治疗重症哮喘的替塞普鲁单抗:提升现有实践,识别上皮驱动的特征。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-09 DOI:10.1186/s12931-024-02998-6
Marco Caminati, A Vatrella, P Rogliani, E Carpagnano, A Spanevello, G Senna
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引用次数: 0

摘要

背景:越来越多的证据表明,上皮细胞与哮喘的病理生物学有着广泛的关联。在临床上,选择性结合主要上皮细胞因子 TSLP 的替塞普鲁单抗已被证明对哮喘患者有效,而无需考虑其具体表型。为了避免将替塞普鲁单抗视为非特异性选择的风险,本观点旨在通过回顾已发表的有关药物作用机制和疗效数据的证据,勾勒出替塞普鲁单抗的最佳合格患者特征,并提出上皮细胞驱动疾病的一些特征:虽然不能依靠标准化或排他性的 "标志物",但环境与哮喘控制不佳之间的关系可能表明上皮屏障功能障碍具有重要的相关性。因此,与特定暴露(病原体、污染物、化学物质)同时出现的过敏和哮喘加重,以及感染易感性的增加,可被视为上皮免疫反应受损的标志。Tezepelumab 对过敏性患者有效,能够减少因接触季节性或常年性过敏原(包括真菌)而导致的哮喘恶化。此外,替塞单抗还能降低呼吸道疾病和哮喘恶化并发症的发病率。在炎症方面,上皮免疫反应与粘液分泌过多和堵塞受损有关。一项安慰剂对照试验显示,接受治疗的患者粘液堵塞现象明显减少。气道高反应性(AHR)、气道阻塞和重塑被描述为上皮协调免疫激活的一种表现形式。值得注意的是,与安慰剂组相比,接受替塞泊单抗治疗的患者甘露醇试验阴性的发生率明显更高。此外,在使用替塞泊单抗的患者中,BD 前 FEV1 提高了 130 毫升。上述数据表明,支气管可逆性和AHR可被视为 "功能性生物标志物",有助于对患者进行表型分析,并确定特珠单抗的最佳应答者:结论:将 "功能性生物标志物 "与炎症性生物标志物相结合,并更好地描述哮喘恶化的特征,可能会为不同的、更具横向性的表型分析铺平道路,从而克服包括 T2 高、过敏性/变应性或 T2 低哮喘在内的 "限制性 "标签。精确定义疾病特征和潜在靶点,即使是符合替塞单抗治疗条件的受试者也能更好地控制病情,这对于避免 "阻断 "诱惑和根据每位患者的个体差异优化个性化医疗方法至关重要。
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Tezepelumab for severe asthma: elevating current practice to recognize epithelial driven profiles.

Background: An increasing amount of evidence supports the relevance of epithelium across the wide spectrum of asthma pathobiology. On a clinical ground tezepelumab, selectively binding TSLP, a major epithelial cytokine, has demonstrated to be effective in asthma patients regardless their specific phenotype. In order to avoid the risk of considering tezepelumab as a not-specific option, the present perspective aims to sketch the tezepelumab best eligible patient profile and to propose some hallmarks of epithelial-driven disease by reviewing the published evidence on the drug mechanism of action and efficacy data.

Main body: Although it cannot rely on standardised or exclusive "markers", the relationship between environment and poor asthma control might suggest a major relevance of the epithelial barrier dysfunction. In that light, allergy and asthma exacerbations concomitant with specific exposures (pathogens, pollutants, chemicals), as well as increased susceptibility to infections can be considered as the hallmark of an impaired epithelial immune response. Tezepelumab is effective in allergic patients, being able to reduce asthma exacerbations precipitated by the exposure to seasonal or perennial aeroallergens, including fungi. In addition, tezepelumab reduced the incidence of co-occurring respiratory illness and asthma exacerbations. In terms of inflammation, epithelial immune response has been related to an impaired mucus hypersecretion and plugging. A placebo-controlled trial demonstrated a significant reduction of mucus plugging in treated patient. Airways hyperreactivity (AHR), airways obstruction and remodelling have been described as an expression of epithelial orchestrated immunological activation. Of note, a significantly higher incidence of mannitol negative test in patients treated with tezepelumab when compared to placebo group has been observed. In addition, A 130 mL improvement in pre-BD FEV1 has been described in patients assuming Tezepelumab. The above-mentioned data suggest that bronchial reversibility and AHR can be considered "functional biomarkers" supporting patients' phenotyping and the identification of tezepelumab best responders.

Conclusion: Integrating "functional biomarkers" to the inflammatory ones and a better characterization of asthma exacerbations might pave the way to a different and more transversal phenotyping, which overcomes the "restrictive" labels including T2 high, allergic/atopic or T2 low asthma. Precisely defining the disease characteristics and potential targets for a better control even in tezepelumab eligible subjects is essential to avoid the block buster temptation and optimize the personalized medicine approach according to each patient's individuality.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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