Letter: Real-Life Evaluation of Effectiveness of Mesenchymal Stem Cell Treatment in Fistulising Crohn's Disease Emphasises the Importance of Appropriate Patient Selection and Centre Expertise

Abstract

Managing complex perianal fistulas in Crohn's disease is challenging as the condition is often refractory to conventional medical treatment strategies and surgery may be associated with significant compromise to quality of life [1]. The real-world retrospective multicentre cohort study by Bacsur et al. [2] offers promising results in the application of CX601 mesenchymal stem cell (MSC) treatment (Darvadstrocel). It is worth examining the superior results compared to two previous significant phase III multicentre randomised control trials by the ADMIRE-CD group [3, 4].

Bacsur et al. demonstrated higher rates of perianal clinical remission defined as closure of all treated fistulas (72.2% at W26 and 62.3% at W52) surpassing secondary endpoints in the treatment cohort of the ADMIRE CD trial (55% at W24) [3] and the more recent ADMIRE CD II trial treatment group (49.8% and 43.1% at W24 and W52, respectively) [4].

Several factors probably contributed to these improved outcomes. Differences in baseline disease severity and degree of prior advanced therapy use are key considerations. Patients in the ADMIRE-CD trials generally experienced longer delay during stable disease prior to commencing darvadstrocel (6 months vs. 3 months in Bacsur study) with longer established fistulas (draining for at least 6 weeks) and higher baseline mean Crohn's Disease Activity Index scores (88.7 vs. 51.1 in the Bacsur study). Moreover, ADMIRE CD excluded patients who had recently received corticosteroids, and had a higher proportion of baseline advanced therapy use (78% anti-TNF usage vs. 42.6% in Bacsur et al.), indicating a focus on patients with more severe disease [5].

The experience level of treating centres may also play a critical role. Bacsur et al. conducted their study in six high-volume centres, some with over 100 prior MSC administrations; ADMIRE CD treated 86 patients (vs. 223 in Bascur et al.) spanning 49 centres. This is in line with earlier findings from a Phase II trial that reported 71% fistula closure at 8 weeks focused in three specialised centres. This suggests the importance of centre expertise in allowing for precise MSC administration, post-procedural management and treatment success [6].

Variations in assessment methods of perianal fistula closure can also lead to disparities in reported results. ADMIRE CD employed masked gastroenterologists who used both visual inspection and manual compression to evaluate fistula closure rigorously [3] while the assessment criteria in the present study was not fully detailed. Moreover, in Bascur et al., treating colorectal surgeons were also allowed to participate in evaluating the outcomes in an un-masked fashion possibly introducing confirmation bias [7].

Bacsur et al. offers valuable insights into the real-world application of MSC therapy for Crohn's disease, underscoring the significance of patient selection, concurrent medication management, proficiency of the medical centre and the reassuring safety profile of MSC therapy. Although clinical trials like ADMIRE CD enforce rigorous standards, these are often impractical in real-world settings, where delays in patient care and complications from ceasing ongoing treatments are concerns. Future research in the real-world setting should be encouraged to offer more insight into this promising therapy.