Sub‐stratification of type‐2 high airway disease for therapeutic decision‐making: A ‘bomb’ (blood eosinophils) meets ‘magnet’ (FeNO) framework

S. Couillard, I. Pavord, L. Heaney, N. Petousi, T. Hinks
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引用次数: 12

Abstract

Biologic therapies targeting components of the type-2 inflammatory response seen in many patients with obstructive airways disease have had a dramatic impact in the clinic. In the severe asthma clinic, extraordinary outcomes are being achieved and the days when the severe asthma clinicians’ job was mainly about overseeing an orderly decline (much of it due to oral corticosteroid-related morbidity) have been confined to the history books. In 2023, it is projected that sales will top $10 billion, accounting for over 30% of total worldwide asthma drug sales. The success of biologics was not predicted by all and there was a view that targeting treatment to a biomarkerdefined subgroup of patients would result in a severely restricted market. In fact, we have seen the opposite. The ability to target treatment to a population who are most likely to benefit has incentivized clinicians to look for these patients, has increased the likelihood of a good response to treatment and has resulted in low rates of treatment failure. It has also made the job of jumping regulatory hurdles and making a compelling cost–benefit case for funding of treatment much more straightforward. We now have four monoclonal antibody targeting strategies inhibiting different aspects of the immune response driving asthma attacks (Figure 1). The target population is patients with persistent airway inflammation despite treatment with a reasonable dose of inhaled corticosteroids (ICS). The persistence of type-2 inflammation indicates that the airway mucosal mechanisms driving recruitment of eosinophils towards the airway epithelium are, or have become, corticosteroid-resistant. In this situation, effective treatment exploits other mechanisms to reduce eosinophilic airway inflammation: depletion of circulating eosinophils (oral corticosteroids and biologics targeting the IL-5 pathway: mepolizumab, benralizumab, reslizumab); prevention of eosinophils leaving the vascular compartment (targeting the IL-4 receptor and inhibiting IL-4/IL-13 responses: dupiliumab); or inhibition of the corticosteroid-resistant airway mucosal drivers of type-2 inflammation by other mechanisms (dupilumab again or targeting thymic stromal lymphopoietin [TSLP] with tezepelumab). A sixth biologic (omalizumab) targets the distal effector of the allergic reaction (IgE) with marginal effects on the type-2 immune response. The presence of multiple biologic options and the absence of any direct head-to-head comparisons mean that finding the right biologic for the right patient has become increasingly challenging. In this commentary article, we suggest that one way forward is to sub-stratify type-2 inflammatory airway disease according to the dominant driving mechanism. This concept is based on the demonstration that the two clinically accessible biomarkers of type-2 inflammation, fractional exhaled nitric oxide (FeNO) and the blood eosinophil count, provide independent prognostic (of exacerbations) and predictive (of corticosteroid response) information because they identify different aspects of type-2 inflammation. Mechanistic support for this idea comes from a recent cross-sectional analysis of induced sputum and serum markers of type-2 inflammation in patients with severe asthma who were confirmed to be adherent to high-dose ICS. We found that FeNO correlated with almost all of the assessed components of the airway type-2 immune response in sputum, whereas the blood eosinophil count correlated with serum IL-5 but not with any assessed measure of airway inflammation (Figure 2). FeNO and blood eosinophils therefore relate to different components and compartments of type-2 inflammation (Figure 2): FeNO reflects airway type-2 activity and the chemotactic pull to the airways (the magnet), whereas blood eosinophils reflect the systemic pool of available effector cells and circulating IL-5 (the bomb). The important clinical corollary of these mechanistic data is observable in randomized clinical trials, where raised values of baseline FeNO and blood eosinophils act synergistically to predict asthma attacks in the placebo arm—an excess risk which is entirely removed by appropriate type-2 targeting anti-inflammatory therapy. These findings imply that we might be in a position to choose the most appropriate biologic for an individual patient based on their biomarker profile and the primary The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Received: 27 April 2022 Accepted: 5 May 2022
用于治疗决策的2型高气道疾病亚分层:一个“炸弹”(嗜酸性粒细胞)与“磁铁”(FeNO)框架相遇
针对在许多阻塞性气道疾病患者中发现的2型炎症反应成分的生物疗法在临床中产生了巨大的影响。在严重哮喘门诊,正在取得非凡的成果,严重哮喘临床医生的工作主要是监督有序的下降(其中大部分是由于口服皮质类固醇相关的发病率)的日子已经局限于历史书。到2023年,预计销售额将超过100亿美元,占全球哮喘药物总销售额的30%以上。并不是所有人都能预测到生物制剂的成功,有一种观点认为,针对生物标志物定义的亚组患者进行靶向治疗将导致市场受到严重限制。事实上,我们看到了相反的情况。针对最有可能受益的人群进行靶向治疗的能力激励了临床医生寻找这些患者,增加了对治疗产生良好反应的可能性,并降低了治疗失败率。它还使跨越监管障碍的工作和为治疗资金提供令人信服的成本效益案例变得更加直接。我们现在有四种单克隆抗体靶向策略,抑制驱动哮喘发作的免疫反应的不同方面(图1)。目标人群是持续气道炎症的患者,尽管接受了合理剂量的吸入皮质类固醇(ICS)治疗。2型炎症的持续存在表明,气道粘膜机制驱动嗜酸性粒细胞向气道上皮募集是或已经成为皮质类固醇抵抗性的。在这种情况下,有效的治疗利用其他机制来减少嗜酸性粒细胞气道炎症:循环嗜酸性粒细胞的消耗(口服皮质类固醇和靶向IL-5途径的生物制剂:mepolizumab, benralizumab, reslizumab);预防嗜酸性粒细胞离开血管室(靶向IL-4受体并抑制IL-4/IL-13反应:dupiliumab);或通过其他机制抑制皮质类固醇抵抗性气道粘膜驱动因子的2型炎症(再次使用dupilumab或使用tezepelumab靶向胸腺基质淋巴生成素[TSLP])。第六种生物制剂(omalizumab)靶向过敏反应(IgE)的远端效应,对2型免疫反应具有边际效应。多种生物制剂选择的存在和任何直接的头对头比较的缺乏意味着为合适的患者找到合适的生物制剂变得越来越具有挑战性。在这篇评论文章中,我们建议一种方法是根据主导驱动机制对2型炎性气道疾病进行亚分层。这一概念是基于两种临床可获得的2型炎症生物标志物,分数呼气一氧化氮(FeNO)和血液嗜酸性粒细胞计数,提供独立的预后(恶化)和预测(皮质类固醇反应)信息,因为它们识别2型炎症的不同方面。这一观点的机制支持来自于最近对严重哮喘患者的诱导痰和血清2型炎症标志物的横断面分析,这些患者被证实坚持使用高剂量ICS。我们发现,FeNO几乎与痰中气道2型免疫反应的所有评估成分相关,而血嗜酸性粒细胞计数与血清IL-5相关,但与气道炎症的任何评估指标无关(图2)。因此,FeNO和血嗜酸性粒细胞与2型炎症的不同成分和区室相关(图2)。FeNO反映气道2型活性和对气道的趋化拉(磁铁),而血嗜酸性粒细胞反映可用效应细胞和循环IL-5(炸弹)的系统池。这些机制数据的重要临床推论在随机临床试验中可以观察到,基线FeNO和血嗜酸性粒细胞的升高协同作用预测安慰剂组哮喘发作-通过适当的2型靶向抗炎治疗完全消除了这种过度风险。这些发现表明,我们可以根据个体患者的生物标志物特征和主要特征来选择最合适的生物制剂。本文所表达的观点仅代表作者的观点,并不一定代表NHS、NIHR或卫生部的观点。收稿日期:2022年4月27日
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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