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

Perianal fistulising Crohn's disease (PFCD) is a common yet challenging phenotype of Crohn's disease, due to its refractory nature and substantial impact on patients' health and quality of life [1]. PFCD is also associated with high direct health care costs that remain high for years beyond the initial presentation of perianal fistulas [2]. While studies have demonstrated the effectiveness of anti-tumour necrosis factor (TNF) therapy for this condition, a substantial proportion of patients remain symptomatic [3]. As a result, innovative treatment strategies are needed. Bacsur and colleagues reported on the effectiveness and safety of locally injected allogenic, adipose-derived mesenchymal stem cells (MSC) (Darvadstrocel) for treatment of complex PFCD [4]. Like the ADMIRE trials, patients underwent fistula tract conditioning by “rigorous” curettage and seton placement before surgical closure of the internal fistula opening and local injection of Darvadstrocel [5, 6]. Among the 204 patients who underwent treatment in this real-world study, 62% achieved fistula closure at week 52. Importantly, closure was determined clinically without radiologic evaluation. Furthermore, the proportion of patients with a perianal disease activity score (PDAI) of > 4 decreased from 58% at baseline to 20% at week 52 (p < 0.001). Only 14% of patients experienced an adverse event requiring hospitalisation; most involved perianal abscess or pain. The impressive rate of fistula closure reported in this study was higher than those reported in the ADMIRE trials (56% in ADMIRE I and 43% in ADMIRE II) [6, 7]. In addition to the open-label study design, the study population probably had a lower fistula disease burden overall given that 42% of patients had a PDAI score of 4 or lower at baseline. Furthermore, only 43% of patients had multiple fistula tracts, and 14% had branching tracts, both of which have been shown to be predictive of anti-TNF failure in PFCD [8]. While these results are promising, this study was uncontrolled. As a result, it is unclear if fistula closure was a result of MSC therapy itself, the surgical intervention that accompanied MSC treatment (curettage and closure of the internal fistula track opening), and/or the natural history of PFCD after seton removal. These are important considerations considering the results of the ADMIRE-II trial. This was a large phase III randomised controlled trial, which found that MSC therapy (Darvadstrocel) administered after fistula tract conditioning and surgical closure was no more effective in achieving combined clinical and radiologic remission at week 24 than fistula tract conditioning and surgical closure alone (49% vs. 46%, p = 0.57) [6]. In contrast, in ADMIRE-I, MSC therapy was significantly more effective than fistula tract conditioning and surgical closure alone (50% vs. 34%, p = 0.024) [5]. Given the tremendous cost of this therapy, future research should prioritise understanding the reasons for the discrepancy in the ADMIRE trials. Furthermore, comparative effectiveness studies to determine the optimal surgical approach to PFCD (fistula conditioning, epithelial ablation techniques and/or closing the internal fistula opening), and the natural history of PFCD after seton removal are required. Answers to these questions will help to determine if MSC therapy truly adds benefit beyond fistula tract conditioning and surgical closure. Jeffrey D McCurdy: conceptualization, writing – original draft. Serre-yu Wong: conceptualization, writing – review and editing. Jeffrey McCurdy: Has received advisory board honorarium or speaker fees from Abbvie, Amgen, BMS, Celltrion, Fresenius Kabi, Johnson & Johnson, Pendopharm, Merk, Pfizer and Takeda. Serre-yu Wong: Has received research support from Takeda and advisory board honorarium from BMS. 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.18427. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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