Refractory Colitis Research Articles

PERSISTENCE, EFFECTIVENESS, AND SAFETY OF UPADACITINIB IN CROHN'S DISEASE AND ULCERATIVE COLITIS IN REAL LIFE: RESULTS FROM A SPANISH NATIONWIDE STUDY (UREAL STUDY): Upadacitinib for IBD.

Real-world data on the effectiveness of upadacitinib for inflammatory bowel disease (IBD) are limited. To assess upadacitinib persistence, effectiveness, and safety in a real-world scenario. Retrospective multicentre study of IBD patients who received upadacitinib before 31st December 2022 and at least 12 weeks before the recruitment date. Clinical effectiveness was assessed based on partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease (CD). We included 100 patients (68 with CD, and 32 with UC). Patients had previously received a median of four advanced therapies. Twenty-three discontinued the treatment (median follow-up 7.6 months). CD (vs. UC) (Hazard Ratio[HR] 3.7;95%Confidence Interval (CI):1.04-12.9), and age below 40 years at upadacitinib initiation (HR 2.4;95%CI:1.0-5.8) were associated with treatment discontinuation in multivariable analysis. Clinical remission for IBD was achieved in 59% of patients at week 8, 64% at week 12, and 42% at week 52. The proportion of patients with UC previously exposed to tofacitinib (n=25) who achieved clinical remission was 78% at week 12, and 50% at week 52. Factors associated with clinical remission at week 12 were UC diagnosis (Odds Ratio[OR] 4.6;95%CI:1.3-17), mild or moderate activity at baseline (OR 8;95%CI:1.1-56) and not smoking (OR 4.4;95%CI:1.5-13). Dose escalation recaptured remission in 60% of patients with relapse. Eighty percent of patients with active immune-mediated diseases or extraintestinal manifestations improved with upadacitinib. Forty-three patients reported adverse events, 11 of them serious. Upadacitinib is effective and safe for treating highly refractory IBD patients, even in previously treated with JAK inhibitors.

Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study

Abstract Background Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), often results in significant morbidity among patients with moderate to severe forms. While biologics and small molecules are effective in inducing remission, many patients experience refractory disease or extra-intestinal manifestations. This study assesses the safety and efficacy of dual-targeted therapy in IBD patients treated at the Inflammatory Bowel Disease Center. Methods This retrospective cohort study examined 79 patients with UC or CD who received dual-targeted therapy at the University from October 2018 to August 2023. Data collected included demographics, disease characteristics, previous treatments, and clinical outcomes. Primary outcomes were endoscopic, radiographic, and patient-reported clinical improvements, with secondary outcomes focusing on safety profiles. Results Among the 79 patients (42 UC, 37 CD), 97 dual-targeted therapy cases were analyzed, primarily involving a biologic combined with a JAK inhibitor (90.7%). The median therapy duration was 39.1 weeks. Endoscopic improvement occurred in 69% of matched samples, with significant differences between pre- and post-dual-targeted therapy Mayo scores for UC (p = 0.002) and SES-CD scores for CD (p = 0.018). The median pre- and post-dual-targeted therapy Mayo scores across matched samples were 3 (range 1-3) and 1 (range 0-3) respectively, and for SES-CD scores were 12 (range 0-36) and 4 (range 0-20) respectively. Clinical improvement was reported by 73.2% of patients, with notable reductions in ESR (median 19 [range 2-124] mm/hr to 9 [range 0-116] mm/hr, p = 0.006), CRP (median 8.0 [range 0.2-78.5] mg/L to 3.0 [range 0.2-68.2] mg/L, p <0.001) , and albumin levels (4.0 [range 2.2-4.9] mg/dL to 4.2 [range 3.4-5.2], p < 0.001). Non-obesity was associated with both more endoscopic improvement (p = 0.002) and clinical improvement (p = 0.007). Adverse events occurred in 37 cases, predominantly upper respiratory tract infections and dermatologic issues, with no thromboembolic events reported. Discussion Dual-targeted therapy demonstrated efficacy in improving clinical and endoscopic outcomes in patients with severe, refractory IBD, and exhibited an acceptable safety profile. Despite the promising results, further research is needed to confirm these findings and determine optimal therapy combinations.

Ginsenoside Rb1 Alleviates DSS-Induced Ulcerative Colitis by Protecting the Intestinal Barrier Through the Signal Network of VDR, PPARγ and NF-κB.

Ginseng (Panax ginseng Meyer) is an herbal medicine used in traditional Chinese medicine (TCM), has the effects of treating colitis and other diseases. Ginsenoside Rb1 (GRb1), a major component of ginseng, modulates autoimmunity and metabolism. However, the mechanism underlying GRb1 treatment of ulcerative colitis (UC) has not yet been elucidated. UC is a refractory inflammatory bowel disease (IBD) with a high recurrence rate, and researches on new drugs for UC have been in the spotlight for a long time. Mice with DSS-induced UC were treated with GRb1 or 0.9% saline for 10 days. Colon tissue of UC mice was collected to detect the levels of intestinal inflammatory cytokines and integrity of the intestinal barrier. RNA-seq and network pharmacology were used to predict the therapeutic targets of GRb1 during UC treatment. GRb1 treatment alleviated intestinal inflammation and improved intestinal barrier dysfunction in UC mice. Specifically, GRb1 downregulated the levels of pro-inflammatory cytokines such as TNF-α and IL-6, while upregulating the level of the anti-inflammatory cytokine IL-10. Additionally, GRb1 treatment increased the levels of tight junction proteins including ZO-1, Occludin, and E-cadherin, which are crucial for maintaining intestinal barrier integrity. Further analyses using RNA-seq and network pharmacology suggested that these effects might involve the regulation of GRb1 in the signal transduction network of VDR, PPARγ, and NF-κB. The study demonstrated that GRb1 effectively alleviated UC by modulating intestinal inflammation and protecting the integrity of the intestinal barrier through the signal transduction network of VDR, PPARγ, and NF-κB.

S2803 Role of Azathioprine as an Effective Alternative Therapy for Patients With Refractory Microscopic Colitis

S2803 Role of Azathioprine as an Effective Alternative Therapy for Patients With Refractory Microscopic Colitis

The Role of Topical Tacrolimus in the Management of Inflammatory Bowel Disease: A Comprehensive Review.

Management of ulcerative colitis and Crohn's disease, the main subtypes of inflammatory bowel disease (IBD), focuses on the induction and maintenance of remission. Tacrolimus, a member of a group of drugs termed calcineurin inhibitors, may have a role in the medical management of IBD when given either systemically or topically. This review aimed to evaluate the available data focusing on the use of topical tacrolimus in the management of IBD. Reports of the use of topical tacrolimus in IBD were extracted from databases up to 31 May 2024. Topical tacrolimus therapy appears to have reasonable efficacy in the induction and maintenance of remission in patients with refractory IBD, with an acceptable safety profile. Overall, the available data are supportive of the use of topical tacrolimus in selected patients. Further comparative clinical studies are required to more fully delineate the role of this drug.

Formononetin ameliorates dextran sulfate sodium-induced colitis via enhancing antioxidant capacity, promoting tight junction protein expression and reshaping M1/M2 macrophage polarization balance

Ulcerative colitis (UC) is a complex, refractory inflammatory bowel disease characterized impared intestinal mucosal barrier and imbalanced M1/M2 macrophage polarization mediating its progression. Formononetin (FN), a bioactive isoflavone with established anti-inflammatory and immunomodulatory properties, shows promise in mitigating UC, yet its therapeutic and underlying mechanisms remain unclear. In this study, colitis was induced in mice by administering 2.5% (w/v) dextran sulfate sodium (DSS) solution for 7 days. Oral (25, 50, and 100 mg/kg) FN for 10 days significantly ameliorated colitis symptoms in a dose-dependent manner, by mitigating body weight loss, reducing disease activity index (DAI), colonic weight, and colonic weight index, while enhancing survival rates and colonic length. Histological analysis revealed FN remarkably suppressed inflammatory damage in colonic tissues. Furthermore, FN modulated the expression of pro- and anti-inflammatory cytokines and enhanced antioxidant capacity. Notably, FN treatment significantly enhanced the expression of tight junction (TJ) proteins (claudin-1, ZO-1, occludin) at both protein and mRNA levels in the colon tissues, suggesting improved intestinal barrier function. Crucially, FN inhibited macrophage infiltration in colonic tissues and rebalanced M1/M2 macrophage polarization. While, macrophage depletion largely abrogated FN’s protective effects against colitis, indicating a crucial role for macrophages in mediating FN’s therapeutic response. Overall, FN effectively alleviated colitis primarily via modulating inflammatory cytokine expression, enhancing antioxidant capacity, upregulating TJs proteins expression, and remodeling M1/M2 macrophage polarization equilibrium. These findings suggest that FN could be the next candidate to unlocking UC’s treatment challenge.

Role of ileal diversion in pediatric inflammatory bowel disease.

Surgical intervention is often indicated in pediatric inflammatory bowel disease (IBD) for medically refractory disease or complications of severe disease. Specifically, surgical intervention via ileal diversion allows for fecal flow to be redirected away from diseased distal bowel and through an ileostomy. It is utilized in patients who have medically refractory colitis, severe perianal disease, or irreversible bowel damage. In patients with ulcerative colitis, it is primarily performed during a restorative proctocolectomy with ileal pouch anal anastomosis to protect the high-risk anastomoses. In the setting of Crohn's disease, ileal diversion reduces the exposure of diseased distal intestine to pro-inflammatory stool. During perioperative planning, it is crucial for the gastroenterologist to partner early with a multidisciplinary team including surgeons, nutritionists, wound ostomy care nurses, psychologists, and social workers. Patients should be assessed for malnutrition and should be optimized nutritionally with enteral or parenteral nutrition. As they are associated with increased risk of postoperative complications, corticosteroids should be significantly reduced or completely discontinued preoperatively. Though ileal diversion may reduce the complications associated with anastomosis, serious postoperative complications can include diversion colitis and high-output fistulae. This review aims to provide an overview of the role of ileal diversion in the treatment of pediatric IBD to pediatric gastroenterologists to inform their medical decision-making and discussions with patients and families.

Inhibition of Transmural Inflammation in Crohn's Disease by Orally Administered Tumor Necrosis Factor-Alpha Deoxyribozymes-Loaded Pyroptosis Nanoinhibitors.

Crohn's disease (CD) is a refractory chronic inflammatory bowel disease (IBD) with unknown etiology. Transmural inflammation, involving the intestine and mesentery, represents a characteristic pathological feature of CD and serves as a critical contributor to its intractability. Here, this study describes an oral pyroptosis nanoinhibitor loaded with tumor necrosis factor-α (TNF-α) deoxyribozymes (DNAzymes) (DNAzymes@degradable silicon nanoparticles@Mannose, Dz@MDSN), which can target macrophages at the site of inflammation and respond to reactive oxygen species (ROS) to release drugs. Dz@MDSN can not only break the inflammatory cycle in macrophages by degrading TNF-α mRNA but also reduce the production of ROS mainly from macrophages. Moreover, Dz@MDSN inhibits excessive pyroptosis in epithelial cells through ROS clearance, thereby repairing the intestinal barrier and reducing the translocation of intestinal bacteria to the mesentery. Consequently, these combined actions synergistically contribute to the suppression of inflammation within both the intestine and the mesentery. This study likely represents the first successful attempt in the field of utilizing nanomaterials to achieve transmural healing for CD, which also provides a promising treatment strategy for CD patients.

Endoscopic Balloon Dilatation of Ileal Pouch-Anal Anastomosis Strictures in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice for medically refractory inflammatory bowel disease (IBD). In this systematic review and meta-analysis, we assess outcomes and safety of endoscopic balloon dilatation (EBD) for IPAA strictures. A systematic search of numerous databases was performed through June 2023 to identify studies reporting on the outcomes of EBD in pouch-related strictures. Outcomes included technical success, clinical success at index dilation and in pouch retention, recurrence of symptoms post-EBD, and adverse events of EBD. Meta-analysis was performed using a random-effects model, and results were expressed in terms of pooled rates along with relevant 95% confidence intervals (CIs). Heterogeneity was assessed using Cochran Q statistical test with I2 statistics. Seven studies with 504 patients were included. The pooled rate of technical success and clinical success of index dilatation was 98.9% (95% CI, 94.8-99.8%; I20%) and 30.2% (95% CI, 7.1-71%; I20%), respectively. The pooled rate of clinical success in pouch retention without the need for additional surgery was 81.4% (95% CI, 69.6-89.3%; I272%). The pooled failure rate of EBD was 18.6% (95% CI, 10.7-30.4%, I272%). The pooled rate of recurrence of symptoms after index dilatation was 58.9% (95% CI, 33.3-80.5%; I213%). The pooled rate of serious adverse events was 1.8% (95% CI, 1-3.5%, I20%). No deaths related to EBD were reported. Endoscopic balloon dilatation is safe and highly effective for management of IPAA strictures. Additional studies are needed to compare its efficacy with surgical interventions.

Intestinal adaptation and rehabilitation in adults with short bowel syndrome.

Over the past decade, trophic gastrointestinal hormonal factors have been included in the intestinal rehabilitation programs for short bowel syndrome (SBS). Up today the only trophic factor approved for clinical practice is the glucagon-like peptide-2 (GLP-2) analogue, teduglutide. A literature review on the last 2-year data on GLP-2 analogues for the treatment of SBS in adults has been performed. Several reports on real-world data on the efficacy and safety of teduglutide treatment for SBS, some case-reports on the use of teduglutide in non-SBS conditions as well as phase 2 trials on new GL-2 analogues on patients with SBS have been retrieved. Real-world data confirmed the teduglutide efficacy not only in weaning off IVS in accurately selected patients but also increased the alert on the risk of development of gastrointestinal polyps related to the drug; the impact of the therapy on patients' QoL deserves further studies and the cost-utility of the treatment is still uncertain. Some case reports highlighted the potential benefit of treatment with teduglutide in non-SBS gastrointestinal diseases, such as graft-versus-host disease, primary amyloidosis and refractory microscopic colitis. Phase 2 RCTs on safety and efficacy of two new long-acting GLP-2 analogues, glepaglutide and apraglutide, were published, and phase 3 RCTs have been completed.

Successful Preoperative Transjugular Intrahepatic Portosystemic Shunt for Portal Decompression in Patients With Inflammatory Bowel Disease and Cirrhosis Requiring Surgical Intervention.

Colorectal surgery in patients with inflammatory bowel disease (IBD) and cirrhosis has increased morbidity, which may preclude surgery. Preoperative transjugular intrahepatic portosystemic shunt (TIPS) is postulated to reduce surgical risk. In this retrospective single-center study, we characterized perioperative outcomes in patients with IBD and cirrhosis who underwent preoperative TIPS. We identified patients with IBD and cirrhosis who had undergone preoperative TIPS for portal decompression between 2010 and 2023. All other indications for TIPS led to patient exclusion. Demographic and medical data were collected, including portal pressure measurements. Primary outcome of interest was perioperative outcomes. Ten patients met the inclusion criteria. The most common surgical indications were dysplasia (50%) and refractory IBD (50%). TIPS was performed at a median of 47 days (IQR 34-80) before surgery, with reduction in portal pressures (22.5 vs. 18.5 mmHg, P < .01) and portosystemic gradient (12.5 vs. 5.5 mmHg, P < .01). Perioperative complications occurred in 80% of patients, including surgical site bleeding (30%), wound dehiscence (10%), systemic infection (30%), liver function elevation (50%), and coagulopathy (50%). No patients required re-operation, with median length of stay being 7 days (IQR 5.5-9.3). The 30-day readmission rate was 40%, most commonly for infection (75%), with 2 patients having intra-abdominal abscesses and 1 patient with concern for bowel ischemia. Ninety-day and one-year survival was 100% and 90%, respectively. Patients with primary sclerosing cholangitis (PSC)-cirrhosis were noted to have higher perioperative morbidity and a 30-day readmission rate. In patients with IBD and cirrhosis, preoperative TIPS facilitated successful surgical intervention despite heightened risk. Nevertheless, significant complications were noted, in particular for patients with PSC-cirrhosis.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the “Disease of immune dysregulation” category. Of 96 Taiwanese patients during 2003–2022, 31 (median 66, range 0.03–675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3–252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Anxiolytic effects of Enterococcus faecalis 2001 on a mouse model of colitis

Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-d-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.

Clinical effectiveness and safety of ustekinumab in youth with refractory inflammatory bowel disease: A retrospective cohort study.

Inflammatory bowel disease (IBD) incidence and prevalence has been increasing worldwide. Limited data exists on the effectiveness of ustekinumab (UST) in children. We aimed to describe the effectiveness and safety of UST in pediatric patients with IBD. A single-center retrospective study was conducted between January 2017 and February 2022. The study included patients ≤16 years of age who were treated with UST and followed up for ≥1 year. Clinical remission was defined as a score of the Pediatric Crohn's Disease (CD) and Pediatric Ulcerative Colitis (UC) Activity Indices ≤10 at week 52. Thirteen patients who had failed anti-tumor necrosis factor-α (anti-TNFα) therapy were included, eight (61.5%) with CD and five (38.5%) with UC. The median age was 13 years (interquartile range [IQR]: 11.5 to 14). UST treatment was initiated at a median age of 3 years (IQR: 2.3 to 7) after diagnosis. Ten patients (76.9%) achieved clinical remission. There were no statistically significant differences in characteristics between patients who achieved and did not achieve clinical remission. Biochemical remission (BioR) was achieved in six patients (46.2%). Body mass index (BMI) significantly improved, C-reactive protein (CRP) significantly decreased, and the need for corticosteroids significantly decreased in the remission group. Endoscopy conducted post-treatment in seven patients confirmed remission in six patients. Adverse events included two cases of infection and one of headache. UST was effective as a secondary biologic therapy for the induction and maintenance of remission in patients with anti-TNFα refractory IBD. At one year, 84% of patients remained on UST with no severe adverse reactions reported.

The Natural History of Patients With Pre-Existing and De Novo Inflammatory Bowel Disease After Solid Organ Transplantation: EITOS Study of GETECCU.

Limited data are available on the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). We describe the natural history of pre-existing IBD and de novo IBD after SOT. This was a retrospective, multicenter study that included patients with pre-existing IBD at the time of SOT and patients with de novo IBD after SOT. The primary outcome was IBD progression, defined by escalation of medical treatment, surgical therapy, or hospitalization due to refractory IBD. Risk factors were identified using multivariate Cox proportional hazard analysis. A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) were included. Most patients with pre-existing IBD (92.5%) were in remission before SOT. During follow-up, 32% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 (interquartile range, 1.3-4.6) years. In the de novo cohort, 55% of patients had disease progression with a median time to flare of 1.9 (interquartile range, 0.8-3.9) years after diagnosis. In the pre-existing IBD cohort, active IBD at the time of SOT (hazard ratio, 1.80; 95% confidence interval, 1.14-2.84; P = .012) and the presence of extraintestinal manifestations (hazard ratio, 3.10; 95% confidence interval, 1.47-6.54; P = .003) were predictive factors for IBD progression. One-third of patients with pre-existing IBD and about half of patients with de novo IBD have disease progression after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for IBD progression.

Contemporary perioperative outcomes after total abdominal colectomy for ulcerative colitis in a tertiary referral centre.

Colectomy for ulcerative colitis (UC) is common despite therapeutic advances. Post-operative morbidity and mortality demonstrate an association between hospital volumes and outcomes. This single-centre retrospective study examines outcomes after emergency colectomy for UC. Patient demographics, perioperative variables and outcomes were collected in Beaumont Hospital between 2010 and 2023. Univariant analysis was used to assess relationships between perioperative variables and morbidity and length of stay (LOS). A total of 115 patients underwent total abdominal colectomy with end ileostomy for UC, 8.7 (±3.8) per annum. Indications were refractory acute severe colitis (88.7%), toxic megacolon (6.1%), perforation (4.3%), or obstruction (0.9%). Over 80% of cases were performed laparoscopically. Pre-operative steroid (93%) and biologic (77.4%) use was common. Median post-operative LOS was 8 days (interquartile range 6-12). There were no 30-day mortalities, and 30-day post-operative morbidity was 38.3%. There was no association between time to colectomy ( P = 0.85) or biologic use ( P = 0.24) and morbidity. Increasing age was associated with prolonged LOS ( P = 0.01). Laparoscopic approach (7 vs. 12 days P =0.01, 36.8% vs. 45% P = 0.66) was associated with reduced LOS and morbidity. This study highlights contemporary outcomes after emergency colectomy for UC at a specialist high-volume, tertiary referral centre, and superior outcomes after laparoscopic surgery in the biologic era.

A76 COMBINING TOFACITINIB AND USTEKINUMAB FOR REFRACTORY ULCERATIVE COLITIS: A CASE REPORT

Abstract Background The paradigm for Inflammatory Bowel Disease (IBD) management has shifted towards prioritizing remission of inflammation over symptom control, emphasizing sustained, corticosteroid-free remission at the clinical, endoscopic, and histologic levels. The shift is due to the recognition that uncontrolled inflammation often causes morbidity; after one year of biological therapy, 40% of patients still experience persistent disease activity. Several approaches have been proposed to address this challenge, including drug level monitoring, dosage titration, antibody screening, and, as a last resort, surgical intervention. Emerging limited studies suggest the potential efficacy of combining two biological agents or a biological agent with small molecules in IBD, contrasting the efficacy and safety concerns encountered with their use in rheumatological diseases. Aims To describe a case of successful combination therapy with Tofacitinib and Ustekinumab in refractory Ulcerative Colitis with a review of the current literature. Methods This case describes a 35-year-old male patient with severe Ulcerative Colitis refractory to 5-ASA, Azathioprine, Infliximab with Methotrexate, Vedolizumab, Ustekinumab and Tofacitinib. His disease persisted with primary treatment failures requiring hospital admissions and rescuing with parenteral steroids. He was switched back to Ustekinumab with minimal symptom improvement but required repeated steroid courses to achieve control. After deliberations, Tofacitinib was added. This combination achieved remission of his symptoms and inflammatory markers, mainly guided by fecal calprotectin (from 3728 µg/g to 46 µg/g), as well as endoscopic and histologic remission. He is being weaned off the oral budesonide he had been on to augment his response. Results After 4 years of combination therapy, he remains in remission with no adverse events or infections. Reassuringly, Janus Kinase inhibitors (i.e., Tofacitinib) have a short half-life, allowing prompt discontinuation if indicated, especially in the event of infection. Furthermore, biologics such as Vedolizumab, Ustekinumab, and Risankizumab offer minimal systemic immunosuppression and do not appear to raise the risk of infection. Apart from safety concerns and limited data on the use of combination therapy, significant economic implications exist. However, the attainability of cheaper generic forms of small molecules (e.g., Tofacitinib roughly costs a quarter of the brand price in Ontario, Canada) adds another advantage to their combination use. Conclusions Combination therapy with biologics and small molecules is a potential consideration for treating severe or refractory Ulcerative Colitis or IBD. To bridge the knowledge gap regarding combination therapies in IBD, further studies are needed on efficacy, safety, long-term effects, and economic impact. Funding Agencies None

A236 THE EFFECTIVENESS AND SAFETY OF DUAL ADVANCED THERAPIES IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: A CASE-SERIES

Abstract Background Patients with inflammatory bowel disease (IBD) refractory to medical therapy and patients with IBD and concurrent extra-intestinal manifestations (EIMs) pose a challenge within gastroenterology. The small number of approved agents for IBD limits therapeutic options for this population. Utilizing a combination of newer biologic therapies with favourable safety profiles may provide a safe and efficacious option for treating patients with refractory disease or patients with well-controlled IBD but uncontrolled EIMs. Aims The aim of our study was to assess the safety and efficacy of dual advanced therapies for patients with IBD. Methods Patients at London Health Sciences Centre and St. Joseph’s Healthcare Centre on dual advanced therapies for inflammatory bowel disease were retrospectively assessed for a minimum period of 12 months. Major bacterial infection, adverse events, endoscopic, histologic, and clinical remission of IBD, and remission of EIMs of IBD were assessed. Results Five patients with Crohn’s disease receiving dual advanced therapies were identified. Stricturing Crohn’s disease was the predominant phenotype in 80% of the patients. One patient had perianal fistulizing disease. Dual therapy was initiated for concurrent management of EIMs in 80% of patients (enteropathic arthritis in 2 patients, spondyloarthritis in 2 patients, rheumatoid arthritis in 1 patient) and for refractory IBD in one patient. The majority of patients were on a combination of a tumour-necrosis-factor inhibitor and vedolizumab. Other advanced therapies included JAK inhibitors and ustekinumab. The patients were predominantly female (80%) and age at diagnosis was ampersand:003C50 years old in 80% of patients. No adverse events or major bacterial infections were observed during dual therapy. At the end of follow-up, all 5 patients were in clinical remission of their IBD and 4 patients demonstrated endoscopic remission. Only 60% of patients had remission of their EIMs within the follow-up period. Conclusions Our findings suggest that dual advanced therapies are safe and may represent a long-term treatment option for complicated patients with IBD. Funding Agencies None

A224 CHARACTERIZATION OF VERY-EARLY-ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN ampersand:003C6 YEARS OF AGE: A SINGLE CENTER EXPERIENCE

Abstract Background Very-early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of six years old, presents a distinct subtype of pediatric inflammatory bowel disease (IBD). This chronic inflammatory condition is believed to result from an abnormal immune response triggered by environmental factors including the gut microbiota, in genetically susceptible individuals. Aims This study aims to analyze the clinical characteristics and management of VEO-IBD patients in a tertiary medical center, evaluating disease presentation, localization and treatment strategies. Methods A retrospective descriptive study was conducted of 28 VEO-IBD patients diagnosed between January 2001 and January 2019 at our institution. Data was abstracted including patient demographics, clinical features, laboratory and histological parameters, treatment, and disease classification based on the revised Porto Criteria. Results Among the 28 patients, Crohn’s disease (CD) was the predominant diagnosis (89%) with predominantly colonic involvement. Thiry-two percent of patients had isolated colitis whereas the upper gastrointestinal (UGI) tract was involved in 57% of the cohort, approximately one third had involvement of the small bowel. The most common presenting symptoms were rectal bleeding and diarrhea, both occurred in 65% of the patients. Patients were followed for a mean duration of 115 months. Despite prior assumptions of its severity, VEO-IBD patients in this cohort responded well to conventional treatments in which 64% were induced with steroid therapy, 25% received biologics and 35% received immunomodulators. Surgical interventions were relatively infrequent. Only 2 patients out the 28 VEO-IBD patients underwent surgery for refractory colitis, one of them in the 1st 2 years of life. There were limited genetic testing results which made it difficult to know our incidence of monogenic IBD. However, only 5 of our patients had full genetic workup done in other centers for research purposes with 1 patient being diagnosed with monogenic IBD consistent IPEX syndrome. Conclusions This study highlights the unique clinical profile of VEO-IBD, with CD being the prevalent diagnosis in this age group in our population. Our cohort did not have a more severe phenotype, emphasizing that there is significant variation within this group Understanding the predictors of response is needed in individual patients with VEO-IBD is vital for tailored management and improved outcomes in this young population. Funding Agencies None

The protective effect of teprenone in TNBS-induced ulcerative colitis rats by modulating the gut microbiota and reducing inflammatory response

Objective Ulcerative colitis (UC), a chronic and refractory nonspecific inflammatory bowel disease, affects millions of patients worldwide and increases the risk of colorectal cancer. Teprenone is an acylic polyisoprenoid that exerts anti-inflammatory properties in rat models of peptic ulcer disease. This in vitro and in vivo study was designed to investigate the effects of teprenone on UC and to explore the underlying mechanisms. Methods Human intestinal epithelial cells (Caco-2 cells) serve as the in vitro experimental model. Lipopolysaccharide (LPS, 1 μg/mL) was employed to stimulate the production of pro-inflammatory cytokines (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α), Toll-like receptor-4 (TLR4), MyD88 expression, and NF-κB activation. A trinitrobenzene sulfonic acid (TNBS)-induced chronic UC rat model was employed for the in vivo assay. Results Pro-inflammatory cytokine stimulation by LPS in Caco-2 cells was inhibited by teprenone at 40 μg/mL through the TLR4/NF-κB signaling pathway. Teprenone attenuated TNBS-induced UC, decreased myeloperoxidase and malondialdehyde, induced TLR4 expression and NF-κB activation, and increased glutathione and zonula occludens-1 level in the rat colonic tissue. Moreover, Fusobacterium, Escherichia coli, Porphyromonas gingivalis elevation, and Mogibacterium timidum decline in UC rats were inhibited by teprenone. Conclusion Based on our results, the protective effects of teprenone for UC may be related to its ability to modulate the gut microbiota and reduce the inflammatory response.