Comments on: “Long-term efficacy of mesenchymal stem cell treatment for complex perianal fistulas: A systematic review and meta-analysis”

We read with great interest the study by Wang et al. [1], who aimed to assess the long-term effects of mesenchymal stem cells (MSCs) on complex perianal fistulas (PFs). We appreciate the authors’ hard work. Also, we have a few comments on the article. First, the meta-analyses indicated that MSC therapy has a long-term effect on the clinical response of complex PFs. We agree with this argument. To date, MSCs have been used as a tolerable and potentially effective second-line therapy for steroid-refractory acute graft-versus-host disease (SR-aGVHD). Also, MSC therapy has been approved for paediatric and adult patients with SR-aGVHD. The study by Jiang et al. indicated that combining MSC treatment with the best available care for patients with SR-aGVHD, particularly those with gut involvement, may provide the greatest benefit by swiftly controlling peak inflammatory responses within days and facilitating immune modulation and the repair of immunological damage within weeks [2]. The study by Cheng et al. [3] also aimed to evaluate the long-term efficacy and safety of MSCs for PF treatment. The authors stated that local MSC therapy promotes long-term and sustained healing of complex PFs and this method is safe. Second, most patients with Crohn’s disease (CD) included in the study of Wang et al. were receiving either infliximab or adalimumab at the time of MSC injection. MSCs were used together with anti-tumor necrosis factor (TNF) in some clinical studies and they share common targets. Their interaction should be studied carefully. The study by Sakha et al. [4] indicated that as an anti-TNF-α agent, infliximab can decrease the inflammation in the microenvironment of MSCs, which might mitigate the immunomodulatory effects of MSCs. However, the study by Duijvestein et al. [5] showed that the exposure of MSCs to physiological concentrations of anti-TNF agents does not affect their survival and their inhibitory effects on peripheral blood mononuclear cell proliferation. So, it is necessary to explore the interaction between treatment approaches in order to optimize treatment strategies in PF patients and reduce the economic burden of patients. Wang et al. [1] did not discuss the effect of anti-TNF and immunosuppressive therapy on the efficacy of MSC treatment for PFs. So, we think it was the limitation of this study. Finally, cells can be carried through fibrin glue, which acts as a temporary matrix that favours cell-matrix interactions and allows local and paracrine functions of MSCs. In the study by Wang et al., some included articles reported efficacy of local fibrin glue combined with MSC therapy for PFs. Whether there was any promotion effect of the MSCs plus fibrin glue therapy remains unknown. Hence, it will be interesting to assess the safety and feasibility of injection of fibrin glue combined with MSCs in PFs. In the future, RCTs are needed to directly compare the long-term effectiveness and safety between MSCs, immunomodulators, biologics, and combination therapies for PFs. This will help the treating physician to determine the optimal disease management strategy.