Crohn's Perianal Fistulas Research Articles

Statement of the polish expert group on the current practice and prospects for the treatment of complex perianal fistulas in Crohn's disease. Update 2021.

Perianal fistulas in Crohn's disease (CD) are a major problem. In majority of patient, inflammation involves the rectum. Perianal fistulas in CD pose a diagnostic and therapeutic challenge due to severe symptoms and worse prognosis compared to cryptogenic fistulas. The accurate diagnosis is crucial for an effective treatment of CD-related perianal fistulas, and the following should be determined: anatomy of the fistula, possible strictures and inflammation of the alimentary tract, including the rectum and the anal canal. Treatment of fistulas might be challenging and requires cooperation between the colorectal surgeon and the gastroenterologist. The combination of surgical and pharmacological therapy is more effective than surgical or pharmacological therapy alone. In conservative treatment, aminosalicylates or steroids have little significance. In everyday practice, antibacterial chemotherapeutics, antibiotics and thiopurines are applied. The most effective are TNF-neutralizing antibodies, i.e. infliximab (IFX), adalimumab (ADA) and certolizumab (CER). Surgical management can be urgent including drainage. Elective procedures include dissection of the fistula (simple fistula) or more complex interventions such as mucosal flap or ligation of the intersphincteric portion of the fistula. Surgical interventions can be enhanced using the video-assisted anal fistula treatment (VAAFT) or negative-pressure therapy. In extreme cases, creation of a stoma may be necessary. Also, tissue glues or so-called plugs may be applied in managing perianal fistulas. The use of stem cells seems promising, i.e. application of multipotent non-hematopoietic stem cells around the fistula in order to induce immunomodulation and wound healing.

Higher Anti-tumor Necrosis Factor-α Levels Correlate With Improved Radiologic Outcomes in Crohn’s Perianal Fistulas

Higher anti-tumor necrosis factor-α (TNF) drug levels are associated with improved clinical healing of Crohn's perianal fistulas. It is unclear whether this leads to improved healing on radiologic assessment. We aimed to evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulising Crohn's disease. A cross-sectional retrospective multicenter study was undertaken. Patients with perianal fistulising Crohn's disease on maintenance infliximab or adalimumab, with drug levels within 6 months of perianal magnetic resonance imaging were included. Patients receiving dose changes or fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary endpoint was radiologic remission (inflammatory subscore= 0). Of 193 patients (infliximab, n= 117; adalimumab, n= 76), patients with radiologic healing had higher median drug levels compared with those with active disease (infliximab 6.0 vs 3.9 μg/mL; adalimumab 9.1 vs 6.2 μg/mL; both P < .05). Patients with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs 3.9 μg/mL; P < .05; adalimumab 9.8 vs 6.2 μg/mL; P= .07). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. Higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulising Crohn's disease, with an incremental improvement at higher drug level tertiles for both infliximab and adalimumab.

DOP57 Predictive modelling to examine long term treatment effectiveness of darvadstrocel in patients with complex perianal fistulas in Crohn’s Disease

Abstract Background Darvadstrocel (DVS) was approved in 2018 by EMA for treatment of complex perianal fistulas in Crohn’s disease (CPF-CD)1, with evidence on long-term effectiveness still accruing. The objective of this study was to synthesize clinical trial data and real-world evidence (RWE) using robust statistical methodologies to predict absolute and relative long-term effectiveness of DVS vs. standard of care (SoC) in patients with CPF-CD. Methods Data was pooled from the pivotal phase 3 trial ADMIRE-CD (n=212; ≤ 2 years data), INSPECT (n=89; chart review study of patients completing ≥52 weeks in ADMIRE-CD, 2-year follow-up post-trial) and PREFACE (n=313; chart review study of patients undergoing SoC treatment, median follow-up of 4 years). Individual anonymized patient data from these studies were combined and analysed with shared covariates of interest included in regression analyses. Weighting procedures were used to adjust for bias due to differences in distribution of outcomes among patients included in INSPECT. Key outcomes were clinical remission, clinical and patient-centric remission (CPC remission), and relapse. Missing values were imputed using a multi-level Bayesian approach. Predictive statistical models extrapolated clinical outcomes beyond the observed follow-up time using parametric curves which were fitted to the defined study populations for each treatment arm and outcome. The models were then implemented within a semi-Markov model, to obtain the resultant number of patients in remission. Results Adult patients with CPF-CD from ADMIRE-CD and PREFACE were similar in age, number of internal and external openings of the perianal fistulas. However, the median CD disease duration was 9.5 vs 6.5 years and prior biologic exposure: 79.5% vs 46.0% for patients in ADMIRE-CD and PREFACE respectively. Patients included in INSPECT were comparable to the overall ADMIRE-CD patients for the covariates of interest. Percentage of patients in CPC remission at 24 months was 39% vs 32% for DVS and SoC respectively for ADMIRE-CD+INSPECT. However, after adding PREFACE data to the predictive model and adjusting for outcome bias, the predicted percentage of patients in CPC remission increased in DVS and SoC groups to 48% vs 35%, respectively. There were small differences by 48 months, after which the remission rates stabilized (Figure). Conclusion In this pooled analysis, we used predictive modelling to examine the effectiveness of DVS vs. SoC over a longer time. Inclusion of RWE to the model indicates possible maintenance of the disease-modifying effect of DVS over a longer time period. Reference 1. Panés et al. Gastroenterology 2018;154:1334–42 Sponsor: Takeda Pharmaceuticals USA, Inc.

P446 Plasma rich in growing factors as treatment for perianal fistulas in Crohn’s disease: unicentre experience

Abstract Background Perianal Crohn’s disease (PCD) adds a significant morbidity and reduced quality of life. Complex fistulas occur in up to 20% of patients. The available treatment of PCD includes immunosuppressive drugs, antibiotics, different surgeries but are associated with high recurrence rates. A new alternative using plasma rich in growth factors (PRGF) for the treatment of complex fistulas has emerged from to achieve better healing with the minimum possible complications without affecting anal continence. This study aims to assess the feasibility, safety and efficacy of local injection of PRGF in patients with PCD. Methods Retrospective observational and descriptive study analyzing 6 Crohn′s Disease (CD) patients undergoing complex anal fistula sealing with PRGF from March 2019 to December 2020. All patients underwent endoanal ultrasound and 60% a pelvic magnetic resonance also. The technique consisted of locating the tract without the use of hydrogen peroxide, active curettage of the tract and closure the internal fistulous orifice (IFO) with single stitches Vicryl® 3/0. Subsequently, 50% of the PRGF-rich fraction was injected in the submucosa of the closed internal fistula orifice. The other 50% is injected in the fistulous tract. With PRGF-poor fraction a three-dimensional fibrin matrix is created and filled the previously curetted fistulous tract. We describe the results in terms of demographic variables, outcomes, surgical procedure and complications. Endpoint was fistula closure by physical examination and endoanal ultrasound. Results Sixty seven percent of the patients were female, mean age was 43 (26y SD). The clinical characteristics of the patients are described in table 1. All of the patients had previous abscess drainage surgery. The most frequent fistula was mid-transsphincteric type. 66.7% had seton at the time of surgery and only one patient had no medical treatment at that time. The median follow-up was 30 months. The recurrence rate was 66.7% with no differences with in age, sex, comorbidity, type of fistula, fistula location, medical treatment and whether they had a seton implanted at the time of surgery. No patient presented complications. The median follow-up was 16 months. Conclusion PRGF sealing appears to be feasible, safe and a promising option in the treatment of PCD. Further studies should be carried out to determine the real use of PRGF in PCD.

DOP11 Fibrosis and MAGNIFI-CD activity-index at MRI to predict treatment outcome in perianal fistulising Crohn’s Disease patients

Abstract Background The aim of this study was to evaluate degree of fibrosis and disease activity using the MAGNIFI-CD index at MRI as predictors of long-term clinical perianal fistula closure in Crohn’s patients who had anti-TNF therapy and/or surgical closure. Methods Perianal Crohn’s patients who had anti-TNF and/or surgery between 2013 and 2020 with a post-treatment MRI and long-term clinical follow-up data were retrospectively included. Two radiologists scored the degree of fibrosis and items of the MAGNIFI-CD index at the post-treatment MRI. Long-term clinical closure was assessed 12 months after the post-treatment MRI and was defined as no production on palpation and/or closed external openings and absence of re-interventions. The accuracy of findings at MRI in predicting long-term clinical closure was evaluated in terms of a receiver operating characteristics (ROC) analysis. An area under the curve (AUC) with 95% confidence interval (CI) was calculated. Results Forty-nine patients were included; 31 female, median age 33 years (IQR 26–46). Post-treatment MRI was performed at a median of 7 months (IQR 4–14) after treatment. At long-term clinical follow-up, 25 patients showed fistula closure and 24 did not. Fourteen patients showed a 100% fibrotic fistula at post-treatment MRI of which all had a closed fistula at long-term clinical follow-up (Figure 1). ROC analysis showed an AUC of 0.90 (95% CI: 0.81–0.99) for degree of fibrosis in predicting long-term clinical closure. The median MAGNIFI-CD index at post-treatment MRI was 0 (IQR 0–5) in patients with long-term clinical closure and 16 (IQR 10–20) in patients without (Figure 2). ROC analysis showed an AUC of 0.95 (95% CI: 0.89–1.00) for the MAGNIFI-CD index in predicting long-term clinical closure. Abstract DOP11 – Figure 1: Degree of fibrosis at the post-treatment MRI in relation to long-term clinical closure. Abstract DOP11 – Figure 2: MAGNIFI-CD index at the post-treatment MRI in relation to long-term clinical closure. Conclusion Degree of fibrosis and MAGNIFI-CD index at post-treatment MRI are accurate in predicting long-term clinical closure of perianal fistulas in Crohn’s patients and can be valuable parameters for radiological follow-up. A completely fibrotic tract at MRI seems a robust indicator for long-term fistula closure.

P320 Combined mesenchymal stromal cells and anti-cytokine therapy of perianal Crohn’s disease

Abstract Background Perianal fistulas are common types of fistulas in Crohn’s disease (CD). Mesenchymal stromal cells (MSC), which have immunomodulatory properties and high regenerative potential, are currently also used for the treatment of fistula CD. The purpose of this study was to compare the effectiveness of combined therapy (local and systemic) mesenchymal stromal cells (MSC) of bone marrow, in the effectiveness of combination therapy MSC (local administration) and infliximab (IFX), as therapy the IFX with immunomodulators on the healing of simple perianal fistulas in Crohn’s disease (CD). Methods Seventy-five patients with CD with perianal lesions were divided into three groups depending on the method of therapy. The first group of СD patients aged 19 to 59 years (Me-29) (n=25) received a culture of MSC systematically according to the scheme and locally. The second group of patients with CD (n=25) aged 20 to 60 years (Me-28) received anti-cytokine therapy with IFX and immunomodulators. The third group of patients with CD (n=25) aged 20 to 62 years (Me-30) received MSC systemically and locally, as well as anti-cytokine therapy with IFX. The dynamics evaluated the complete closure of the external opening of the fistula. Ano-and rectosigmoscopy was performed 2 and 12 months after the start of therapy. The comparative analysis was performed using four-field tables using nonparametric statistical criteria. Results After 2 months in the first group of patients, healing of simple fistulas was observed in 15/25 (60.0%), in the third group-22/25 patients (88.0%) (RR–1.467; 95% CI - 1.032-2.084; x2= 3.742; p=0.02948). After 2 months in the second group, healing of simple fistulas was observed in 16/25 (64.0%) (RR-1.37; 95% CI 0.991-1.908; x2=4.091; p=0.056). After 12 months in the first group of patients, healing of simple fistulas was observed in 17/25 (68.0%), in the third group-24/25 (96.0%) patients (RR 1.412; 95% CI 1.066–1.869; x2=7.399; p=0.0124). After 12 months in the second group, healing of simple fistulas occurred in 18/25 (72.0%) (RR -0.750; 95% CI 0.580– 0.970; x2=5.922; p=0.0488). Conclusion Combined cells and anti-cytokine therapy of CD with perianal lesions contributes to more frequent and prolonged closure of simple fistulas, compared with MSC monotherapy and IFX monotherapy.

OP18 Treatment of perianal fistulas in Crohn’s Disease: Surgical closure after anti-TNF induction treatment versus anti-TNF without surgery (PISA II) - A patient preference RCT

Abstract Background Current guidelines on Crohn’s perianal fistulas recommend anti-TNF treatment and suggest to consider surgical closure in amendable patients. However, long-term outcome of both treatments have not been directly compared. The aim of this study was to assess MRI healing in a patient preference RCT comparing both treatment modalities. Methods This multicentre, international trial compared surgical closure following anti-TNF induction (4 months) to anti-TNF therapy without surgery. Patients were counselled for both treatment arms and randomised if there was no preference. Due to the combination of a preference and randomised cohort, the appropriate sample size to detect a clinically relevant increase of 25% closure (from 15% to 40%) was flexible and adjusted for a possible skewed distribution (86 patients in case of 1:1 treatment allocation). All Crohn’s patients ≥ 18 years with a (re)active high perianal fistula and a single internal opening were eligible. Exclusion criteria were previous failure of anti-TNF, recto-vaginal fistula, proctitis, or stoma. Patients received seton placement prior to treatment. Primary outcome was MRI healing after 18 months (defined as a complete fibrotic fistula or MAGNIFI-CD score of 0–5). Secondary outcomes included clinical healing, re-interventions and fistula recurrence. Results Between September 2013 and December 2019, 7 hospitals in the Netherlands and Italy included 93 patients (59% females, median age 34 years) of which 32 were randomised. Thirty-seven patients were treated in the surgical closure group and 56 in the anti-TNF group, with comparable baseline characteristics. After 18 months, MRI healing was significantly higher after surgical closure (41% vs 11%; P=0.002). Although a trend was seen in favour of surgical closure, clinical healing rates and surgical re-interventions were not significantly different between groups (65% vs 45%, P=0.07 and 19% vs 34%, P=0.1). After median 38 months follow-up, 12 patients in the anti-TNF group crossed over to surgical closure. Both long-term MRI healing and clinical closure in the per protocol analysis remained significantly higher for the surgical closure group (46% vs 11%, P=0.002 and 65% vs 29%, P=0.006). One patient (4%) with a MAGNIFI-CD score ≤5 developed a recurrent fistula after 46 months, whereas recurrences occurred in 37% of patients with MAGNIFI-CD score &amp;gt;5 (P=0.004). Conclusion These results demonstrate that surgical closure following anti-TNF induction treatment induces MRI healing more frequently than anti-TNF alone. This is associated with increased long-term clinical closure and reduced recurrences. These data suggest that Crohn’s perianal fistula patients amendable for surgical closure should be counselled for this therapeutic approach.

Hyperbaric oxygen therapy for the treatment of rectovaginal fistulas in patients with Crohn's disease: results of the HOT-REVA pilot study.

BackgroundPositive effects of hyperbaric oxygen (HBO) on perianal fistulas in Crohn’s disease (CD) have been described, but the effect on rectovaginal fistulas (RVFs) has not yet been studied. The aim was to investigate the efficacy, safety and feasibility of HBO in patients with RVF in CD.MethodsIn this prospective study, consecutive CD patients between November 2018 and February 2020 presenting with RVF at the outpatient fistula clinic of the Amsterdam University Medical Centre were included and selected to receive treatment with 30 daily HBO sessions, if fistulas were actively draining and any concomitant treatment regimen was stable at least 6 weeks prior to start of HBO. Patients with a stoma were excluded. The primary endpoint was clinical closure at 3-month follow-up, defined as cessation of complaints and/or closure of the external orifice if visible at baseline. Secondary outcomes were improvement of concomitant perianal fistulas as measured by the perianal disease activity index (PDAI) and fistula drainage assessment (FDA), as well as improvement in patient-reported outcomes (visual analogue scale (VAS), inflammatory bowel disease questionnaire (IBDQ), faecal incontinence quality of life scale (FIQL) and female sexual functioning index (FSFI)) at 3-month follow-up.ResultsOut of 14 eligible patients, nine patients (median age 50 years) were treated, all of whom had previously had one or more unsuccessful medical and/or surgical treatments for their RVF. Clinical closure occurred in none of the patients at 3-month follow-up. There was no improvement in PDAI and patient-reported outcomes (VAS, IBDQ, FIQL and FSFI). Two patients had concomitant perianal fistulas; using FDA, one patient had a clinical response and one patient was in clinical remission 3 months after HBO. There were two treatment-related adverse events during HBO concerning claustrophobia and fatigue. Furthermore, two patients had a surgical intervention due to RVF and two patients were treated with antibiotics for a urinary tract infection during follow-up. One patient had a dose reduction of ustekinumab because of decreased luminal complaints.ConclusionTreatment with HBO was feasible, but in this therapy-refractory cohort without deviating ostomy no clinical closure of RVF or improvement in quality of life was seen 3 months after HBO. Treatment with HBO alone in this specific group of patients therefore appears to be ineffective.

Surgical options for perianal fistula in patients with Crohn's disease: A comparison of seton placement, fistulotomy, and stem cell therapy

ObjectiveThis study was designed to assess the demographic characteristics of patients with Crohn's perianal fistula (CPF) who were treated at a tertiary referral institution. Surgical outcomes were compared in groups of patients who underwent seton placement, fistulotomy, and stem cell therapy. MethodsPatients who underwent surgery for CPF between 2015 and 2017 at Asan Medical Center, Seoul, Korea, were retrospectively evaluated. Patients were divided into groups who underwent seton placement, fistulotomy, and stem cell therapy. Their clinical variables and closure rates were compared. ResultsThis study included 156 patients who underwent a total of 209 operations. More than half of the operations consisted of seton placement (67%), followed by stem cell therapy (18%) and fistulotomy (15%) patients. Of the 209 fistulas, 153 (73%) were complex, with an overall closure rate of 38% during a median follow-up of 29 months. Closure rates following fistulotomy, stem cell therapy, and seton placement were 90%, 70%, and 18%. Seton placement was more significantly frequently used than the other procedures in patients with complex fistula and those with abscesses. Of the 79 fistulas that achieved complete closure, 11 (14%) recurred. The recurrence rates did not differ among the various techniques. ConclusionSurgical treatment of CPF is dependent on lesion type. Seton placement was the primary draining procedure for complex fistulas and abscesses, resulting in low closure rates. Fistulotomy was the definite procedure for low type and simple fistula. Stem cell therapy showed high closure rates as definitive treatment, even for complex fistulas.

Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn's disease: A case series.

Even with optimal medical and surgical therapy, perianal fistulas in patients with Crohn's disease (CD) have low closure rates. As a new therapeutic option, administration of local mesenchymal stem cells (MSCs) has proved to be an innovative option after failure of treatment with immunosuppressive or immunomodulatory agents. The aim of this work is to share our first experience with MSC administration and demonstrate its efficacy, safety and feasibility outside a clinical trial. A total of 11 CD patients with complex perianal fistulas with nonactive or mildly active luminal disease were treated with local injection of 120 million allogeneic adipose-derived stem cells at a tertiary hospital between February 2019 and June 2020. The mean age of the 11 patients was 38.3years, 72.7% were men and 27.2% were smokers. The mean duration of fistula manifestation was 7.8years and, except for one patient (therapy with tacrolimus), all other patients had been treated with an antitumour necrosis factor agent without fistula healing in the last 6months. After a mean follow-up time of 41.5weeks, 72.7% (8/11) of patients had complete closure of their fistula and three patients failed MSC treatment. Complete fistula healing could be observed 4-6weeks postoperatively in half of the patients, while 36.5% (4/11) of patients developed a perianal abscess which had to be drained. One patient experienced cytomegalovirus viraemia 2weeks after MSC administration and one patient developed a testicular carcinoma 16weeks after treatment. This case series demonstrates that the efficacy and safety of darvadstrocel in the ADMIRE trial can be replicated outside a clinical trial. This new modality in the treatment of complex perianal fistulas appears to be a promising therapeutic option for a challenging patient population.

Long-term efficacy of fibrin glue injection for perianal fistulas in patients with Crohn's disease.

The treatment of perianal fistulas in Crohn's disease remains challenging. Fibrin glue injection has previously shown short-term efficacy in a randomized controlled trial. No long-term data are available to assess the benefit of this treatment. This retrospective multicentre study included all patients with drained fistulas treated by at least one fibrin glue injection between January 2004 and June 2015 in three tertiary French centres. The primary end-point was the rate of complete clinical remission at 1year after injection defined by the closure of all fistula tracts with no need for iterative anal surgery or for optimization of immunosuppressants and/or biologics. In all, 119 patients (median age 33years, complex fistulas 65%, median previous anal surgery two, median Harvey Bradshaw score 3, immunosuppressants exposure 50%, anti-tumor necrosis factor exposure 60% with median time of administration of 1.1year) were analysed with a median follow-up of 18.3months. The complete clinical remission rate at 1year was 45.4%. The primary end-point was achieved in 63% of the cases in the combination therapy group and 37% in other patients. The only predictor of complete clinical remission at 1 year was combination therapy at the time of injection (P=0.01). The rate of early reintervention after glue injection was 2.5%. The cumulative incidence of iterative anal surgery and ostomy in the whole population was 54% and 5.6% respectively at 5 years. An adjunct of fibrin glue to conventional medical therapy may be an effective and safe treatment for perianal fistulas in patients with Crohn's disease.

Differences in amino acid and lipid metabolism distinguish Crohn's from idiopathic/cryptoglandular perianal fistulas by tissue metabonomic profiling and may offer clues to underlying pathogenesis.

Few studies have investigated perianal fistula etiopathogenesis, and although the cryptoglandular theory is widely accepted in idiopathic cases, in Crohn's disease, it is thought to involve the interplay between microbiological, immunological and genetic factors. A pilot study was conducted to assess for metabolic variations in Crohn's perianal fistula tissue that might differ from that of idiopathic (cryptoglandular) perianal fistula tissue as a comparator. The goal was to identify any potential biomarkers of disease, which may improve the understanding of pathogenesis. Fistula tract biopsies were obtained from 30 patients with idiopathic perianal fistula and 20 patients with Crohn's anal fistula. Two different assays were used in an ultra-high-performance liquid chromatography system coupled with a mass spectrometric detector to achieve broad metabolome coverage. Univariate and multivariate statistical data analyses were used to identify differentiating metabolic features corresponding to the perianal fistula phenotype (i.e. Crohn's disease vs. idiopathic). Significant orthogonal partial least squares discriminant analysis predictive models (validated with cross-validated-analysis of variance P value <0.05) differentiated metabolites from tissue samples from Crohn's vs. idiopathic anal fistula patients using both metabolic profiling platforms. A total of 41 metabolites were identified, suggesting alterations in pathways, including amino acid, carnitine and lipid metabolism. Metabonomics may reveal biomarkers of Crohn's perianal fistula. Further work in larger numbers is required to validate the findings of these studies as well as cross-correlation with microbiome work to better understand the impact of host-gut/environment interactions in the pathophysiology of Crohn's and idiopathic perianal fistulas and identify novel therapeutic targets.

Comparison of the Efficacy of the Various Treatment Modalities in the Management of Perianal Crohn's Fistula: A Review.

Crohn's disease (CD) is a transmural inflammatory bowel disease (IBD) that can affect any part of the gastrointestinal (GI) tract. With the disease's progression, adhesions and transmural fissuring, intra-abdominal abscesses, and fistula tracts may develop. An anal fistula (or fistula-in-ano) is a chronic abnormal epithelial lined tract communicating the anorectal lumen (internal opening) to the perineal or buttock skin (external opening). The risk of fistula development varies from 14%-38%. It can cause significant morbidity, which adversely impacts the quality of life. It is mostly believed that an anal crypt gland infection causes anal abscesses, leading to fistula development. Crohn's disease's pathogenesis involves Th1 and Th17 hypersensitivity due to an unknown antigen within the intestinal mucosa.Evidence to support this review was gathered via the Pubmed database. Search terms used were combinations of "Perianal fistula," "seton," "immunotherapy." Studies were reviewed and cross‐referenced for additional reports.Setons are surgical thread loops passed from the external to the internal opening of the fistula tract and exteriorized through the anorectal canal, facilitating abscess drainage and inciting a local inflammatory reaction, thus promoting the resolution of the fistula. Biologicals such as anti-tumor necrosis factor (TNF) antibody (infliximab, adalimumab, certolizumab), anti-IL-12/23 (ustekinumab), and anti-α₄β₇ integrin antibody (vedolizumab) have been approved for Crohn's disease targeting the Th1/Th17-mediated inflammation. Other therapeutic modalities are fistulotomy, cyanoacrylate glue, bioprosthetic plugs, mucosal advancement flap, ligation of inter-sphincteric fistula tract (LIFT), diverting stoma, proctectomy, video-assisted anal fistula treatment (VAAFT), and fistula laser closure (FiLaC).Our review found that chronic seton therapy should be the primary approach, especially if the patient has a perianal abscess. It has a low incidence of re-intervention, recurrent abscess formation, and side-branching of the fistulous tract, with preservation of the fistulous tract's patency and cost-effectiveness. The major disadvantage of seton therapy is the discomfort and time to achieve stability. Among the biologicals, infliximab is the only therapy which has a statistically significant effect on the healing rate of perianal Crohn's fistula compared to placebo, but the major disadvantage associated with anti-TNF as sole therapy is high re-intervention rate, prolong maintenance therapy, high recurrence rate, and severe side effects. We hypothesize that the two aspects should be addressed concurrently to increase the fistula healing or closure rate. First, the seton should be used as initial therapy to maintain tract patency to allow abscess drainage and minimize the intestinal flora colonization within the tract mucosa, thereby leukocytic infiltration and propagation of inflammation within the tract. The second aspect that has to be considered is that we should target the initial stimulation of the Th1/Th17 mediated hypersensitivity instead of a factor/cytokine involved in the inflammation mediation. Although the unknown antigen triggering such hypersensitivity is not clear, we could target the RAR-related orphan receptor γ (RORγ)-T (transcription factor involved in activation of Th17 cells) and the T-bet (transcription factor involved in activation of Th17 cells) within the GI mucosa by a novel target immune therapy.

Magnetic resonance imaging after ligation of the intersphincteric fistula tract for high perianal fistulas in Crohn's disease: a retrospective cohort study.

AimLigation of the intersphincteric fistula tract (LIFT) is increasingly being used for surgical closure of high perianal fistulas in Crohn’s disease. Currently, data on postoperative MRI findings are scarce, although they are considered important for assessing healing and recurrence. Our aim, therefore, was to evaluate fistula characteristics on MRI and their relationship with clinical outcomes after LIFT.MethodConsecutive Crohn's patients treated with LIFT between 2007 and 2018 who underwent baseline and follow‐up MRI were retrospectively included. MRIs were scored by two radiologists according to characteristics based on the original and modified Van Assche indices. MRI findings, with emphasis on fibrosis, and the relationship with clinical healing, re‐interventions and recurrences are described.ResultsTwelve patients were included [four men, median age 34 (interquartile range 28–39) years]. Follow‐up MRI was performed at a median of 5.5 months (interquartile range 2.5–6.0) after LIFT. At baseline, all patients showed a tract with predominantly granulation tissue, which changed to predominantly fibrotic in seven (in three of whom it was completely fibrotic). All patients with a (predominantly) fibrotic tract had clinical closure and no re‐interventions or recurrences during long‐term follow‐up. In contrast, of the five patients with persisting granulation tissue, two reached clinical healing, two needed re‐intervention and one had a recurrence.ConclusionMarkedly decreased fistula activity can be observed on MRI after LIFT. The majority of patients develop a predominantly fibrotic tract relatively soon after LIFT without clinical recurrence, suggesting a highly effective therapy. Unfavourable clinical outcomes were only present in patients with persisting granulation tissue, indicating the potential prognostic value of MRI.

Mesenchymal stem cells in perianal Crohn's disease.

The use of mesenchymal stem cells has resulted in a breakthrough for the treatment of complex perianal fistulas in Crohn's disease. This novel treatment is associated with a minimally invasive surgical technique that can be well defined. However, our previous experience has taught us that neglecting any of the critical steps in the operation can result in frequent treatment failure. We have put together a comprehensive guide, a stepwise algorithm, for our minimally invasive approach to identify common pitfalls and reduce treatment failures. Using data we have collected over the past 15years from drug development, execution of clinical trials, and enacting an advanced educational training program, we spelt out each stage of the minimally invasive surgical intervention for stem cell delivery for perianal Crohn's disease. In this article, we provide 21 tips for a correct approach during the five major phases of the surgical procedure. To optimize the efficacy of mesenchymal stem cells for perianal Crohn's disease, a standardized minimally invasive technique including a reliable and reproducible series of key steps should be utilized.

Stem Cell Therapy for Perianal Crohn’s Disease

Abstract The goal of the study was to compare the effect of combination therapy (local and systemic administration) with bone marrow mesenchymal stromal cells (MSC), anticytokine therapy with infliximab (IFX), and antibiotic (AB)/immunosuppressive (IS) therapy on the frequency of healing of simple perianal fistulas in Crohn’s disease. Three patient groups were used in our study. The 1st group of patients (age 19 to 58 years, mean 29 years, n = 12) received MSCs culture systemically and locally. The 2nd group of patients with CD (age 20 to 68 years, mean age 36 years, n = 10) received anticytokine therapy with infliximab (IFX). The 3rd group of patients with CD (age 20 to 62 years, mean age 28 years, n = 14) received antibiotics (AB) and immunosuppressors (IS). Treatment effect was assessed by the index of perianal activity of Crohn’s disease (PCDAI) and the frequency of relapses. After 12 weeks, in the 1st group, healing of simple fistulas was noted in 8/12 patients (66.6%), in the 2nd group in 6/10 (60.0%) and in the 3rd group in 1/14 patients (7.1%). After six months, in the 1st group of patients healing of simple fistulas occurred in 8/12 (66.6%), in the 2nd group in 6/10 (60.0%) and in the 3rd group in 1/14 patients (7.1%). After 12 months, in the 1st group, healing of simple fistulas was observed in 7/12 (58.3%), in the 2nd group in 6/10 (60.0%) and in the 3rd group in 2/14 patients (14.3%). After 24 months, among the patients of the 1st group, fistula closure was observed in 5/12 patients (41.6%), in the 2nd group in 4/10 (40.0%) and in the 3rd group in 0/14 patients (0.0%). Combined cellular and anticytokine therapy of CD with perianal lesions significantly contributes to more frequent and prolonged closure of simple fistulas, as compared to antibiotics/immunosuppressors, and to a decrease in the frequency of recurrence of the disease.

P734 Should we have a higher threshold for anti-TNF serum levels in Crohn’s disease patients with perianal disease?

Abstract Background Tumour necrosis factor (TNF) inhibitors are potent drugs effective for the treatment of both luminal disease and perianal fistulas in Crohn’s disease (CD). Recently, there is some evidence that patients with perianal disease might need higher concentrations of anti-TNF levels compared with patients without perianal disease. The aim of this study was to compare anti-TNF serum concentrations: IFX (infliximab) or ADA (adalimumab) between patients with active and closed perianal fistulas with CD. Methods Retrospective study including that was on anti-TNF for at least 6 months. Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging/ultrasound. Results We included 55 patients with CD and perianal disease, 54.5% males, median age of 31 (interquartile range: 18–71) years. Forty-two were on IFX and 13 on ADA. Median IFX serum concentrations [IQR] were higher in patients with closed fistulas (n = 19) compared with patients with actively draining fistulas (n = 23): 7.7 mg/ml [0–32.6] vs. 1.5 mg/ml [0–9.5], respectively (p &amp;lt; 0.001). A similar difference was seen in patients treated with ADA: median serum concentrations were 9.6 mg/ml [6–21.9] in 10 patients with closed fistulas vs. 4 mg/ml [4–4.3] in 3 patients with producing fistulas, p = 0.007. Serum concentrations superior or equal to 4.68 mg/ml for IFX (AUC of 0.87; 95% CI: 0.73–0.96) were associated with fistula closure. Conclusion Higher serum levels of anti-TNF drugs were associated with perianal fistula closure. Patients with CD and perianal disease may benefit from intensification of biological therapy.

P581 Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn’s disease: First real-life experiences

Abstract Background Since treatment of perianal fistulas in patients with Crohn’s disease (CD) has low durable fistula closure rates even with optimal medical and surgical therapy, new therapies are needed. According to a pivotal phase 3 study program, darvadstrocel, a mesenchymal stem cell therapy, appears to be a promising new treatment option after failure or incomplete response to biologics and immunosuppressive agents. However, until now, no data on the real-life efficacy of darvadstrocel is available. Methods A total of 7 CD patients with complex perianal fistulas without luminal disease were treated with local injection of 120 million allogenic adipose-derived stem cells at our academic tertiary referral centre on an outpatient basis. MRI and fistula conditioning with seton loop placement were performed at least 6 weeks pre-operatively. Furthermore, CD remission was confirmed endoscopically in advance. Results The mean age of patients was 39.4 years, 86% were male and 29% smokers. The mean duration of fistula manifestation was 8.1 years. All patients (except one treated with tacrolimus) had previously received anti-TNF treatment without fistula healing. One patient had CD of an ileoanal pouch following restorative proctocolectomy. Postoperatively, the secretion from the wounds stopped after a few days and in 2 patients clinically fistula healing occurred already after 4 weeks. In 3 patients the fistulas healed after 6 weeks. One patient developed repeated abscesses without fistula healing. Another patient showed improvement of symptoms but without healing of the fistula at 8 weeks. Interestingly, symptomatic CMV viremia occurred two weeks after darvadstrocel injection in one patient, but his two fistulas healed. Conclusion Our initial experience of seven patients treated with darvadstrocel for perianal CD fistulas demonstrates promising results with rapid resolution of local complaints and full clinical healing in five patients until now. Taken together, darvadstrocel appears to be a promising therapeutic option for the challenging group of patients suffering from complex perianal CD fistulas.

P329 ECCO grant recipient: preliminary results of the HOT-TOPIC trial (Hyperbaric Oxygen Therapy for the Treatment Of Perianal fistulas In Crohn’s disease)

Abstract Background Beneficial effects of hyperbaric oxygen (HBO) therapy for perianal fistulising Crohn’s disease (pCD) have been suggested in previous publications. The HOT-TOPIC study was designed to further investigate its feasibility and therapeutic effect in 20 therapy-refractory patients with pCD. Here we present the preliminary results. Methods 17 patients with pCD refractory to conventional-therapy &amp;gt; 6 months (medical and/or surgical, no patients with deviating stoma) were treated with 40 sessions of HBO therapy (243–253 kPa, 110 min per session throughout 8 weeks). Medical treatment remained stable from screening, seton drain(s) were removed after 30 treatment. Co-primary outcomes were clinical response as measured by the perianal disease activity index (PDAI) and MRI improvement measured by the modified van Assche index. Secondary outcomes were clinical response as assessed by fistula drainage assessment (FDA), biochemical response and patient-reported outcomes. All outcomes were assessed at baseline and 2 months after HBO. Results 17 patients (6 female, median age 34 years, median duration of disease 13 years) were treated. Median PDAI scores decreased from 8 to 4 (p &amp;lt; 0.001) and MRI scores from 9.4 to 7.3 (p = 0.001). Defined as PDAI of 4 or less, 11 out of 17 patients had inactive perianal disease after treatment, with 3 patients also having a predominantly fibrotic tract on MRI. Of the 45 external openings draining at baseline, 22 were clinically closed after treatment (49%, assessed by FDA). Four patients, three with one external opening and one with five openings at baseline, had no remaining openings after treatment. Median C-Reactive Protein and faecal calprotectin levels decreased from 5.0 and 416 to 2.3 and 31 (p = 0.002 and p = 0.003), respectively. Median scores of the inflammatory bowel disease questionnaire (IBDQ) increased from 169 to 185 (p = 0.001) and VAS scores from the Euroqol-5-dimensions questionnaire increased from 65 to 75 (p = 0.07), higher scores reflecting better quality of life. When asked on a validated decision regret scale if patients regretted their decision to undergo HBO, the mean score was 12.5 (0–100, higher scores indicating higher regret). During follow-up, none of the patients needed new (experimental) medication, re-interventions or stoma. Seven out of 17 patients experienced trouble equalising middle ear pressure during HBO, with four patients showing signs of barotrauma after otoscopy. Three patients needed tympanostomy tubes. No other clinically relevant adverse events occurred, and no adverse events led to discontinuation of the treatment. Conclusion Based on preliminary data, HBO treatment is associated with significant improvement in pCD, as measured by clinical and MRI endpoints.

P359 Platelet-rich stroma injection (PRS) as a novel surgical treatment of refractory perianal fistulas in Crohn’s disease: A pilot study

Abstract Background Perianal fistulizing Crohn’s disease (FCD) comes with significant morbidity and severe reduced quality of life. Treatment of FCD is challenging and includes immunosuppressive drugs, antibiotics and surgery. All therapies are associated with high recurrence rates. Platelet-rich stroma (PRS) is a combination of platelet-rich plasma (PRP) and stromal vascular fraction (SVF). Autologous PRS includes stromal cells in their matrix with stimulating factors, plays an essential role in wound repair and defence mechanisms against infection and is easy to obtain and inject. Because of its operating mechanism, PRS could be of additional value in patients with refractory FCD. This study aims to assess the feasibility, safety and efficacy of local injection of PRS in patients with refractory FCD. Methods After informed consent, 10 patients (age ≥16 years) with refractory FCD were included between March 2018 and July 2019. Exclusion criteria were rectovaginal fistulas, persistent proctitis and pelvic abscesses. All patients underwent surgery with harvesting of subcutaneous fat and venous blood sampling to obtain 6 ml of PRS (1 ml of SVF resp. 5 ml of PRP), excision of the external opening(s), fistula curettage, and injection of PRS in the fistula wall and closure of the internal opening. A pre- and postoperative MRI was performed. Endpoints were clinical outcome, both closure and absence of discharge at physical examination, patient-reported outcome (no effect/moderate effect/major effect), as well as radiological outcome (van Assche score). From 3 months postoperative, re-injection of PRS was considered in patients with unfavourable clinical and/or radiological outcome. Results All patients (4:6 female:male; median age 33 (IQR 22.9–38.7) had infralevatoric fistulas with a median van Assche score of 17 [range 14–20] without rectal involvement and abscesses. Median follow-up was 6 months [4–12]. The median duration of FCD was 4 years (IQR 2–5). The median number of drugs given were 4 [1–7] and number of operations 3 [2–3], including stoma formation in 2 patients. Crohn’s disease activity outside the anorectum was present in all patients. 7 patients underwent 1 PRS injection and 3 patients 2 injections. There were no complications of the PRS injection. Fistula closure was present in 5 patients and open in 5 patients, of which 2 patients had no signs of discharge. One patient underwent restoration of bowel continuity. Of 7 postoperative MRIs available to date, median decrease of van Assche score was 4 (17 vs. 13)[0–15]. Patient-reported outcome was major effect in 4, moderate effect in 3, and no effect in 3 patients. Conclusion Autologous PRS appears to be feasible, safe and promising in the treatment of refractory perianal fistulizing Crohn’s disease.