Complex Perianal Fistulas Research Articles

Collagen Paste Injection in Crohn's Disease Perianal Fistula: Long-term Outcomes of a Pilot, Prospective Cohort Study.

Crohn's perianal fistula represents a challenging condition to treat. Sphincters-preserving surgical techniques are increasingly being adopted as repeated surgical procedures may lead to various degrees of incontinence. This prospective study aims to assess the long-term efficacy of collagen paste application in patients with simple and complex Crohn's perianal fistulas. Patients with Crohn's perianal fistula (simple or complex) and inactive luminal disease were enrolled. The fistula tract was treated by curettage and injection of acellular, porcine dermal collagen paste between 2019 and 2021. The primary endpoint was the clinical healing of the fistula at 12 and 24 months, defined as the absence of suppuration on clinical examination. The trial was preregistered on a public repository (ClinicalTrials.gov; NCT03776825). Fourteen patients were included in the study, ten patients (71%) had complex perianal fistula. All patients underwent previous fistula operations. Nine patients (64%) reached complete clinical remission at 12 months, two patients (14%) had a clinical recurrence six months after surgery, and three patients (21%) at 12 months follow-up. Three relapsed patients presented postoperative abscesses. Twelve patients (86%) were followed up at 24 months, no further clinical recurrences or complications were observed and the complete healing rate was 58%. No continence disturbances were recorded after collagen paste injection. The results suggest that collagen paste injection may represent a safe and effective option for Crohn's perianal fistulas, worth further investigation in larger trials.

Persistence, effectiveness and safety of ustekinumab and vedolizumab therapy for complex perianal fistula in Crohn's disease: The HEAL study from GETECCU

The efficacy of ustekinumab and vedolizumab for treating complex perianal fistula in Crohn's disease has been barely studied. We aimed to assess treatment persistence, clinical remission, and safety of these drugs in this context. Crohn's disease patients who had received ustekinumab or vedolizumab for the indication of active complex perianal fistula, were included. Clinical remission was defined according to Fistula Drainage Assessment Index (no drainage through the fistula upon gentle pressure) based on physicians' assessment. Of 155 patients, 136 received ustekinumab, and 35 vedolizumab (16 received both). Median follow-up for ustekinumab was 27 months. Among those on ustekinumab, 54 % achieved remission, and within this group, 27 % relapsed during follow-up. The incidence rate of relapse was 11 % per patient-year. Multivariate analysis found no variables associated with treatment discontinuation or relapse. Median follow-up time for patients receiving vedolizumab was 19 months. Remission was achieved in 46 % of the patients receiving vedolizumab, and among them, 20 % relapsed during follow-up. The incidence rate of relapse was 7 % per patient-year. Adverse events were mild in 6 % on ustekinumab and 8 % on vedolizumab. Ustekinumab and vedolizumab appear effective, achieving remission in around half of complex perianal fistula patients, with favorable safety profiles.

Validation of a 3D-printed model of cryptoglandular perianal fistulas.

Visualising the course of a complex perianal fistula on imaging can be difficult. It has been postulated that three-dimensional (3D) models of perianal fistulas improve understanding of the perianal pathology, contribute to surgical decision-making and might even improve future outcomes of surgical treatment. The aim of the current study is to investigate the accuracy of 3D-printed models of perianal fistulas compared with magnetic resonance imaging (MRI). MRI scans of 15 patients with transsphincteric and intersphincteric fistulas were selected and then assessed by an experienced abdominal and colorectal radiologist. A standardised method of creating a 3D-printed anatomical model of cryptoglandular perianal fistula was developed by a technical medical physicist and a surgeon in training with special interest in 3D printing. Manual segmentation of the fistula and external sphincter was performed by a trained technical medical physicist. The anatomical models were 3D printed in a 1:1 ratio and assessed by two colorectal surgeons. The 3D-printed models were then scanned with a 3D scanner. Volume of the 3D-printed model was compared with manual segmentation. Inter-rater reliability statistics were calculated for consistency between the radiologist who assessed the MRI scans and the surgeons who assessed the 3D-printed models. The assessment of the MRI was considered the 'gold standard'. Agreement between the two surgeons who assessed the 3D printed models was also determined. Consistency between the radiologist and the surgeons was almost perfect for classification (κ = 0.87, κ = 0.87), substantial for complexity (κ = 0.73, κ = 0.74) and location of the internal orifice (κ = 0.73, κ = 0.73) and moderate for the percentage of involved external anal sphincter in transsphincteric fistulas (ICC 0.63, ICC 0.52). Agreement between the two surgeons was substantial for classification (κ = 0.73), complexity (κ = 0.74), location of the internal orifice (κ = 0.75) and percentage of involved external anal sphincter in transsphincteric fistulas (ICC 0.77). Our 3D-printed anatomical models of perianal fistulas are an accurate reflection of the MRI. Further research is needed to determine the added value of 3D-printed anatomical models in preoperative planning and education.

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

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

Experience in the treatment of complex perianal fistulas in a public hospital. 2018-2022

Introducción: El tratamiento de la fistula perianal compleja es controvertido, requiere de un conocimiento anatómico preciso y de métodos auxiliares de diagnóstico para ofrecer el mejor resultado posible al paciente. Objetivos: Describir la experiencia en el tratamiento de las Fístulas Perianales complejas en un Hospital Público en el periodo 2018 - 2022. Material y Métodos: Estudio observacional descriptivo de corte transversal, no probabilístico de casos consecutivos de pacientes con diagnóstico de fistula perianal compleja ingresados en el servicio de coloproctología del Hospital Nacional de Itauguá en el periodo de enero de 2018 hasta diciembre de 2022, de los cuales 21 cumplen con los criterios de inclusión de fistula perianal compleja. Resultados: De los 21 pacientes, 76% fueron hombres, con una media de edad de 35 años ± 10, el principal motivo de consulta fue secreción anal en 19 pacientes. En cuanto al tipo de fístula se identificó un 81% de fístula transesfinteriana alta, en cuanto al tratamiento, se realizó en un 48% fistulectomìas, en cuanto a las complicaciones, solo en un 10 % de los pacientes se constató recidiva de la fístula que fue tratada con fistulotomía con colocación sedal. Conclusión: La fístula perianal compleja es una patología periorificial poco frecuente, son fundamentales los datos obtenidos por el examen físico y la posibilidad de efectuar estudios complementarios con recursos tecnológicos avanzados para su resolución satisfactoria.

The impact of adipose fat tissue on the pathogenesis of crypto-glandular anal fistula.

<b>Indroduction:</b> Cryptoglandular perianal fistula represents a prevalent benign anorectal condition, primarily addressed through surgical interventions, occasionally posing considerable therapeutic challenges. The associated decline in patient quality of life underscores the significance of effective management. However, the lack of a fully understood pathogenesis complicates the treatment approach. Recent research has proposed the involvement of adipose fat tissue in the inflammatory response and pathogenesis of cryptoglandular anal fistula.<b>Aim:</b> The study aims to characterize the role of adipose fat tissue in the pathogenesis of cryptoglandular anal fistula, with a specific focus on understanding the potential involvement of proinflammatory cytokines in the development of chronic inflammation.<b>Materials and methods:</b> This study involved the characterization of serum levels of inflammatory cytokines and adipose tissue hormones. A total of 35 samples from both simple and complex cryptoglandular perianal fistula cases were collected during surgical procedures.<b>Results:</b> Serum levels of leptin, resistin, IL-1β, and IL-8 were significantly elevated in patients operated on due to complex cryptoglandular perianal fistula when compared to patients with simple fistula. Adiponectin was significantly lowered in samples from complex perianal fistula in comparison to simple fistula.<b>Conclusions:</b> Complex perianal cryptoglandular fistula has a reduced level of anti-inflammatory adipokines i.e. adiponectin, and an increased level of proinflammatory resistin, leptin, IL-1β, and IL-8.

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

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

Role of Adipose Tissue Hormones in Pathogenesis of Cryptoglandular Anal Fistula.

The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.

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

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

OP18 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

Abstract Background Complex perianal fistulas are a serious complication in patients with Crohn’s disease (CD). Darvadstrocel (DVS), a suspension of expanded adult allogeneic adipose-derived mesenchymal stem cells, is approved in Europe and Japan for treatment of complex Crohn’s perianal fistulas (CPF). The global ADMIRE-CD II phase 3 randomized double-blind placebo-controlled study evaluated the efficacy and safety of DVS for treatment of complex CPF. Methods Patients aged 18–75 years with clinically controlled, inactive or mildly active CD and complex CPF (≤2 internal openings [IO] and ≤3 external openings [EOs]) who had an inadequate, or a loss of response to immunosuppressive agents or biologics were included. Patients were randomized 1:1 to receive a local injection of DVS as a single dose (120 x 106 cells/24 mL) or placebo. In all patients, fistula preconditioning included vigorous curettage and seton placement 2–3 weeks before treatment, and seton removal, a further curettage and closure of IOs immediately before treatment. The primary endpoint was combined remission (closure of all treated EOs that were draining at baseline, despite gentle finger compression, and absence of collections >2 cm confirmed by MRI) at 24 weeks. Secondary endpoints included combined remission at 52 weeks, clinical remission (closure of all treated EOs without MRI confirmation) at 24 and 52 weeks, and time to clinical remission at 24 weeks. Safety was monitored up to 52 weeks. Results From 19 Oct 2017 to 26 Jul 2023, 568 patients received DVS (n = 283) or placebo (n = 285) with fistula preconditioning; 56.3% of patients enrolled in Europe and Israel, and 43.7% in North America. Mean (SD) age, sex and race were similar in the DVS and placebo arms (38.4 [11.9] vs 37.7 [10.8] years; 42.8% vs 45.6% female; 85.9% vs 89.1% White). Combined remission rates at 24 weeks did not statistically differ between treatments (48.8% DVS vs 46.3% placebo) and there were no differences in secondary endpoints (Table 1; Figure 1). Based on health authority guidelines, post hoc analyses of patients randomized before COVID-19 (11 March 2020; n = 141 DVS, n = 143 placebo) were performed: combined remission rates at 24 weeks were 46.8% (DVS) and 38.5% (placebo). The safety profile for DVS was consistent with prior studies with no new safety signals (Table 1). Conclusion The efficacy outcomes assessed did not statistically differ between DVS and placebo, and the placebo response rate (with fistula preconditioning) was higher than expected. Post hoc analyses revealed lower placebo response rates in patients randomized before COVID-19 (similar to the pivotal ADMIRE CD I study) than the overall placebo arm. DVS was well tolerated.

P402 Early diagnosis of Crohn’s disease with perianal lesions as first clinical symptom: Development and validation of a new MR imaging-based model disease

Abstract Background Early diagnosis is crucial for the treatment and prognosis of Crohn's disease. Perianal fistulae or abscesses may present as the initial manifestation of Crohn's disease (CD) in patients. Despite magnetic resonance imaging (MRI) is the gold standard for the clinical assessment of perianal fistulae, there is shortage of MRI properties for clinical use in early perianal fistula diagnosis in CD. Methods Data from patients with a definitive diagnosis of PFCD and cryptoglandular disease (CGD) between September 2013 and December 2020 were examined retrospectively. The data was splited into training and test sets at a 7:3 ratio. The MRI characteristics were reviewed by two gastroenterology radiologists in consensus. The characteristics were then used to train a random forest classification model to predict a diagnosis of PFCD. The validity of the model was assessed using the area under the receiver operating characteristic curve (AUROC) and confusion matrix. Predictor importance was determined using the Shapley additive explanation (SHAP) framework. Results A total of 144 patients diagnosed with PFCD and 406 patients diagnosed with CGD were included. Utilizing the Boruta algorithm, 12 significant features which confirmed important for the diagnosis of PFCD, and a random forest classification model was developed. The model demonstrated an area under the receiver operating characteristic curve (AUROC) of 0.9294 (95% CI: 0.8706-0.9882), an accuracy of 0.9515 (95% CI: 0.9067-0.9788) and a kappa of 0.8779. SHAP values was utilized to estimate the variable importance, and the top five features were ulceration in rectal wall, thickened rectal wall, T2 hyperintensity, submucosal fistula and age. The model for predicting PFCD diagnosis based on MRI was dynamically visualised using a web display approach (https://doctoryang1971.shinyapps.io/forceplot/). Conclusion We have developed a multi-modal visual dynamic prediction model that can be effectively used to guide the early diagnosis of patients with Crohn's disease who present with perianal fistula at their first clinical visit. PFCD is likely to originate as transmural ulcers leading to submucosal inflammation or fistulae before penetrating the anal sphincter and developing into complex perianal fistulae.

DOP66 INSPIRE: Preliminary data from an observational post-marketing registry on the effectiveness and safety of darvadstrocel in patients with Crohn’s Disease and complex perianal fistulas

Abstract Background Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF). INSPIRE (EUPAS24267) is a European observational post-approval study evaluating real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months. Here we report preliminary clinical and safety outcomes from INSPIRE. Methods Patients with complex CPF who had received DVS according to local standard practice were eligible to enrol. Clinical response (closure of ≥50% of external openings [EOs]) and clinical remission (closure of all EOs) of DVS-treated fistulas that were draining at baseline, were evaluated in the all-treated (AT; received ≥1 dose of DVS with an evaluation for fistula response after 6 months) and per-protocol (PP; received DVS as per label-approved guidelines) cohorts. Treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were reported for the safety cohort (all patients treated with DVS). Results As of April 2023, 652 patients had enrolled (Table 1). Complete data to evaluate 12-month clinical response and remission were available for 134 (AT cohort) and 124 (PP cohort) patients, of whom 79.9% (AT, n = 107) and 79.8% (PP, n = 99) had a clinical response and 76.1% (AT, n = 102) and 76.6% (PP, n = 95) had clinical remission (Figure 1). From baseline to Month 12, there was a decrease in the mean (standard deviation [SD]) Perianal Disease Activity Index score (–3.5 [3.3]; n/N = 96/302 and –3.7 [3.2]; n/N = 89/249) and a decrease in the mean (SD) Harvey–Bradshaw Index for Crohn’s disease activity (-0.3 [2.8]; n/N = 102/302 and -0.4 [2.9]; n/N = 95/249) in the AT and PP cohorts, respectively. Complete safety data were available for 619 patients (median [min–max] follow-up 480 [6–1595]) days. Overall, 26% (n = 162) had ≥1 TEAE and 10% (n = 63) ≥1 serious TEAE. The most frequent TEAEs were anal abscess (6.9%), COVID-19 (1.9%) and proctalgia (1.1%). No deaths were reported. One breast cancer lymph node metastasis and one ovarian epithelial cancer were reported; both events were confounded by immunosuppressant treatment and were not considered related to DVS treatment. Conclusion These preliminary data are consistent with the pivotal ADMIRE-CD study and demonstrate a single dose of DVS in patients with complex CPF is associated with positive clinical outcomes in up to 80% of patients, and a favourable safety profile, both of which are maintained after 12 months. The inherent limitations of registry-based studies mean these data should be interpreted with caution. However, the ongoing INSPIRE study will provide longer follow-up data to confirm these observations with respect to any study limitations.

P764 Darvastrocel in Treatment of 152 Patients with Perianal Crohn's Disease - Observational Study

Abstract Background Complex perianal fistulas significantly affect quality of life and treatment costs in patient with Crohn's disease (CD). Application of adult allogeneic expanded adipose-derived mesenchymal stem cells (Darvastrocel, Takeda Pharmaceuticals) represents novel treatment modality for this challenging condition. The aim of this study was to examine the long-term effects of Darvastrocel (DVS) in patients with complex perianal fistula associated with Crohn’s disease. Methods The study was conducted at two Czech medical facilities (NH Hospital, Horovice and ISCARE, Prague). All consecutive CD patients with complex perianal fistula (up to 2 internal and 3 external openings) treated by the same team with DVS between August 2019 and July 2023 were enrolled into the study and followed prospectively. All fistulas persist despite previous biologic and surgical treatment. The technique of DVS application was based on the ADMIRE CD study protocol and was in accordance with SPC. Fistula tract was curetted, internal opening closed and leak test performed under GA. DVS was applied below the internal opening and along the fistula tract subsequently. Perianal area was then assessed at week 3, month 3 and 6 and then every year postoperatively. Results In total, 152 patients (53.9% male, 46.1% female) with median age of 36.6 (20-72) years were enrolled (tab. 1). Primary success rate detected within the period of 19.8 (4.2-50.2) months after application was 80.3% (122 patients). Fistula recurred in 9 patients (at the site of original fistula in 6 and in a new location in 3 cases), resulting in a sustained healing rate of 74.3% (113 patients) observed within average of 27.2 months. The Perianal Crohn's Disease Index was significantly lower 3, 6, and 12 months after application in the healed compared to failed group - 1 (0-9), 0 (0-8) and 0 (0-9) vs. 7 (1-13, 8 (0-12) and 6 (0-12), p<0.005. Postoperatively, 48 patients (31.6%) were prescribed antibiotics due to inflammatory changes in perianal area. Out of 122 healed patients 31 (25.4%) received antibiotics for 17 (5-37) days, while 17 (56,6%) patients with treatment failure were treated for 16 (7-70) days. Conclusion This real-life study showed that Darvastrocel is highly effective in treatment of complex perianal Crohn’s disease resistant to conservative and surgical management. Moreover, for some patients (anal stricture, chronic changes in anorectum) this may be the only available therapeutic option. Intermittent antibiotic treatment did not affect long-term outcomes. We consider clinical response (crucial for the patient's quality of life) sufficient for predicting sustained long term remission.

P967 Allogeneic bone marrow-derived mesenchymal stromal cell therapy for complex perianal and rectovaginal fistulas in Crohn´s disease: a retrospective single-centre study

Abstract Background Perianal fistulising Crohn´s disease (CD) is associated with a high burden of disease and treatment of fistulas remains challenging. Promising data on short-term efficacy of bone marrow-derived mesenchymal stromal cell (bmMSC) treatment emerged in the recent past, but there is limited data regarding long-term efficacy and safety. Methods Between February 2013 and January 2016, patients with non-active CD (Harvey-Bradshaw Index < 5) and draining complex, treatment-refractory perianal or rectovaginal fistulas underwent local bmMSC therapy as compassionate use. After curettage of the fistula tract, patients received three local bmMSC injections biweekly with 20 million cells each. In case of incomplete clinical and radiological healing 3 to 12 months after the first treatment, up to six additional injections with 40 million cells each were administrated, resulting in a maximal cumulative dose of 300 million bmMSC (table 1). We retrospectively analysed patient records for disease course and documentation of adverse events. Clinical remission was defined by closure of external fistula openings without discharge at digital pressure. The modified Van Assche index was assessed before bmMSC treatment as well as in short- and long-term MRI follow-up. Results Six female patients (median age 35 years, range 19 – 46 years) with two or three complex fistulas each were included. In total, 13 fistulas (9 transsphincteric, 2 extrasphincteric and 2 rectovaginal) underwent local bmMSC application (table 1). Median radiological and clinical follow up was 80 months (range, 44 – 98 months) after first local bmMSC injection. 8 of 13 fistulas (62%) exhibited complete closure at last observation. For rectovaginal fistulas, long-term remission was 50 % (1 of 2). Excluding rectovaginal fistulas, 4 of 6 patients (67%) showed long-term closure of all other fistulas. Pelvic MRI showed a decrease in modified Van Assche index from baseline (median score 7.8, range 6.2-9.7) to long-term follow up (median score 2.1, range 1.5-11.7). No immediate adverse events related to bmMSC injections were observed. One patient (p1) was diagnosed with a local adenocarcinoma of the rectum (pT1, pN0, R0) 106 months after first bmMSC injection. MRI control 11 months prior showed complete fistula remission. The tumor exhibited a female karyotype, while bmMSC had been derived from a male volunteer. Conclusion More than 60% of all treatment-refractory CD perianal fistulas showed long-term remission up to 8 years after local allogenic bmMSC therapy.

Mesenchymal stem cell therapy for Crohn's perianal fistula-a real-world experience.

Remission rates of medically and surgically treated complex perianal fistulas in Crohn's disease are low. Recently, trials have demonstrated the potential for long-term remission with local injection of allogeneic adipose-derived mesenchymal stem cells (darvadstrocel). Our aim was to analyse outcomes from our real-world experience with this new treatment. All patients with Crohn's disease suffering complex perianal fistulas who consecutively underwent administration of darvadstrocel at two centres were followed up and evaluated. Patients were assessed for clinical remission, response, failure, and any complications during follow-up. The results of all patients with a minimum of 3 months' follow-up are presented. Thirty-three patients with Crohn's disease and complex perianal fistulas were included. Of these, 20 (61%) experienced clinical remission that was maintained for a mean follow-up of 14 (3-32) months. A total of 24 of 33 (73%) experienced at least 3 months of clinical remission, with four later having recurrence (3-12 months). Among the remaining nine patients who did not experience clinical remission, two (6%) had partial remission (such as one of two fistulas closing), two (6%) showed signs of response but not remission, and five (15%) showed no signs of healing. The mean time to maintained clinical remission was 6 weeks (range 2 weeks to 6 months), and there were no severe adverse events. In this real-world experience, treatment of Crohn's disease complex perianal fistulas with darvadstrocel had a 61% success rate for maintained clinical remission.

Extrapulmonary Tuberculosis – a Rare Cause of Difficult Evolution in a Case Of Extensive Anoperianal Suppuration

Extrapulmonary tuberculosis is very rare, representing around 15% of all tuberculosis (TB) cases. Intestinal localization of extrapumonary TB occurs in 1% of the cases and is usually associated with HIV infection. The last portion of the ileum and the ileocecal region are most frequently involved, while perianal localization is extremely rare and has clinical and paraclinical aspects similar to Crohn’s disease, thus leading to difficulties in establishing the diagnosis. We present the case of a 41-year-old patient who came to the proctology department with perianal pain and purulent discharge. He was diagnosed by clinical examination and colonoscopy with multiple simple and complex perianal fistulas complicated with a supralevator abscess. Multiple biopsies were taken and the result was necrotizing granulomatous inflammation. The Ziehl-Neelsen test confirmed the suspicion of perianal TB.

Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up

Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI-9.0 to-4.0, p=0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI-3.9 to-0.6, p=0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p=0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant2018.

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

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

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

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

Allogenic stem cells for Crohn's anal fistulas: Treating early improves the deep remission rate.

The aim of this study was to evaluate the real-life clinical and radiological efficacy of darvadstrocel injection into complex perianal fistulas in Crohn's disease. Secondary endpoints were to assess symptomatic efficacy, adverse effects and factors associated with complete combined clinical-radiological response (deep remission). After marketing the product in France, all first patients treated consecutively were included. A complete clinical response was defined by a complete closure of all external openings with no discharge on pressure. A complete radiological response (MRI), evaluated at least after six months of follow-up, was defined by a completely fibrotic sequela without abscess. A deep remission was defined as the association of a complete clinical response with a complete radiological response. A total of 43 patients were included (M/F: 22/21, median age 37 [26-45] years). The fistulas were already drained with seton(s) and were on biologic treatment. After a median follow-up of 383 (359-505) days, 28 (65%) patients showed a clinical response (22 complete and 6 partial) and 16 (37%) achieved a deep remission. The Perineal Disease Activity Index decreased significantly after treatment: 39 (91%) patients reported symptomatic improvement in terms of discharge, pain, and induration, and 28 (65%) no longer had any perineal symptoms. No severe adverse events were reported. A short history of Crohn's disease <3 years was significantly associated with deep remission (OD 4.5 [1.0-19.1], p = 0.04). Darvadstrocel injection resulted in a clinical response for two thirds of patients and deep remission for one third. A shorter duration of Crohn's disease was associated with deep remission.