Stage of prolonged survival in ALS - Author's reply.
Stage of prolonged survival in ALS - Author's reply.
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ALS 延长生存阶段 - 作者的回复。
DOI：
10.1016/s1474-4422(18)30208-4
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Al-Chalabi A
中科院分区：
文献类型：
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作者：
Al-Chalabi A
近四分之一个世纪后，方东和他的同事们对利鲁唑治疗肌萎缩性侧索硬化症（ALS）患者的确切获益时间提供了一个敏锐的见解。Seibold及其同事先前使用基于模型的随机森林方法对ALS临床试验（PRO-ACT）数据库进行了探索，发现利鲁唑对肺活量较低的ALS患者有更大的治疗效果。通过使用King 's临床ALS分期系统，Fang和同事在他们的新分析中发现，在最初的利鲁唑剂量范围临床试验中，六分之一的患者在入组时患有4期ALS。在我们的渐冻症多学科诊所，第一次见到的病人中大约有一半是4期渐冻症。在clinicbased观察性研究中,我们报告说,生存显著延长患者利鲁唑(log-rank p = 0·019),从平均14·6个月(平均13·0,95% CI 9·8-19·6)后开始非侵入式正压通风(NIV)在ALS患者最大吸气压力低的超过60公分水柱不是利鲁唑(n = 18),的意思是22·3个月(平均25·0,95%置信区间18.5 - -26.1)在ALS患者利鲁唑(n = 47)。我们的研究结果表明，在已经接受NIV治疗但最大吸气压力较低（< -60 cm H20）的ALS患者中，当他们接受利鲁唑治疗时，可能会提高生存率，这引起了人们对未来道路复杂性的关注。首先，我们要问的是，是否应该监测最大吸气压力和肺活量，因为最大吸气压力的变化可能与肺活量的变化不一致。其次，我们必须问利鲁唑和NIV治疗的效果是否在ALS的整个呼吸期都是协同的。目前，我们在患者出现呼吸损害之前使用利鲁唑进行治疗，并且不知道利鲁唑是否可以通过分期使用来增强效果。与Fang及其同事的报道一致，Vittacca及其同事发现，在ALS患者中早期引入NIV可能会增加益处。我们是否需要更仔细地建立利鲁唑药代动力学与新发现的呼吸衰竭阶段之间的联系，在这个阶段利鲁唑治疗对延长生命最有效？也许我们还可以专门研究呼吸治疗对利鲁唑的反应，努力了解利鲁唑在肌萎缩性侧索硬化这一阶段的作用机制。利鲁唑对脊髓损伤患者呼吸功能障碍的影响，是我们可以借鉴的一个有利点。
After nearly a quarter century, Ton Fang and colleagues1 have provided a keen insight into the mystery regarding the precise timing of the benefit of riluzole in the treatment of patients with amyotrophic lateral sclerosis (ALS). Seibold and colleagues2 had preiously identified a larger treatment effect of riluzole in patients with ALS with lower vital capacity, after exploration of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with a method of model-based random forests. By use of the King’s clinical ALS staging system, Fang and colleagues identified in their novel analysis that one in six of the patients in the original dose-ranging clinical trial of riluzole had stage 4 ALS at enrollment. Around half of the patients that we first see in our ALS multidisciplinary clinics have stage 4 ALS. In a clinicbased observational study, 3 we reported that survival was extended significantly in patients on riluzole (log-rank p= 0· 019), from a mean of 14· 6 months (median 13· 0, 95% CI 9· 8–19· 6) post start of non-invasive positive pressure ventilation (NIV) in patients with ALS with a maximal inspiratory pressure lower than–60 cm H20 not on riluzole (n= 18), to a mean of 22· 3 months (median 25· 0, 95% CI 18.5–26.1) in patients with ALS on riluzole (n= 47). Our findings identified the possible enhanced survival in patients with ALS that are already on NIV, but with low maximal inspiratory pressure (<–60 cm H20), when they are treated with riluzole, bringing attention to the complexities of the road ahead. Firstly, we must ask if maximal inspiratory pressure as well as vital capacity should be monitored, since the changes in maximal inspiratory pressure might not be in line with the changes in vital capacity. Secondly, we must ask if the effects of treatment with riluzole and NIV are synergistic throughout the respiratory stage of ALS. Currently, we treat patients with riluzole before they have respiratory compromise, and do not know whether the effect of riluzole might be enhanced by stage-specific utilisation. In agreement with what has been reported by Fang and colleagues, Vittacca and colleagues4 have identified a potential enhanced benefit of early introduction of NIV in patients with ALS.Do we need to more carefully establish the link between riluzole pharmacokinetics, and the newly identified stage of respiratory compromise at which riluzole treatment is most effective in prolonging life? Perhaps we could also look specifically at respiratory treatment responses to riluzole administration, in an effort to understand the mechanism of action of riluzole at this stage of ALS. The effect of riluzole on respiratory dysfunction in spinal cord injury, 5 for instance, is a vantage point we could learn from.