Systematic review with meta‐analysis: Safety and efficacy of local injections of mesenchymal stem cells in perianal fistulas

Abstract

Perianal fistulas in Crohn's disease (CD) represent a highly debilitating and difficult‐to‐treat condition. Given emerging supportive evidence, we conducted a systematic review and meta‐analysis of all trials/observational studies to establish the safety and efficacy of local injections of mesenchymal stem cells (MSCs). The PRISMA‐P statement was applied for planning and reporting, and MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, ClinicalTrials.gov database, and ECCO 2017 proceedings were searched for published observational studies and one‐arm and randomized clinical trials (RCTs). Safety was assessed in terms of acute local/systemic events, long‐term events, and relatedness with MSC treatment. Efficacy was evaluated in terms of external and/or radiological closure of fistula tracks. After a review of 211 citations, 23 studies, including 696 participants, were evaluated. Four were RCTs with a total of 483 patients. Overall, fistula closure occurred in 80% of MSC‐treated patients. In RCTs, this rate was 64% in the MSC arm and 37% in the control arm (relative risk (RR) = 1.54). Radiological response occurred in 83% of MSC‐treated patients. Treatment‐related adverse events occurred in 1% of MSC‐treated patients, with severe treatment‐related adverse events reaching 0% over a median follow‐up of 6 months. In RCTs, treatment‐related adverse events occurred in 13% in the MSC arm and 24% in the control arm (RR = 0.65). The relapse rate was 0. These results suggest that a local MSC injection is safe and efficacious. Further clinical trials with standardized end‐points are required to ensure the timely implementation of this new therapy in the management of perianal CD.

Treatment Algorithms for Crohn’s Disease

“…Recently, several studies about fistula curettage and mesenchymal stem cell therapy have been published and analyzed in a recent recent systematic review and metaanalyis (23 studies with 696 patients) [75], showing significant results concerning fistula closure (overall 80% success rate). However, the 4 randomized controlled trials (483 patients) revealed a closure rate of 64% (vs. 37% in the control arm).…”

Developing cell therapies as drug products

“…Moreover, fistula healing was maintained in most cases (56.3%) at 1 year (Panés et al, 2018), although further studies showed that the proportion of patients relapsing upon a longer follow‐up increased over time (Ciccocioppo et al, 2015). Importantly, no safety concerns were reported, thus confirming the tolerability of the treatment, while, again, a sustained increase of regulatory T‐cells was invariably observed in those cases where it was investigated (Ciccocioppo, Klersy, et al, 2019).…”

“…Clearer and more unambiguous results were obtained when using MSC local injections for fistulizing refractory Crohn's disease. This new treatment option gave excellent results in terms of both safety and efficacy (Ciccocioppo et al, 2019). Notably, the results of the first phase III multicentre trial, where 212 patients were enrolled and randomly assigned to receive a single local injection of an industrial preparation of allogeneic adipose tissue derived‐MSCs (Darvadstrocel, formerly Cx601®) or placebo, showed that MSCs performed better than placebo to achieve combined remission (51.5% vs. 35.6% at week 24) within a shorter period of time (Panés et al, 2016).…”

Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm

“…18,19 In this regard, it should be emphasized that MSC administration may be performed by using different routes: intravenously with access from a peripheral or central vein, intra-arterial depending on the target organ, but also directly in the damaged tissue as in fistulizing Crohn's disease where local injections have proved successful in inducing closure of fistula tracks refractory to standard treatment. 67 Additionally, delivery routes such as intrathecal, intra-articular, and intradermal have been shown feasible in patients suffering from amyotrophic lateral sclerosis, osteoarthritis, and scleroderma, respectively. [68][69][70] It is conceivable therefore, that also in the case of COVID-19 patients, intratracheal administration might work better.…”