美泊利珠单抗治疗后，iEO丰度和嗜酸性粒细胞存活率越高，临床结果越差。监测循环嗜酸性粒细胞表型和存活率可能有助于预测重症哮喘的生物治疗反应。
Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma
Michael Fricker, John Harrington, Sarah A Hiles, Peter G Gibson
Abstract
Background: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.
Methods: We performed a cross-sectional observational study of severe asthma (eosinophilic n = 32, non-eosinophilic n = 23, mepolizumab-treated n = 25), with longitudinal follow-up of 30 eosinophilic participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.
Results: iEO proportion was significantly lower in mepolizumab-treated participants in both the cross-sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow-up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non-eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab-treated participants, which was associated with significantly better asthma control and spirometry.
Conclusions: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab-treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.
背景：嗜酸性粒细胞是重症哮喘的关键治疗靶点，可被IL5（美泊利珠单抗）和IL5受体（贝那利珠单抗）拮抗剂抑制。IL5途径生物制剂对最近描述的稳态（hEO）和炎性（iEOs）嗜酸性粒细胞亚群的影响尚不清楚。我们的目的是确定美泊利珠单抗和贝那利珠单抗治疗对嗜酸性粒细胞亚群和表型的相对影响，并探讨嗜酸性粒细胞亚群与重症哮喘特征和治疗反应的临床关联。
方法：我们对重症哮喘（嗜酸性粒细胞性n=32，非嗜酸性粒蛋白性n=23，美泊利珠单抗治疗n=25）进行了横断面观察研究，并在美泊利单抗（n=20）或贝那利珠单抗（n=10）开始治疗后的两个时间点（4-24周，>24周）对这30名嗜酸性参与者进行了纵向随访。通过流式细胞术评估表面CD62L蛋白来测量血液hEO和iEOs。
结果：在横断面和纵向研究中，美泊珠单抗治疗的参与者iEO比例显著降低。美泊利珠单抗和贝那利珠单抗在相似程度上耗尽了iEO，但在随访时，美泊利珠单抗受试者体内仍有更多的hEO。在嗜酸性粒细胞性哮喘中，iEO比例越大，哮喘控制越差，但与非嗜酸性粒细胞性哮喘无关。美泊利珠单抗治疗个体中，较高的残留iEO比例与较差的哮喘控制相关。在大约一半接受美泊珠单抗治疗的参与者中观察到血液嗜酸性粒细胞存活率降低，这与哮喘控制和肺活量测定明显改善有关。
结论：美泊利珠单抗可耗尽重症哮喘患者的iEOs并降低循环嗜酸性粒细胞的存活率，但保留了循环hEO的残留种群。相比之下，贝那利珠单抗会耗尽iEOs和hEOs。美泊利珠单抗治疗后，iEO丰度和嗜酸性粒细胞存活率越高，临床结果越差。监测循环嗜酸性粒细胞表型和存活率可能有助于预测重症哮喘的生物治疗反应。
(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)
(Allergy. 2024 Aug 8. doi: 10.1111/all.16267.)
(Allergy. 2024 Aug 8. doi: 10.1111/all.16267.)
Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma
Michael Fricker, John Harrington, Sarah A Hiles, Peter G Gibson
Abstract
Background: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.
Methods: We performed a cross-sectional observational study of severe asthma (eosinophilic n = 32, non-eosinophilic n = 23, mepolizumab-treated n = 25), with longitudinal follow-up of 30 eosinophilic participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.
Results: iEO proportion was significantly lower in mepolizumab-treated participants in both the cross-sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow-up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non-eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab-treated participants, which was associated with significantly better asthma control and spirometry.
Conclusions: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab-treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.
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减少贫困学龄儿童哮喘发作:一项2型实施-有效性混合试验的研究方案(更好的儿童哮喘控制，BACK)
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