Servicio de Alergología, Hospital Universitario de Navarra, CIBER de Enfermedades Respiratorias (CIBERES), Pamplona, Spain.
Allergy Department, Fundación Jiménez Díaz, CIBER de Enfermedades Respiratorias (CIBERES), School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
J Investig Allergol Clin Immunol. 2022 Jun 20;32(3):165-180. doi: 10.18176/jiaci.0823. Epub 2022 May 6.
Five biological drugs are currently marketed for treatment of uncontrolled severe asthma. They all block type 2 inflammatory pathways by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/IL-13 pathway (dupilumab). Hypereosinophilia has been observed in 4%-25% of patients treated with dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. Cases of EGPA have been reported with all biologics, including anti-IL-5 agents, and with leukotriene receptor antagonists in publications or in the EudraVigilance database. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti-IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti-IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. Blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/μL), in which case an anti-IL-5/IL-5R agent is preferable. Furthermore, when switching from an anti-IL-5/5R to an anti-IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation. This approach can prevent the development of EGPA and other types of symptomatic hypereosinophilia while maintaining control of nasal polyposis. In the near future, it will be possible to use a new generation of biological therapies for the treatment of severe asthma. These act at a higher level of the inflammatory cascade, as is the case of the antialarmins tezepelumab and itepekimab.
目前有五种生物药物被批准用于治疗无法控制的严重哮喘。它们通过针对 IgE（奥马珠单抗）、IL-5 通路（美泊利珠单抗、瑞利珠单抗、贝那利珠单抗）或 IL-4/IL-13 通路（度普利尤单抗）来阻断 2 型炎症途径。在接受度普利尤单抗治疗的患者中，有 4%-25%观察到嗜酸性粒细胞增多症，在大多数情况下是短暂的，尽管有持续性症状性嗜酸性粒细胞增多症的报道，符合嗜酸性肉芽肿性多血管炎（EGPA）、嗜酸性肺炎、嗜酸性血管炎和哮喘症状突然恶化。在出版物或 EudraVigilance 数据库中，有报道称所有生物制剂（包括抗 IL-5 药物）和白三烯受体拮抗剂均可引起 EGPA。在许多情况下，EGPA 出现在全身皮质类固醇减量期间或从抗 IL-5 生物制剂转换为度普利尤单抗后，表明全身皮质类固醇或抗 IL-5 药物掩盖了血管炎。本综述探讨了度普利尤单抗引起的嗜酸性粒细胞增多症的可能机制，并综述了与度普利尤单抗相关的症状性嗜酸性粒细胞增多症病例。阻断 IL-4/IL-13 通路可通过抑制嗜酸性粒细胞趋化因子-3、VCAM-1 和 TARC，减少嗜酸性粒细胞在血液中的迁移和聚集，而不会同时抑制骨髓中的嗜酸性粒细胞生成。在选择最佳生物制剂时，似乎需要考虑是否存在嗜酸性粒细胞增多症（>1500/μL），在这种情况下，抗 IL-5/IL-5R 药物是首选。此外，当从抗 IL-5/5R 转换为抗 IL-4/13R 药物时，应密切监测血液嗜酸性粒细胞和临床进展。然而，为了实现最佳控制，可能需要双重抗 IL-5/5R 和抗 IL4/IL-13R 药物治疗，因为 IL-5 和 IL-4/IL-13 通路都可以同时促进气道炎症。这种方法可以预防 EGPA 和其他类型的症状性嗜酸性粒细胞增多症的发生，同时保持对鼻息肉的控制。在不久的将来，将有可能使用新一代生物疗法治疗严重哮喘。这些药物在炎症级联的更高水平起作用，如抗警报素 tezepelumab 和 itepekimab。
