Fistulas are openings in organ systems that connect with another system. They usually result from wounds or erosions in the lining of a tube or duct that gets deeper and deeper and eventually opens into another tube or duct. Physical injuries can cause fistulas, but so can diseases such as Crohn’s disease. Anal fistulas result from erosions of the rectum that open to the outside and are typically very painful and do not readily heal.
Damián García-Olmo and his colleagues at the Universidad Autónoma de Madrid have conducted several clinical trials that have examined the ability of adipose-derived stem cells (ASCs) to facilitate the healing of fistulas in Crohn’s disease patients. A phase I study, which primarily examines safety, was published in 2005 (see García-Olmo D., et al., Dis Colon Rectum 2005; 48:1416-1423). According to this study, “No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up, 12 months; maximum follow-up, 30 months; follow-up average, 22 months).” The Phase II study was published in 2009 (García-Olmo, D., et al., Dis Colon Rectum 2009; 52:79-86). According to the results of this study, fistula healing was observed in 71 percent of patients who were treated with ASCs in combination with fibrin glue compared with 16 percent of patients who received fibrin glue alone. Quality of life scores were also higher in patients who received ASCs than in those who received fibrin glue alone. Once again, the stem cell treatments were well tolerated. The third study was a multicenter, randomized, single-blind clinical trial that enrolled 200 adult patients from 19 centers that were randomly assigned to three groups. The first group received 20 million stem cells (group A, 64 patients). The second group received 20 million adipose-derived stem cells plus fibrin glue (group B, 60 patients). The third group received only fibrin glue (group C, 59 patients). In treatment of anal fistulas in Crohn’s disease patients, a dose of 20 or 60 million adipose-derived stem cells alone or in combination with fibrin glue were demonstrably safe and did promote healing. However, there were no statistically significant differences between the three groups once the 3 groups were compared.
These studies suggest that stem cells from fat might have a place in the treatment of fistulas in Crohn’s disease patients. The application of the stem cells is feasible and safe, and requires no new equipment or skill. The stem cells also might augment the healing of these fistulas.
Unfortunately, anal fistulas are not the only type of fistulas that Crohn’s disease patients can experience. Female Crohn’s disease patients can have fistulas that open from their rectum into their birth canal. These rectovaginal fistula can deposit the contents of the gastrointestinal tract into the lower reproductive tract. While Crohn’s disease is not the only cause rectovaginal fistulas, Crohn’s disease patients are at higher risks for complications, which include: loss of control over stool deposition (fecal incontinence), hygiene problems combined with recurrent vaginal or urinary tract infections, inflammation of the birth canal and skin around the anus (perineum), abscess formation, which can become life-threatening if not treated, and recurrence of the fistula. Surgical treatment of rectovaginal fistulas requires that the tissue be free of inflammation before surgery, which can take time and cause extensive amounts of patient suffering.
Garcia-Olmo and his colleagues have conducted a small phase I-IIa clinical trial to evaluate the possibility of banked fat-based stem cells to treat recto-vaginal fistulas in female Crohn’s patients. This study has several limitations because it is so small and they have to exclude at least half of the participants because of complications beyond their control. Therefore, this study is not statistically significant. However, it does show what might be the beginnings of a stem-based treatment for this horrid condition.
The design of the study included 11 subjects who were initially enrolled in the study, but one of those recruited patients did not meet the criteria for the study. Therefore, ten subjects, all of whom suffered from Crohn’s disease and had rectovaginal fistulas were treated with 20 million fat-based stem cells that had been donated by a healthy volunteer in addition to surgical repair of their fistulas. These donated fat-based stem cells were provided by a Spanish biotechnology company called Cellerix S.L. Three months after this stem cell treatment, two patients were healed and the other either were given an additional treatment of 40 million fat-based stem cells. Of this group, four were healed. However, five of these patients experienced severe flare-ups of their Crohn’s disease that required treatment with biological agents, which disqualified these patients from further consideration from this study. The biological agents used to treat the Crohn’s disease flare-ups are very powerful medicines and can significantly influence the outcome of this study. Thus half of the subjects in this study had to be excluded. Of the five subjects that remained, 3 showed healing of their fistulas, and 2 did not.
The authors present the data as a “final efficacy rate of 60%.” However, given the high rate of exclusion and the very low numbers of subjects in this study, all we can say with any confidence is that based on the previous successes of this treatment in other studies, there is precedent for such a technique to be safe and somewhat effective, and that the data in this study are in a favorable direction. However, that’s about it.
One feature of this study that differs from the other clinical trials done by this same group is that the previous studies utilized the patient’s own fat-based stem cells, whereas this study used stem cells from a healthy donor. The authors stress that this modification greatly simplifies the procedure and decreases its expense. Because of the ease of the treatments, it reduces postoperative hospitalization and is minimally invasive. This new trial suggests that further work is warranted and the results or even minimally hopeful.
This work was published in the journal Stem Cells Translational Medicine 2016; 5(11): 1441-1446.