Safety of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistulas Not Associated With Crohn’s Disease: A Phase I Clinical Trial

Abstract

BACKGROUND: Anal fistula treatment aims to eradicate the fistula, preserve the sphincter, prevent recurrence, and allow an early return to daily activities for the patient. Because of the difficulty of achieving these goals, stem cell-based therapy has emerged for the treatment of complex perianal fistula with promising results. OBJECTIVE: The objective of this study was to evaluate the safety of allogeneic mesenchymal stem cells in the treatment of complex anal fistula in patients without Crohn’s disease. DESIGN: This was a prospective nonrandomized phase I clinical trial. SETTINGS: This study was conducted at a second-level hospital. PATIENTS: Twenty consecutive patients diagnosed with a complex fistula were included. INTERVENTIONS: All patients received 40 × 106 allogeneic mesenchymal stem cells. In patients with 2 tracts, 20 × 106 stem cells were applied on each tract. MAIN OUTCOME MEASURES: The patients were discharged 24 hours after the procedure and were evaluated at 1, 2, 4, 8, 16, and 24 weeks after the application. The long-term follow-up was performed 1 year after the procedure. RESULTS: The procedure was performed in a total of 20 patients from October 1, 2016, to October 31, 2017; 1 patient was eliminated from the final data analysis. No adverse effects were reported within the first 24 hours, and all the patients were discharged asymptomatic. Three patients (15%) presented with perianal abscess. In 1 patient, the abscess appeared at the fourth week, and, in the other 2 patients, the abscess was diagnosed at week 8. Complete closure was achieved in 13 (69%) patients. LIMITATIONS: This was a nonrandomized controlled trial. CONCLUSION: The use of allogeneic mesenchymal stem cells as a treatment is a safe option for the management of complex perianal fistula not associated with Crohn’s disease. See Video Abstract at http://links.lww.com/DCR/B443. SEGURIDAD DE LAS CÉLULAS MADRE MESENQUIMALES ALOGÉNICAS DERIVADAS DEL TEJIDO ADIPOSO PARA EL TRATAMIENTO DE FÍSTULAS PERIANALES COMPLEJAS NO ASOCIADAS CON LA ENFERMEDAD DE CROHN: ENSAYO CLÍNICO DE FASE I ANTECEDENTES: El tratamiento de la fístula anal tiene como objetivo erradicar la fístula, preservar el esfínter, prevenir la recurrencia y permitir un retorno temprano a las actividades diarias del paciente. Debido a la dificultad de alcanzar estos objetivos, ha surgido una terapia basada en células madre para el tratamiento de la fístula perianal compleja con resultados prometedores. OBJETIVO: El objetivo de este estudio fue evaluar la seguridad de las células madre mesenquimales alogénicas en el tratamiento de la fístula anal compleja en pacientes sin enfermedad de Crohn. DISEÑO: Este fue un ensayo clínico prospectivo no aleatorizado de fase I. AMBIENTE: Este estudio se realizó en un hospital de segundo nivel. PACIENTES: Veinte pacientes consecutivos diagnosticados de fístula compleja. INTERVENCIONES: Todos los pacientes recibieron 40 x 106 células madre mesenquimales alogénicas, en pacientes con dos tractos, se aplicaron 20 x 106 células madre en cada tracto. PRINCIPALES MEDIDAS DE RESULTADO: Los pacientes fueron dados de alta 24 horas después del procedimiento y fueron evaluados 1, 2, 4, 8, 16, 24 semanas después de la aplicación. El seguimiento a largo plazo se realizó un año después del procedimiento. RESULTADOS: El procedimiento se realizó en un total de 20 pacientes desde el 1 de octubre de 2016 al 31 de octubre de 2017; un paciente fue eliminado del análisis de datos final. No se informaron efectos adversos en las primeras 24 horas, todos los pacientes fueron dados de alta asintomáticos. Tres pacientes (15%) presentaron absceso perianal. En un paciente, el absceso apareció a la cuarta semana y en los otros dos pacientes el absceso se diagnosticó en la octava semana. El cierre completo se logró en 13 (69%) de los pacientes. LIMITACIONES: Este fue un ensayo controlado no aleatorio. CONCLUSIÓN: El uso de células madre mesenquimales alogénicas como tratamiento es una opción segura para el manejo de la fístula perianal compleja no asociada con la enfermedad de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B443.

Mesenchymal Stem Cells for Cryptoglandular Anal Fistula: Current State of Art

“…Another recent study on fistula surgery with or without injection of ASCs in complex anal fistulas reported that the healing rate was 63.8% in the experimental group compared with 15.5% in the group treated with surgery alone ( p < 0.001), with a better postoperative course in terms of pain ( 30 ). A previous step with the seton drainage and closure of the internal opening seems to be the standardization in the technique, agreeing with a recent study in the literature ( 31 ). In recent metanalysis healing rate is similar (61,5%), in the group with cryptoglandular fistula treated with ASCs, but there is no a systematic description of complications ( 32 ).…”

“…The association with fibrin glue was constant in the first studies ( 26 , 27 ), rare the use of other procedures like anal plug ( 28 ). In last year it seems to be essential for the technique to associate the closure of the internal orifice of the fistula tract ( 20 , 22 , 30 , 31 ), with sometimes a previous application of a seton. It is not possible to evaluate the use of ASCs alone, without those described procedures, because considered as integral part of the technique.…”

The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula

“…However, more trials are needed before recommendations can be made regarding the use of MSCs for cryptoglandular fistulas. [263][264][265][266][267]…”

Essential updates 2020/2021: Colorectal diseases (benign)—Current topics in the surgical and medical treatment of benign colorectal diseases

“… 38 Further trials on autologous tissue implantation have been attempted for fistulas in patients with CD in phase 1 trials and RCTs. Autologous subcutaneous, 39 adipose‐derived, 40 and allogeneic mesenchymal stem cells, 41 as well as bone marrow‐derived mesenchymal stromal cells, 42 were harvested in these trials, and the results suggested that such treatments for fistulas may be effective and feasible (Table 3 ). In a meta‐analysis (n = 1252), the stem cell treatment group had a higher rate of fistula healing than the placebo group (61.8% vs 40.5%, OR: 2.21).…”