Editorial: Mesenchymal Stem Cell Therapy for Perianal Fistulising Crohn's Disease—Effective or Hype? Authors' Reply

IF 6.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Péter Bacsur, Klaudia Farkas, Tamás Molnár
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引用次数: 0

Abstract

We appreciate the thoughtful comments by Drs. McCurdy and Wong regarding our study on the effectiveness and safety of mesenchymal stem cell treatment for fistulising Crohn's disease. We analysed 223 patients in an international, multicentre setting, who underwent darvadstrocel treatment [1, 2]. They clearly highlighted the unmet need for new therapeutic approaches for perianal fistulising Crohn's disease (PFCD) in their editorial. We agree that discrepancies between the effectiveness results of large clinical trials and observational studies need to be carefully reconsidered to support position statements on the use of mesenchymal stem cell treatment in PFCD.

First, in our real-world study, preparation—including curettage and seton placement—preceded the administration of darvadstrocel in all cases, in accordance with the protocols followed in pivotal clinical trials. Controlled, high-quality perianal surgery can achieve a high success rate, even in refractory cases, if performed in a highly experienced centre [3]. Due to the structural design of our real-world study, it is not possible to determine the exact contribution of darvadstrocel to the improvements observed in our patients, relative to the surgical intervention. However, the 62% closure rate is clearly higher than the closure rate seen in the placebo arm of the ADMIRE studies.

Second, we acknowledge that increased effectiveness rates are often observed in real-world settings compared with randomised trials, particularly in the field of pharmacological sciences. This discrepancy is probably due to differences in population characteristics, inclusion criteria, study design, data collection methods and statistical considerations (such as the handling of confounders). We reported clinical remission rates of 72.2% at Week 26 and 62.3% at Week 52, which align with the cumulative effectiveness of 68.1%–77.2% in a systematic review of observational trials with darvadstrocel, with negligible between-study heterogeneity [4]. It is also worth noting that combined remission (defined as the MRI endpoint of absence of collections > 2 cm) was observed in 60.6% of patients at Week 26 and 52.3% at Week 52.

Third, while evaluating combined remission can provide a robust end point, it has limitations. MRI assessment of PFCD requires expert interpretation, and the precise definitions of fistula healing remain inconclusive [5]. Furthermore, regular monitoring of fistula healing with MRI is not yet part of standard clinical practice, as evidenced by our real-world results. From a patients' perspective, the cessation of fistula drainage and the resolution of symptoms such as the feeling of uncleanliness are considered more important than MRI findings.

Furthermore, we found that approximately 80% of patients expressed satisfaction with the treatment after 1 year, highlighting its positive impact on quality of life, especially given the challenges of managing PFCD. However, this end point is inherently subjective and difficult to measure objectively.

In conclusion, while the effectiveness data remain debated, potential predictors of treatment success have been identified. Nevertheless, further research is necessary to definitively determine whether darvadstrocel treatment is truly effective or simply a treatment hype.

Péter Bacsur: conceptualization, writing – original draft. Klaudia Farkas: conceptualization, writing – original draft. Tamás Molnár: conceptualization, writing – review and editing.

This article is linked to Bacsur et al papers. To view these articles, visit https://doi.org/10.1111/apt.18359 and https://doi.org/10.1111/apt.18408.

社论:间充质干细胞治疗肛周瘘管性克罗恩病有效还是炒作?作者的回复
我们感谢李博士深思熟虑的意见。McCurdy和Wong就我们关于间充质干细胞治疗瘘管性克罗恩病的有效性和安全性的研究进行了评论。我们在一个国际多中心环境中分析了223例接受达伐司特治疗的患者[1,2]。在他们的社论中,他们明确强调了对肛周瘘管性克罗恩病(PFCD)新治疗方法的需求。我们同意,大型临床试验和观察性研究的有效性结果之间的差异需要仔细重新考虑,以支持在PFCD中使用间充质干细胞治疗的立场声明。首先,在我们真实世界的研究中,根据关键临床试验中遵循的协议,在所有病例中,准备工作(包括刮除和设置)都先于达伐司特沙给药。有控制的、高质量的肛周手术即使在难治性病例中,如果在经验丰富的中心进行,也能取得很高的成功率。由于我们现实世界研究的结构设计,相对于手术干预,我们不可能确定达伐司特铁对我们患者观察到的改善的确切贡献。然而,62%的关闭率明显高于安慰剂组的关闭率。其次,我们承认,与随机试验相比,在现实环境中经常观察到更高的有效率,特别是在药理学领域。这种差异可能是由于人口特征、纳入标准、研究设计、数据收集方法和统计考虑(如混杂因素的处理)的差异。我们报告的临床缓解率在第26周为72.2%,在第52周为62.3%,这与一项观察性试验的系统评价中累积有效性为68.1%-77.2%一致,研究间异质性可以忽略不计[4]。同样值得注意的是,在第26周和52周,60.6%的患者观察到联合缓解(定义为MRI终点没有收集物2 cm)。第三,虽然评估联合缓解可以提供一个可靠的终点,但它有局限性。PFCD的MRI评估需要专家解释,瘘管愈合的精确定义仍然没有定论。此外,通过MRI定期监测瘘管愈合还不是标准临床实践的一部分,正如我们的实际结果所证明的那样。从患者的角度来看,瘘管引流的停止和不洁感等症状的缓解被认为比MRI表现更重要。此外,我们发现大约80%的患者在1年后对治疗表示满意,突出了其对生活质量的积极影响,特别是考虑到管理PFCD的挑战。然而,这个终点本质上是主观的,很难客观地衡量。总之,尽管有效性数据仍有争议,但已经确定了治疗成功的潜在预测因素。然而,需要进一步的研究来明确地确定达伐司特尔治疗是真正有效还是仅仅是一种治疗炒作。
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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来源期刊
CiteScore
15.60
自引率
7.90%
发文量
527
审稿时长
3-6 weeks
期刊介绍: Alimentary Pharmacology & Therapeutics is a global pharmacology journal focused on the impact of drugs on the human gastrointestinal and hepato-biliary systems. It covers a diverse range of topics, often with immediate clinical relevance to its readership.
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