Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn’s Disease: Rationale, Clinical Results and Perspectives

Between 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.

Long-term outcome of surgery for perianal Crohn’s fistula

Objective Perianal fistulizing disease is a problem in patients with Crohn’s disease (CD) because they often need repetitive surgeries. Among the various available procedures, none of them proves to be superior. In addition, the long-term outcome of fistula Seton drainage is not well described. The aims of this study were to analyze the long-term healing and recurrence rates of perianal fistulas in CD patients, stratified according to the first procedure performed. Methods Database analysis of a prospective Swiss cohort of patients with perianal CD. Results 365 patients with 576 interventions and a median follow-up of 7.5 years (0 - 12.6) were analyzed. 39.7% of patients required more than one surgery. The first surgical interventions were fistulectomies (58.4%), Seton drainage (26.9%), fistula plugs (2.2%) and combined procedures (9.9%). Fistulectomy patients required no more surgery in 67.6%, one additional surgery in 25.4% and more than one additional surgery in 7.7%. In these 3 groups of patients, after a median follow-up of 12.1 years, perianal fistula closure was achieved in 77.1%, 74.1% and 66.7%, respectively. In patients with Seton drainage as index surgery, 50.3% required no more surgery and over 75% achieved fistula closure after 10 years. 49.7% of patients with Seton required one or more surgeries. At median follow up of 7.5 years, closure rates were 64.2% and 60.5% in patients with one and more than one surgeries, respectively. There was no difference in demographics in Seton patients with closed or not closed fistulas. Non-closure patients had a higher Crohn Disease Activity Index (33 vs. 6) and more frequent anti-TNF medication (57.4% vs. 48.1%). Conclusion First line fistulectomies achieved the highest healing rates in perianal CD but 1/3 of patients require additional surgeries and 1/4 patients will remain with a fistula at 10 years. Initial seton drainage and concurrent medical therapy can achieve fistula closure in 75%. However, in 50% of patients more surgeries are performed with a seton staying in place up to 5 years and fistula closure in only 2/3 patients.

Knotless seton for perianal fistulas: feasibility and effect on perianal disease activity

Patients with perianal fistulas are frequently treated by a knotted seton which is well-known for causing complaints. We aimed to assess the feasibility of the knotless SuperSeton and advantages with respect to perianal disease activity. In a prospective cohort study, we included all consecutive adult patients with a knotted seton in situ or a perianal fistula requiring new seton drainage. Primary endpoint was seton feasibility (maintenance of the connection for minimally three months). Secondary endpoints included improvement of the Perianal Disease Activity Index (PDAI), complications and re-interventions within three months of follow-up. PDAI scores of patients with a knotted seton were crossover compared to PDAI scores after knotless seton replacement. Sixty patients (42% male, mean age 42 (SD 13.15), 41 with Crohn’s disease) were included between August 2016 and April 2018. Of 79 knotless setons, 69 (87.3%) stayed connected for ≥ 3 months. Overall, the knotless seton significantly decreased discharge (P = 0.001), pain (P < 0.001) and induration (P < 0.001) measured by the PDAI when compared to baseline. In patients with a knotted seton, replacement by the knotless seton significantly decreased discharge (P = 0.005) and pain (P < 0.001) measured by the PDAI. Furthermore, 71% of patients reported fewer cleaning problems compared to the knotted seton. Ten patients developed a perianal abscess, and five patients required a re-intervention. This study supports the feasibility of the knotless seton with promising short-term results. The knotless seton might be preferred over the knotted seton in terms of perianal disease activity.

Fistulotomy followed by anal sphincter reconstruction – indications, benefits and pitfalls of the method

Fistula-in-ano is a disease which has challenged surgeons for centuries because of high postoperative complication rates including recurrences, and symptoms of postoperative gas and stool incontinence. The paper addresses the surgical method of fistula excision followed by sphincter reconstruction. The procedure is not new, but it has gained popularity in recent years. The primary indications for its use include complex high anal fistulas, posterior transsphincteric fistulas in patients with good baseline continence, and fistulas of “borderline” height, involving approximately 50% of the external sphincter mass. In cases of high and/or complex fistulas, the first stage of management is typically loose seton drainage to reduce the risk of infection. Prior to surgical intervention, it is important to assess the patient’s preoperative continence status. The paper presents the surgical technique of the intervention, outlines possible complications, and reviews the literature reporting the experiences of other authors who use the method. Fistulotomy followed by sphincter reconstruction is a bold surgical approach. It requires extensive experience in performing colorectal surgical procedures, and it is suitable for a selected group of patients. On account of possible complications including impaired postoperative gas and stool continence, the patient should receive appropriate information before surgery, and sign the surgical consent form. Fistulotomy followed by sphincter reconstruction is a good therapeutic option in patients with recurrent high anal fistulas unsuccessfully treated by other methods.

MULTISTAGE MINIMALLY INVASIVE TREATMENT FOR PERIANAL ABSCESS

AIM: to improve the results of treatment for perianal abscess using ultrasound navigation, seton drainage of the internal fistula and subsequent minimally invasive treatment of fistula.PATIENTS AND METHODS: seventy-two patients with perianal abscess were included in cohort retrospective study. At the first stage the abscess opening and seton under ultrasound navigation with contrast was performed. On the second stage the FiLaC procedure was performed. RESULTS: follow-up was 8-14 weeks, 29 (53.7%) patients had subcutaneous or submucosal seton displacement, while 8 (11.1%) produced complete healing. Twenty-one (29.2%) patients required fistulectomy. In 25 (46.3%) patients, intra- and transsphincteric fistulas were detected in 18 (33.3%) and 7 (12.9%) cases, respectively. All these patients underwent laser coagulation of the fistula. After a single laser coagulation, fistula healing within 4 weeks was found in 19 (76.0%) patients. Six (24.0%) patients underwent second laser coagulation of the fistula, while healing was observed in 2 (8.0%) patients. Four (16.0%) patients after second coagulation produced recurrence and have underwent surgery (LIFT procedure or advancement flap).CONCLUSION: perianal abscess opening with seton provides recovery in 14.8% and produces «ideal» fistula for laser ablation in 46.2% within 10-14 weeks after. Multistage minimally multistage approach provides healing and not affects anal continence in 84.0%.

Treatment of Perianal Fistulas in Crohn’s Disease, Seton Versus Anti-TNF Versus Surgical Closure Following Anti-TNF [PISA]: A Randomised Controlled Trial

Background and Aims Most patients with perianal Crohn’s fistula receive medical treatment with anti-tumour necrosis factor [TNF], but the results of anti-TNF treatment have not been directly compared with chronic seton drainage or surgical closure. The aim of this study was to assess if chronic seton drainage for patients with perianal Crohn’s disease fistulas would result in less re-interventions, compared with anti-TNF and compared with surgical closure. Methods This randomised trial was performed in 19 European centres. Patients with high perianal Crohn’s fistulas with a single internal opening were randomly assigned to: i] chronic seton drainage for 1 year; ii] anti-TNF therapy for 1 year; and iii] surgical closure after 2 months under a short course anti-TNF. The primary outcome was the cumulative number of patients with fistula-related re-intervention[s] at 1.5 years. Patients declining randomisation due to a specific treatment preference were included in a parallel prospective PISA registry cohort. Results Between September 14, 2013 and November 20, 2017, 44 of the 126 planned patients were randomised. The study was stopped by the data safety monitoring board because of futility. Seton treatment was associated with the highest re-intervention rate [10/15, versus 6/15 anti-TNF and 3/14 surgical closure patients, p = 0.02]. No substantial differences in perianal disease activity and quality of life between the three treatment groups were observed. Interestingly, in the PISA prospective registry, inferiority of chronic seton treatment was not observed for any outcome measure. Conclusions The results imply that chronic seton treatment should not be recommended as the sole treatment for perianal Crohn’s fistulas.

P395 Management of pouch vaginal fistulae in ulcerative colitis: A 35-year experience

Background Pouch vaginal fistulae (PVF) occur following restorative proctocolectomy with an incidence of 6%. The overall rate of pouch failure is 10% but may be as high as 29% with a PVF. PVF can be relatively asymptomatic, with low volume vaginal mucus discharge alone, or can cause considerable morbidity with persistent, passive leakage of faeces and gross perianal excoriation. Management is challenging with a range of reparative techniques reported and no gold standard. Despite a lack of evidence, anti-TNF agents are increasingly used. It is unclear whether there are factors which may predict fistula closure with anti-TNF therapy. The primary aim of fistula therapy should be fistula eradication or amelioration of fistula symptoms without worsening pouch function. Methods This is a retrospective analysis of the management of PVF in ulcerative colitis in a tertiary referral centre. Demographic, clinical history and presenting symptoms of fistula including pouch function were collected. Symptomatic burden related to the fistula and the presence or absence of gastrointestinal continuity were assessed. Results Fifty patients with PVF were identified between 1984 and 2019 and complete clinical notes were available and analysed for 30 of these. The median age at diagnosis was 36 (range 19–52) years. The median follow-up from pouch creation was 12.5 years. A PVF developed in 30% within 1 year of pouch creation and in 70% after 1 year. In this cohort, 17 (56%) maintained gastrointestinal continuity, of whom 13 were asymptomatic of fistula symptoms (11 after intervention), while 4 were symptomatic but declined intervention. Of the 11 patients who were asymptomatic following treatment, 3 had perianal pouch advancement, 1 had a redo transabdominal pouch, 2 had transvaginal repair, 2 had seton drainage and 3 patients were managed with anti-TNF therapy. Anti-TNF agents were used in 5 patients, 1 of whom was already defunctioned. Three achieved quiescence of symptoms, with 1 requiring pouch excision due to ongoing symptoms. Three patients with poor pouch function prior to anti-TNF therapy noted an improvement in pouch function. Pouch excision or permanent defunctioning was performed in 13 patients (predominantly due to the burden of fistula symptoms rather than poor pouch function). Conclusion Around 50% of patients with PVF required pouch excision or permanent defunctioning. The burden of fistula symptoms drove this decision, rather than overall poor pouch function. Anti- TNF therapy improved pouch function and fistula symptoms in a small group of patients but the evidence supporting its use and indications remain limited.