Treatment Of Complex Perianal Fistulas Research Articles

A new treatment option for complex perianal fistulas in Crohn's disease patients; development of darvadstrocel (allogeneic expanded adipose-derived mesenchymal stem cells) in Japan

Crohn's disease (CD) is a chronic and relapsing inflammatory bowel disease affecting the entire gastrointestinal tract. The prevalence of CD among Japanese people is increasing. One of the most frequent complications of CD is perianal fistulas. People living with CD may experience complex perianal fistulas, which can cause intense pain, bleeding, swelling, infection, and anal discharge. Despite medical and surgical advancements, complex perianal fistulas in CD remain challenging for clinicians to treat. CD patients living with perianal fistulas reported a negative impact on many aspects of their quality of life. Darvadstrocel is a cell therapy product containing a suspension of allogeneic expanded adipose-derived mesenchymal stem cells. It has been approved in Europe and Japan for the treatment of complex perianal fistulas that have shown an inadequate response to at least one conventional or biologic therapy in adult patients with non-active/mildly active luminal CD. By exhibiting immunomodulatory and local anti-inflammatory effects at the site of inflammation, it offers a new treatment option for complex perianal fistulas in CD patients. In this manuscript, the characteristic of darvadstrocel, the summary of results from the pivotal phase 3 studies in Europe and Japan, and the development strategy in Japan were introduced.

Traitement des fistules anales réfractaires à l’Infliximab au cours de la maladie de Crohn : Mise au point

Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab. Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab. A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded. Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated. Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

P541 Long-term follow-up results of darvadstrocel for complex perianal fistulas in patients with Crohn's disease: 3-year outcomes from a Japanese phase 3 study

Abstract Background Darvadstrocel (DVS), a suspension of expanded human allogeneic mesenchymal stem cells extracted from adipose tissue, is for the treatment of complex perianal fistulas in patients with Crohn's disease (CD). In Japan, DVS was approved in 2021 based on the Japanese phase 3 study Week 52 data combined with the pivotal study ADMIRE-CD data. Patients who participated in the Japanese study were monitored for 3 years, and we report the results at Week (W) 156. Methods This was an open-label, uncontrolled, phase 3 study (converted to a post-marketing clinical study after approval) conducted from March 2019 to February 2023 in Japan. Subjects had complex Crohn’s perianal fistulas (CPF) refractory to conventional treatments with a maximum of 2 internal openings (IO) and 3 external openings (EO). The fistula tract was curetted approximately 2-3 weeks before DVS administration, and a drainage seton was placed. On the day of administration, seton was removed, fistula tracts were curetted again, and IO was sutured. A total of 24 mL of DVS (including 120x106 cells) was administered around the IO and into the wall of fistula tracts. During the 2-year follow-up period after W52, medical and surgical treatment for CD and CPF was given as needed, and subjects were assessed every 6 months. Results 22 Japanese patients were enrolled from 9 sites. The mean (SD) age was 36.4 (10.4) years, 63.6% were male, and the mean (SD) duration of CD was 11.3 (6.6) years. By W156, most frequently reported adverse events (AE) were anal fistula (7/22), proctalgia (7/22), and nasopharyngitis (6/22). New serious AE occurred after W52 were found in 9 subjects: COVID-19 (4), CD (2), perianal fistula, small bowel obstruction, premature labour (1 each). None of these were considered DVS-related. At W156, the combined remission rate (clinical and MRI assessment) was 15/22 (68.2%, 95% CI [48.7%, 87.6%]), clinical remission rate (clinical assessment) was 15/22 (68.2%, 95% CI [48.7%, 87.6%]), response rate (no drainage from ≥50% of treated EOs) was 20/22 (90.9%, 95% CI [78.9%, 100.0%]), and relapse rate (at least 1 relapse by W156 after achieving remission at W52) was 3/15 (20.0%, 95% CI [0.0%, 40.2%]). Mean Perianal Disease Activity Index (PDAI) total score (SD) was 4.8 (2.2) at baseline, which was decreased to 2.1 (2.1) at W52, and 1.7 (2.0) at W156. Mean Crohn's Disease Activity Index (CDAI) total score (SD) was 94.3 (60.1) on the day of administration, which was decreased to 73.7 (73.6) at W52, and 71.4 (51.2) at W156. Conclusion This is the first prospectively observed clinical outcomes in CPF for 3 years after DVS administration. There were no new safety findings, and fistula remission observed at W52 was maintained until W156.

Efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells for the treatment of complex perianal fistula in Crohn’s disease: a pilot study

ObjectivesThe aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn’s disease (CD).MethodsThis was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections larger than 2 cm measured by magnetic resonance imaging (MRI) at 24 weeks after cell administration.ResultsA total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24, respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of remaining recurrence-free was 70% at week 52.ConclusionThe study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337).Trial Registration: The study was retrospectively registered on www.ClinicalTrials.gov (NCT04939337) on June 25, 2021.

Injection of Freshly Collected Adipose Tissue for the Treatment Complex Cryptoglandular Anal Fistula: Case Report

AbstractIntroduction Perianal fistula is a common colorectal disease which is caused mainly by cryptoglandular disease. Although most cases are treated successfully by surgery, management of complex perianal fistulas (CPAF) remains a challenge with limited results in recurrence and sometimes associated with fecal incontinence. The CPAF treatment with autologous adipose-derived mesenchymal stem cells (ASCs) had become a research hotspot. The technique started to be used in the treatment of Crohn's disease (CD) fistulas, where the studies showed safe and goods result from the procedure. Cultured ASCs have been used but this approach requires the preceding collection of adipose tissue, time for isolation of ASCs and subsequent in vitro expansion, need for laboratory facilities, and expertise in cell culturing. These factors have been getting over by using the commercially available alternative, allogenic ASCs. Treatment with allogeneic ASCs has shown good results in patients with CD fistulas, however with the disadvantage of being expensive. Objective To show that the injection with freshly collected adipose tissue is an alternative to treatment with autologous or allogenic ASCs with several advantages. Methods: In this case report, we show our first experience in the treatment of CPAF with the application of collected adipose tissue in a tertiary referral hospital from Belo Horizonte, Brazil. Results The patient had a good postoperative recuperation with a complete fistula healing after 8 months without adverse effects. Conclusion Injection with freshly collected adipose tissue is a promising and apparently safe sphincter-sparing technique in the treatment of CPAF.

Efficacy and feasibility of stromal vascular fraction containing adipose derived stem cells obtained from freshly prepared lipoaspirate for treatment of complex anorectal fistulas- A novel approach

BackgroundAnal fistulas are relatively common. Despite diverse treatment modalities and tremendous advance and optimization of surgical approaches, considerable recurrence and high failure rates are not uncommon especially after surgery for complex anal fistulas. Therefore, autologous adipose-derived stem cell therapy for the treatment of complex perianal fistula can be an innovative and promising option with potential high cure rate and long-term healing. AimTo assess the efficacy and feasibility intralesional administration of stromal vascular fraction containing autologous, adipose-derived stem cells prepared from fresh lipoaspirate for management of complex and recurrent anal fistula. MethodsTotally, 28 patients with complex perianal fistulas were enrolled in this prospective case-series study from March 2018 and August 2022. They were 22 male and 6 females patient) with 38.8 years average ages (ranges from 26 to 54 years). All patients were assigned to receive intralesional injection with autologous freshly prepared adipose-derived stem cells from lipoaspirate suction in a concentration of 1 × 107 cell/ml. The healing of fistulas, confirmed by clinical assessment and magnetic resonance imaging was evaluated at week 6 weeks, 12 weeks and 6 months after treatment. If no evidence of healing was not seen at 6 weeks, a second dose of same concentration was administered. In addition to fistula healing, adverse effect (functional outcomes), complications and procedure safety were also evaluated. ResultsThe overall healing rate of fistulas treated by injection of ADSCs was 60.7% (17/28), while healing rate after first injection was 50% (14/28) and after second injection was 30% (3/10).Three patients were lost after first injection. During the follow up period of 6 months none of the patients who showed complete healing, recorded relapse of their fistulas (recurrence 0%). Further, none of the patients recorded complications or adverse reactions related to stem cell therapy during the study and none of them had worsening fecal incontinence during follow-up period. Postoperative pain assessed by.VAS score was significantly low (>3). Fecal continence assessed by Wexner score of all patients was not changed or affected. ConclusionsInjection of complex perianal fistulas by freshly prepared autologous ADSCs could be a valid and effective treatment modality. It is safe, feasible and minimally invasive procedure that lacks the risk of injury to anal sphincter complex, unlike other surgical procedures that endanger the anal continence.Further, second dose of ADSCs injection could improve the rate of healing, without adding adverse effects.

Safety and efficacy of injection of human placenta mesenchymal stem cells derived exosomes for treatment of complex perianal fistula in non-Crohn's cases: Clinical trial phase I.

A perianal fistula is an abnormal tract that connects anal canal to skin. Current medical and surgical interventions have a high failure rate particularly in complex and refractory cases. MSC-derived exosomes have demonstrated immunomodulatory effects without the conventional complications; hence, in this study, we evaluated the safety of their application for complex perianal fistula. Placenta-derived MSCs were cultured, and exosomes were isolated using ultracentrifugation. Exosome injections were administered in the operating room to 11 patients with complex perianal fistula (presence of fistulas for at least 1year alongside medical and surgical treatment). The patients were followed for 6months, and the patients were evaluated using physical examination, face-to-face interviews, and magnetic resonance imaging (MRI). Among 11 patients only one did not show any improvement upon physical examination. Five patients showed complete tract resolve. While the discharge was stopped in eight patients, two patients showed only reduction. None of the patients showed any acute or latent allergic reaction or injection related complications. Administration of exosomes isolated from MSCs demonstrates safety and a satisfactory therapeutic effect in treatment complex perianal fistulae; therefore, it can be a candidate for future studies and might play a significant role in treatment.

S191 Efficacy and Safety of Adipose-Derived Stem Cell Therapy for the Treatment of Complex Perianal Fistula Not Associated With Crohn’s Disease: A Systematic Review and Meta-Analysis

Introduction: Given the high recurrence rate and the risk of fecal incontinence with surgical options, Injection of adipose tissue-derived stem cells (ASC) has been arising as a novel method for treating complex perianal fistulas (CPAF). Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of ASC in the management of CPAF not associated with Crohn’s disease. Methods: We systematically searched Medline and Embase databases through April 20, 2022, for all studies that assessed the efficacy and safety of ASC for the treatment of CPAF not associated with Crohn’s disease. We excluded patients with rectovaginal fistulas and perianal fistulas associated with Crohn’s disease. Our primary outcome was the complete closure. The secondary outcomes included overall nonserious adverse events (NSAE), serious adverse events (SAE), and perianal abscess rate. All meta-analyses were conducted using a random-effect model. The publication bias was assessed by Egger’s test. Results: Ten studies (eight clinical trials and two observational studies) with 271 patients were included in the pooled analysis. Eight studies used autologous stem cells, one used allogeneic stem cells, and one did not report the source of stem cells. The mean age of the patients was 43.7 years. The follow-up period ranged from 3 months to 2 years. The pooled complete closure rate was 59.7% (95% confidence interval (CI): 0.46-0.73, Figure 1A). On subgroup analysis based on country of origin, six studies with 213 patients were conducted in European countries, and four studies with 58 patients were conducted in non-European countries. The complete closure rate was higher in European countries than non-European countries, 64.1% vs. 52.6%. Eight studies reported overall NSAEs with the pooled NSAE rate of 22.5% (95% CI: 0.11-0.34, Figure 1B). Seven studies reported SAEs with the pooled SAE rate of 1.7% (95% CI: 0.001-0.034, Figure 1C). Seven studies reported the perianal abscess rate with a pooled perianal abscess rate of 7.1% (95% CI: 0.016-0.125, Figure 1D). No evidence of publication bias was found (Egger’s test: P=0.36). Conclusion: Our meta-analysis demonstrated that ASC is a promising therapeutic option for CPAF not associated with Crohn’s disease with a clinically adequate efficacy and low rate of adverse events. However, more studies with larger sample sizes are needed to provide a definitive assessment of the effectiveness of ASCs for CPAF not associated with Crohn’s disease.Figure 1

Autologous adipose-derived stromal vascular fraction and platelet concentrates for the treatment of complex perianal fistulas

BackgroundComplex perianal fistulas are a major challenge for modern surgery since 10–35% of patients have functional problems after treatment. Sphincter-saving techniques have a wide range of efficacy (10–80%). We hypothesised that autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma is a new therapeutic strategy with enhanced cure and function preservation rates.MethodsAdult patients with complex cryptoglandular perianal fistulas were treated with injection of autologous adipose-derived stromal vascular fraction in combination with platelet rich plasma around and inside the fistulous tract between May 2018 and April 2019 at the General and Emergency Surgery Operative Unit of the University Hospital “P. Giaccone” of Palermo. Fistulas were confirmed by magnetic resonance imaging. Patients completed the Short Form-36 score on quality of life and the Wexner and Vaizey scores on faecal incontinence, and they were functionally studied using a three-dimensional anorectal manometry. The clinical and functional follow-up was performed at 1 year and 2 years after surgery.ResultsNine patients (4 males, 5 females; median age 42 years [19–63 years]) with high trans-sphincteric or horseshoe fistulas were treated. The average number of previous surgeries per patient was 4.8. At 1 year follow-up, 77.7% of patients were cured, while at 2 years there was 1case of relapse. The variation in Short Form-36 score in cured patients was not significant (p = 0.0936). No statistically significant differences were found in continence scores.ConclusionsThe proposed treatment is a treatment option that preserves sphincter integrity and function, potentially avoiding postoperative incontinence and the need of repeated treatments.

Anti TNF treatment of complex perianal fistulas in children without luminal Crohn's disease: Is it an option?

ObjectivesComplex perianal fistulas (CPFs) in children even in the absence of luminal symptoms prompt evaluation for Crohn's disease (CD). Reports of isolated CPF in children, however, are sparse. In perianal CD, antitumor necrosis factor α (anti TNF) therapy is recommended. We aimed to describe our experience with anti TNF therapy in children with isolated CPF without evidence of luminal CD. MethodsWe retrospectively reviewed charts of patients with isolated CPF who were treated with anti TNF agents between 2011 and 2019 in a tertiary center. MRI pelvis findings at baseline versus end of follow up were scored using MAGNIFI-CD. Outcomes included clinical remission, radiological response and radiological remission based on MAGNIFI-CD score at end of follow up. ResultsOverall, 17 patients were identified, [10 males (59%), mean age at anti TNF initiation 13.4 ± 2.9 years]. Median time from perianal disease onset to anti TNF was 16.5 months (IQR 9.4–36.4). None of the patients had luminal inflammation. Prior to anti TNF, all patients had been treated with antibiotics without sufficient improvement, and 9/17 with abscess drainage and or Seton insertion. Nine patients (53%) were treated with infliximab while 8 (47%) received adalimumab. Median duration of follow up was 30.7 months (IQR = 12.7–44.8). At the end of follow up 9 patients (53%) achieved clinical remission. When comparing MRI prior to and after anti TNF, 36% (5/14) had radiologic response, of whom 2 (14%) achieved radiologic resolution. ConclusionAnti TNF agents may be an effective treatment option for children with isolated CPF. Whether these patients should be considered part of the CD phenotypic spectrum or a distinct entity is unclear. Levels of EvidenceTherapeutic.

3D visualization of perianal fistulas using parametric models.

Magnetic resonance imaging (MRI) is used as a standard for assessment of complex perianal fistulas. Apart from textual description of the case, 3D reconstructed models from MRI further aid in understanding the entire anatomy of the fistula tract and its relation to the pelvic floor. This information is crucial as it helps surgeons to understand the extent and complexity of the disease before surgical treatment. However, 3D model generation from MRI is a time-consuming step for a radiologist as it requires tedious manual delineations to be performed on every slice of the images. The aim of this study was to develop a method that could enable radiologists to present enhanced information to surgeons for treatment of complex perianal fistulas while simultaneously reducing the manual efforts and time required to generate the information. A method was proposed to depict relevant anatomies of complex perianal fistula as parametric models in three-dimensional (3D) space. A plugin inside 3D Slicer software was developed for the generation of the parametric models from MRI. The levator ani muscle, internal sphincter, and external sphincter are represented as tubular structures, whereas fistula tracks and abscess are presented as splines. Parametric models were generated to depict three cases of complex perianal fistulas and similarity measures were computed for ten cases. Visual comparison of the parametric models was made with the 3D models generated by the standard approach. The parametric models took less time to create and were able to visually present enriched information as compared to the 3D models generated by the standard approach. The proposed method, using parametric models, shows potential for faster generation and better visualization of the 3D information required for the treatment of complex perianal fistula cases.

P390 Efficacy and safety of mesenchymal stem cell therapy with darvadstrocel for complex perianal fistulizing Crohn′s disease: multicentric experience in the Basque Country and Navarre

Abstract Background Perianal fistulizing Crohn′s disease has a negative impact on patients′quality of life and despite advances in medical and surgical treatment, high rates of recurrence are still reported. Mesenchymal stem cell therapy has recently been authorized for the treatment of complex perianal fistulas in adult patients with Crohn’s disease, and it may be an effective and safe alternative. The aim of this study was to evaluate the results of efficacy, defined as combined clinical and radiological remission, and safety after administration of darvadstrocel. Methods A retrospective and observational analysis of patients with complex perianal disease treated with darvadstrocel at three centers in Spain were included. The inclusion criteria and the surgical technique followed the specifications from the Ministry of Health and Consumption. Follow-up visits were performed at, 6 and, 12 months after the treatment and evaluated by clinical disease activity and pelvis magnetic resonance. Results From November, 2020 to July, 2021, 13 patients (mean age, 39 years, IQR, 30–48, 69% males) were treated with mesenchymal stem cell therapy. The most common type of fistulas were transsphinteric (77%), high intersphinteric (15%) and the suprasphinteric (15%), the latter associated with other types of fistulas. All patients received concomitant anti-TNF (61%), ustekinumab (31%) or vedolizumab (8%). Eight patients (62%) have reached the, 6-month follow-up, five (62%) of them have had combined response, one patient (13%) had radiologic response and two (25%) showed disease progression (Figure, 1). Among those patients with <6 months follow-up, four (80%) of them have shown clinical response. Most of the patients (77%) had no adverse events related to therapy. One patient had rectal bleeding and two patients developed a new fistula or abscess, with no need for reintervention in any of them. Conclusion The initial experience with mesenchymal stem cell therapy show promising results in terms of effectiveness and safety in the short term in complex perianal disease. A longer follow-up period is still needed to confirm these promising data.

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.

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.

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.

Efficacy and Safety of Mesenchymal Stem Cells in Treatment of Complex Perianal Fistulas: A Meta-Analysis.

Complex perianal fistula is a highly debilitating and difficult to treat condition. Local mesenchymal stem cell (MSC) therapy for perianal fistula has shown considerable promise but still remains controversial. Therefore, we performed the meta-analysis to evaluate the efficacy and safety of local MSC therapy for complex perianal fistula. PubMed and Embase databases were searched for published randomized clinical trials (RCTs) that reported local MSC therapy for complex perianal fistulas. The effectiveness and safety data analysis was conducted using RevMan5.3. Subgroup analyses were performed based on the characteristics of the studies. Seven RCTs with 730 participants were included. Local MSC treatment showed significantly higher healing rate (HR) of perianal fistulas compared to control (odds ratio (OR) = 2.03; 95% confidence interval (CI) 1.50, 2.74; P < 0.00001). MSCs combined with fibrin glue therapy can improve the HR compared with fibrin glue alone (OR = 3.27; 95% CI 1.15, 9.28; P = 0.03). Subgroup analyses showed that local therapy can improve the HR in patients with perianal fistulas associated with Crohn's disease (CD) (OR = 2.05; 95% CI 1.41, 3.00; P = 0.0002) and cryptoglandular origin (no-Crohn) (OR = 2.98; 95% CI 0.86, 10.29; P = 0.08). The pooled OR for studies that combined reepithelialization of the external opening with pelvic magnetic resonance imaging (MRI) to evaluate the healing of fistulas was 1.77 (95% CI 1.28, 2.45; P = 0.0006). The pooled OR for studies where fistula healing was defined as complete reepithelialization of external openings was 5.92 (95% CI 1.34, 26.15; P = 0.02). Both autologous MSCs (OR = 3.19; 95% CI 1.05, 9.65; P = 0.04) and allogeneic MSCs (OR = 1.97; 95% CI 1.34, 2.91; P = 0.0006) can obtain higher HR for perianal fistula compared with control. The adipose-derived MSC group can obtain higher HR than the control group (OR = 2.29; 95% CI 1.38, 3.79; P = 0.001). There were no significant differences in adverse events (AEs) (OR = 1.06; 95% CI 0.71, 1.59; P = 0.77). None of the adverse events was judged to be related to MSCs. Our study supported that local MSC therapy alone or combined with fibrin glue is safe and efficacious for complex perianal fistula. In the future, more RCTs are needed to confirm this conclusion.

3D-Printed Surgical Steel Curettes for the Treatment of Perianal Fistula.

Need. The diversity of approaches proposed for the treatment of complex perianal fistulas reflects the fact that no method has yet been shown to be fully satisfactory. We believe the successful treatment of this condition is directly proportional to the amount of fibrous tissue that can be removed. Technical solution. We use a kit of small curettes, of different thicknesses and sizes, incorporating spicules that enable the physician to remove fibrous tissue from the fistula tract. The small size and varying thicknesses of the curettes enable them to mould to the curves of the fistula tract and to remove tissue by deroofing from the shallowest to the deepest layers, thus excising the entire fibrous tract. Our hospital has recently incorporated into clinical practice a new model of 3D-printed surgical steel curette, flanked by 2 lateral rings through which the suture is threaded. The central part of the curette contains radially graduated discs, the tips of which perform the debriding action, removing the fibrous tissue from the tract. Proof of concept. By using these curettes in conjunction with our standard technique (plugging the tract with platelet-rich fibrin), we have improved the success rate from 67% to 88%. Next steps. We have contacted several companies with a view to marketing this product. Conclusion. The results obtained are significantly better than those offered by the techniques in current use for the treatment of complex fistulas, without prejudice to outcomes such as anal continence and morbidity and mortality.

Ligation of the Intersphincteric Fistula Tract (LIFT) Technique in the Treatment of Complex Perianal Fistula: Experience of First 50 Cases

Perianal fistula is a common disease and surgery is the only treatment option. Many surgical techniques have been described. Ligation of intersphincteric fistula tract (LIFT) is a sphincter saving surgical technique in which fistula tract is ligated and excised through intersphincteric approach. The aim of study is to present our experience of first 50 LIFT procedures particularly healing rate, recurrence rate and complications from the procedure. This is a prospective observational study started from March 2018 on whom underwent LIFT procedure for primary complex perianal fistula of infective origin at Faridpur Central Hospital and Faridpur Medical College Hospital. In this study, 50 patients (42 male and 8 female) of average age of 39±7.6 years with complex fistula were included. The mean operative time was 34.7±5.67 minutes and most of the fistulas were transsphincteric variety (90%). Median wound healing time was 21.45±6.34 days for intersphincteric wound and 26.78±6.93 days for the external opening of the fistula. Mean follow up period was 10.5 months. Seven patients of our series developed recurrent fistula, making the overall success of 86%. None of the patient in our series developed incontinence. LIFT procedure has the advantage of preservation of anal sphincter, minimal tissue injury, shorter healing time, relatively easy to perform, and high success rate. It's a good choice for treatment of complex perianal fistula.&#x0D; Faridpur Med. Coll. J. Jan 2020;15(1): 3-7

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.

Darvadstrocel for the treatment of complex perianal fistulas

Darvadstrocel (Alofisel) – indicated for the treatment of complex perianal fistulas caused by Crohn's disease – is the first allogeneic stem‐cell therapy to be approved in the EU. This article examines its administration, efficacy and place in therapy.