严重哮喘生物疗法的安全性：WHO药物警戒数据库中报告的疑似不良反应分析
2024/05/28
摘要
背景：自从新型生物疗法出现以来，对不受控制的严重哮喘的管理有了很大的改善。截至2022年8月，已有五种生物制剂被批准用于2型哮喘表型：抗IgE（奥马珠单抗），抗IL5（美泊利单抗，瑞利珠单抗，贝那利珠单抗）和抗IL4（度普利尤单抗）单克隆抗体。这些药物通常耐受性良好，尽管长期安全性信息有限，一些不良事件尚未完全描述。自发报告系统是检测潜在信号和评估所有已上市药物实际安全性的基石。
目的：本研究的目的是使用世界卫生组织全球药物警戒数据库VigiBase提供严重哮喘生物制剂安全性数据的概述。
方法：我们选择了截至2022年8月31日，VigiBase中5种已获批的用于治疗严重哮喘的生物制剂(奥马珠单抗、美泊利单抗、瑞利珠单抗、贝那利珠单抗和度普利尤单抗)的所有重复病例安全性报告（ICSRs）。对ICSRs进行了描述性频率分析，既作为整个类别，也作为单个产品。采用95%可信区间（Cis）的报告优势比（ROR）作为研究药物与所有其他可疑药物（参考组1,RG1）或吸入皮质类固醇加长效β激动剂（ICSs/LABAs）（参考组2,RG2）或口服皮质类固醇（OCSs）（参考组3,RG3）相关的可疑药物不良反应（ADRs）的歧化程度的衡量标准。
结果：总体而言，在VigiBase中鉴定了31,724,381个ICSR，其中167,282个（0.5%）与研究药物有关;其余报告被视为RG1。按治疗适应症对所有生物制剂相关的ICSR进行分层，约29.4%（n=48,440）与哮喘使用有关;奥马珠单抗主要被指为疑似药物（n = 20,501），其次是度普利尤单抗、美泊利单抗、贝那利珠单抗和瑞利珠单抗。大多数哮喘ICSR涉及成人（57%）和妇女（64.1%）。哮喘生物制剂显示严重疑似ADR报告的频率高于RG1（41.3% vs 32.3%）。报告最多的疑似ADR包括哮喘、呼吸困难、产品使用问题、药物无效、咳嗽、头痛、疲劳和喘息。哮喘生物制剂与几种未知或记录较少的不良事件不成比例的相关，例如恶性肿瘤、肺栓塞和深静脉血栓形成与奥马珠单抗相关；脱发和扁平苔藓与度普利尤单抗相关；脱发和疱疹感染与美泊利单抗相关；脱发，带状疱疹和嗜酸性肉芽肿病伴多血管炎与贝那利珠单抗相关；脱发与使用瑞利珠单抗相关。
结论：VigiBase中最常报告的哮喘生物制剂疑似ADR证实了存在众所周知的不良反应，例如一般性紊乱、注射部位反应、鼻咽炎、头痛和超敏反应，而其他一些不良反应（例如哮喘再激活或治疗失败）可归因于使用适应症。此外，对不成比例报告信号的分析表明存在恶性肿瘤、对心血管系统的影响、脱发和自身免疫性疾病，需要进一步评估和调查。
Safety of Biological Therapies for Severe Asthma: An Analysis of Suspected Adverse Reactions Reported in the WHO Pharmacovigilance Database.
Paola Maria, Cutroneo, Elena, Arzenton,
Abstrast
Background：The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs.
Objective: The aim of this study was to provide an overview of safety data of biologics for severe asthma using VigiBase, the World Health Organization global pharmacovigilance database.
Methods: We selected all de-duplicated individual case safety reports (ICSRs) attributed to five approved biologics for severe asthma in VigiBase, up to 31st August 2022 (omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab). Descriptive frequency analyses of ICSRs were carried out both as a whole class and as individual products. Reporting odds ratios (ROR) with 95% confidence intervals (CIs) were used as the measure of disproportionality for suspected adverse drug reactions (ADRs) associated with the study drugs compared with either all other suspected drugs (Reference Group 1, RG1) or inhaled corticosteroids plus long-acting β-agonists (ICSs/LABAs) (Reference Group 2, RG2) or with oral corticosteroids (OCSs) (Reference Group 3, RG3).
Results：Overall, 31,724,381 ICSRs were identified in VigiBase and 167,282 (0.5%) were related to study drugs; the remaining reports were considered as RG1. Stratifying all biologic-related ICSRs by therapeutic indication, around 29.4% (n = 48,440) concerned asthma use; omalizumab was mainly indicated as the suspected drug (n = 20,501), followed by dupilumab, mepolizumab, benralizumab and reslizumab. Most asthma ICSRs concerned adults (57%) and women (64.1%). Asthma biologics showed a higher frequency of serious suspected ADR reporting than RG1 (41.3% vs 32.3%). The most reported suspected ADRs included asthma, dyspnea, product use issue, drug ineffective, cough, headache, fatigue and wheezing. Asthma biologics were disproportionally associated with several unknown or less documented adverse events, such as malignancies, pulmonary embolism and deep vein thrombosis with omalizumab; alopecia and lichen planus with dupilumab; alopecia and herpes infections with mepolizumab; alopecia, herpes zoster and eosinophilic granulomatosis with polyangiitis related to benralizumab; and alopecia with reslizumab.
Conclusions: The most frequently reported suspected ADRs of asthma biologics in VigiBase confirmed the presence of well-known adverse effects such as general disorders, injection-site reactions, nasopharyngitis, headache and hypersensitivity, while some others (e.g. asthma reactivation or therapeutic failure) could be ascribed to the indication of use. Moreover, the analysis of signals of disproportionate reporting suggests the presence of malignancies, effects on the cardiovascular system, alopecia and autoimmune conditions, requiring further assessment and investigation.
背景：自从新型生物疗法出现以来，对不受控制的严重哮喘的管理有了很大的改善。截至2022年8月，已有五种生物制剂被批准用于2型哮喘表型：抗IgE（奥马珠单抗），抗IL5（美泊利单抗，瑞利珠单抗，贝那利珠单抗）和抗IL4（度普利尤单抗）单克隆抗体。这些药物通常耐受性良好，尽管长期安全性信息有限，一些不良事件尚未完全描述。自发报告系统是检测潜在信号和评估所有已上市药物实际安全性的基石。
目的：本研究的目的是使用世界卫生组织全球药物警戒数据库VigiBase提供严重哮喘生物制剂安全性数据的概述。
方法：我们选择了截至2022年8月31日，VigiBase中5种已获批的用于治疗严重哮喘的生物制剂(奥马珠单抗、美泊利单抗、瑞利珠单抗、贝那利珠单抗和度普利尤单抗)的所有重复病例安全性报告（ICSRs）。对ICSRs进行了描述性频率分析，既作为整个类别，也作为单个产品。采用95%可信区间（Cis）的报告优势比（ROR）作为研究药物与所有其他可疑药物（参考组1,RG1）或吸入皮质类固醇加长效β激动剂（ICSs/LABAs）（参考组2,RG2）或口服皮质类固醇（OCSs）（参考组3,RG3）相关的可疑药物不良反应（ADRs）的歧化程度的衡量标准。
结果：总体而言，在VigiBase中鉴定了31,724,381个ICSR，其中167,282个（0.5%）与研究药物有关;其余报告被视为RG1。按治疗适应症对所有生物制剂相关的ICSR进行分层，约29.4%（n=48,440）与哮喘使用有关;奥马珠单抗主要被指为疑似药物（n = 20,501），其次是度普利尤单抗、美泊利单抗、贝那利珠单抗和瑞利珠单抗。大多数哮喘ICSR涉及成人（57%）和妇女（64.1%）。哮喘生物制剂显示严重疑似ADR报告的频率高于RG1（41.3% vs 32.3%）。报告最多的疑似ADR包括哮喘、呼吸困难、产品使用问题、药物无效、咳嗽、头痛、疲劳和喘息。哮喘生物制剂与几种未知或记录较少的不良事件不成比例的相关，例如恶性肿瘤、肺栓塞和深静脉血栓形成与奥马珠单抗相关；脱发和扁平苔藓与度普利尤单抗相关；脱发和疱疹感染与美泊利单抗相关；脱发，带状疱疹和嗜酸性肉芽肿病伴多血管炎与贝那利珠单抗相关；脱发与使用瑞利珠单抗相关。
结论：VigiBase中最常报告的哮喘生物制剂疑似ADR证实了存在众所周知的不良反应，例如一般性紊乱、注射部位反应、鼻咽炎、头痛和超敏反应，而其他一些不良反应（例如哮喘再激活或治疗失败）可归因于使用适应症。此外，对不成比例报告信号的分析表明存在恶性肿瘤、对心血管系统的影响、脱发和自身免疫性疾病，需要进一步评估和调查。
(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)
(BioDrugs 2024 May;38(3):425-448; doi: 10.1007/s40259-024-00653-6. IF：5.313)
(BioDrugs 2024 May;38(3):425-448; doi: 10.1007/s40259-024-00653-6. IF：5.313)
Safety of Biological Therapies for Severe Asthma: An Analysis of Suspected Adverse Reactions Reported in the WHO Pharmacovigilance Database.
Paola Maria, Cutroneo, Elena, Arzenton,
Abstrast
Background：The management of uncontrolled severe asthma has greatly improved since the advent of novel biologic therapies. Up to August 2022, five biologics have been approved for the type 2 asthma phenotype: anti-IgE (omalizumab), anti-IL5 (mepolizumab, reslizumab, benralizumab), and anti-IL4 (dupilumab) monoclonal antibodies. These drugs are usually well tolerated, although long-term safety information is limited, and some adverse events have not yet been fully characterized. Spontaneous reporting systems represent the cornerstone for the detection of potential signals and evaluation of the real-world safety of all marketed drugs.
Objective: The aim of this study was to provide an overview of safety data of biologics for severe asthma using VigiBase, the World Health Organization global pharmacovigilance database.
Methods: We selected all de-duplicated individual case safety reports (ICSRs) attributed to five approved biologics for severe asthma in VigiBase, up to 31st August 2022 (omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab). Descriptive frequency analyses of ICSRs were carried out both as a whole class and as individual products. Reporting odds ratios (ROR) with 95% confidence intervals (CIs) were used as the measure of disproportionality for suspected adverse drug reactions (ADRs) associated with the study drugs compared with either all other suspected drugs (Reference Group 1, RG1) or inhaled corticosteroids plus long-acting β-agonists (ICSs/LABAs) (Reference Group 2, RG2) or with oral corticosteroids (OCSs) (Reference Group 3, RG3).
Results：Overall, 31,724,381 ICSRs were identified in VigiBase and 167,282 (0.5%) were related to study drugs; the remaining reports were considered as RG1. Stratifying all biologic-related ICSRs by therapeutic indication, around 29.4% (n = 48,440) concerned asthma use; omalizumab was mainly indicated as the suspected drug (n = 20,501), followed by dupilumab, mepolizumab, benralizumab and reslizumab. Most asthma ICSRs concerned adults (57%) and women (64.1%). Asthma biologics showed a higher frequency of serious suspected ADR reporting than RG1 (41.3% vs 32.3%). The most reported suspected ADRs included asthma, dyspnea, product use issue, drug ineffective, cough, headache, fatigue and wheezing. Asthma biologics were disproportionally associated with several unknown or less documented adverse events, such as malignancies, pulmonary embolism and deep vein thrombosis with omalizumab; alopecia and lichen planus with dupilumab; alopecia and herpes infections with mepolizumab; alopecia, herpes zoster and eosinophilic granulomatosis with polyangiitis related to benralizumab; and alopecia with reslizumab.
Conclusions: The most frequently reported suspected ADRs of asthma biologics in VigiBase confirmed the presence of well-known adverse effects such as general disorders, injection-site reactions, nasopharyngitis, headache and hypersensitivity, while some others (e.g. asthma reactivation or therapeutic failure) could be ascribed to the indication of use. Moreover, the analysis of signals of disproportionate reporting suggests the presence of malignancies, effects on the cardiovascular system, alopecia and autoimmune conditions, requiring further assessment and investigation.
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