Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study
Tomoko TajiriMotohiko SuzukiHirono NishiyamaYoshiyuki OzawaRyota KurokawaNorihisa TakedaKeima ItoKensuke FukumitsuYoshihiro KanemitsuYuta MoriSatoshi FukudaTakehiro UemuraHirotsugu OhkuboMasaya TakemuraKen MaenoYutaka ItoTetsuya OguriKenji IzuharaAkio Niimi
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Abstract:
Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.Keywords:
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特应性皮炎(又称 AD 或湿疹)是一种常见的皮肤病,可引起强烈和持续的瘙痒和皮疹。对于一些中度至重度 AD 患者来说,护肤霜或软膏不合适或不起效。这些患者可能需要口服或注射药物。 其中一些口服或注射治疗可能具有毒性,常常会产生不想要的副作用,特别是在使用时间较长的情况下,因此必须定期对患者进行检测,查看这些治疗是否在损害他们的血液或器官。 Dupilumab 是一种治疗中度至重度 AD 的较新的注射药物。Dupilumab 专门作用于体内导致 AD 的关键分子。在安慰剂对照临床试验中已经在 2000 多名患者身上对 Dupilumab 进行了长达一年的测试。在这些试验中,患者在接受 Dupilumab 或安慰剂(模拟药物)治疗时提供血液和尿液样本进行实验室检测。 本文中,来自德国和美国的作者分析了血细胞、血生化和尿生化在治疗过程中的变化,以检查是否可以在不需要进行定期实验室检测的情况下安全地使用 Dupilumab。 在对患者的血液和尿液进行了许多常规实验室检测后,他们发现,检测结果中没有可能与 Dupilumab 有关的临床重要变化。因此得出结论,使用 Dupilumab 治疗的中度到重度 AD 患者不需要进行定期实验室检测。 本摘要涉及研究: Dupilumab 治疗中重度特应性皮炎的实验室安全性: 三项 III 期试验 (LIBERTY AD SOLO 1、LIBERTY AD SOLO 2 LIBERTY AD CHRONOS)的结果
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Dupilumab is a monoclonal antibody that represents the first approved targeted biological therapy for adults, adolescents, and children older than 6 years with moderate-to-severe atopic dermatitis (AD). Dupilumab binds the shared chain of the interleukin-4 and interleukin-13 receptor blocking the downstream signaling of these cytokines. The clinical improvements induced by dupilumab were associated with remission of the dysregulated immune mechanisms linked with AD. Dupilumab reversed the epidermal barrier defects and improved the global molecular signature of AD. This review seeks to provide an overview on the development of dupilumab as the first target-specific biological treatment for AD, with a description of the clinical trials that have been performed in different age groups, their outcomes, and reported adverse effects. Novel aspects of dupilumab treatment, as well as the current knowledge on the molecular and cellular mechanisms underlying the treatment of AD with dupilumab, are summarized and discussed.
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Mucus retention in the lungs is a feature of several chest diseases. It is unclear to what extent suboptimal mucus transportability is responsible for the poor clearance of lung secretions. We describe a new model, the mucus-depleted bovine trachea, for measurement of the ciliary transportability of respiratory mucus. Mucus depletion was demonstrated microscopically and functionally, and it was accomplished by simple physical means without impairing ciliary action. Control mucus from the tracheas of humans and animals was transported rapidly on this system. However, sputum from 54 patients with bronchiectasis was transported slowly, at a mean of 15% of the rate of control mucus. There was no correlation between sputum transportability and either purulence or the presence of Pseudomonas aeruginosa. This work suggests that there is a serious defect in the ciliary transportability of sputum that is unrelated to the presence of infection. The model should allow in vitro assessment of agents designed to aid mucociliary clearance.
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Dupilumab is a monoclonal antibody that represents the first approved targeted biological therapy for adults, adolescents, and children older than 6 years with moderate-to-severe atopic dermatitis (AD). Dupilumab binds the shared chain of the interleukin-4 and interleukin-13 receptor blocking the downstream signaling of these cytokines. The clinical improvements induced by dupilumab were associated with remission of the dysregulated immune mechanisms linked with AD. Dupilumab reversed the epidermal barrier defects and improved the global molecular signature of AD. This review seeks to provide an overview on the development of dupilumab as the first target-specific biological treatment for AD, with a description of the clinical trials that have been performed in different age groups, their outcomes, and reported adverse effects. Novel aspects of dupilumab treatment, as well as the current knowledge on the molecular and cellular mechanisms underlying the treatment of AD with dupilumab, are summarized and discussed.
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Introduction: Current treatment options for moderate-to-severe atopic dermatitis (AD) are limited and have potentially dangerous side effects. Dupilumab is a novel monoclonal antibody that was recently studied in adult patients with moderate-to-severe AD. Dupilumab inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling and was previously found to be effective in asthma. Considering that both AD and asthma are Th2 cell-mediated inflammatory processes, it is reasonable to suspect that dupilumab would be beneficial in AD.`Areas covered: This article is a review of the one major clinical trial that assessed the efficacy of dupilumab in patients with AD. Its goal is to provide a comparison to the current modalities for the treatment of AD and expert insight regarding future studies.Expert opinion: The results of this study are a significant therapeutic advancement. Dupilumab was shown to provide a mean percent change in Eczema Area and Severity Index score of −74% ± 3.6, in addition to, statistically and clinically significant reductions the severity, symptomatology, and morbidity associated with AD. However, the small sample size makes it difficult to assess the magnitude of this effect. As a result, dupilumab will likely be reserved for cases of severe AD unresponsive to traditional modalities.
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结膜炎是一种导致眼睛变红、瘙痒和渗出的常见疾病。它在特应性皮炎(也称为湿疹)和其他过敏性疾病(包括哮喘)的患者中常见。除了过敏,感染、化学品、刺激物和其他疾病也可引起结膜炎。Dupilumab 是一种处方药,在美国批准用于不能通过局部外用(外用到皮肤)处方药控制或不能局部外用药物的≥ 12 岁中重度 AD 患者,在其他国家批准用于通过现有治疗无法控制的 AD 成人,和用于通过当前用药无法控制的≥12 岁中重度哮喘患者的维持治疗。Dupilumab 可阻滞导致这些过敏性疾病的特定物质的活性。在大部分 AD 研究中,接受dupilumab治疗患者中的结膜炎发生率多于安慰剂(模拟药物)组。为了研究这一作用,作者们评估了在 AD、哮喘、慢性鼻窦炎伴鼻息肉(CRSwNP) 和嗜酸性粒细胞性食管炎(EoE) 中开展的 11 项 dupilumab 研究中的结膜炎的发生率、风险因素、严重程度和结局。在 6 项 AD 研究的 5 项中,dupilumab治疗患者较安慰剂治疗患者更容易发生结膜炎。没有确认因感染导致的结膜炎,其性质似乎也不是过敏性的。进入这些研究时 AD 较严重患者或之前曾患过结膜炎的患者更容易患结膜炎。在哮喘和 CRSwNP 研究中,dupilumab 和安慰剂组的结膜炎发生率均低于 AD 研究,且dupilumab 和安慰剂组相似。在 EoE 研究中,没有人患有结膜炎。在所有研究中,结膜炎大部分为轻中度;大部分病例在治疗期间恢复。需要进一步研究 dupilumab治疗患者中的结膜炎原因。
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Purpose of review Dupilumab is an emerging medication that has shown efficacy for multiple atopic conditions. This review provides insight into the common conditions that are treated, mechanism of action, and continued innovation with the medication. Recent findings There continues to be applicability of dupilumab in treating a growing number of atopic conditions. Increasingly younger patient populations with eosinophil based conditions are being approved for this therapy. It is also considered as an additional option treatment for patients who cannot tolerate oral therapy or have adverse effects from other agents. Patients with more severe conditions are finally finding symptom stability while also being able to reduce reliance on corticosteroids. Patients as young as 6 months of age have benefited from treatment. Summary As atopic conditions become more prevalent, dupilumab has been shown to be successful in inducing remission of symptoms. Overall, it continues to be a promising treatment for reducing the burden of disease severity as well as improving the quality of life of affected children.
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特应性皮炎 (AD) 是一种湿疹,在儿童中非常常见,但也影响全世界 2%‐10% 的成年人。主要症状是瘙痒,其严重程度足以妨碍患者正常入睡。它可以发生在任何部位的皮肤上(包括脸部),但最常见的区域是肘部、膝盖、腕部和颈部。发病的皮肤通常是红色和干燥的,并且可能因刮擦而出血。 目前,对于患有中度至重度 AD 患者的治疗可能是有效的,但可能有局限性,例如副作用。Dupilumab 是注册用于治疗中度至重度 AD 的第一个生物制剂类别药物。大型临床试验已证明其疗效、耐受性(指患者是否能够继续接受治疗)和安全性。但是,关于 Dupilumab 的日常实践数据有限。 这项研究的目的是评估日常实践中使用 Dupilumab 治疗 AD 患者,作者纳入荷兰两家大学医院 95 例接受 Dupilumab 治疗的 AD 患者。62 例患者从一开始(基线)使用全身性免疫抑制剂治疗,在 Dupilumab 治疗期间 43 例继续使用全身性免疫抑制剂。 这项研究使用了各种系统来监测每位患者湿疹的改善情况,可由医生或患者报告。从基线到治疗的 16 周,疾病严重程度评分(湿疹面积和严重程度指数评分 (0‐72),供医生记录湿疹的严重程度)从 18.6 降低到 7.3,患者报告的评分(由患者回答问题来表明症状是否有所改善或恶化)改善了 41%‐66%。 5 例患者由于副作用或无效而停止了 Dupilumab 治疗。据报道,分别有 62% 和 8% 的患者出现眼部症状和口面(非眼)单纯疱疹病毒 (HSV) 再激活。 作者得出的结论是,在日常实践中使用 Dupilumab 治疗显示医师报告的分数和患者报告的分数均具有临床意义的改善,这与来自临床试验的疗效数据一致。除了经常报告的眼部症状和口面部(非眼部)HSV 再激活以外,没有明显的安全性问题。 本摘要涉及研究: Dupilumab 治疗 95 例特应性皮炎的有效性: 日常实践数据
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特应性皮炎 (AD) 也称为湿疹, 其表现为皮肤发红、渗液和干燥并可能发生开裂和感染。剧烈瘙痒可能非常麻烦, 而且可能导致睡眠障碍, 是 AD 患者的主要主诉。 AD 通常从儿童开始, 而且影响全世界 1/4 的青少年。对于青少年, AD 皮肤的瘙痒和外观可显著降低生活质量,但适合长期使用的中度至重度 AD 有效治疗选择很少。 Dupilumab 是一种新的药物, 其可阻断导致过敏症状(如 AD)的关键分子。研究显示, 该药物对治疗成人中度至重度 AD 是有效的, 而且长期使用相对安全。 这项研究在 40 例年龄 12 至 17 岁的接受 dupilumab 治疗最长一年的患者中进行, 涉及欧洲和加拿大多个中心。研究人员希望了解 dupilumab 是否对治疗 AD 有效以及这类患者长期使用是否安全 。他们还希望了解 dupilumab 在此年龄段 AD 患者中的身体处理方式。 他们发现, dupilumab 治疗在这些年轻患者中显著改善了皮肤和 AD 症状(包括瘙痒), 而且不会造成任何意外的副作用。他们还发现 dupilumab 在这些年轻患者中的处理方式与成人相同。在整个一年治疗期内维持了改善。 研究结果支持使用 dupilumab 持续治疗中度至重度 AD 青少年患者。 This summary relates to the study: dupilumab 用于未控制的中度至重度特应性皮炎青少年患者中:IIA 期开放标签试验和随后的 III 期开放标签扩展研究结果
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