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.

我们感谢 McCurdy 博士和 Wong 博士对我们关于间充质干细胞治疗克罗恩病的有效性和安全性的研究的深思熟虑的评论。我们分析了 223 例在国际、多中心环境中接受 darvadstrocel 治疗的患者 [1， 2]。他们在社论中明确强调了对肛周瘘管性克罗恩病 （PFCD） 新治疗方法的未满足需求。我们同意，需要仔细重新考虑大型临床试验和观察性研究的有效性结果之间的差异，以支持关于在 PFCD 中使用间充质干细胞治疗的立场声明。

首先，在我们的真实世界研究中，根据关键临床试验中遵循的方案，在所有情况下，准备工作（包括刮除术和挂线放置）都在 darvadstrocel 给药之前进行。如果在经验丰富的中心进行受控、高质量的肛周手术，即使在难治性病例中也能达到很高的成功率 [3]。由于我们真实世界研究的结构设计，相对于手术干预，无法确定 darvadstrocel 对在我们患者中观察到的改善的确切贡献。然而，62% 的闭合率明显高于 ADMIRE 研究的安慰剂组的闭合率。

其次，我们承认，与随机试验相比，在现实世界中经常观察到有效率增加，尤其是在药理学领域。这种差异可能是由于人群特征、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。我们报告了第 26 周的临床缓解率为 72.2%，第 52 周的临床缓解率为 62.3%，这与 darvadstrocel 观察性试验的系统评价中 68.1%-77.2% 的累积有效性一致，研究间异质性可以忽略不计 [4]。还值得注意的是，在第 26 周和 第 52 周分别在 60.6% 和 52% 的患者中观察到联合缓解 （定义为 MRI 终点没有收集 > 2 cm）。

第三，虽然评估联合缓解可以提供一个稳健的终点，但它也有局限性。PFCD 的 MRI 评估需要专家解读，瘘管愈合的确切定义尚无定论 [5]。此外，正如我们的真实结果所证明的那样，使用 MRI 定期监测瘘管愈合尚未成为标准临床实践的一部分。从患者的角度来看，瘘管引流的停止和不洁感等症状的消退被认为比 MRI 结果更重要。

此外，我们发现大约 80% 的患者在 1 年后对治疗表示满意，这凸显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，虽然有效性数据仍存在争议，但已经确定了治疗成功的潜在预测因素。尽管如此，还需要进一步的研究来明确确定 darvadstrocel 治疗是真的有效还是仅仅是一种治疗炒作。