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

Rachele Ciccocioppo, Catherine Klersy, Daniel A Leffler, Raquel Rogers, Dimitri Bennett, Gino Roberto Corazza, Rachele Ciccocioppo, Catherine Klersy, Daniel A Leffler, Raquel Rogers, Dimitri Bennett, Gino Roberto Corazza

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.

Keywords: Crohn's disease fistulas; cryptoglandular fistulas; efficacy; mesenchymal stem cells; safety.

Figures

Figure 1
Figure 1
PRISMA flowchart showing study disposition from the bibliographic yield.
Figure 2
Figure 2
(a) Cumulative incidence of clinical healing by study design. Diamonds represent the meta‐analytical estimate of the cumulative incidence (95% CI) of clinical healing for observational studies (OBS), for clinical trials (TRIAL), and overall. Dots and whiskers represent the incidences and 95% CIs derived from the single studies. The dotted vertical line corresponds to the overall incidence. (b) Cumulative incidence of clinical healing by treatment arm in the four randomized clinical trials (RCTs). (c) Relative risk (RR) of healing in the four RCTs. The diamond represents the meta‐analytical estimate of the RR (95% CI) of clinical healing. Dots and whiskers represent the RRs and 95% CIs derived from the single studies. The continuous vertical line corresponds to null effect, the dotted vertical line to the meta‐analytical RR.
Figure 3
Figure 3
Funnel plots for the identification of publication bias for the efficacy end‐points in terms of clinical healing (a) and combined healing (b) and for the safety end‐points in terms of adverse events (c) and treatment‐related adverse events (d). (LN_IRR, log‐transformed incidence rate ratio; s.e., standard error).

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