Mesenchymal stem cells transplantation for perianal fistulas: a systematic review and meta-analysis of clinical trials

Abstract

Background: Perianal fistulas, characterised as granulomatous inflammation of fistulas around the anal canal, are associated with significant morbidity resulting in a negative impact on quality of life and a tremendous burden to the healthcare system. Treatment of anal fistulas usually consists of anal surgery; however, results of closure rates are not satisfactory especially with complex perianal fistulas, after which many patients may suffer from anal incontinence. Recently, the administration of mesenchymal stem cells (MSCs) has shown promising efficacy. Herein, we aim to explore whether MSCs are effective for complex perianal fistulas and if they have either short-term, medium-term, long-term or over-long-term efficacy. Additionally, we want to elucidate whether factors such as drug dosage, MSC source, cell type, and disease aetiology influence treatment efficacy. We searched four online databases and analysed data based on information within the clinical trials registry. The outcomes of eligible trials were analysed with Review Manager 5.4.1. Relative risk and related 95% confidence interval were calculated to compare the effect between the MSCs and control groups. In addition, the Cochrane risk of bias tool was applied to evaluate the bias risk of eligible studies. Meta-analyses showed that therapy with MSCs was superior to conventional treatment for complex perianal fistulas in short-, long- and over-long-term follow-up phases. However, there was no statistical difference in treatment efficacy in the medium term between the two methods. Subgroup meta-analyses showed factors including cell type, cell source and cell dosage were superior compared to the control, but there was no significant difference between different experimental groups of those factors. Besides, local MSCs therapy has shown more promising results for fistulas as a result of Crohn's Disease (CD). Although we tend to maintain that MSCs therapy is effective for cryptoglandular fistulas equally, more studies are needed to confirm this conclusion in the future.

Short conclusion: MSCs Transplantation could be a new therapeutic method for complex perianal fistulas of both cryptoglandular and CD origin showing high efficacy in the short-term to over-long-term phases, as well as high efficacy in sustained healing. The difference in cell types, cell sources and cell dosages did not influence MSCs' efficacy.

Keywords: Clinical trials; Efficacy and safety; Healing rate; Mesenchymal stem cells transplantation; Perianal fistulas; Randomised controlled trial; Systematic review and meta-analysis.

Fig. 1

Flow diagram study selection

Fig. 2

Risk of bias graph of eligible publications

Fig. 3

Risk of bias summary of eligible publications

Fig. 4

Efficacy of MSCs group versus the control group in short-term follow-up phase (forest plot and funnel plot)

Fig. 5

Efficacy of MSCs group versus the control group in mediate-term follow-up phase (forest plot and funnel plot)

Fig. 6

Efficacy of MSCs group versus the control group in long-term follow-up phase (forest plot and funnel plot)

Fig. 7

Efficacy of MSCs group versus the control group in over long-term follow-up phase (forest plot and funnel plot)

Fig. 8

Efficacy of MSCs for different types of cryptoglandular or CD complex perianal fistulas (forest plot)

Fig. 9

Forest plot of different cell types of MSCs for the treatment of complex perianal fistulas (forest plot and funnel plot)

Fig. 10

Different sources of MSCs for the treatment of complex perianal fistulas (forest plot and funnel plot)

Fig. 11

Different dosage of MSCs for the treatment of complex perianal fistulas (forest plot and funnel plot)