Table 1 Results of the Crohn’s disease analysis
Author and year | Design (as appears in the paper) | N | Intervention | Evidence level and IF | Main outcomes |
|---|---|---|---|---|---|
Minimal invasive surgery | |||||
 Serrero 2019 [13] | One harm clinical trial | 10 | Local microinjection combining autologous microfat and adipose-derived stromal vascular fraction | 3; 17.373 | • Three adverse events were reported of which two required hospitalization • 70% percent of patients had a clinical response at week 12 and 80% at week 48 • 20% and 60% of patients had combined remission at weeks 12 and 48, respectively • Both results confirmed by magnetic resonance imaging • A significant improvement in perianal disease severity was observed with a decreased PDAI score (7.3 at baseline, 3.8 at week 12 and 3.4 at week 48; p = 0.002) and an increased quality of life score (p = 0.038) |
 Panes 2018 [14] | Randomized, placebo-controlled Phase III clinical trial | 212 | Stem cell therapy | 1++; 17.373 | • Patients were randomized to receive administration of adipose stem cells (Cx601) (n = 107) or placebo (n = 105) • At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) versus controls (38.6%) (a difference of 17.7%; 95% CI 4.2–31.2%; p = 0.010), and clinical remission (59.2% versus 41.6% of controls, for a difference of 17.6%; 95% CI 4.1–31.1%; p = 0.013) • Results confirmed by magnetic resonance imaging • Safety was maintained until week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% patients in the control group |
 Serrero 2017 [15] | Open, non-comparative, phase I-II, monocentric study | 9 | Autologous adipose-derived stromal vascular fraction | 3; 8.658 | • No serious adverse events have been reported • Fistula closure was also evaluated via radiological assessment with magnetic resonance imaging • The only side effect was moderate pain at the lipoid suction site • Efficacy data at week 12 for the first 7 treated patients were 71% response and 28% complete healing, significant reduction in discharge (p < 0.001), significant reduction in the severity of perianal disease (p = 0.045) and significant improvement in quality of life (p = 0.039) |
 Wilhem 2017 [16] | Prospective study | 117 | Laser FiLaC® | 3; 2.721 | • The study analysed 117 patients in a follow-up period of 25.4 months (median) (range 6–60 months) with 13 patients (11.1%) CD-related fistulas • Primary healing rate was 75/117 (64.1%) overall, and 63.5% in cryptoglandular versus 69.2% in CD-fistulas • The secondary healing rate at the end of the study was 103/117 (88.0%) overall and 85.5% for cryptoglandular versus 92.3% associated with CD • There were no differences between the two populations |
 Dietz 2017 [17] | Phase I clinical trial | 12 | Autologous mesenchymal stem cells | 3; 17.373 | • At 6 months, 10/12 patients (83%) presented complete clinical healing and radiographic markers of response • No serious adverse events were related to mesenchymal stem cells |
 Hermann 2016 [18] | Retrospective observational study | 47 | Noncutting setons (group 2, n = 23) vs. vacuum-assisted closure (group 1, n = 24) (VAC) | 2+; 3.111 | • Significant differences were observed between groups (p = 0.006) in the closure of fistulas after 6 months of treatment; 18 patients (75%) group 1 versus 8 patients (35%) Group 2 • Partial response occurred in five patients (21%) from group 1 and in five patients (22%) from group 2 • Closure of fistulous tracts was visualized via magnetic resonance in nine patients (37.50%) from group 1, more than twice the number of patients from group 2 • Results confirmed by magnetic resonance imaging • PDAI scores decreased significantly in both patient groups, from 9 to 1 in patients treated with VAC and from 11 to 5 (p < 0.0001) in patients with seton placement (p < 0.0001) • Preliminary results showed a high closing rate of CD-related fistulas after application of VAC |
 Panes 2016 [19] | Clinical trial phase III, randomized, double-blind, placebo-controlled | 212 | Single local administration of stem cells derived from allogenic adipose tissue | 1++; 60.392 | • 212 patients were randomized: 107 to Cx601 and 105 to placebo • A significantly higher proportion of patients treated with Cx601 achieved combined remission in intention to treat (53 out of 107 [50%] versus 36 out of 105 [34%]; difference 15.2%, CI 97.5% (0.2–30.3; p = 0.024) and in modified intention to treat population (53 out of 103 [51%] vs 36 of 101 [36%]; 15.8%, 0.5–31.2; p = 0.021) • 17% of the patients receiving Cx601 versus 30 (29%) of the 130 in the placebo group experienced treatment-related AE • Results confirmed by magnetic resonance imaging • The most common AE was anal abscess (6 in the Cx601 vs 9 group in the placebo group) and proctalgia (5 vs 9) |
 Molendijk 2015 [20] | Double-blind placebo-controlled clinical trial | 21 | Bone marrow mesenchymal mother cells (MMC) | 1+; 17.373 | • AE were not associated with any of the MMC doses • The random assignment of the treatment was: Group 1 (n = 5) injection of 1 × 107; Group 2 (n = 5) injection of 3 × 107; Group 3 (n = 5) injection of 9 × 107 and placebo (cell less solution) (n = 6) • Week 6: healing in 3 patients in group 1 (60%), in 4 of group 2 (80%) 1 in group 3 (20%) vs. 1 patient in the placebo group (16.7%). (P = 0.08 for group 2 vs placebo) • Week 12: healing in 2 patients in group 1 (40%), in 4 of group 2 (80%) 1 in group 3 (20%) vs. 2 patients sin the placebo group (33.3%) • Results confirmed by magnetic resonance imaging • Week 24: effects were maintained and even increased to 4 patients (80%) in group 1 |
 Senjeoux 2015 [21] | Open clinical trial, multicentre randomized | 54 | Fistula plug as intervention against seton removal as control | 1++; 8.658 | • Fistula closure at week 12 was achieved in 31.5% of patients in the intervention group and 23.1% in control. The relative risk was not statistically significant, p = 0.19 • No differences in outcomes were found in patients with complex perianal fistulas, 33.3%, versus simple fistulas 30.8% in intervention; 15.4% and 25.6% in controls respectively, p = 0.45 • Results confirmed by magnetic resonance imaging • Regarding to safety, at week 12, 17 patients developed at least one AE in the group intervention versus 8 at the controls (p = 0.07) • The intervention showed no superiority over control |
 Park 2015 [22] | Multicentre open pilot clinical trial | 6 | Comparison of two doses of stem cells derived from allogenic adipose tissue | 3; 1.095 | • Patients were included sequentially in two dosing groups with 3 patients each. The first 3 patients (group 1) received 1 × 107 cells/ml depending on the length and diameter of the fistula tract • After 4 weeks, when the safety of this dose was determined, the next 3 patients (group 2) received a higher dose of 3 × 107 cells/ml • There was no Grade 3 or 4 AE or AE related to treatment • Two patients in group 1 achieved complete closure of the fistula in month 4 and month 6. A patient in group 2 achieved complete closure at 8 weeks • The closure remained until month 8 in 3 of those patients • Magnetic resonance imaging was performed to evaluate the reduction of the fistula and confirm that the tract lacked inflammation |
 Göttgens 2015 [23] | Pilot study | 10 | Fistulectomy with platelet-rich plasma | 3; 2.721 | • Half of the patients had previous fistula surgery Fistula healing was 70% at 12 months 95% CI (33–89) • One patient (10%) had a recurrence and in two (20%) fistula was persistent after treatment • One patient (10%) reported a persistent fistula and produced an abscess after the operation. No other complications were observed • In case of doubt about closure, magnetic resonance imaging was performed to visualize a possible fistula tract • The median in Vaizey’s incontinence severity scale score was 8.0 (range 0–21) indicating a moderate to severe continence impairment (0 perfect continence–24 total incontinence) |
 Cho 2013 [24] | Phase I clinical trial, open, dose escalation, multicentre | 10 (safety assessment) and 9 (efficiency assessment) | Mother cells derived from adipose tissue | 3; 3.341 | • There were no Grade 3 or 4 related AE • Curation (complete fistula closure and internal and external openings without drainage or signs of inflammation) was obtained in 50% of the patients treated with at least 2 × 107 cells/ml after a single injection |
 Lee 2013 [25] | Phase II clinical trial | 43 | Treatment of stem cells derived from autologous adipose tissue | 3; 3.341 | • Thirty-six patients completed the 8 weeks of follow-up after the final dose of stem cells. Of these, 33 formed the protocol analysis population • Complete fistula healing was observed in 27/33 patients (82%) after 8 weeks • Of 27 patients with fistula healing, 26 patients completed an additional observation study for 1 year and 23 patients (88%) kept the full closure • There were no AE related to stem cell administration • The treatment was well tolerated, with a favourable therapeutic result • The full closure was sustained |
 De la Portilla 2013 [26] | Phase I, open, multicenter, single-arm clinical trial | 24 | Mother cells derived from adipose tissue | 3; 2.108 | • The full analysis of efficacy data at week 24 showed 69.2% of the patients with a reduction in the number of draining fistulas, 56.3% of the patients achieved complete closure of the treated fistula achieved, and 30% of the cases presenting complete closure of all existing fistula tracts • Magnetic resonance images showed a reduction in week 24 |
 Ciccocioppo 2011 [27] | Series of consecutive cases | 12 | Mesenchymal stem cells derived from bone marrow | 3; 19.819 | • Seven cases made complete closure • Three cases made partial closures • Results confirmed by magnetic resonance imaging • The disease improved in patients with reduced CDAI and PDAI indices • No AE were reported |
Classic techniques | |||||
 Graf 2016 [28] | Retrospective observational study | 119 | Results after different surgical treatment with seton the most frequent | 3; 1.095 | • Of the 119 patients, 62 (52%) were healed at final follow-up. Fourteen healed after one procedure and the remaining 48 healed after a further median of 4.0 (2–20) procedures • Ten patients (8%) underwent a proctectomy • Healing was most common in patients operated with a procedure aimed at eradicating fistula (p = 0.0001), patients without proctitis (p = 0.02) and patients with a shorter duration of CD (p = 0.0019) • Results confirmed by magnetic resonance imaging |
 Gingold 2014 [29] | Prospective observational study | 15 | Fistula path intersphynterial ligation (LIFT technique) | 3; 10.13 | • At 2 months of follow-up, remission was observed in 9 patients (60%) without fecal incontinence • Clinical remission corresponded to an improvement in quality of life scales (Wexner and PDAI p = 0.001 and p = 0.0001 respectively) • At 12-month follow-up, only 33% (5/9) of patients who had remission maintained it |
 Galis-Rozen 2010 [30] | Retrospective review | 77 17 (CD), 60 (non-CD) | Permanent loose seton in the treatment of high fistulas in patients with CD (29 procedures in total) and two-stage fistulotomy in patients without EC (107 procedures in total) | 3; 2.769 | • Early postoperative complications (within the first month) were observed in 8 patients (10%) (5 patients without CD, 3 with CD) • Perioperative complications, mainly local sepsis and bleeding, were recorded in 8 patients (10%) and long-term (> 1 month after operation), complications were observed in 9 patients without EC and 4 patients with EC • After 24 months (range 6–48) of follow-up, the recurrence rate was 40% in patients with CD and 47% in patients without CD • Five patients (4 patients without CD and one CD patient) developed some degree of faecal incontinence |