Fistula Remission Research Articles

P0346 Pouch Fistulas: Experience From a Tertiary Center

Abstract Background Ileoanal pouch-related fistulas (IAPRF) occur in up to 15% of patients with ulcerative colitis (UC) who undergo total proctocolectomy (TPC) with ileal pouch-anal anastomosis (IPAA). This study aimed to describe the frequency, risk factors, and outcomes of IAPRF in a large, single-center cohort of patients. Methods This is a retrospective study of patients who underwent TPC with IPAA at Mount Sinai Hospital between 2007 and 2022. The outcomes of interest were fistula development and remission defined as the resolution of both pain and drainage and closure of all external openings confirmed by imaging. Categorical data were presented as frequencies/percentages and quantitative data as mean ± SD. Associations were tested using chi-squared tests for categorical and Wilcoxon rank-sum for quantitative variables. Results Of the 772 patients who underwent IPAA at Mount Sinai Hospital, 98 (12.7%) developed pouch fistula. Among these, 34 had early-onset fistulas (within 12 months of the final surgical stage) and 64 had late-onset (beyond 12 months of the final surgical stage). The mean time to fistula occurrence was 3.8 months in the early-onset group and 5.1 years in the late-onset group. Of the 98 patients with IAPRF, 108 fistulas were identified, with the most common types being perianal (59.2%), pouch-vaginal (20.4%), enterocutaneous (11.1%), and enteroenteric (6.5%). Patients with early-onset IAPRF had higher rates of postoperative complications, including pelvic sepsis (5% vs. 2%, p=0.018), abscess formation (20% vs. 9%, p<0.001), anastomotic leak (13% vs. 7%, p=0.017), abdominal pain (42% vs. 13%, p<0.001), and fever (47% vs. 29%, p<0.001) compared to those with late-onset IAPRF. In contrast, patients with late-onset IAPRF had higher rates of Crohn’s disease-like pouch inflammation (CDLPI) diagnosis (72% vs. 32%, p<0.001) compared to those with early-onset IAPRF. Fistula remission occurred in 56% of early-onset and 38% of late-onset patients, and the incidence of pouch failure was similar (20.6% early-onset vs. 26.6% late-onset, p=0.53). Conclusion Early-onset fistulas were associated with post-operative complications, while late-onset were linked to CDLPI, highlighting the importance of understanding patient’s surgical history for accurate diagnosis and treatment.

P0535 Crohn’s Anal Fistula - Quality of Life (CAFQOL) for disease control and remission in patients with perianal fistulizing Crohn’s disease: a new standard in assessing clinical outcome?

Abstract Background Perianal Fistulizing Crohn’s Disease (PFCD) has a major impact on quality of life (QOL). QOL improvement is a key clinical goal, whether the aim is surgical repair, or symptom control. This prospective study evaluated the CAFQOL (Crohn’s Anal Fistula-QOL) questionnaire for disease monitoring in PFCD patients. Methods This study included patients with PFCD starting on anti-TNF therapy, mesenchymal stem cell injection, or hyperbaric oxygen therapy followed by surgical closure. We collected patient-reported CAFQOL and IBDQ-32, as well as Fistula Drainage Assessment (FDA), Perianal Disease Activity Index (PDAI) and MRI (MAGNIFI-CD) outcomes at baseline, and at weeks 9, 26, and 52. QOL changes over time were analyzed using a linear mixed-effects model, and correlations between outcomes were assessed using Spearman correlation coefficients. Internal consistency was assessed with Cronbach’s alpha. The underlying structure of CAFQOL was evaluated with exploratory factor analysis (EFA) to identify distinct dimensions of quality of life. Responsiveness of CAFQOL and PDAI were reported in standardized response mean (SRM). Target CAFQOL values at week 52 for patients in complete remission by week 26 (PDAI≤4, MAGNIFI-CD=0) were calculated with a linear mixed-effects model. Receiver Operating Characteristic (ROC) model was used to evaluate CAFQOL in relation to clinical remission (FDA). Results We included 62 patients with a mean CAFQOL of 59.8 (SD 16.4) at baseline (Table 1). CAFQOL showed significant improvement over time, with average improvements of 8 points (95% CI 4 – 11) at week 9, 12 points (95% CI 8 - 16) at week 26, and 22 points (95% CI 18 - 26) at week 52 (all p<0.0001) (Figure 1). CAFQOL was strongly correlated with IBDQ-32 (r = -0.78; p<0.001) supporting convergent validity, while correlations with FDA (r = 0.48; p<0.0001), PDAI (r = 0.33; p=0.131), and MAGNIFI-CD (r = 0.11; p=0.548) were weak to negligible, supporting discriminant validity. A Cronbach’s alpha of 0.80 supported internal consistency. EFA revealed three main factors: social-practical impacts, emotional-mental health impacts, and physical discomfort explaining 53% of the QOL variance. By week 52, SRM of CAFQOL and PDAI were -1.26 and -1.79 respectively, suggesting large effect sizes. CAFQOL ≤ 37 was associated with complete fistula remission (PDAI≤4, MAGNIFI-CD=0), and was able to detect clinical remission with 80% (95% CI: 58–92) sensitivity and 56% (95% CI 39–71) specificity (AUROC=0.735; p=0.0038). Conclusion The CAFQOL is a reliable and consistently responsive tool that captures meaningful changes in quality of life over time regardless of the treatment modality.

Induction and maintenance of mucosal healing in Crohn’s disease with ustekinumab in clinical practice across all care levels in Germany (MUCUS)

The impact of ustekinumab (UST) on mucosal- and fistula healing and extraintestinal manifestations (EIM) in Crohn’s disease (CD) were not fully elucidated in the registration trials. In this prospective, multicenter study (EudraCT number: 2017-005151-83) we evaluated the German label real-world-effectiveness of UST to achieve the primary endpoint of combined clinical and endoscopic response at week 52 and several secondary endpoints. Of 79 screened we enrolled 52 patients (female n = 28, bionaïve n = 13, biologic n = 39). At week 52 (per protocol analysis), 52% (n = 13/25) of patients achieved the primary endpoint [50% (n = 3/6) in the bionaïve, 45.5% (n = 5/11) biologic, 62.5% (n = 5/8 ) multiple biologics cohorts, respectively with age as independent predictor [OR 95% CI 0.933 (0.873, 0.998) p = 0.043], 60% (n = 15/25) achieved endoscopic response [50% (n = 3/6) in the bionaïve, 54.5% (n = 6/11) biologic, 75% (n = 6/8) multiple biologics cohorts, respectively], 36% (n = 9/25) achieved endoscopic remission [50% (n = 3/6) in the bionaïve, 27.3% (n = 3/11) biologic, 37.5% (n = 3/8) multiple biologics cohorts, respectively], 48% (n = 12/25) achieved mucosal healing [50% (n = 3/6) in the bionaïve, 36.4% (n = 4/11) biologic, 62.5% (n = 5/8) multiple biologics cohorts, respectively]. All achieved a fistula response and 33.3% (n = 1/3) in the multiple biologics group fistula remission at week 52. EIM decreased (week 0 28.2% vs. week 52 8%). CRP, FCP, PRO-2, EQ-5D-5L improved throughout. 36 patients (69.2%) experienced ≥ 1 treatment emergent adverse event, in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to UST discontinuation, but no very severe events or deaths. The effectiveness of UST was better than in the registration trials.

A phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn’s Disease

BackgroundPerianal fistulas (PF) affect one-third patients with Crohn’s disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population.MethodsAn open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn’s disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model.ResultsTen patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time.ConclusionsAllogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing.Trial registrationThe study was prospectively registered on Clinical trials registry – India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in.

P700 The efficacy of adalimumab combined with surgery for rectovaginal fistula in Crohn's disease：a single-center retrospective study

Abstract Background To assess the efficacy of adalimumab(ADA)combined with surgery in the treatment of Crohn's disease patients with rectovaginal fistulas. Methods A single-center retrospective study. The baseline data of patients with Crohn’s rectovaginal fistulas who visited the Anorectal Department of the Affiliated Hospital of Nanjing University of Chinese Medicine from January 2020 to July 2022 and accepted ADA combined with surgery treatment were included. Crohn’s disease Activity Index(CDAI), perianal disease activity index(PDAI) and inflammatory parameters, including Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP), were statistically analyzed at weeks0, 48. Follow-up was performed every 8 weeks. The outcomes included clinical response, clinical remission, fistula response, fistula remission, fistula remission under MRI, endoscopic response and endoscopic remission. Results A total of 43 RVF patients were included, 53.4% (23/43) patients were treated with Seton,44.1% (19/43) patients were treated with Advancement flap and 2.3%(1/43) patient was treated with Fecal diversion, with a median follow-up of 11.0 (2.5-15.0) months. After 48 weeks of treatment, CDAI[325(262,397)vs.197(134,396)], PDAI[8(6,9) vs. 5(3,6)], ESR[31(8,50) mm/h vs. 10(4,28)mm/h]and CRP[4.62(0.85, 14.45)mg/L vs.0.5(0.5,2.14)mg/L] were significantly lower than 0 week (Table 1) . CDAI, PDAI, ESR and CRP at the 48th week of treatment were significantly lower than those before treatment (p&amp;lt;0.05). At the last follow-up, 62.7%(27/43) patients achieved clinical response, 30.2%(13/43) achieved clinical remission. Meanwhile 69.7%(30/43) of patients achieved fistula response,32.5%(14/43) achieved fistula remission(Table 2),and 25.5%(11/43) achieved fistula remission under MRI; A total of 37 patients completed endoscopic re-examination, including 54.0% (20/37) of patients with endoscopic response and 24.3%(9/37) with endoscopic remission. Conclusion ADA combined with surgery is effective in the treatment of patients with Crohn’s rectovaginal fistulas.

P882 A Phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn’s Disease

Abstract Background Perianal fistulas affect one-third patients with Crohn’s disease with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells in this population. Methods An open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn’s disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically till 104 weeks, and MRI at 24 and 104 weeks. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with &amp;lt;2cm perianal collection on MRI, and fistula response was decrease in drainage by ≥50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model. Results Ten patients (male:8, mean age:27.4±12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index(P=0.008), Van Assche Index(P=0.008) and improvement in quality-of-life(P=0.001) were observed over time. Conclusion Allogeneic BMSCs are safe and effective for the treatment of PF in CD with significant improvement in clinical severity and radiological healing.

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.

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 &amp;lt; 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.

P707 Real-world Long-term efficacy of ustekinumab in the treatment of Perianal Fistulizing Crohn's disease: Results from a single-center retrospective study

Abstract Background The efficacy of ustekinumab (UST) in treating perianal fistulizing Crohn's disease (PFCD) remains inconclusive. This study aimed to investigate the long-term efficacy and prognostic factors of UST in the treatment of PFCD patients. Methods This is a retrospective single-center analysis of PFCD patients who had at least one year of follow-up and began UST treatment between November 2020 and September 2022. The primary outcome was fistula clinical remission at any time point. Secondary outcomes included fistula clinical response, intestinal clinical remission, and response. Factors associated with long-term fistula clinica remission were screened using the univariate analysis, LASSO regression and extreme gradient boosting (XGBoost) model, and visualized using SHAP. Results A total of 131 patients were included in the study, the mean follow-up was 70.39 weeks. Among these patients, 51 (38.9%), 72 (55.0%), and 82 (62.6%) achieved clinical fistula remission at weeks 24, 52, and the last follow-up, respectively. 111 patients (84.7%) achieved intestinal clinical remission and 119 patients (90.8%) achieved intestinal clinical response. Ninety-one patients (69.5%) had prior exposure to other biologics. This study did not ascertain a significant difference in the outcome of UST for CD between biologics Naïve and biologics Exposure patients. The XGBoost model integrated eight independent variables: Montreal L3, Montreal A2, CDAI, PDAI, ESR, body mass index, simple fistula, and re-operation events. The model revealed a favourable discrimination ability with AUC was 0.798 in the internal cohorts. Conclusion This study defined the effectiveness and eight risk factors of UST in long-term clinical fistula remission in PFCD patients, which is helpful for early identification of UST beneficiaries.

Network meta-analysis: efficacy and safety of treatments for fistulising Crohn's disease.

Fistulas are a debilitating complication of Crohn's disease and treatment options remain limited. There is a lack of head-to-head comparisons between treatments. To our knowledge, this is the first network meta-analysis on the efficacy of medical therapies in achieving fistula remission and maintenance of fistula closure in Crohn's disease. Biomedical databases and the Cochrane Central Registry were searched between 1978 and 2022 for randomized controlled trials (RCTs) reporting on treatments. A network meta-analysis was performed using the frequentist model with pooled relative risks (RRs) and P -scores used to rank treatments. Twenty-five RCTs were included for analysis with 2239 patients included. At the 16-24 week time point, infliximab produced the only statistically significant result with the 5 mg/kg dose proving the most effective [RR, 2.30; 95% confidence interval (CI), 1.40-3.77]. At 44 weeks, ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24-4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06-3.99) and infliximab 5 mg/kg (RR, 1.68; 95% CI, 1.03-2.75) also producing a statistically significant result. Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising Crohn's disease, biologics such as ustekinumab, vedolizumab and adalimumab show promising results.

P615 The safety and efficacy of ustekinumab combined with sphincter-preserving surgery for perianal fistulizing Crohn’s disease:a single-center retrospective study

Abstract Background To assess the clinical efficacy and safety of ustekinumab(UST) combined with sphincter-preserving surgery in the treatment of perianal fistulizing Crohn’s disease(pfCD). Methods A single-center retrospective study. The baseline data of pfCD patients who met the inclusion and exclusion criteria and visited the Anorectal Department of the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2020 to March 2022 were collected. Patients were assessed for fistula response and remission by rectal magnetic resonance image(MRI) and perianal disease activity index(PDAI). Patients' fistula response and remission were assessed by rectal MRI and PDAI. Patients were assessed for clinical response and remission by using Crohn's disease activity Index( CDAI). Patients' anal function was assessed by using the Wexner score. The differences in CDAI,PDAI and inflammatory parameters, including C-reactive protein(CRP) and erythrocyte sedimentation rate(ESR), at 0 week, 8 weeks and 16 weeks were statistically analyzed. Results A total of 64 pfCD patients were included. Fistula response was 23.4% (8 weeks), 40.6% (16 weeks), and 51.6% (follow-up endpoint); fistula remission was 21.9% (follow-up endpoint); fistula MRI remission was 9.3% (follow-up endpoint); clinical response was 68.8% (8 weeks) and 79.7% (16 weeks); and clinical remission was 46.9% (8 weeks) and 59.4% (16 weeks). CDAI, PDAI and inflammatory parameters at the 8th and 16th week of treatment were significantly lower than those before treatment (p&amp;lt;0.05). There was no significant difference in postoperative anal function (p&amp;lt;0.05). The incidence of adverse events was 1.6%. Conclusion UST combined with sphincter-preserving surgery is safe and effective in the treatment of pfCD.This therapy can effectively improve the fistula condition and systemic manifestations.

P642 Network meta-analysis: efficacy and safety of treatments for fistulising Crohn’s disease

Abstract Background Fistulas are a debilitating complication of Crohn’s disease (CD) and treatment options remain limited, with sub-optimal efficacy. It is essential that other treatment options are considered, and there is a lack of head-to-head comparisons between them making positioning treatments challenging. To our knowledge this is the first network meta-analysis to help position all treatments for fistulising CD. Methods MEDLINE, EMBASE, EMBASE classic, the Cochrane central registry and Cochrane Specialised Trial Register were searched between 1978 and 2022 for randomised controlled trials (RCTs) reporting on treatments for fistulising CD. The primary outcomes were the efficacy of medical therapies at achieving fistula remission and maintenance of fistula closure. A network meta-analysis was performed using the frequentist model with pooled relative risks and P scores used to rank treatments, in accordance to PRISMA guidelines [Figure 1]. Results 964 studies were identified with the search criteria, with 28 RCTs after screening included for analysis with a total of 2,239 patients. At the 8 – 12 week end-point, none of the interventions were statistically significant, with tacrolimus ranked first at 4 times better than placebo (RR, 4.56; 95% CI, 0.76 – 27.30) at inducing remission of fistulas [Figure 2]. At the 16 – 24 week time point, infliximab produced the only statistically significant result with the 5mg/kg dose proving most effective (RR, 2.30; 95% CI, 1.40 – 3.77) [Figure 3]. At 44 weeks ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24 – 4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06 – 3.99) and infliximab 5mg/kg (RR, 1.68; 95% CI, 1.03 – 2.75) also producing a statistically significant result [Figure 4]. A limitation of this network meta-analysis is the significant heterogeneity between studies and variations in end-point definition, with certain small numbers in certain intervention groups limiting generalisability. Conclusion Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising CD, other biologics such as ustekinumab and adalimumab may have a role. Future RCTs with standardised end-points are needed to further investigate biologics, especially ustekinumab and adalimumab, head-to-head against infliximab in the treatment of fistulising CD.

Fistula Remission 8 Weeks after Induction of Biologics is an Independent Influencing Factor for Long-term Prognosis in Bio Naïve Patients with Crohn&apos;s Perianal Fistulas

Fistula Remission 8 Weeks after Induction of Biologics is an Independent Influencing Factor for Long-term Prognosis in Bio Naïve Patients with Crohn&apos;s Perianal Fistulas

Relationship between clinical remission of perianal fistulas in Crohn's disease and serum adalimumab concentrations: A multi-center cross-sectional study.

BACKGROUNDCrohn’s disease (CD) is complicated by perianal fistulas in approximately 20% of patients. Achieving permanent fistula closure remains a challenge for physicians. An association between serum anti-tumor necrosis factor-α concentrations and clinical outcomes in patients with CD has been demonstrated; however, little information is available on serum adalimumab (ADA) concentrations and remission of perianal fistulas in such patients.AIMTo study the relationship between serum ADA concentrations and clinical remission of CD-associated perianal fistulas.METHODSThis cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018. At the time of each serum ADA concentration measurement, we collected information about the patients and their fistulas. The primary study endpoint was clinical remission of fistulas defined as the absence of drainage (in accordance with Present’s criteria), with a PDAI ≤ 4, absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center. We also assessed fistula healing [defined as being in clinical and radiological (magnetic resonance imaging, MRI) remission] and adverse events.RESULTSThe study cohort comprised 34 patients who underwent 56 evaluations (patients had between one and four evaluations). Fifteen patients had clinical remissions (44%), four of whom had healed fistulas on MRI. Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not [14 (10-16) vs 10 (2-15) μg/mL, P = 0.01]. Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas [11 (7-14) vs 10 (4-16) μg/mL, P = 0.69]. The adverse event rate did not differ between different serum ADA concentrations.CONCLUSIONWe found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.

OP18 Efficacy and safety of filgotinib for the treatment of perianal fistulizing Crohn’s Disease: Results from the phase 2 DIVERGENCE 2 study

BackgroundTreatment of perianal fistulizing Crohn’s disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412).MethodsPatients (18–75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1–3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn’s Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic.ResultsBaseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%; 90% confidence interval [CI]: 26.0–68.9) than in the PBO group (25.0%; 90% CI: 7.2–52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%; CI: 26.0–68.9] versus PBO [16.7%; CI: 3.0–43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups. ConclusionIn this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.

Ustekinumab is effective for perianal fistulising Crohn's disease: a real-world experience and systematic review with meta-analysis

BackgroundPerianal Crohn’s disease (pCD) is a debilitating complication affecting up to 30% of Crohn’s disease (CD) population, leading to increased morbidity, mortality and decreased quality of life. Despite the growing...

In Silico Preliminary evaluation of Cx601 as new therapeutic approach in hospital clinical paths

Abstract Crohn's disease is a chronic inflammatory bowel disease characterized by transmural inflammation and fistula formation. Perianal fistulas are a common complication of Crohn's disease and are estimated to affect up to 28% of patients in the first two decades after diagnosis, particularly those with colonic disease and rectal involvement. Complex perianal fistulas in Crohn's disease are challenging to treat, severely impair patients' quality of life and cause substantial morbidity. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach, although their high cost is often discouraging. We aimed at assessing the safety and efficacy of this treatment in patients with complex perianal fistulas in patients with Crohn's disease. Therefore, we conducted a meta-analysis in order to evaluate this new therapeutic approach before introducing it as standard of care. We examined 8 studies published in the last 10 years, 5 of which were selected for the final analysis. The primary outcome assessed was the combined fistula remission (clinical + imaging) assessed through the clinical examination and MRI, the control being the traditional medical strategies (ie, antibiotics, immunomodulators and anti-tumour necrosis factor agents). We registered a total of 128 events (lack of remission) in the control group vs 94 in the experimental one (Confidence Interval for OR of 0,12-0,31, P &amp;lt; 0,001). Our “in silico” assessment is reliable, being the introduction of (Cx601) an innovative and effective treatment. Further insights will be provided by the INSPIRE registry, a multinational post-marketing study whose main objective is the evaluation of the real-world clinical effectiveness and safety of (Cx601) in patients affected by Crohn's disease with complex perianal fistulas for a duration of 36 months, to which our University “Federico II” is actively taking part. Key messages Disability reduction is an important goal in cronh therapeutic path of care. Our “in silico” assessment may support the introduction of (Cx601) an innovative and effective treatment.

P286 Ustekinumab for Crohn’s Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, a Nationwide Prospective Observational Cohort Study

Abstract Background Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin (IL)-12 and IL-23. It is registered for the treatment of Crohn’s disease (CD) and ulcerative colitis. We assessed the two-year efficacy and safety of ustekinumab in a real world, prospective cohort of CD patients. Methods CD patients who started ustekinumab in regular care were prospectively enrolled in the nationwide Initiative on Crohn and Colitis Registry. At week 0, 12, 24, 52 and 104, clinical remission (HBI ≤ 4 points), biochemical remission (fecal calprotectin (FC) ≤200 μg/g and/or CRP ≤5 mg/L), peri-anal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. Patients starting therapy less than two years ago were excluded for the current evaluation. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patient with at least two years of follow up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission at week 12, 24, 52 and 104 was 32.3% (81/251), 41.4% (104/251), 39% (97/249) and 34.0% (84/247), respectively. Of the 97 patients in corticosteroid free clinical remission at week 52, 58 (59.8%) were still in corticosteroid-free clinical remission at week 104. In patients with combined clinical and biochemical disease activity at baseline (n=122), the corticosteroid-free clinical remission rates were 23.8% (29/122), 35.2% (43/122), 40.0% (48/120) and 32.8% (39/119) at week 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks was 64.3% and 54.8%, respectively. There were no predictive factors associated with corticosteroid-free clinical remission at week 104 on univariate and multivariate analysis. Most common adverse events were headache, skin reaction and musculoskeletal complaints. Two patients stopped ustekinumab due to an infection after 8 and 30 weeks of treatment (mild fever syndrome and moderate upper airway infection, respectively). The main reason for discontinuing treatment after 52 weeks was loss of response (66.7%). Conclusion Ustekinumab was effective and relatively safe in our real world, prospective cohort of CD patients. After 104 weeks of ustekinumab treatment, one third of patients were in corticosteroid-free clinical remission.

Ustekinuma b for Crohn's Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, a Nationwide Prospective Observational Cohort Study.

Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn's disease [CD]. Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index≤ 4 points], biochemical remission (faecal calprotectin ≤ 200 μg/g and/or C-reactive protein ≤5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104. In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission was 32.3% [81/251], 41.4% [104/251], 39% [97/249] and 34.0% [84/247] at weeks 12, 24, 52 and 104, respectively. In patients with combined clinical and biochemical disease activity at baseline [n = 122], the corticosteroid-free clinical remission rates were 23.8% [29/122], 35.2% [43/122], 40.0% [48/120] and 32.8% [39/119] at weeks 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks in all patients was 64.3% and 54.8%, respectively. The main reason for discontinuing treatment after 52 weeks was loss of response [66.7%]. No new safety issues were observed. After 104 weeks of ustekinumab treatment, one-third of CD patients were in corticosteroid-free clinical remission.

Effectiveness of Infliximab on Deep Radiological Remission in Chinese Patients with Perianal Fistulizing Crohn's Disease.

Information concerning deep radiological healing of perianal fistulas in Chinese patients with CD is limited. The present study aimed to establish the effectiveness of infliximab on CD-related perianal fistulas using magnetic resonance imaging (MRI) and identify predictors of deep radiological remission of fistulas. We retrospectively reviewed patients with CD with draining perianal fistulas treated with infliximab and included only those who underwent clinical assessment and MRI before and after infliximab therapy. Among 178 patients who underwent repeated MRI and clinical assessment, 65.2% had complex fistulas. Post-infliximab therapy, 55.1% of patients with perianal fistulizing CD showed clinical remission and 26.4% presented a clinical response; 38.2% had deep radiological remission, and 34.3% had a partial response based on the Ng score; the Van Assche scores decreased obviously compared with baseline. Prolonged infliximab infusion (18 times) presented higher radiological remission rates in patients with CD with complex fistulas. Concomitant treatment with azathioprine increased the fistula healing rate compared with infliximab alone (50% vs. 36.9%, P < 0.001). Younger age at diagnosis of CD, proctitis and requiring perianal surgery were identified as predictors of poor deep radiological remission of fistulas. Eight of ten patients who stopped infliximab and switched to an alternative agent retained a status of fistula healing in the first year of follow-up. Infliximab induced deep radiological remission of perianal fistulas in Chinese patients with CD. Routine MRI should be used to monitor fistula healing. Patients with younger age at diagnosis of CD, proctitis, and/or requiring perianal surgery should receive combined therapy and careful monitoring.