Hellings P W, Verhoeven E, Fokkens W J
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; Department of Otorhinolaryngology, University Hospital Ghent, Laboratory of Upper Airway Research, Ghent, Belgium;Department of Otorhinolaryngology, Head and Neck Surgery, Academic Medical Centre (AMC), Amsterdam, the Netherlands.
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium.
Rhinology. 2021 Apr 1;59(2):151-163. doi: 10.4193/Rhin20.570.
The majority of patients with uncontrolled severe CRSwNP, asthma and atopic dermatitis share a similar T helper 2 type inflammation linked to their underlying phenotype. This discovery has triggered new research around treatments targeting specific cytokines driving inflammation in CRSwNP like IL-4, IL-13, IL-5 and IgE. Biologicals are increasingly tested as additional tre- atment for patients suffering from severe chronic rhinosinusitis with nasal polyps (CRSwNP). Their efficacy has been demonstrated in multiple studies. All studies differ in terms of baseline characteristics of included patients and outcome parameters analysed.
A comparative analysis of the efficacy of reported biologicals for CRSwNP based on the published data for phase 2 and 3 studies. The aim was to provide a comprehensive overview across the different biologicals and outcome parameters.
In a first step we critically selected out of all available phase 2 and 3 clinical trials the ones containing the most rigorous and compatible study designs. Meaning studies that comply with a need for a clear definition of CRSwNP, at least two administra- tion doses, comparable timeframes and the same outcome parameters studied. This assessment was performed using a PRISMA search. We retained 7 studies with significant data for dupilumab, mepolizumab and omalizumab. In a second step the effect-sizes of treatment with those biologicals were compared for the most important outcome parameters both patient relevant (nasal con- gestion, smell loss and SNOT-22 scores) and patient irrelevant (CT scan Lund-Mackay, smell test and nasal polyp scores). Therapy duration of 16 to 25 weeks was chosen for evaluation of efficacy.
A direct comparison of efficacy between dupilumab, mepolizumab and omalizumab is challenging given differences in inclusion criteria, outcome parameters and time-points of analyses. We have been able to conclude that effect sizes of dupilumab, mepolizumab and omalizumab seem large enough to reflect a major reduction in symptom burden as experienced by patients suffering from refractory CRSwNP. The effect size of dupilumab on both patient relevant and patient irrelevant parameters of smell loss are clearly significant and reflect the clinical experience of major reduction of smell impairment in treated patients.
Despite the heterogeneity of protocols, dosages and time-points of analyses of biological trials in CRSwNP, this over- view highlights outcomes of biological treatment in CRSwNP in a comprehensive way. Real-life registries, comparative trials and/ or endotype-driven treatment plans are needed to provide the answers to the multiple questions that are still open today.
大多数未得到控制的重度慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）、哮喘和特应性皮炎患者都有与潜在表型相关的类似2型辅助性T细胞炎症。这一发现引发了针对驱动CRSwNP炎症的特定细胞因子（如白细胞介素-4、白细胞介素-13、白细胞介素-5和免疫球蛋白E）的治疗的新研究。生物制剂越来越多地被作为重度慢性鼻-鼻窦炎伴鼻息肉（CRSwNP）患者的额外治疗方法进行测试。其疗效已在多项研究中得到证实。所有研究在纳入患者的基线特征和分析的结局参数方面均有所不同。
基于已发表的2期和3期研究数据，对报道的用于CRSwNP的生物制剂的疗效进行比较分析。目的是全面概述不同的生物制剂和结局参数。
第一步，我们从所有可用的2期和3期临床试验中严格挑选出研究设计最严谨且具有可比性的试验。即符合对CRSwNP进行明确定义、至少两种给药剂量、可比的时间框架以及研究相同结局参数要求的研究。这项评估采用PRISMA检索进行。我们保留了7项关于度普利尤单抗、美泊利单抗和奥马珠单抗的具有重要数据的研究。第二步，针对最重要的结局参数（包括与患者相关的参数（鼻塞、嗅觉丧失和SNOT-22评分）以及与患者无关的参数（CT扫描Lund-Mackay、嗅觉测试和鼻息肉评分））比较这些生物制剂治疗的效应量。选择16至25周的治疗持续时间来评估疗效。
鉴于纳入标准、结局参数和分析时间点的差异，直接比较度普利尤单抗、美泊利单抗和奥马珠单抗的疗效具有挑战性。我们能够得出结论，度普利尤单抗、美泊利单抗和奥马珠单抗的效应量似乎足够大，足以反映难治性CRSwNP患者症状负担的显著减轻。度普利尤单抗对与患者相关和与患者无关的嗅觉丧失参数的效应量均明显显著，反映了治疗患者嗅觉障碍大幅减轻的临床经验。
尽管CRSwNP生物试验的方案、剂量和分析时间点存在异质性，但本综述以全面的方式突出了CRSwNP生物治疗的结果。需要真实世界登记研究、比较试验和/或内型驱动的治疗计划来回答目前仍然悬而未决的多个问题。
