This case series shows the radiological outcomes after surgical closure of the internal opening combined with MST in 30 patients with Crohn’s perianal fistulas. In 43%, this procedure resulted in radiological remission after a median follow-up of 5.0 months. The median MAGNIFI-CD decreased significantly from 15.0 to 8.0 (p = < 0.001). Clinical closure was seen in 70% of the patients, with only 14% recurrence. The current closure and recurrence rates are slightly better than the previously presented results in the ADMIRE trial, where 50% combined clinical and radiological remission in the intervention group was seen, with > 50% recurrences within three years [7, 9]. The definition of radiological remission in the ADMIRE trial, the absence of a collection > 2 cm on MRI, was probably related to the disappointing long-term outcomes. Although we only have a median follow-up of 16.5 months in this case series, the relatively high rate of radiological remission is probably related to the low recurrence rate, as it has been previously demonstrated that no recurrences are seen in patients with radiological remission [10].

The results are even more remarkable considering the fact that this was a therapy-refractory patient group with a median CD duration of 8.5 years, median fistula duration of 4.0 years and a median of 6.0 previous surgical fistula interventions. Although it is difficult to speculate why the results are better in the current series, it does not seem to be related to a defunctioning ostomy, as outcomes were comparable between defunctioned and non-defunctioned patients. It can be hypothesized that the results reflect specialised care in a tertiary referral centre for Crohn’s fistulas, with all patients optimised in medical treatment, pre-treated with seton drainage, and extensive surgical experience with closure of the internal opening. Other single centre series confirm the possibility of good results after closure of the internal opening combined with MST. A French prospective cohort study investigating 27 patients treated with stem cell injections found a clinical closure rate of 52% and a combined clinical- radiological response of 35% [15]. The results are also in line with the results from the PISAII trial, where radiological healing was seen in 32% of the surgical closure group (advancement plasty or ligation of the intersphincteric fistula tract) with 68% clinical closure [10]. This further emphasizes the potential of inducing radiological remission in therapy-refractory patients with good long-term results after MST, as the current group all previously underwent surgical closure in the same centre.

The median decrease of 7.0 points in the MAGNIFI-CD score in the current series supports the clinical findings. A study by Beek et al. [16] demonstrated that a decrease of 2.0 points in the MAGNIFI-CD can be used as a cut-off for clinical response. Although this validation cohort did not include patients treated with MST, the median decrease in MAGNIFI-CD in this case-series could be considered as highly clinically relevant. Moreover, the absolute MAGNIFI-CD score in this patient group might even be an underestimation of the actual effect, as with this scoring technique only the worst feature is scored and one third of these patients had more than one fistula tract where a better result was not taken into account.

For patients with Crohn’s perianal fistulas, quality of life, rather than radiological outcomes, is the most important outcome parameter. The good clinical results of closure of the internal opening combined with MST were also reflected in the PDAI, which overall decreased from 10.5 to 4.0. Although the PDAI is not officially a patient reported outcome parameter, as it measures disease burden by patients and doctors combined, it is a validated score system that can be interpreted as quality of life [12]. It has been demonstrated that a PDAI ≤ 4 can be considered as inactive perianal disease [17]. In that light, the overall decrease in PDAI to 4.0 within nine months can be considered a good result and shows that even if surgical closure of the internal opening combined with MST is not capable of inducing radiological remission, patients benefit from this treatment. However, the more interesting finding is probably the median PDAI of 0.0 achieved in patients with radiological remission. This result is generally not seen after medical treatment alone, despite complete clinical closure. This highlights the importance of trying to achieve radiological remission in patients with Crohn’s perianal fistulas. The fact that no recurrences were seen in this group further emphasizes the clinical importance of aiming for radiological remission.

Obviously, as with all surgical interventions aiming for fistula closure, the MST procedure was not without (serious) adverse events. Six patients needed reinsertion of a seton due to a postoperative abscess or ongoing fistula symptoms (6/30 = 20%). This incidence is comparable to other series presenting results on advancement plasty or LIFT [10, 13]. One patient developed a necrotic wound and rectovaginal fistula due to pressure necrosis after MST. This complication was seen in a short, epithelialized, anterior fistula tract, which suggests that care should be taken when injecting the high volume of darvadstrocel (24 cc) in small fistulas.

A few limitations of the current study need to be considered. First, the small number of patients with only 30 patients included in three years. However, in the Netherlands, only patients with treatment refractory Crohn’s perianal fistulas failing both anti-TNF and surgical closure are eligible for treatment with stem cell injections, so this is a reflection of daily clinical practice. Second, data was collected retrospectively. Nonetheless, every patient treated with closure of the internal opening in combination with MST at the Amsterdam UMC receives the same close monitoring follow-up, including standard MRI after three to six months, thus the retrospective design did not lead to missing data. The strength of the study is the reading of MRIs by a specialised senior radiologist, which makes the primary endpoint independent of interpretation by the treating physician, which is a well-known confounder in generally used primary outcomes parameters like clinical closure and fistula drainage assessment, which were previously qualified as imprecise [18].

In conclusion, closure of the internal fistula opening in combination with MST is a promising treatment strategy for therapy refractory Crohn’s perianal fistulas, resulting in > 40% radiological remission and clinical closure in 70%. MST also resulted in improved quality of life with an overall significant decrease in PDAI to 4.0, reflecting inactive perianal disease. Moreover, in the group with radiological remission, a median PDAI of 0.0 was achieved, with no recurrences in long-term follow-up. This highlights the importance of striving for radiological remission in perianal fistula treatment. Research is needed to gain insight in which patients or fistula characteristics MST is most likely to induce radiological remission to further improve outcomes.