Closing the internal opening with a rectal advancement flap increases the efficacy of mesenchymal stem-cell injection for complex Crohn's disease anal fistulas

Closing the internal opening with a rectal advancement flap increases the efficacy of mesenchymal stem-cell injection for complex Crohn's disease anal fistulas | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Closing the internal opening with a rectal advancement flap increases the efficacy of mesenchymal stem-cell injection for complex Crohn's disease anal fistulas Nadia Fathallah, Mohamed Amine Haouari, Amine Alam, Amélie Barré, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4481309/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Techniques in Coloproctology → Version 1 posted 9 You are reading this latest preprint version Abstract Background The efficacy of injections of mesenchymal stem cells (MSC) for anal fistula treatment may be impaired by the persistence of stools passing into the fistula, causing bacterial contamination and a local inflammatory reaction. We aimed to compare remission rates between patients treated by MSC injection with simple sutures and those treated with a rectal advancement flap. Methods This single-center prospective study compared the first patients who underwent internal opening closure with sutures, with the subsequent patients treated with a flap. Complete clinical remission was defined as complete closure of the external opening(s) without pain or discharge, and complete radiological remission was defined as a Magnifi-CD score of 0. Results We compared the first 42 patients who had sutures with the 20 subsequent patients who had an advancement flap. The median follow-up was 15.5 months [8.8–24.9 months]. The cumulative incidence of complete clinical response at M12 was 53.8% [38.1–69.6%] in the suture group versus 93.3% [77.4–100.0] in the flap group ( p < 0.001). The Magnifi-CD score was 0 for 72.7% [39.0%-63.9%]) of patients treated with a flap versus 41.7% [25.5%-59.2%]) of patients treated with sutures ( p = 0.093). Anal incontinence score did not differ between the 2 groups. Practicing an advancement flap was the only significant factor associated with complete clinical remission over time (adjusted HR [95% CI] of 2.6 [1.4–4.9], p = 0.003). Conclusions Complete clinical remission rates following MSC injection are significantly higher for the closure of the internal opening with a rectal flap than for closure with sutures, with no consequences for anal continence. anal fistulas Crohn’s disease stem cells advancement flap clinical and remission quality of life Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Anal fistulas are a real challenge in Crohn's disease. Indeed, this common condition affects at least one in three patients with Crohn’s disease at some point in their illness. In addition, these lesions are often severe, recurrent, and significantly alter the quality of life of patients [ 1 – 3 ]. Finally, despite revolutionary treatments based on anti-TNF agents [ 4 ], long-term remission is still not achieved in many patients [ 5 , 6 ]. Various complementary surgical techniques for closing fistula tracts have been proposed to increase the efficacy of biological treatment [ 7 – 9 ]. However, these various surgical approaches (biological glue injection, plug placement, rectal advancement flap, intersphincteric ligation of the fistulous tract, VAAFT (video-assisted anal fistula treatment), and FiLaC laser (fistula laser closure), etc.) have proved disappointing [ 10 ]. Following the double-blind randomized controlled study ADMIRE-CD [ 11 ], mesenchymal stem cells (MSCs) obtained marketing authorization in Europe in 2020. In France, their use is reimbursed for the treatment of complex anal fistulas caused by Crohn's disease when conventional treatment has failed. They act on damaged tissues through anti-inflammatory, immunomodulatory, and repair mechanisms. Real-life studies remain scarce, with small samples and a relatively short follow-up [ 12 – 18 ]. However, they have generally confirmed the results of the ADMIRE-CD study, and the good safety profile of MSC injections. These results are encouraging, but some patients do not respond to treatment. One possible explanation for treatment failure is the persistence of the passage of stools into the fistulous tract, despite closure of the internal opening with cruciate sutures, as in the ADMIRE-CD study. This passage of stools can lead to continuous microbial contamination, limiting the anti-inflammatory and immunomodulatory action of MSCs. We hypothesized that treatment outcome could be optimized by closing the internal opening with a rectal advancement flap to create a more hermetic seal, thereby improving cure rates. In this study, we compared the results for the treatment of complex anal fistulas in the context of Crohn's disease by injections of allogeneic MSCs of adipocyte origin between the first patients of our series, who underwent classic closure of the internal opening with simple sutures and subsequent patients treated with a flap. Materials and Methods We studied a single-center cohort of consecutive patients with Crohn's disease treated for complex anal fistulas by the injection of allogeneic MSCs of adipocyte origin marketed under the name Darvadstrocel (Takeda Pharmaceuticals). None of the patients opposed inclusion in the study. The study took place between July 2020 and July 2023. The database was frozen at the end of January 2024. The first patients, treated from July 2020 to June 2022, underwent MSC injections with suturing of the internal opening. Subsequent patients, treated from July 2022 to July 2023, underwent internal opening closure with a flap. All patients were managed according to the ADMIRE CD study protocol [ 11 ]. The indication for treatment was validated in a multidisciplinary consultation meeting. Colonic disease, particularly rectal disease, either in remission or mildly active, was required for inclusion in the study. An anoperineal MRI was performed for all patients before MSC injection, to check the quality of drainage. The indication for MSC injection was a fistulous tract with an inflammatory radiological signal (hyperintensity on T2 and enhancement on T1 images after gadolinium injection). All patients underwent surgical exploration under general anesthesia two to three weeks before the injection, to confirm good drainage of the fistula. Surgical procedure All patients underwent surgery under locoregional or general anesthesia on an outpatient basis. The first patients in the series underwent the classic injection protocol: curettage and washing of the fistula tract, closure of the internal opening with several separate sutures, and the injection of 120 million MSCs, half of which were delivered to the internal opening, the other half being delivered to the area around the fistula tract(s). Patients seen later in the series underwent closure of the internal opening with a rectal musculo-mucosal advancement flap and the same MSC injection protocol. Evaluation criteria Patients attended postoperative follow-up visits 1, 3, 6, 12, 24, and 36 months after the procedure (M1, M3, M6, M12, M24, and M36). Patients were evaluated with the Montreal classification for Crohn's disease, the Parks classification for fistulas, the PDAI (Perineal Disease Activity Index) [ 19 ] for anoperineal disease activity, the Jorge and Wexner score [ 20 ] for continence and the CAF-QoL score (Crohn’s Anal Fistula Quality of Life scale) [ 21 ] for quality of life. A control anoperineal MRI was performed 12 months after treatment. The Magnifi-CD radiological score [ 22 ] was calculated for all patients. Primary endpoint The primary endpoint was complete clinical remission at 12 months of follow-up (M12). It was defined as the complete non-catheterizable closure of all external openings with no discharge or pain on pressure. Secondary endpoints The secondary endpoints were: - Predictive factors for complete clinical remission - Complete radiological remission, defined as a Magnifi-CD score of 0. - Symptomatic remission (PDAI) at M12 - Quality of life (CAFQoL) at M12 - Anal continence (Jorge and Wexner score) at M12 - The duration of the surgical procedure (minutes) - Long-term results (up to M36) - The learning curve for the CSM injection technique. Statistical analysis The general characteristics of the patients and their disease were described, together with the type of procedure (sutures or flap). Continuous variables (age, BMI, scores, duration, etc.) are presented as the mean and standard deviation, or as the median and range or interquartile range, depending on the normality or non-normality of the distribution (verified by a Shapiro-Wilk test). Statistical comparisons were performed with Student's t tests or their non-parametric equivalent (Mann-Whitney U tests). Binary and qualitative variables are presented as numbers and percentages and were compared in Pearson’s chi-squared tests. The primary and continuous secondary endpoints were analyzed as indicated above. Binary criteria (success/failure) were analyzed by calculating their rate, with estimation of the confidence interval by the Clopper-Pearson method and comparisons in Fisher's exact tests. Long-term clinical remission was analyzed by univariate and multivariate Cox regression analysis (with a stepwise selection algorithm for Cox regression). The results of this test are illustrated graphically as an incidence curve, with Gray’s test used to compare the curves. The alpha risk for statistical tests was set to 5% and 95% confidence intervals were calculated. All statistical and graphical analyses were conducted with R software (v4,3,2), with the ‘survival’ and ‘ggplot2’ packages. Ethics The study protocol was approved by the local ethics committee of the Paris Saint-Joseph Hospital Group (IRB number 00012157) and was registered with clinicaltrials.gov (NCT05177003). Results Study population We included 68 consecutive patients in this study. None of the patients refused participation. The first 42 patients had sutures for the internal opening and 20 of the remaining patients underwent internal opening closure with a flap. Six patients underwent no closure procedure due to anal stenosis. The demographic characteristics of the study population and their Crohn's disease are summarized in Table 1 . The characteristics of anoperineal involvement are summarized in Table 2 . Table 1 Characteristics of the study population at inclusion Mean (± SD), n (%) Total population ( n = 68) Sutures ( n = 42) Flap ( n = 20) P Age (years) 38.0 ± 13.8 38.6 ± 12.7 34.9 ± 12.9 0.203 Women 34 (50.0) 21 (50.0) 9 (45.0) 0.923 BMI (kg/m 2 ) 24.7 ± 4.7 25.2 ± 5.1 23.3 ± 3.5 0.262 Active smoker 12 (17.6) 9 (22.5) 2 (10.5) 0.113 Extra-digestive signs 2 (2.9) 2 (4.8) 0 (0.0) 0.551 Duration of Crohn's disease (years) 10 (2; 42) [ 5 – 16 ] 10 (3; 38) [5.25–15.5] 9 (2; 42) [ 4 – 17 ] 0.576 Duration of anoperineal Crohn's disease (years) 10 (2; 42) [ 5 – 16 ] 7 (3; 32) [ 5 – 10 ] 6 (2; 26) [ 4 – 9 ] 0.203 Localization 0.923 Ileal 20 (29.4) 13 (31.0) 6 (30.0) 0.262 Colonic 20 (29.4) 12 (30.0) 5 (25.0) 0.113 Ileo-colonic 23 (33.9) 15 (35.7) 7 (35.0) 0.551 Exclusively anoperineal 5 (7.3) 2 (4.8) 3 (15.0) 0.165 PDAI 6.3 ± 2.4 6.0 ± 2.2 6.4 ± 2.6 0.203 Wexner score 0 (0; 0) [0–16] 0 (0; 0) [0–11] 0 (0; 0) [0–16] 0.165 CAF-QoL 52.1 ± 24.8 54.2 ± 23.8 51.2 ± 20.7 0.576 Table 2 Characteristics of anoperineal involvement Mean (± SD), n (%) Total population ( n = 68) Sutures ( n = 42) Flap ( n = 20) P History of proctological surgery ≥ 3 40 (58.8) 27 (64.3) 11 (55.0) 0.113 History of sphincter-sparing surgery 16 (23.5) 13 (31.0) 3 (15.8) 0.551 Biotherapy 68 (100.0) 42 (100.0) 20 (100.0) 0.165 Infliximab 47 (69.1) 31 (73.8) 12 (60.0) 0.576 Immunosuppressant in combination therapy 51 (75.0) 33 (78.6) 14 (70.0) 0.203 Fistula with more than one external opening 33 (48.5) 18 (42.9) 11 (55.0) 0.923 Principal suprasphincteric tract 4 (5.9) 4 (9.5) 0 (0..0) 0.113 Horseshoe tract 11 (16.2) 5 (11.9) 5 (20.0) 0.262 Supralevator secondary tract 13 (19.1) 7 (16.7) 4 (20.0) 0.165 Anorectovaginal tract 3 (4.4) 2 (4.8) 1 (5.0) 0.551 Ileo-anal anastomosis 3 (4.4) 2 (4.8) 1 (5.0) 0.576 Mean Magnifi-CD score 15.5 ± 4.7 16.4 ± 4.8 13.5 ± 4.5 0.923 Multibranched tract on MRI 40 (58.8) 24 (57.1) 13 (65.0) 0.262 Visible collection < 20 mm on MRI 13 (19.2) 10 (23.8) 2 (10.0) 0.113 The mean duration of anoperineal disease was 10 years old [5–16 years]. More than half the patients had undergone more than three prior operations and prior sphincter-sparing surgery had failed in almost a quarter of the patients. All patients were on biotherapy, mostly infliximab, and in three quarters of the patients were on combination therapy. Approximately half the patients had more than one external opening, and more than half had a multibranched tract. A horseshoe tract was found in 16.2% of patients. Therapeutic results Primary endpoint With a median follow-up of 15.5 months [8.8–24.9 months], the overall complete clinical remission rate at M12 was 63.2% (43/68 patients). We observed early remission, at M1, in 31 of these patients, corresponding to 72.1% of the patients in complete remission at M12. The median follow-up was 21.9 months [11.7–27.4 months] for patients treated with sutures versus 9.7 months [5.4–21 months] for those treated with a flap. At the end of follow-up, 23 (54.8%) in the suture group were in complete clinical remission versus 18 (90.0%) of those in the flap group ( p < 0.001). The cumulative incidence of complete clinical remission at M12 was 53.8% [38.1–69.6] in the suture group versus 93.3% [77.4–100.0] in the flap group (Gray’s test p < 0.001) (Fig. 1). Six patients had an abscess requiring surgical drainage: five from the suture group and one from the flap group. All abscesses occurred early, before the M3 visit. No repeat surgery was performed in the other patients considered to have clinical treatment failure. The pharmacological treatments of these patients were changed ( n = 9), or even stopped if symptoms and quality of life were considered to have improved sufficiently ( n = 10). Secondary endpoints Factors predictive of complete clinical remission Univariate and multivariate analyses including all the demographic data, the characteristics of the disease and fistulas, and the procedure used to close the internal opening showed that only flap creation was significantly associated with complete clinical remission over time (adjusted HR [95% CI]: 2.6 [1.4–4.9], p = 0.003). Complete radiological remission At M12, 52/68 patients underwent follow-up MRI. The mean Magnifi-CD score decreased significantly from 15.5 ± 4.7 at baseline to 5.9 ± 7.0 at M12 ( p < 0.001) (Fig. 2). Half the patients (26/52) had a Magnifi-CD score of 0. The median Magnifi-CD score was 6 [0–12] for patients treated with sutures versus 0 [0–4] for patients treated with flaps ( p = 0.165). A score of 0 was obtained for 15/32 (41.7% [25.5%-59.2%]) patients treated with sutures versus 8/11 (72.7% [39.0%-63.9% ]) patients treated with flaps ( p = 0.093). Symptomatic remission Median PDAI score for all patients decreased significantly from 6.3 ± 2.4 before injection to 1.5 ± 2.6 at M12 ( p < 0.001) (Fig. 3). Median PDAI score at M12 was 0 [0–11] for patients treated with sutures versus 0 [0–0] for patients treated with flaps ( p = 0.048). Quality of life Mean CAFQoL score for all patients was 52.1 ± 24.8 at baseline, decreasing to 19.8 ± 19.9 at M12 ( p < 0.001) (Fig. 4). The median score was 16 [6–35] for patients treated with sutures versus 5 [55 − 12] for patients treated with flaps ( p = 0.159). Anal continence The 3rd quartile Jorge and Wexner anal incontinence score at M12 was 0 for both groups ( p = 0.216). Duration of the procedure The mean duration of the procedure for all patients considered together was 29.5 ± 9.0 min. The median duration (range) [IQR] of the operation was significantly longer for flap creation than for closure by sutures: 37 min (19–55 min) [32–41 min] versus 26 min (12–47 min) [22–32 min] ( p < 0.001). Long-term efficacy of MSC treatment The long-term remission data following MSC injection for our series are summarized in Table 3 and Figs. 1–4. Only patients undergoing closure by sutures were included in this analysis because only this group had a follow-up of more than one year for all patients. Table 3 Long-term efficacy of MSC injection for patients undergoing closure of the internal opening by sutures Mean ± SD, n (%) M24 ( n = 34) M36 ( n = 12) Complete clinical remission 25 (73.5) 10 (83.3) Magnifi-CD score 6.0 ± 7.4 4.7 ± 9.0 PDAI score 1.4 ± 2.9 0.8 ± 1.8 CAF-QoL score 13.4 ± 17.3 5.5 ± 1.3 Learning curve Finally, there was no difference ( p = 0.697) in the results obtained for closure by sutures between the three consecutive years 2020, 2021, and 2022 (Fig. 5). Discussion In our series, patients treated by MSC injection with closure of the internal opening by a rectal advancement flap had a complete clinical remission rate of 90% after 9.7 months of follow-up. This rate was significantly higher than that in patients undergoing closure of the internal opening by simple sutures (54.8%). This result is encouraging because the complete clinical remission rate was only 59% after 52 weeks of follow-up in the ADMIRE randomized controlled trial [ 11 ]. Complete clinical remission rate also ranged from 52 to 73% for patients similar to ours in open studies published since the marketing of MSCs for this indication [ 12 – 18 ]. It was much lower in the ADMIRE CD 2 study (43.1% at 52 months) [ 23 ]. The complete radiological cure rate was 72.1% for flap-treated patients. This rate did not differ significantly from that in patients treated with sutures (41.7%), possibly because the sample size was too small. Indeed, this rate is high and the combined clinical-radiological cure rate is higher than in any previous study [ 11 , 14 , 24 – 25 , 17 – 18 ]. The symptoms and quality of life of our patients improved significantly after treatment, as shown in a previous study by our group [ 17 ]. In the study described here, the improvement was numerically greater for patients treated with a flap, but significance was reached only for the PDAI, not the CAF-QoL, probably due to a lack of power. There was no significant change in Jorge and Wexner score after treatment. This result is of particular importance because continence disorders have been reported as sequelae in 9 to 13% of cases after the creation of a musculo-mucosal advancement flap [ 26 ]. The mean duration of the flap procedure was significantly longer than that of the suture procedure, as expected. However, the mean difference was only 11 minutes, which is modest in view of the clinical benefit. We observed a maintenance of clinical remission after MSC injection at M36 for 82.4% of patients with complete closure at M12. In addition to the long-term prospective clinical evaluation, these patients also underwent radiological, symptomatic, and quality-of-life evaluations, with positive results in each case. No other real-life study has reported results with such a long period of complete follow-up after a single MSC injection. Finally, we observed no learning curve in terms of the technique or therapeutic indications that could have accounted for the difference in clinical efficacy between the two groups. Indeed, our results for suturing of the primary opening were similar at the start of the study in 2020 and after three years of using this technique. This study has several limitations, including the limited number of patients, the absence of randomization, the shorter follow-up period for patients treated by the flap technique, the absence of a third arm of patients treated only with a flap and the small number of patients with long-term follow-up. However, 72.1% of patients in remission at M12 were already in remission at M1 and all patients who underwent surgery for an abscess did so during the first three months of follow-up. Furthermore, we considered including a third arm of patients who had undergone a simple rectal advancement flap without MSC injection in the analysis. However, in the absence of randomization, this analysis would have been biased. Indeed, at our center, the patients selected for simple flap procedure are those with a completely fibrous fistulous tract without inflammatory enhancement on MRI, whereas clear signs of inflammation are an essential criterion for the injection of MSCs. In conclusion, this study argues for optimization of the closure of the internal opening by a rectal musculo-mucosal advancement flap rather than simple sutures. We believe that this closure technique should now be adopted as the gold standard for closing the internal opening of complex Crohn's disease anal fistulas treated by MSC injection. Abbreviations MSC: mesenchymal stem cells MRI: magnetic resonance imaging PDAI: Perianal Disease Activity Index CAF-QoL: Crohn’s Anal Fistula-Quality of Life scale BMI: body mass index CRP: C-reactive protein M0: month 0, inclusion M1, M3, M6, M12, M24, M36: months of follow-up Declarations Competing Interests Nadia Fathallah and Vincent de Parades: Takeda company: grants and research support, consultantThe other authors have no conflicts of interest to declare. Author Contribution Nadia Fathallah collected data and wrote the main manuscript.Mohamed Amine Haouari performed and reread all the MRI scans in the studyAll the other co-authors participated to include patients and to review the final manuscript. Acknowledgement We would like to thank Dr Catarina O’Neill, working in Centro Hospitalar de Lisboa Ocidental-Hospital de Egas Moniz, Gastroenterology in Portugal, for her help in collecting data. Data Availability This article’s data are available at request and can easily be accessed online at REDCap which is a secure web platform generated for the study. References Gecse KB, Sebastian S, Hertogh Gd, Yassin NA, Kotze PG, Reinisch W, Spinelli A, Koutroubakis IE, Katsanos KH, Hart A, van den Brink GR, Rogler G, Bemelman WA. Results of the Fifth Scientific Workshop of the ECCO [II] (2016) Clinical Aspects of Perianal Fistulising Crohn's Disease-the Unmet Needs. J Crohns Colitis 10:758-65. Mahadev S, Young JM, Selby W, Solomon MJ. Quality of life in perianal Crohn's disease: what do patients consider important? (2011) Dis Colon Rectum 54:579-85. 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Hindryckx P, Jairath V, Zou G, Feagan BG, Sandborn WJ, Stoker J, Khanna R, Stitt L, van Viegen T, Shackelton LM, Taylor SA, Santillan C, Mearadji B, D'Haens G, Richard MP, Panes J, Rimola J (2019) Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease. Gastroenterology 157:1233-1244.e5. Serclova Z. Efficacy and safety of darvadstrocel treatment in patients with complex perianal fistulas and Crohn’s Disease: results from the global ADMIRE-CD II phase 3 study. OP18, ECCO 2023. Chambaz M, Verdalle-Cazes M, Desprez C, Thomassin L, Charpentier C, Grigioni S, Armengol-Debeir L, Bridoux V, Savoye G, Savoye-Collet C (2019) Deep remission on magnetic resonance imaging impacts outcomes of perianal fistulizing Crohn's disease. Dig Liver Dis 51:358-63. van Rijn KL, Meima-van Praag EM, Bossuyt PM, D'Haens GR, Gecse KB, Horsthuis K, Snijder HJ, Tielbeek JAW, Buskens CJ, Stoker J (2022) Fibrosis and MAGNIFI-CD Activity Index at Magnetic Resonance Imaging to Predict Treatment Outcome in Perianal Fistulizing Crohn's Disease Patients. J Crohns Colitis 16:708-716. Soltani A, Kaiser AM (2010) Endorectal advancement flap for cryptoglandular or Crohn's fistula-in-ano. Dis Colon Rectum 53:486-95. Additional Declarations Competing interest reported. Nadia Fathallah and Vincent de Parades: Takeda company: grants and research support, consultant The other authors have no conflicts of interest to declare. Cite Share Download PDF Status: Published Journal Publication published 02 Sep, 2024 Read the published version in Techniques in Coloproctology → Version 1 posted Editorial decision: Revision requested 10 Jul, 2024 Reviews received at journal 09 Jul, 2024 Reviews received at journal 07 Jul, 2024 Reviewers agreed at journal 30 Jun, 2024 Reviewers agreed at journal 29 Jun, 2024 Reviewers invited by journal 27 Jun, 2024 Editor assigned by journal 22 Jun, 2024 Submission checks completed at journal 27 May, 2024 First submitted to journal 26 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4481309","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307469925,"identity":"da8aed00-42cd-4250-85c8-3b8d33650003","order_by":0,"name":"Nadia Fathallah","email":"data:image/png;base64,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","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":true,"prefix":"","firstName":"Nadia","middleName":"","lastName":"Fathallah","suffix":""},{"id":307469926,"identity":"e26fd4a1-dde0-4ea2-a3bb-fc5195b03085","order_by":1,"name":"Mohamed Amine Haouari","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"Amine","lastName":"Haouari","suffix":""},{"id":307469927,"identity":"ed4a7772-7779-40fa-85af-c31e527fa662","order_by":2,"name":"Amine Alam","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Amine","middleName":"","lastName":"Alam","suffix":""},{"id":307469930,"identity":"c4e79985-6cf8-4b91-ba5d-58e76a9f854a","order_by":3,"name":"Amélie Barré","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Amélie","middleName":"","lastName":"Barré","suffix":""},{"id":307469931,"identity":"7ec3f795-be64-4b1e-9305-6965882e3d5b","order_by":4,"name":"Déborah Roland","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Déborah","middleName":"","lastName":"Roland","suffix":""},{"id":307469933,"identity":"22235a50-472b-4c9f-bfa0-f370f55212b5","order_by":5,"name":"Lucas Spindler","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Lucas","middleName":"","lastName":"Spindler","suffix":""},{"id":307469934,"identity":"3eb6a77a-88cc-4f76-8c53-d2bca70a7730","order_by":6,"name":"Eric Saf Far","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"Saf","lastName":"Far","suffix":""},{"id":307469935,"identity":"3a4099ce-ba7d-4810-83f4-de09b254e8c8","order_by":7,"name":"Vincent de Parades","email":"","orcid":"","institution":"Hôpital Paris Saint-Joseph","correspondingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"","lastName":"de Parades","suffix":""}],"badges":[],"createdAt":"2024-05-26 20:30:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4481309/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4481309/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10151-024-02990-8","type":"published","date":"2024-09-02T16:04:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58171050,"identity":"e3b993a9-bd61-4330-9d45-e9f8786cc64f","added_by":"auto","created_at":"2024-06-12 03:40:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":632217,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of complete clinical remission\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/5b3ab3de751cc8ee7002bb96.png"},{"id":58171591,"identity":"ed809b30-4d03-40e7-8729-451bbe669a82","added_by":"auto","created_at":"2024-06-12 03:48:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":126977,"visible":true,"origin":"","legend":"\u003cp\u003eChange in mean Magnifi-CD score\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/351bd3ff4c82cd4c55944708.png"},{"id":58171592,"identity":"8a3858e4-0343-4aeb-ac57-031f46fc1a1b","added_by":"auto","created_at":"2024-06-12 03:48:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82015,"visible":true,"origin":"","legend":"\u003cp\u003eChange in median PDAI score\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/952aafbc4942c61f23afbcb5.png"},{"id":58171052,"identity":"cbcd5f53-b7a4-4830-9bcd-b5b41580eef8","added_by":"auto","created_at":"2024-06-12 03:40:17","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":143666,"visible":true,"origin":"","legend":"\u003cp\u003eChange in mean CAFQoL score\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/3725cba8d538b1b38b59ab56.png"},{"id":58171053,"identity":"48a56a6c-2cb0-4482-9967-61f68510ba12","added_by":"auto","created_at":"2024-06-12 03:40:17","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":94615,"visible":true,"origin":"","legend":"\u003cp\u003eRate of complete clinical remission for patients treated with sutures, by year\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/451b94cf300e6bddf4985d3d.png"},{"id":64185653,"identity":"43b1cdf6-7348-4613-84fe-c5071a5788ed","added_by":"auto","created_at":"2024-09-09 16:19:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1521543,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4481309/v1/732dcbd6-bb89-445b-affb-d1a45e45c472.pdf"}],"financialInterests":"Competing interest reported. Nadia Fathallah and Vincent de Parades: Takeda company: grants and research support, consultant\nThe other authors have no conflicts of interest to declare.","formattedTitle":"Closing the internal opening with a rectal advancement flap increases the efficacy of mesenchymal stem-cell injection for complex Crohn's disease anal fistulas","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnal fistulas are a real challenge in Crohn's disease. Indeed, this common condition affects at least one in three patients with Crohn\u0026rsquo;s disease at some point in their illness. In addition, these lesions are often severe, recurrent, and significantly alter the quality of life of patients [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Finally, despite revolutionary treatments based on anti-TNF agents [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], long-term remission is still not achieved in many patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVarious complementary surgical techniques for closing fistula tracts have been proposed to increase the efficacy of biological treatment [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, these various surgical approaches (biological glue injection, plug placement, rectal advancement flap, intersphincteric ligation of the fistulous tract, VAAFT (video-assisted anal fistula treatment), and FiLaC laser (fistula laser closure), etc.) have proved disappointing [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFollowing the double-blind randomized controlled study ADMIRE-CD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], mesenchymal stem cells (MSCs) obtained marketing authorization in Europe in 2020. In France, their use is reimbursed for the treatment of complex anal fistulas caused by Crohn's disease when conventional treatment has failed. They act on damaged tissues through anti-inflammatory, immunomodulatory, and repair mechanisms. Real-life studies remain scarce, with small samples and a relatively short follow-up [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, they have generally confirmed the results of the ADMIRE-CD study, and the good safety profile of MSC injections. These results are encouraging, but some patients do not respond to treatment. One possible explanation for treatment failure is the persistence of the passage of stools into the fistulous tract, despite closure of the internal opening with cruciate sutures, as in the ADMIRE-CD study. This passage of stools can lead to continuous microbial contamination, limiting the anti-inflammatory and immunomodulatory action of MSCs. We hypothesized that treatment outcome could be optimized by closing the internal opening with a rectal advancement flap to create a more hermetic seal, thereby improving cure rates.\u003c/p\u003e \u003cp\u003eIn this study, we compared the results for the treatment of complex anal fistulas in the context of Crohn's disease by injections of allogeneic MSCs of adipocyte origin between the first patients of our series, who underwent classic closure of the internal opening with simple sutures and subsequent patients treated with a flap.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe studied a single-center cohort of consecutive patients with Crohn\u0026apos;s disease treated for complex anal fistulas by the injection of allogeneic MSCs of adipocyte origin marketed under the name Darvadstrocel (Takeda Pharmaceuticals). None of the patients opposed inclusion in the study.\u003c/p\u003e\n\u003cp\u003eThe study took place between July 2020 and July 2023. The database was frozen at the end of January 2024. The first patients, treated from July 2020 to June 2022, underwent MSC injections with suturing of the internal opening. Subsequent patients, treated from July 2022 to July 2023, underwent internal opening closure with a flap.\u003c/p\u003e\n\u003cp\u003eAll patients were managed according to the ADMIRE CD study protocol [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. The indication for treatment was validated in a multidisciplinary consultation meeting. Colonic disease, particularly rectal disease, either in remission or mildly active, was required for inclusion in the study. An anoperineal MRI was performed for all patients before MSC injection, to check the quality of drainage. The indication for MSC injection was a fistulous tract with an inflammatory radiological signal (hyperintensity on T2 and enhancement on T1 images after gadolinium injection). All patients underwent surgical exploration under general anesthesia two to three weeks before the injection, to confirm good drainage of the fistula.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eSurgical procedure\u003c/h2\u003e\n \u003cp\u003eAll patients underwent surgery under locoregional or general anesthesia on an outpatient basis.\u003c/p\u003e\n \u003cp\u003eThe first patients in the series underwent the classic injection protocol: curettage and washing of the fistula tract, closure of the internal opening with several separate sutures, and the injection of 120\u0026nbsp;million MSCs, half of which were delivered to the internal opening, the other half being delivered to the area around the fistula tract(s).\u003c/p\u003e\n \u003cp\u003ePatients seen later in the series underwent closure of the internal opening with a rectal musculo-mucosal advancement flap and the same MSC injection protocol.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eEvaluation criteria\u003c/h2\u003e\n \u003cp\u003ePatients attended postoperative follow-up visits 1, 3, 6, 12, 24, and 36 months after the procedure (M1, M3, M6, M12, M24, and M36).\u003c/p\u003e\n \u003cp\u003ePatients were evaluated with the Montreal classification for Crohn\u0026apos;s disease, the Parks classification for fistulas, the PDAI (Perineal Disease Activity Index) [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e] for anoperineal disease activity, the Jorge and Wexner score [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e] for continence and the CAF-QoL score (Crohn\u0026rsquo;s Anal Fistula Quality of Life scale) [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e] for quality of life.\u003c/p\u003e\n \u003cp\u003eA control anoperineal MRI was performed 12 months after treatment. The Magnifi-CD radiological score [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e] was calculated for all patients.\u003c/p\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003ePrimary endpoint\u003c/h2\u003e\n \u003cp\u003eThe primary endpoint was complete clinical remission at 12 months of follow-up (M12). It was defined as the complete non-catheterizable closure of all external openings with no discharge or pain on pressure.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eSecondary endpoints\u003c/h2\u003e\n \u003cp\u003eThe secondary endpoints were:\u003c/p\u003e\n \u003cp\u003e- Predictive factors for complete clinical remission\u003c/p\u003e\n \u003cp\u003e- Complete radiological remission, defined as a Magnifi-CD score of 0.\u003c/p\u003e\n \u003cp\u003e- Symptomatic remission (PDAI) at M12\u003c/p\u003e\n \u003cp\u003e- Quality of life (CAFQoL) at M12\u003c/p\u003e\n \u003cp\u003e- Anal continence (Jorge and Wexner score) at M12\u003c/p\u003e\n \u003cp\u003e- The duration of the surgical procedure (minutes)\u003c/p\u003e\n \u003cp\u003e- Long-term results (up to M36)\u003c/p\u003e\n \u003cp\u003e- The learning curve for the CSM injection technique.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eThe general characteristics of the patients and their disease were described, together with the type of procedure (sutures or flap). Continuous variables (age, BMI, scores, duration, etc.) are presented as the mean and standard deviation, or as the median and range or interquartile range, depending on the normality or non-normality of the distribution (verified by a Shapiro-Wilk test). Statistical comparisons were performed with Student\u0026apos;s \u003cem\u003et\u003c/em\u003e tests or their non-parametric equivalent (Mann-Whitney \u003cem\u003eU\u003c/em\u003e tests). Binary and qualitative variables are presented as numbers and percentages and were compared in Pearson\u0026rsquo;s chi-squared tests.\u003c/p\u003e\n \u003cp\u003eThe primary and continuous secondary endpoints were analyzed as indicated above. Binary criteria (success/failure) were analyzed by calculating their rate, with estimation of the confidence interval by the Clopper-Pearson method and comparisons in Fisher\u0026apos;s exact tests. Long-term clinical remission was analyzed by univariate and multivariate Cox regression analysis (with a stepwise selection algorithm for Cox regression). The results of this test are illustrated graphically as an incidence curve, with Gray\u0026rsquo;s test used to compare the curves.\u003c/p\u003e\n \u003cp\u003eThe alpha risk for statistical tests was set to 5% and 95% confidence intervals were calculated. All statistical and graphical analyses were conducted with R software (v4,3,2), with the \u0026lsquo;survival\u0026rsquo; and \u0026lsquo;ggplot2\u0026rsquo; packages.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eEthics\u003c/h2\u003e\n \u003cp\u003eThe study protocol was approved by the local ethics committee of the Paris Saint-Joseph Hospital Group (IRB number 00012157) and was registered with clinicaltrials.gov (NCT05177003).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003eStudy population\u003c/h2\u003e\n \u003cp\u003eWe included 68 consecutive patients in this study. None of the patients refused participation. The first 42 patients had sutures for the internal opening and 20 of the remaining patients underwent internal opening closure with a flap. Six patients underwent no closure procedure due to anal stenosis.\u003c/p\u003e\n \u003cp\u003eThe demographic characteristics of the study population and their Crohn\u0026apos;s disease are summarized in Table \u003cspan\u003e1\u003c/span\u003e. The characteristics of anoperineal involvement are summarized in Table \u003cspan\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv align=\"char\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eCharacteristics of the study population at inclusion\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean (\u0026plusmn;\u0026thinsp;SD), \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal population (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSutures\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFlap\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.0\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eActive smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (22.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExtra-digestive signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.551\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of Crohn\u0026apos;s disease (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (2; 42)\u003c/p\u003e\n \u003cp\u003e[\u003cspan\u003e5\u003c/span\u003e\u0026ndash;\u003cspan\u003e16\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (3; 38) [5.25\u0026ndash;15.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (2; 42)\u003c/p\u003e\n \u003cp\u003e[\u003cspan\u003e4\u003c/span\u003e\u0026ndash;\u003cspan\u003e17\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDuration of anoperineal Crohn\u0026apos;s disease (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (2; 42)\u003c/p\u003e\n \u003cp\u003e[\u003cspan\u003e5\u003c/span\u003e\u0026ndash;\u003cspan\u003e16\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (3; 32)\u003c/p\u003e\n \u003cp\u003e[\u003cspan\u003e5\u003c/span\u003e\u0026ndash;\u003cspan\u003e10\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (2; 26)\u003c/p\u003e\n \u003cp\u003e[\u003cspan\u003e4\u003c/span\u003e\u0026ndash;\u003cspan\u003e9\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIleal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eColonic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIleo-colonic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.551\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExclusively anoperineal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePDAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWexner score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0; 0)\u003c/p\u003e\n \u003cp\u003e[0\u0026ndash;16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0; 0)\u003c/p\u003e\n \u003cp\u003e[0\u0026ndash;11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0; 0)\u003c/p\u003e\n \u003cp\u003e[0\u0026ndash;16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCAF-QoL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.1\u0026thinsp;\u0026plusmn;\u0026thinsp;24.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.2\u0026thinsp;\u0026plusmn;\u0026thinsp;23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51.2\u0026thinsp;\u0026plusmn;\u0026thinsp;20.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eCharacteristics of anoperineal involvement\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean (\u0026plusmn;\u0026thinsp;SD), \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal population\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;68)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSutures\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFlap\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistory of proctological surgery\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHistory of sphincter-sparing surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.551\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInfliximab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47 (69.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31 (73.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImmunosuppressant in combination therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14 (70.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFistula with more than one external opening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrincipal suprasphincteric tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0 (0..0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHorseshoe tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSupralevator secondary tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnorectovaginal tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.551\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIleo-anal anastomosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.576\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean Magnifi-CD score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.923\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultibranched tract on MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40 (58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisible collection\u0026thinsp;\u0026lt;\u0026thinsp;20 mm on MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eThe mean duration of anoperineal disease was 10 years old [5\u0026ndash;16 years]. More than half the patients had undergone more than three prior operations and prior sphincter-sparing surgery had failed in almost a quarter of the patients. All patients were on biotherapy, mostly infliximab, and in three quarters of the patients were on combination therapy. Approximately half the patients had more than one external opening, and more than half had a multibranched tract. A horseshoe tract was found in 16.2% of patients.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eTherapeutic results\u003c/h2\u003e\n \u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003ePrimary endpoint\u003c/h2\u003e\n \u003cp\u003eWith a median follow-up of 15.5 months [8.8\u0026ndash;24.9 months], the overall complete clinical remission rate at M12 was 63.2% (43/68 patients). We observed early remission, at M1, in 31 of these patients, corresponding to 72.1% of the patients in complete remission at M12.\u003c/p\u003e\n \u003cp\u003eThe median follow-up was 21.9 months [11.7\u0026ndash;27.4 months] for patients treated with sutures versus 9.7 months [5.4\u0026ndash;21 months] for those treated with a flap. At the end of follow-up, 23 (54.8%) in the suture group were in complete clinical remission versus 18 (90.0%) of those in the flap group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n \u003cp\u003eThe cumulative incidence of complete clinical remission at M12 was 53.8% [38.1\u0026ndash;69.6] in the suture group versus 93.3% [77.4\u0026ndash;100.0] in the flap group (Gray\u0026rsquo;s test \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cp\u003eSix patients had an abscess requiring surgical drainage: five from the suture group and one from the flap group. All abscesses occurred early, before the M3 visit. No repeat surgery was performed in the other patients considered to have clinical treatment failure. The pharmacological treatments of these patients were changed (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9), or even stopped if symptoms and quality of life were considered to have improved sufficiently (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eSecondary endpoints\u003c/h2\u003e\n \u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eFactors predictive of complete clinical remission\u003c/h2\u003e\n \u003cp\u003eUnivariate and multivariate analyses including all the demographic data, the characteristics of the disease and fistulas, and the procedure used to close the internal opening showed that only flap creation was significantly associated with complete clinical remission over time (adjusted HR [95% CI]: 2.6 [1.4\u0026ndash;4.9], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eComplete radiological remission\u003c/h2\u003e\n \u003cp\u003eAt M12, 52/68 patients underwent follow-up MRI. The mean Magnifi-CD score decreased significantly from 15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 at baseline to 5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0 at M12 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;2). Half the patients (26/52) had a Magnifi-CD score of 0.\u003c/p\u003e\n \u003cp\u003eThe median Magnifi-CD score was 6 [0\u0026ndash;12] for patients treated with sutures versus 0 [0\u0026ndash;4] for patients treated with flaps (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.165). A score of 0 was obtained for 15/32 (41.7% [25.5%-59.2%]) patients treated with sutures versus 8/11 (72.7% [39.0%-63.9% ]) patients treated with flaps (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.093).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\"\u003e\n \u003ch2\u003eSymptomatic remission\u003c/h2\u003e\n \u003cp\u003eMedian PDAI score for all patients decreased significantly from 6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 before injection to 1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 at M12 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;3). Median PDAI score at M12 was 0 [0\u0026ndash;11] for patients treated with sutures versus 0 [0\u0026ndash;0] for patients treated with flaps (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\"\u003e\n \u003ch2\u003eQuality of life\u003c/h2\u003e\n \u003cp\u003eMean CAFQoL score for all patients was 52.1\u0026thinsp;\u0026plusmn;\u0026thinsp;24.8 at baseline, decreasing to 19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;19.9 at M12 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;4). The median score was 16 [6\u0026ndash;35] for patients treated with sutures versus 5 [55\u0026thinsp;\u0026minus;\u0026thinsp;12] for patients treated with flaps (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.159).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\"\u003e\n \u003ch2\u003eAnal continence\u003c/h2\u003e\n \u003cp\u003eThe 3rd quartile Jorge and Wexner anal incontinence score at M12 was 0 for both groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.216).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec19\"\u003e\n \u003ch2\u003eDuration of the procedure\u003c/h2\u003e\n \u003cp\u003eThe mean duration of the procedure for all patients considered together was 29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0 min. The median duration (range) [IQR] of the operation was significantly longer for flap creation than for closure by sutures: 37 min (19\u0026ndash;55 min) [32\u0026ndash;41 min] versus 26 min (12\u0026ndash;47 min) [22\u0026ndash;32 min] (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\"\u003e\n \u003ch2\u003eLong-term efficacy of MSC treatment\u003c/h2\u003e\n \u003cp\u003eThe long-term remission data following MSC injection for our series are summarized in Table \u003cspan\u003e3\u003c/span\u003e and Figs. 1\u0026ndash;4. Only patients undergoing closure by sutures were included in this analysis because only this group had a follow-up of more than one year for all patients. \u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eLong-term efficacy of MSC injection for patients undergoing closure of the internal opening by sutures\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eM24\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eM36\u003c/p\u003e\n \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eComplete clinical remission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25 (73.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMagnifi-CD score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePDAI score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCAF-QoL score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\"\u003e\n \u003ch2\u003eLearning curve\u003c/h2\u003e\n \u003cp\u003eFinally, there was no difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.697) in the results obtained for closure by sutures between the three consecutive years 2020, 2021, and 2022 (Fig. 5).\u003c/p\u003e\n\u003c/div\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eIn our series, patients treated by MSC injection with closure of the internal opening by a rectal advancement flap had a complete clinical remission rate of 90% after 9.7 months of follow-up. This rate was significantly higher than that in patients undergoing closure of the internal opening by simple sutures (54.8%). This result is encouraging because the complete clinical remission rate was only 59% after 52 weeks of follow-up in the ADMIRE randomized controlled trial [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Complete clinical remission rate also ranged from 52 to 73% for patients similar to ours in open studies published since the marketing of MSCs for this indication [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. It was much lower in the ADMIRE CD 2 study (43.1% at 52 months) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe complete radiological cure rate was 72.1% for flap-treated patients. This rate did not differ significantly from that in patients treated with sutures (41.7%), possibly because the sample size was too small. Indeed, this rate is high and the combined clinical-radiological cure rate is higher than in any previous study [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe symptoms and quality of life of our patients improved significantly after treatment, as shown in a previous study by our group [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the study described here, the improvement was numerically greater for patients treated with a flap, but significance was reached only for the PDAI, not the CAF-QoL, probably due to a lack of power.\u003c/p\u003e \u003cp\u003eThere was no significant change in Jorge and Wexner score after treatment. This result is of particular importance because continence disorders have been reported as sequelae in 9 to 13% of cases after the creation of a musculo-mucosal advancement flap [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe mean duration of the flap procedure was significantly longer than that of the suture procedure, as expected. However, the mean difference was only 11 minutes, which is modest in view of the clinical benefit.\u003c/p\u003e \u003cp\u003eWe observed a maintenance of clinical remission after MSC injection at M36 for 82.4% of patients with complete closure at M12. In addition to the long-term prospective clinical evaluation, these patients also underwent radiological, symptomatic, and quality-of-life evaluations, with positive results in each case. No other real-life study has reported results with such a long period of complete follow-up after a single MSC injection.\u003c/p\u003e \u003cp\u003eFinally, we observed no learning curve in terms of the technique or therapeutic indications that could have accounted for the difference in clinical efficacy between the two groups. Indeed, our results for suturing of the primary opening were similar at the start of the study in 2020 and after three years of using this technique.\u003c/p\u003e \u003cp\u003eThis study has several limitations, including the limited number of patients, the absence of randomization, the shorter follow-up period for patients treated by the flap technique, the absence of a third arm of patients treated only with a flap and the small number of patients with long-term follow-up. However, 72.1% of patients in remission at M12 were already in remission at M1 and all patients who underwent surgery for an abscess did so during the first three months of follow-up. Furthermore, we considered including a third arm of patients who had undergone a simple rectal advancement flap without MSC injection in the analysis. However, in the absence of randomization, this analysis would have been biased. Indeed, at our center, the patients selected for simple flap procedure are those with a completely fibrous fistulous tract without inflammatory enhancement on MRI, whereas clear signs of inflammation are an essential criterion for the injection of MSCs.\u003c/p\u003e \u003cp\u003eIn conclusion, this study argues for optimization of the closure of the internal opening by a rectal musculo-mucosal advancement flap rather than simple sutures. We believe that this closure technique should now be adopted as the gold standard for closing the internal opening of complex Crohn's disease anal fistulas treated by MSC injection.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMSC: mesenchymal stem cells\u003c/p\u003e\n\u003cp\u003eMRI: magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003ePDAI: Perianal Disease Activity Index\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCAF-QoL: Crohn\u0026rsquo;s Anal Fistula-Quality of Life scale\u003c/p\u003e\n\u003cp\u003eBMI: body mass index\u003c/p\u003e\n\u003cp\u003eCRP: C-reactive protein\u003c/p\u003e\n\u003cp\u003eM0: month 0, inclusion\u003c/p\u003e\n\u003cp\u003eM1, M3, M6, M12, M24, M36: months of follow-up\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNadia Fathallah and Vincent de Parades: Takeda company: grants and research support, consultantThe other authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eAuthor Contribution\u003c/p\u003e\n\u003cp\u003eNadia Fathallah collected data and wrote the main manuscript.Mohamed Amine Haouari performed and reread all the MRI scans in the studyAll the other co-authors participated to include patients and to review the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe would like to thank Dr Catarina O\u0026rsquo;Neill, working in Centro Hospitalar de Lisboa Ocidental-Hospital de Egas Moniz, Gastroenterology in Portugal, for her help in collecting data.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThis article\u0026rsquo;s data are available at request and can easily be accessed online at REDCap which is a secure web platform generated for the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGecse KB, Sebastian S, Hertogh Gd, Yassin NA, Kotze PG, Reinisch W, Spinelli A, Koutroubakis IE, Katsanos KH, Hart A, van den Brink GR, Rogler G, Bemelman WA. Results of the Fifth Scientific Workshop of the ECCO [II] (2016) Clinical Aspects of Perianal Fistulising Crohn\u0026apos;s Disease-the Unmet Needs. J Crohns Colitis 10:758-65. \u003c/li\u003e\n\u003cli\u003eMahadev S, Young JM, Selby W, Solomon MJ. Quality of life in perianal Crohn\u0026apos;s disease: what do patients consider important? (2011) Dis Colon Rectum 54:579-85.\u003c/li\u003e\n\u003cli\u003eSpinelli A, Yanai H, Girardi P, Milicevic S, Carvello M, Maroli A, Avedano L (2023) The Impact of Crohn\u0026apos;s Perianal Fistula on Quality of Life: Results of an International Patient Survey. Crohns Colitis 360 25;5:otad036. \u003c/li\u003e\n\u003cli\u003eLichtenstein GR, Yan S, Bala M, Blank M, Sands BE (2005) Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn\u0026rsquo;s disease. Gastroenterology 128:862-9.\u003c/li\u003e\n\u003cli\u003eSands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ (2004) Infliximab maintenance therapy for fistulizing Crohn\u0026apos;s disease. N Engl J Med 350:876-85.\u003c/li\u003e\n\u003cli\u003eVuyyuru SK, Solitano V, Narula N, Lee MJ, MacDonald JK, McCurdy JD, Singh S, Ma C, Jairath V (2023) Pharmacological therapies for the management of fistulising Crohn\u0026apos;s disease: A systematic review and meta-analysis. J Crohns Colitis 2:jjad185.\u003c/li\u003e\n\u003cli\u003eAdamina M, Bonovas S, Raine T, Spinelli A, Warusavitarne J, Armuzzi A, Bachmann O, Bager P, Biancone L, Bokemeyer B, Bossuyt P, Burisch J, Collins P, Doherty G, El-Hussuna A, Ellul P, Fiorino G, Frei-Lanter C, Furfaro F, Gingert C, Gionchetti P, Gisbert JP, Gomollon F, Gonz\u0026aacute;lez Lorenzo M, Gordon H, Hlavaty T, Juillerat P, Katsanos K, Kopylov U, Krustins E, Kucharzik T, Lytras T, Maaser C, Magro F, Marshall JK, Myrelid P, Pellino G, Rosa I, Sabino J, Savarino E, Stassen L, Torres J, Uzzan M, Vavricka S, Verstockt B, Zmora O (2020) ECCO Guidelines on Therapeutics in Crohn\u0026apos;s Disease: Surgical Treatment. J Crohns Colitis 14:155-168. \u003c/li\u003e\n\u003cli\u003eMeima-van Praag EM, van Rijn KL, Wasmann KATGM, Snijder HJ, Stoker J, D\u0026apos;Haens GR, Gecse KB, Gerhards MF, Jansen JM, Dijkgraaf MGW, van der Bilt JDW, Mundt MW, Spinelli A, Danese S, Bemelman WA, Buskens CJ (2022) Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy in the treatment of perianal fistulas in Crohn\u0026apos;s disease (PISA-II): a patient preference randomised trial. Lancet Gastroenterol Hepatol 7:617-626.\u003c/li\u003e\n\u003cli\u003eLaland M, Fran\u0026ccedil;ois M, D\u0026apos;Amico F, Zallot C, Brochard C, Dewitte M, Siproudhis L, Peyrin-Biroulet L, Bouguen G (2023) Identification of the optimal medical and surgical management for patients with perianal fistulising Crohn\u0026apos;s disease. Colorectal Dis 25:75-82. \u003c/li\u003e\n\u003cli\u003eFung M, Farbod Y, Kankouni H, Singh S, McCurdy JD (2024) Does combined medical and surgical treatment improve perianal fistula outcomes in patients with Crohn\u0026apos;s disease? A systematic review and meta-analysis. J Crohns Colitis 16:jjae035.\u003c/li\u003e\n\u003cli\u003ePan\u0026eacute;s J, Garc\u0026iacute;a-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Diez MC, Tagarro I, Leselbaum A, Danese S; ADMIRE CD Study Group Collaborators (2018) Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn\u0026apos;s Disease. Gastroenterology 154:1334-1342.e4.\u003c/li\u003e\n\u003cli\u003eCabalzar-Wondberg D, Turina M, Biedermann L, Rogler G, Schreiner P (2021) Allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulas in Crohn\u0026apos;s disease: A case series. Colorectal Dis 23:1444-50.\u003c/li\u003e\n\u003cli\u003eSchwandner O (2021) Stem cell injection for complex anal fistula in Crohn\u0026apos;s disease: A single-center experience. World J Gastroenterol 27:3643-53.\u003c/li\u003e\n\u003cli\u003eFurukawa S, Mizushima T, Nakaya R, Shibata M, Yamaguchi T, Watanabe K, Futami K (2023) Darvadstrocel for complex perianal fistulas in Japanese adults with Crohn\u0026apos;s disease: a phase 3 study. J Crohns Colitis 17:369-378.\u003c/li\u003e\n\u003cli\u003eWhite I, Yanai H, Avni I, Slavin M, Naftali T, Tovi S, Dotan I, Wasserberg N (2024) Mesenchymal stem cell therapy for Crohn\u0026apos;s perianal fistula-a real-world experience. Colorectal Dis 26:102-109.\u003c/li\u003e\n\u003cli\u003eDawoud C, Widmann KM, Czipin S, Pramhas M, Scharitzer M, Stift A, Harpain F, Riss S (2024) Efficacy of cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn\u0026apos;s disease-A prospective nationwide multicenter cohort study. Wien Klin Wochenschr. Wien Klin Wochenschr 136:289-294.\u003c/li\u003e\n\u003cli\u003eFathallah N, Akaffou M, Haouari MA, Spindler L, Alam A, Barr\u0026eacute; A, Pommaret E, Fels A, de Parades V (2023) Deep remission improves the quality of life of patients with Crohn\u0026apos;s disease and anoperineal fistula treated with darvadstrocel: results of a French pilot study. Tech Coloproctol 27:1201-1210.\u003c/li\u003e\n\u003cli\u003eFathallah N, Siproudhis L, Akaffou M, Haouari MA, Landemaine A, Pommaret E, Spindler L, Brochard C, Bouguen G, de Parades V (2023) Allogenic stem cells for Crohn\u0026apos;s anal fistulas: Treating early improves the deep remission rate. Colorectal Dis 25:2170-2176. \u003c/li\u003e\n\u003cli\u003eIrvine EJ (1995) Usual therapy improves perianal Crohn\u0026apos;s disease as measured by a new disease activity index, McMaster IBD Study Group, J Clin Gastroenterol 20:27-32.\u003c/li\u003e\n\u003cli\u003eJorge JM, Wexner SD (1993) Etiology and management of fecal incontinence, Dis Colon Rectum 36:77-97.\u003c/li\u003e\n\u003cli\u003eAdegbola SO, Dibley L, Sahnan K, Wade T, Verjee A, Sawyer R, Mannick S, McCluskey D, Bassett P, Yassin N, Warusavitarne J, Faiz O, Phillips R, Tozer PJ, Norton C, Hart AL (2021) Development and initial psychometric validation of a patient-reported outcome measure for Crohn\u0026apos;s perianal fistula: the Crohn\u0026apos;s Anal Fistula Quality of Life (CAF-QoL) scale. Gut 70:1649-56.\u003c/li\u003e\n\u003cli\u003eHindryckx P, Jairath V, Zou G, Feagan BG, Sandborn WJ, Stoker J, Khanna R, Stitt L, van Viegen T, Shackelton LM, Taylor SA, Santillan C, Mearadji B, D\u0026apos;Haens G, Richard MP, Panes J, Rimola J (2019) Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn\u0026apos;s Disease. Gastroenterology 157:1233-1244.e5. \u003c/li\u003e\n\u003cli\u003eSerclova Z. Efficacy and safety of darvadstrocel treatment in patients with complex perianal fistulas and Crohn\u0026rsquo;s Disease: results from the global ADMIRE-CD II phase 3 study. OP18, ECCO 2023.\u003c/li\u003e\n\u003cli\u003eChambaz M, Verdalle-Cazes M, Desprez C, Thomassin L, Charpentier C, Grigioni S, Armengol-Debeir L, Bridoux V, Savoye G, Savoye-Collet C (2019) Deep remission on magnetic resonance imaging impacts outcomes of perianal fistulizing Crohn\u0026apos;s disease. Dig Liver Dis 51:358-63.\u003c/li\u003e\n\u003cli\u003evan Rijn KL, Meima-van Praag EM, Bossuyt PM, D\u0026apos;Haens GR, Gecse KB, Horsthuis K, Snijder HJ, Tielbeek JAW, Buskens CJ, Stoker J (2022) Fibrosis and MAGNIFI-CD Activity Index at Magnetic Resonance Imaging to Predict Treatment Outcome in Perianal Fistulizing Crohn\u0026apos;s Disease Patients. J Crohns Colitis 16:708-716.\u003c/li\u003e\n\u003cli\u003eSoltani A, Kaiser AM (2010) Endorectal advancement flap for cryptoglandular or Crohn\u0026apos;s fistula-in-ano. Dis Colon Rectum 53:486-95.\u003cstrong\u003e\u003cstrong\u003e\u003cstrong\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"anal fistulas, Crohn’s disease, stem cells, advancement flap, clinical and remission, quality of life","lastPublishedDoi":"10.21203/rs.3.rs-4481309/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4481309/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe efficacy of injections of mesenchymal stem cells (MSC) for anal fistula treatment may be impaired by the persistence of stools passing into the fistula, causing bacterial contamination and a local inflammatory reaction. We aimed to compare remission rates between patients treated by MSC injection with simple sutures and those treated with a rectal advancement flap.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis single-center prospective study compared the first patients who underwent internal opening closure with sutures, with the subsequent patients treated with a flap. Complete clinical remission was defined as complete closure of the external opening(s) without pain or discharge, and complete radiological remission was defined as a Magnifi-CD score of 0.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe compared the first 42 patients who had sutures with the 20 subsequent patients who had an advancement flap. The median follow-up was 15.5 months [8.8\u0026ndash;24.9 months]. The cumulative incidence of complete clinical response at M12 was 53.8% [38.1\u0026ndash;69.6%] in the suture group versus 93.3% [77.4\u0026ndash;100.0] in the flap group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The Magnifi-CD score was 0 for 72.7% [39.0%-63.9%]) of patients treated with a flap versus 41.7% [25.5%-59.2%]) of patients treated with sutures (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.093). Anal incontinence score did not differ between the 2 groups. Practicing an advancement flap was the only significant factor associated with complete clinical remission over time (adjusted HR [95% CI] of 2.6 [1.4\u0026ndash;4.9], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eComplete clinical remission rates following MSC injection are significantly higher for the closure of the internal opening with a rectal flap than for closure with sutures, with no consequences for anal continence.\u003c/p\u003e","manuscriptTitle":"Closing the internal opening with a rectal advancement flap increases the efficacy of mesenchymal stem-cell injection for complex Crohn's disease anal fistulas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-12 03:40:12","doi":"10.21203/rs.3.rs-4481309/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-10T18:16:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-09T06:40:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-07T10:41:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"150390378411146384881863342308148591789","date":"2024-06-30T14:08:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"183000430191417253281706649721403606607","date":"2024-06-29T22:47:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-27T21:12:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-22T19:28:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-28T02:08:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Techniques in Coloproctology","date":"2024-05-26T20:28:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"techniques-in-coloproctology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tcol","sideBox":"Learn more about [Techniques in Coloproctology](http://link.springer.com/journal/10151)","snPcode":"10151","submissionUrl":"https://submission.nature.com/new-submission/10151/3","title":"Techniques in Coloproctology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1b6234c1-f79a-438e-8df5-0ada8a423e3b","owner":[],"postedDate":"June 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-09T16:09:38+00:00","versionOfRecord":{"articleIdentity":"rs-4481309","link":"https://doi.org/10.1007/s10151-024-02990-8","journal":{"identity":"techniques-in-coloproctology","isVorOnly":false,"title":"Techniques in Coloproctology"},"publishedOn":"2024-09-02 16:04:58","publishedOnDateReadable":"September 2nd, 2024"},"versionCreatedAt":"2024-06-12 03:40:12","video":"","vorDoi":"10.1007/s10151-024-02990-8","vorDoiUrl":"https://doi.org/10.1007/s10151-024-02990-8","workflowStages":[]},"version":"v1","identity":"rs-4481309","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4481309","identity":"rs-4481309","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}