Perianal Crohn Research Articles

Knowledge of perianal Crohn's disease among nurses in an Italian tertiary centre

Background: Patients with Crohn's disease can develop anal and perianal lesions, such as fistulas, ulcers, skin tags, perianal abscesses and strictures. Perianal Crohn's disease (PCD) is a condition that has a major impact on patients' quality of life. The multidisciplinary team includes a nurse who manages the patient according to evidence-based medicine. Clinical practice and post-registration training are the way forward for nurses to acquire the skills needed to deliver quality care. Aims: This study explored the assessment of nurses' knowledge of PCD. A cross-sectional survey was used to look at the nurses' knowledge. Methods: The questionnaire was administered over 2 months, between September and October 2019. The questionnaire was anonymous, validated by a panel of experts in the field and consisted of 30 questions to assess knowledge and two questions to assess the need for training. It was directed to 120 clinical nurses in the departments of medicine and abdominal surgery. Results: There were 120 nurses enrolled, and 64.2% of nurses had cared for patients with PCD at least once. The survey showed a fairly low level of knowledge of the diagnostic and therapeutic care pathways for patients affected by PCD. On the other hand, a high need for training and in-depth study of the subject emerged. Conclusion: The nurse, an integral part of the multidisciplinary team, plays an important role in the education of these patients. Nurses' present level of knowledge can certainly be improved thanks to their willingness to undertake training courses or to use information tools.

Placebo Response Rates in Randomized Controlled Trials for Perianal Crohn's Disease: A Systematic Review and Meta-Analysis.

Perianal fistulizing disease is a common complication of Crohn's disease [CD], for which new therapies are urgently needed. To assist the design of clinical trials for novel therapeutics, we conducted a systematic review and meta-analysis of randomised controlled trials [RCTs] to quantify placebo rates and identify factors influencing them in perianal CD [pCD]. We searched MEDLINE, Embase and CENTRAL from inception to June 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for pCD. Placebo fistula response and remission rates for induction and maintenance trials were extracted and pooled using a random-effects model. Mixed-effects meta-regression was used to evaluate the impact of patient and study-level characteristics on point estimates. In 17 RCTs [13 induction, five maintenance] the pooled placebo fistula response and remission rate for induction trials was 25% (95% confidence interval [CI] 17-36%) and 17% [95% CI 11-25%], respectively. For maintenance trials, the pooled placebo fistula response and remission rate was 23% [95% CI 17-32%] and 19% [95% CI 14-25%], respectively. Trials enrolling patients with less disease activity and a higher proportion with ileal predominant disease were associated with significantly higher placebo response rates. Trials originating in Europe [compared to North America], therapies requiring perianal injection and a longer timepoint to measure remission were associated with higher placebo remission rates. Placebo response and remission rates in pCD trials are influenced by patient and disease-related factors, as well as the type of intervention being studied. These contemporary rates will inform trial design for novel therapeutics.

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

Perianal Crohn's Disease and the Development of Colorectal and Anal Cancer: A Systematic Review and Meta-analysis.

The aim of this systematic review was to assess the literature on the incidence and risk factors for colorectal cancer and anal cancer in patients with perianal Crohn's disease. A systematic review of the literature was performed using PubMed, Embase and Google Scholar. A meta-analysis was then conducted using a random-effects model. Five studies were included in the systematic review. Of the total patients, 26.5% had perianal Crohn's disease. The median follow-up was 6 years. In total, 127 cases of colorectal cancer were found [0.43% of the included Crohn's disease patients]. Perianal involvement was present in 50% of colorectal cancer patients [0.89% of the population]. Three of the studies specified the cancer to be rectal or anal, which were present in 68 and 24 cases [0.3% and 0.1% of patients], respectively. In a subgroup analysis of rectal and anal cancer, perianal involvement was most frequent in anal cancer, accounting for 46% of the cases. In the rectal cancer group, 37% had perianal involvement. The higher incidence of colorectal cancer in patients with perianal Crohn's disease was confirmed in a meta-analysis. Half of the patients with colorectal cancer and anal cancer were found to have perianal Crohn's disease. In patients with perianal involvement, there was a higher percentage of anal cancer compared with rectal cancer. These results support the theory that patients with perianal Crohn's disease are at increased risk for developing colorectal and anal cancer. Studies collecting more detailed data regarding patients and their cancers are needed to further specify the disease course.

Identification of the optimal medical and surgical management for patients with perianal fistulising Crohn's disease.

The aim of our study was to assess the best medical and surgical approaches for perianal Crohn's disease (PCD) in order to identify an optimal combined medical and surgical treatment. Medical records of all patients with PCD treated with TNFα antagonists in two referral centres between 1998 and 2018 were reviewed. Predictors of long-term outcomes were identified using a Cox proportional hazard model. A total of 200 patients were included. Fifty-three patients (26.5%) were treated with adalimumab and 147 (73.5%) with infliximab. A combination of TNFα antagonist with an immunosuppressant and the presence of proctitis were independently associated with fistula closure. Seton was placed in 127 patients (63.5%) before starting biological therapy. Eighty patients (40%) underwent additional perineal surgery. Prior PCD surgery, seton positioning, additional perineal surgery, and additional surgery within 52 weeks of anti-TNFα treatment were associated with an increased rate of fistula closure. Finally, medical combination therapy (anti-TNFα plus immunosuppressant) along with seton placement and additional surgery within 1 year was the best management for PCD patients (p= 0.02). Combined medical and surgical management is required for the treatment of PCD patients. Medical combination therapy associated with seton placement and additional surgery within 1 year is the best management for PCD patients.

Examination Under Anesthesia May Not Be Universally Required Prior to Anti-TNF Therapy in Perianal Crohn's Disease: A Comparative Cohort Study.

Multidisciplinary care involving exam under anesthesia (EUA) and tumor necrosis factor (TNF) inhibitors is recommended for perianal Crohn's disease. However, the impact of this combined approach is not well established. We performed a comparative cohort study between 2009 and 2019. Patients with perianal Crohn's disease treated with EUA before anti-TNF therapy (combined modality therapy) were compared with anti-TNF alone. The primary outcome was fistula closure assessed clinically. Secondary outcomes included subsequent local surgery and fecal diversion. Multivariable analysis adjusted for abscesses, concomitant immunomodulators, and time to anti-TNF initiation was performed. Anti-TNF treatment was initiated 188 times in 155 distinct patients: 66 (35%) after EUA. Abscesses (50% vs 15%; P < .001) and concomitant immunomodulators (64% vs 50%; P = .07) were more common in the combined modality group, while age, smoking status, disease duration, and intestinal disease location were not significantly different. Combined modality therapy was not associated with higher rates of fistula closure at 3 (adjusted odds ratio [aOR], 0.7; 95% confidence interval [CI], 0.3-1.8), 6 (aOR, 0.8; 95% CI, 0.4-2.0) and 12 (aOR, 1.0; 95% CI, 0.4-2.2) months. After a median follow-up of 4.6 (interquartile range, 5.95; 2.23-8.18) years, combined therapy was associated with subsequent local surgical intervention (adjusted hazard ratio, 2.2; 95% CI, 1.3-3.6) but not with fecal diversion (adjusted hazard ratio, 1.3; 95% CI, 0.45-3.9). Results remained consistent when excluding patients with abscesses and prior biologic failure. EUA before anti-TNF therapy was not associated with improved clinical outcomes compared with anti-TNF therapy alone, suggesting that EUA may not be universally required. Future prospective studies controlling for fistula severity are warranted.

Transperineal ultrasonography for treatment response evaluation in children with perianal Crohn's disease.

PurposeThis study assessed the performance of transperineal ultrasonography (TPUS) in evaluating the treatment response in children with perianal Crohn’s disease (PACD) compared with pelvic magnetic resonance imaging (MRI).MethodsThis retrospective study was approved by the Institutional Review Board of our institution, which waived the requirement for informed consent. Twenty-nine patients (19 boys and 10 girls; median age, 14 years [range, 8 to 18 years]) with 56 fistulas were examined. Each fistula’s thickness and abscess size were measured using both modalities, and treatment response was classified as positive or negative based on each modality. The concordance of the classifications was compared between TPUS and pelvic MRI. A receiver operating characteristic curve (ROC) was used to evaluate the performance of TPUS.ResultsTPUS found 80.4% (45/56) of the fistulas. On MRI, 39 fistulas (70%) were classified as having positive treatment responses, and the remaining 17 as having no response. The agreement of the classifications between TPUS and MRI was moderate (κ=0.486; P<0.001; Spearman ρ=0.573; P<0.001). Based on the ROC analysis with the MRI findings as a reference to distinguish positive from negative treatment responses, TPUS exhibited sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 63.3%, 93.3%, 95.0%, 56.0%, and 73.3%, respectively.ConclusionTPUS can be an appropriate adjuvant imaging modality for pelvic MRI to evaluate the treatment response of PACD in children when initial TPUS detects PACD with a location and imaging features comparable to those visualized on MRI.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUNDTumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.AIMTo determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODSIn this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test.RESULTSOne hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].CONCLUSIONHigher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

Management of Perianal Crohn's Disease with Porcine Urinary Bladder Matrix.

Management of Perianal Crohn's Disease with Porcine Urinary Bladder Matrix.

Potential use of mesenchymal stem cells in the treatment of inflammatory bowel disease - a systematic review of the literature.

The incidence of inflammatory bowel disease is increasing worldwide and, despite advances in conservative and surgical treatment, a significant proportion of patients do not achieve complete remission and have to undergo repeated surgical procedures. Stem cell therapy is a new alternative to immunomodulatory therapy. We performed a systematic review of the literature dealing with the use of mesenchymal stem cells for the treatment of IBD. The PubMed database was searched and original studies published between 2015 and 2021 were included. A total of 80 citations were found, of which 21 clinical studies and 47 experimental studies were included in the review. The efficacy of MSCs in the treatment of perianal Crohns disease is at least comparable to current therapies. A positive effect of MSC administration has also been demonstrated in animal models of luminal disease or enterocutaneous fistula. The results after systemic administration in IBD patients are still ambiguous. inflammatory bowel disease.

Therapeutic drug monitoring in inflammatory bowel disease: At the right time in the right place.

Therapeutic drug monitoring (TDM) was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease (IBD) was regarded with great anticipation. But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values, assay variable sensitivity in detecting drug levels and antibodies and, most importantly, individual pharmacokinetics. While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy, the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence. Described here, there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes: Patients with perianal Crohn’s disease, patients with severe ulcerative colitis, pregnant women with IBD and children. As the future of IBD management moves towards personalizing treatment, TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.

A Microbial Signature for Paediatric Perianal Crohn's Disease.

Perianal fistulising disease can affect up to 25% of patients with Crohn's disease [CD] and lead to significant morbidity. Although the role of the gut microbiota in inflammatory bowel disease [IBD] has been increasingly recognised, its role in fistula development has scarcely been studied. Here, we aimed to define the microbial signature associated with perianal fistulising CD in children. A prospective observational study including children age 6-18 years with a diagnosis of perianal fistulising CD was conducted. Stool samples and rectal and perianal fistula swabs were collected. Stool samples and rectal swabs from children with CD without perianal disease and healthy children were included as comparison. Whole shotgun metagenomic sequencing was performed. A total of 31 children [mean age 15.5 ± 3.5 years] with perianal CD were prospectively enrolled. The fistula-associated microbiome showed an increase in alpha diversity and alteration in the abundance of several taxa compared with the rectal- and faecal-associated microbiome with key taxa belonging to the Proteobacteria phylum. Genes conferring resistance to the clinically used antibiotic regimen ciprofloxacin and metronidazole were found in the three sample types. In comparison with children without the perianal phenotype [N = 36] and healthy controls [N = 41], the mucosally-associated microbiome of children with perianal CD harboured a reduced butyrogenic potential. Linear discriminant analysis identified key taxa distinguishing the rectal mucosally-associated microbiome of children with perianal CD from children without this phenotype. The microbial community within CD-related anorectal fistula is compositionally and functionally unique. Taken together, these findings emphasise the need to better understand the ecosystem of the fistula milieu to guide development of novel microbiome-based strategies in this CD phenotype.

Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN).

Both perianal and pediatric-onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult-onset perianal CD and their disease course. We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD-9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease. A total of 12,905 patients were included (2186 [17%] pediatric-onset, 10,719 [83%] adults), with a median follow-up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6-4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1-3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid-dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age. PCD is more common in pediatric-onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.

A148 IMPACT OF EXAMINATION UNDER ANESTHESIA PRIOR TO ANTI-TUMOR NECROSIS FACTOR THERAPY ON FISTULA HEALING FOR PERIANAL CROHN’S DISEASE PATIENTS: A COMPARATIVE COHORT STUDY

Abstract Background Current guidelines recommend a combined approach consisting of an examination under anesthesia (EUA) and anti-TNF therapy for perianal Crohn’s Disease (PCD). However, the impact of this approach on fistula healing and long-term outcomes is unknown. Aims To assess the effect of EUA on fistula healing and long term outcomes in patients with perianal Crohn’s disese who are treated with anti-TNF therapy. Methods We performed a retrospective, single-center, comparative cohort study between 2009 and 2019. We compared patients with PCD who received EUA prior to anti-TNF therapy (combined therapy) to anti-TNF therapy alone. Our primary outcome was fistula closure by clinical assessment. Secondary outcomes included subsequent local surgery and fecal diversion. Logistic regression and multivariable cox-proportional hazard models adjusted for abscesses, concomitant immunomodulators, and time to anti-TNF initiation were performed. Results A total of 155 patients underwent 188 distinct anti-TNF starts: 66 (35%) after an EUA. Patients who underwent an EUA prior to anti-TNF therapy were more likely to have an abscess (50% vs. 15%; p &amp;lt; 0.001) and concomitant immunomodulator usage (64% vs. 50%; p = 0.07). Otherwise, there were no differences between cohorts in age, smoking status, disease duration, and location of luminal disease. There were no significant differences in fistula closure at 3, 6, or 12 months between cohorts overall (Table 1). The results remained consistent in sensitivity analyses that excluded patients with abscesses and prior biologic treatment failure. The results were also similar when defining the combined therapy group as those with setons. After a median follow-up of 4.6 years (IQR, 5.95) patients who underwent an EUA prior to anti-TNF therapy were more likely to require a subsequent EUA (aHR 2.2; 95% CI, 1.3–3.6) (Figure 1) but not fecal diversion (aHR 1.3; 95% CI, 0.45–3.9). Conclusions In this single center study, combined therapy (EUA prior to anti-TNF therapy) was not associated with improved clinical outcomes compared with anti-TNF therapy alone. These findings suggest that EUA may not be necessary in every patient with PCD prior to initiation of anti-TNF therapy. Future prospective studies that control for fistula complexity are warranted. Table 1: Unadjusted rates of fistula closure after anti-TNF therapy comparing patients with and without an exam under anesthesia Funding Agencies University of Ottawa Department of Medicine

Evaluating the safety and efficacy of mesenchymal stem cell-derived exosomes for treatment of refractory perianal fistula in IBD patients: clinical trial phase I.

Exosome administration is a novel medical approach that promises excellent immunomodulatory properties without the conventional side effects of current antitumor necrosis factor drugs and stem cells. This study aimed to assess the safety and efficacy of using mesenchymal stem cell (MSC) exosomes to treat refractory fistulas in patients with inflammatory bowel disease. MSCs were derived from the umbilical cords and their exosomes were isolated. Five patients with refractory perianal Crohn's disease fistulas with a median age of 35 years (range 31-47 years) were enrolled in the study. Exosome injections were administered in the operating room to patients with refractory fistula (fistulas that are irresponsive to anti-tumor necrosis factor-α administration within 6 months). Six months later, a physical examination, face-to-face interviews, and magnetic resonance imaging were employed to evaluate the therapy responses of patients. The outcomes within 6 months after initiation of therapy showed that four patients had responded to therapy. Three patients who received exosome injections exhibited complete healing, while one reported no improvement and active discharge from the fistula site. In addition, five patients (100%) reported neither systemic nor local adverse effects. Injection of exosomes extracted from MSCs demonstrates safety and a satisfactory therapeutic effect, as evidenced in this and other studies, and may play a significant role in the future treatment of gastrointestinal fistulas.

Impact on Quality of Life of Seton Placing in Perianal Crohn's Disease

IntroductionOften, in perineal Crohn's disease (CD), a seton is placed to guarantee a constant drainage and prevent septic complication while biologic therapy is ongoing. This study aimed to assess the long-term quality of life after surgery for perineal CD in relation to seton placing.Patients and MethodsData of 65 consecutive patients with CD and non-CD operated on from 2014 to 2019 for perianal fistula or abscess were retrieved. Forty-three had CD and 14 of them had a seton placed during surgery and they kept it on while they had anti-TNF-alpha therapy. Patients were interviewed with the Cleveland Global Quality of Life (CGQL) and SF-12 quality of life questionnaires. Disease activity was defined as Harvey-Bradshaw Index (HBI) and Perianal Disease Activity Index (PDAI). Comparisons between groups were carried out with the nonparametric tests, and multiple regression models were used to assess predictors of quality of life.ResultsThe total CGQL score and SF-12 mental component score (MCS) were significantly higher (and thus better) in the seton group than in patients treated without seton. On the contrary, SF-12 physical component score (PCS) was not different between the two groups. HBI was significantly better in patients in the seton group. At multivariate analysis, seton placement and HBI were confirmed to be independent predictors of long-term SF-12 MCS whereas only HBI confirmed to be a predictor of total CGQL score.ConclusionsSeton placing during anti-TNF-alpha therapy is independently associated with a better MCS. Unexpectedly, this device, instead of to cause psychological distress, seems to assure patients during their biologic therapy providing psychological benefit beyond the mere medical effect.

OP20 Perianal fistulas are characterised by expansion of interleukin-22 producing invariant natural killer T-cells and CD4+ T-cells which drive dysregulation of the extracellular matrix

Abstract Background Perianal fistulas are a common complication of Crohn’s disease (CD) affecting approximately 25% of patients, often predicting a more complicated disease course. Dysregulated immune responses and epithelial-to-mesenchymal transition (EMT) are hypothesised to contribute to fistulizing disease; however, they have been poorly studied. In this study, we investigated the immune phenotype of patients with perianal fistulizing disease and its relationship with tissue remodelling. Methods Immune cells were isolated from fistula curettage samples (n=31) and paired peripheral blood from patients with perianal Crohn’s (pCD) or idiopathic fistulizing disease. Multiparameter flow cytometry was performed to evaluate lymphocyte populations including invariant natural killer T-cells (iNKTs), gamma-delta (γδ) T-cells, CD161+ mucosal-associated invariant T-cells (MAIT), CD4+ T-cells and CD8+ T-cells. Gene expression profiling of fistula (Crohn’s n=11, idiopathic n=11) and rectal tissue (Crohn’s n=9, idiopathic n=9) was performed by RNA-sequencing. Cellular deconvolution of transcriptomic data using CIBERSORTx was performed to define the cellular phenotype of perianal fistulas. Cytokine treated intestinal epithelial organoids were used to probe the impact of selective cytokines on disease relevant pathways in perianal fistulas, using gene-set enrichment analysis (GSEA). Results Perianal fistulas were characterised by expansion of iNKTs and CD4+ T-cells when compared to peripheral blood. Deeper analysis of the phenotype of these populations revealed enrichment of CD8- CD4- CD161+ iNKTs producing interleukin-22 (IL22), and CD4+ CD161+ T-cells producing interleukin-13 (IL13) and IL22. Surprisingly, pCD and idiopathic fistulas displayed similar immunophenotypes. Fistulas exhibited distinct transcriptional profiles to rectal tissue, although the phenotype of pCD and idiopathic fistulas appeared similar. Pathways related to the extracellular matrix (ECM) and EMT were more activated in fistulas compared to rectum. Gene-set enrichment analysis and cellular deconvolution identified an increase in the abundance of iNKTs, activated memory CD4+ T-cells, activated NK cells and neutrophils in fistula versus rectal tissue. IL13, IL22 and TNFα responsive transcripts were enriched in fistula tissue, and in the case of IL22, was shown to regulate key matrisome components. Conclusion Perianal fistulas are characterised by increased infiltration of CD161+ iNKT cells and CD4+ T-cells, producing IL22 and IL13. These pro-inflammatory cytokines are likely important drivers of ECM dysregulation and tissue remodelling in perianal fistulizing disease.

P428 A Phase IB/IIA study of remestemcel-L, an allogeneic bone marrow derived mesenchymal stem cell product, for the treatment of medically refractory Crohn’s colitis: A preliminary analysis

Abstract Background Mesenchymal stem cells (MSCs) have been successfully used for the treatment of perianal Crohn’s fistulizing disease by direction injection. However, no studies have looked at the direct injection of MSCs for luminal Crohn’s disease. Methods Following screening and informed consent, patients with medically refractory Crohn’s colitis who had a washout of at least, 4 weeks from monoclonal antibody treatment were randomized in a, 2:1 fashion to receive remestemcel-L, an ex vivo expanded allogeneic bone marrow derived MSC product versus placebo. If randomized to treatment, patients received, 150 million MSCs delivered via direct injection using a, 23 G sclerotherapy needle at the time of colonoscopy. Patients were included if they had medically refractory Crohn’s colitis defined as an established diagnosis for at least, 6 months prior to study enrollment and had lost response to at least one monoclonal antibody in the past, no small bowel involvement, and no colorectal stricture. Patients were evaluated with validated clinical and endoscopic scoring systems at, 2 weeks, 6 weeks, and, 3 months. Patients randomized to control crossed over at, 3 months to receive MSC treatment. Results A total of six patient have been enrolled;, 4 treatment and, 2 controls. There were, 7 reported adverse events, none of which were related to the investigational product (2 with eye pain, 1 with hiatal hernia, 1 with abdominal pain, 1 with partial small bowel obstruction, 1 with arthritis symptoms, 1 with Crohn’s flare requiring hospital admission and treatment with infliximab and intravenous corticosteroids). With regard to efficacy, in the treatment group (n=4), the SES-CD dropped from, 17 at baseline to, 5 by, 3 months, the CDAI from, 228 to, 200, and the fecal calprotectin from, 231 to, 67. In the control cohort, the SES-CD increased from, 15.5 to, 25, the CDAI increased from, 146 to, 158, and the fecal calprotectin increased from, 330 to, 505. Conclusion MSCs offer a safe alternative therapeutic for the treatment of medically refractory Crohn’s colitis. Early data suggests improved clinical and endoscopic scores by as early as two weeks following MSC delivery.

P297 Treatment of patients with complex perianal Crohn’s disease with darvadstrocel: a single-institution real life experience

Abstract Background Complex perianal disease in patients with Crohn’s disease (CD) represents a therapeutic challenge since, despite biological treatment, half of the patients do not achieve an adequate response. Treatment with allogenic expanded adipose-derived mesenchymal stem cells (Darvadstrocel) has proven to be an innovative treatment in patients refractory to treatment with immunomodulators and anti-TNF antibodies. Methods To assess the efficacy of Darvadstrocel treatment in clinical practice in patients with CD and complex perianal fistula. Method: We performed a prospective descriptive study in patients with CD and complex perianal fistula (high intersphincteric, transsphincteric, extrasphincteric or suprasphincteric; presence or ≥ 2 external opening or abscesses), refractory to antiTNF treatment, treated consecutively with Darvadstrocel at our Crohn’s and Colitis Attention Unit. Each patient was treated with 120 million stem cells (half of the dose was injected along the tract walls and the other half around the internal opening/s). Response to treatment was assessed as combined remission according to the criteria of the ADMIRE study (clinical assessment of closure of all treated external openings that drained before treatment and absence of collections&amp;gt; 2 cm confirmed by MRI). Results From July 2020 to October 2021 12 patients (10M / 2H) have been treated with Darvadstrocel. All patients were in clinical remission (luminal disease) and had perianal disease refractory to anti-TNF treatment. In addition, 7/12 patients were also refractory to ustekinumab. The patients had previously been treated with a mean of 5.7 perianal surgeries (1–16), most of them curettage and seton placement or replacement. One patient had previously been treated with mesenchymal stem cells in 2014 (ADMIRE participant). All fistulas were complex, 5 with a single tract, 2 with a branched tract and 5 with a double tract; 7 were transsphincteric, 1 intersphincteric (double), 1 supraelevator, 1 suprasphincteric, and 2 extrasphincteric. 6/10 patients underwent a previous conditioning surgery (cleaning, curettage and seton placement) two weeks before cell administration. Six of the 10 patients with a follow-up of at least 6 months had combined remission (60%). Two of the three patients with a 1-year follow-up presented combined remission. Regarding safety, no relevant adverse effects have been observed: 2 patients presented abscesses in the immediate postoperative period (self-drained without subsequent recurrence). Conclusion In real-life clinical practice, treatment with Darvadstrocel can be an effective and safe therapy in patients with CD and complex perianal disease refractory to biological treatment.

P407 A Phase IB/IIA study of remestemcel-L, an allogeneic bone marrow derived mesenchymal stem cell product, for the treatment of medically refractory ulcerative colitis: An interim analysis

Abstract Background Direct injection of mesenchymal stem cells (MSCs) have been used for the treatment of perianal Crohn’s fistulizing disease. However, no studies have looked at the direct injection of MSCs for luminal ulcerative colitis (UC). Methods Following screening and informed consent, patients with medically refractory UC were randomized in a, 2:1 fashion to receive remestemcel-L, an ex vivo expanded allogeneic bone marrow derived MSC product, at a dose of, 150 or, 300 million MSCs versus placebo delivered via direct injection using a, 23 G sclerotherapy needle at the time of colonoscopy. Patients were included if they had medically refractory UC defined as an established diagnosis for at least, 6 months prior to study enrollment and had lost response to at least one monoclonal antibody in the past. Patients were evaluated with validated clinical and endoscopic scoring systems at, 2 weeks, 6 weeks, and, 3 months post MSC delivery. Patients randomized to control crossed over at, 3 months to receive MSC treatment and followed the same schedule for post MSC evaluation. Results A total of six patients were enrolled and treated;, 4 were randomized to treatment and, 2 to placebo. All had been on prior anti-TNF or anti integrin-therapy. There were no adverse and serious adverse events related to investigational product. In the treatment group (n=4), the Mayo score and Mayo endoscopic severity score decreased in all patients by two weeks after MSC delivery. By six weeks post MSC treatment, all treated patients had achieved clinical and endoscopic remission as defined by the Mayo score and Mayo endoscopic severity score. Patient reported number of daily bowel movements decreased as did urgency and presence of blood in the stool. With regard to patient reported outcomes, at three months, based on the inflammatory bowel disease patient reported treatment impact (IBD-PRTI), all patients were extremely satisfied or satisfied with their MSC treatment. Treated response was described as excellent or good in all patients. In the control group (n=2), the Mayo score did not decrease. Patient reported number of daily bowel movements increased as did the number reporting blood in their stool; urgency remained unchanged. With regard to patient reported outcomes, at three months, based on the IBD-PRTI, one patient was neutral, and one patient was dissatisfied. Treated response was described as poor or unchanged in control patients. Conclusion MSCs offer a safe alternative therapeutic for the treatment of medically refractory UC. Early data suggests improved clinical and endoscopic scores by as early as two weeks following MSC delivery.