Ulcerative Colitis Cohort Research Articles

Response to Upadacitinib in Patients with Inflammatory Bowel Disease Previously Treated with Tofacitinib.

Upadacitinib is an oral selective Janus kinase (JAK) inhibitor approved in the United States for ulcerative colitis (UC) and Crohn's disease (CD). However, data regarding its use following prior treatment with the JAK inhibitor tofacitinib is sparse. As such, we aimed to evaluate the effectiveness of upadacitinib therapy following tofacitinib exposure. This is a multicenter retrospective study of patients with confirmed diagnosis of UC or CD who received upadacitinib after prior treatment with tofacitinib. The primary outcome of interest was patient-reported clinical improvement at first follow-up. Secondary outcome included discontinuation of corticosteroids, change in Mayo Endoscopic Score (MES) and change in inflammatory marker levels. A total of 31 patients met the inclusion criteria. Following upadacitinib initiation, 80.6% (25/31) of patients had clinical improvement, including 92.3% (24/26) of those with UC and 20% (1/5) of those with CD. Of the patients initially requiring systemic corticosteroid therapy, 80% (12/15) were able to discontinue corticosteroids. Individual mean change of fecal calprotectin was a decrease of 501.5mcg/g ± 608.6 (P value = 0.01) while C-reactive protein decreased on average by 14.8mg/L ± 25.3 (P value = 0.02) compared to when patients were on tofacitinib, with significant changes observed in the UC cohort. In patients with UC, individual MES after initiating upadacitinib decreased compared to prior to tofacitinib discontinuation (P value = 0.04). Our study demonstrates that upadacitinib therapy in patients with prior tofacitinib exposure is associated with clinical improvement and a decrease in objective markers of inflammation in patients with UC.

Specific bacterial co-abundance groups are associated with inflammatory status in patients with ulcerative colitis.

While there is increasing interest in microbiome-directed therapies for patients with ulcerative colitis (UC), the identification of microbial targets remains elusive, underlining the need for novel approaches. Utilizing metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease, available via the IBD Plexus Program of the Crohn's & Colitis Foundation, we used a tree-based dichotomous approach to assemble distinct clusters of species-level bacterial co-abundance groups (CAGs). We evaluated the abundance of bacterial CAGs and fungal taxa during remission (n=166) and activity (n=46). We examined if the bacterial CAGs identified in our cohorts were conserved in 2 healthy cohorts and in a Korean UC cohort. CAG3 and CAG8, dominated by bacteria from family Lachnospiraceae, were associated with remission. Low CAG8 and elevated Candida genus were predictive of active UC. Constituents from CAG8 were influential hub species of the remission-associated microbial UC network, including Ruminococcus gnavus, Erysipelatoclostridium ramosum, Blautia and Dorea species. These hub species interactions were preserved in 2 healthy cohorts and were partially recapitulated in a Korean UC cohort. CAG8 abundance correlated with the secondary bile acid production pathway. Bacterial CAGs did not correlate with Candida, however Bifidobacterium adolescentis and Alistipes putredinis were negatively associated with Candida. Lachnospiriceae-dominated bacterial CAGs were associated with remission in UC, with key bacterial interactions within the CAG also observed in 2 healthy cohorts and a Korean UC cohort. Bacterial CAG-based analyses may help to inform the design of candidate consortia for microbiome-based therapeutics.

An integrative multi-omic analysis defines gut microbiota, mycobiota, and metabolic fingerprints in ulcerative colitis patients.

Ulcerative colitis (UC) is a multifactorial chronic inflammatory bowel disease (IBD) that affects the large intestine with superficial mucosal inflammation. A dysbiotic gut microbial profile has been associated with UC. Our study aimed to characterize the UC gut bacterial, fungal, and metabolic fingerprints by omic approaches. The 16S rRNA- and ITS2-based metataxonomics and gas chromatography-mass spectrometry/solid phase microextraction (GC-MS/SPME) metabolomic analysis were performed on stool samples of 53 UC patients and 37 healthy subjects (CTRL). Univariate and multivariate approaches were applied to separated and integrated omic data, to define microbiota, mycobiota, and metabolic signatures in UC. The interaction between gut bacteria and fungi was investigated by network analysis. In the UC cohort, we reported the increase of Streptococcus, Bifidobacterium, Enterobacteriaceae, TM7-3, Granulicatella, Peptostreptococcus, Lactobacillus, Veillonella, Enterococcus, Peptoniphilus, Gemellaceae, and phenylethyl alcohol; and we also reported the decrease of Akkermansia; Ruminococcaceae; Ruminococcus; Gemmiger; Methanobrevibacter; Oscillospira; Coprococus; Christensenellaceae; Clavispora; Vishniacozyma; Quambalaria; hexadecane; cyclopentadecane; 5-hepten-2-ol, 6 methyl; 3-carene; caryophyllene; p-Cresol; 2-butenal; indole, 3-methyl-; 6-methyl-3,5-heptadiene-2-one; 5-octadecene; and 5-hepten-2-one, 6 methyl. The integration of the multi-omic data confirmed the presence of a distinctive bacterial, fungal, and metabolic fingerprint in UC gut microbiota. Moreover, the network analysis highlighted bacterial and fungal synergistic and/or divergent interkingdom interactions. In this study, we identified intestinal bacterial, fungal, and metabolic UC-associated biomarkers. Furthermore, evidence on the relationships between bacterial and fungal ecosystems provides a comprehensive perspective on intestinal dysbiosis and ecological interactions between microorganisms in the framework of UC.

Gut microbiota-based discriminative model for patients with ulcerative colitis: A meta-analysis and real-world study.

Gut microbiota directly interacts with intestinal epithelium and is a significant factor in the pathogenesis of ulcerative colitis (UC). A meta-analysis was performed to investigate gut microbiota composition of patients with UC in the United States. We also collected fecal samples from Chinese patients with UC and healthy individuals. Gut microbiota was tested using 16S ribosomal RNA gene sequencing. Meta-analysis and 16S ribosomal RNA sequencing revealed significant differences in gut bacterial composition between UC patients and healthy subjects. The Chinese UC group had the highest scores for Firmicutes, Clostridia, Clostridiales, Streptococcaceae, and Blautia, while healthy cohort had the highest scores for P-Bacteroidetes, Bacteroidia, Bacteroidales, Prevotellaceae, and Prevotella_9. A gut microbiota-based discriminative model trained on an American cohort achieved a discrimination efficiency of 0.928 when applied to identify the Chinese UC cohort, resulting in a discrimination efficiency of 0.759. Additionally, a differentiation model was created based on gut microbiota of a Chinese cohort, resulting in an area under the receiver operating characteristic curve of 0.998. Next, we applied the model established for the Chinese UC cohort to analyze the American cohort. Our findings suggest that the diagnostic efficiency ranged from 0.8794 to 0.9497. Furthermore, a combined analysis using data from both the Chinese and US cohorts resulted in a model with a diagnostic efficacy of 0.896. In summary, we found significant differences in gut bacteria between UC individuals and healthy subjects. Notably, the model from the Chinese cohort performed better at diagnosing UC patients compared to healthy subjects. These results highlight the promise of personalized and region-specific approaches using gut microbiota data for UC diagnosis.

Computed tomography-based body composition parameters can predict short-term prognosis in ulcerative colitis patients.

Emerging evidence suggests a potential relationship between body composition and short-term prognosis of ulcerative colitis (UC). Early and accurate assessment of rapid remission based on conventional therapy via abdominal computed tomography (CT) images has rarely been investigated. This study aimed to build a prediction model using CT-based body composition parameters for UC risk stratification. In total, 138 patients with abdominal CT images were enrolled. Eleven quantitative parameters related to body composition involving skeletal muscle mass, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured and calculated using a semi-automated segmentation method. A prediction model was established with significant parameters using a multivariable logistic regression. The receiver operating characteristic (ROC) curve was plotted to evaluate prediction performance. Subgroup analyses were implemented to evaluate the diagnostic efficiency of the prediction model between different disease locations, centers, and CT scanners. The Delong test was used for statistical comparison of ROC curves. VAT density, SAT density, gender, and visceral obesity were significantly statistically different between remission and invalidation groups (all p < 0.05). The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of the prediction model were 82.61%, 95.45%, 69.89%, and 0.855 (0.792-0.917), respectively. The positive predictive value and negative predictive value were 70.79% and 93.88%, respectively. No significant differences in the AUC of the prediction model were found in different subgroups (all p > 0.05). The predicting model constructed with CT-based body composition parameters is a potential non-invasive approach for short-term prognosis identification and risk stratification. Additionally, VAT density was an independent predictor for escalating therapeutic regimens in UC cohorts. The CT images were used for evaluating body composition and risk stratification of ulcerative colitis patients, and a potential non-invasive prediction model was constructed to identify non-responders with conventional therapy for making therapeutic regimens timely and accurately. • CT-based prediction models help divide patients into invalidation and remission groups in UC. • Results of the subgroup analysis confirmed the stability of the prediction model with a high AUC (all > 0.820). • The visceral adipose tissue density was an independent predictor of bad short-term prognosis in UC.

A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF PSYLLIUM FIBER AND FECAL MICROBIOTA TRANSPLANTATION FOR MILD TO MODERATE ULCERATIVE COLITIS

Abstract BACKGROUND Emerging clinical data shows potential for fecal microbiota transplantation (FMT) in treating ulcerative colitis (UC), though factors affecting clinical response remain poorly defined. Pre-clinical data suggest the role of dietary fiber in enhancing microbial metabolites to mitigate colitis severity. This study aimed to evaluate the role of the prebiotic psyllium in improving the clinical outcomes of FMT for mild to moderate UC, with the long-term goal of enhancing FMT as a therapeutic strategy for UC. METHODS In a randomized, placebo-controlled clinical trial, 32 participants were screened, and 27 adults with mild to moderate UC were enrolled. Baseline fiber intake was assessed through a food frequency questionnaire. Subjects were randomly assigned to receive FMT alone, FMT with daily fiber (10g of psyllium), or a placebo with or without fiber. The primary endpoint was clinical response by Mayo score at week 8. Secondary endpoints included clinical response by partial Mayo (pMayo) score, endoscopic sub-score, and clinical remission. At week 8, participants underwent crossover treatment with clinical evaluation at week 12. The study ended early due to the manufacturer discontinuing fecal microbiota preparation supply. RESULTS Analysis of primary and secondary endpoints in "FMT alone" and "FMT with fiber" groups revealed no statistically significant differences in clinical response (55.56% alone, N=9 vs. 22.22% fiber, N=9, p=0.1686). Participants with low and high dietary fiber consumption had similar response rates, regardless of supplemental fiber. Consequently, we combined the "FMT" and "no FMT" groups, which showed a significantly higher proportion of subjects achieving clinical response in the FMT group as defined by the partial Mayo score (50.00% FMT group (N=18) and 11.1% in the no FMT group (N=9), p=0.0485). A similar trend was observed for clinical response as defined by the total Mayo score and endoscopic sub-score, where the FMT group outperformed the placebo (38.89% FMT, N=18, vs. 11.11% placebo, N=9, p=0.1362). Among the 9 subjects who received FMT at week 0 and exhibited clinical response defined by pMayo, 77.8% (n=7) maintained their response at week 12. Additionally, 2 patients who initially had no response at week 8 achieved a clinical response by week 12. CONCLUSION The results demonstrate a robust effect of single-dose FMT via colonoscopy in a mild to moderate UC cohort. Given the low cohort size, our results lack the statistical power to reveal the clinical impact of fiber supplementation in FMT. Notably, a substantial proportion of initially responsive FMT recipients maintained their clinical response at week 12, indicating the potential for sustained benefits. Microbiome and metabolomic analyses are currently underway to assess the functional impact of dietary fiber in shaping the effectiveness of FMT for UC.

P103 Natural compounds in Ulcerative Colitis and Irritable Bowel Syndrome: Insights from immune-metabolic profiles

Abstract Background Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent chronic and occasionally disabling conditions, necessitating innovative treatment strategies. Covering 14% of Ireland's landscape, bogland ecosystems house unique plant biodiversity, yielding biologically active secondary metabolites. Informed by traditional medicinal knowledge and in vitro screening for immunomodulatory potential, three plant extracts (NTP0226A, NTP0127B, NTP0206EA) were selected for exploration of their potential to treat IBD and IBS within the "Unlocking Nature’s Pharmacy from Bogland Species" project. Methods Patients undergoing colonoscopy were prospectively recruited in three cohorts: healthy controls, IBS, and ulcerative colitis (UC). Recto-sigmoid biopsies were collected and cultured for 24 h with treatments (Infliximab, NTP0226A, NTP0127B, NTP0206EA). Colonic tissue explants underwent real-time energy metabolism profiling and quantification of 10 inflammatory mediators using Seahorse Xfe24 analyser and multiplex ELISA, respectively. P values &amp;lt;0.05 were considered significant in analyses. Results Twenty-seven patients were recruited (6 healthy controls, 6 IBS, and 15 UC). UC patient explants exhibited elevated glycolytic metabolism and increased IL-4, IL-6, and IL-12p70 secretion compared to non-UC patients. No differences were observed between healthy controls and IBS patients. Linear regression did not show correlation between age and mitochondrial bioenergetics. There was no change in metabolism profiles of any cohort following treatment with Infliximab or the 3 novel extracts. In the UC tissue, treatment with Infliximab reduced IL-12p70 secretion (p=0.0098), this reduction was not seen in the other 2 cohorts. NTP0206EA reduced IL-10 secretion in the UC cohort (p=0.0255). In the IBS cohort; NTP0127B reduced IL-10 secretion (p=0.0048) and NTP0226A reduced IL-4 (p=0.004) and IL-6 (p=0.0219) secretion. Principal component analysis demonstrated reduced separation between the immune-metabolic profiles of UC patients and healthy controls following treatment with NTP0226A (Figure 1). Conclusion Using an explant model, we have shown that UC patients have a distinct immune-metabolic profile modifiable by a standard IBD therapy and novel plant extracts. Blockade of IL-6 trans-signalling has recently shown promise as an effective treatment target in IBD. Our natural extract NTP0226A reduced IL-6 secretion in IBS patients and is a promising candidate for therapeutic exploration. These findings contribute to our understanding of the complex interplay in the colonic microenvironment and highlight potential avenues for novel therapeutic interventions.

P540 Non-serious adverse events in patients with ulcerative colitis receiving etrasimod: An analysis of the phase 2 OASIS and phase 3 ELEVATE UC 52 and ELEVATE UC 12 clinical trials

Abstract Background Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Adverse events (AEs) pertaining to tolerability, laboratory and serious AEs are described elsewhere1,2; we present a post hoc analysis of the incidence, onset and duration of the most commonly occurring non-serious AEs in the etrasimod UC clinical programme. Methods Data from the pooled Placebo-controlled UC cohort, derived from the phase 2 OASIS (NCT02447302) and phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) double-blind clinical trials, were included. Cohorts comprised OASIS and ELEVATE UC 12 12-week induction periods alongside the ELEVATE UC 52 12-week induction and 40-week maintenance periods utilising a "treat-through" design. Patients (pts) with moderately to severely active UC were eligible for the etrasimod UC clinical programme. Pts were randomised to etrasimod 1 mg once daily (QD; OASIS only), etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) of non-serious AEs (MedDRA v24.1 Preferred Terms of headache, pyrexia, nausea, fatigue and dizziness) were analysed in the Placebo-controlled UC cohort. Results Among 943 pts (any dose of etrasimod, N=629 [288.1 pt years (PY)]; placebo, N=314 [115.1 PY]), there were 77, 36, 30, 15 and 23 headache, pyrexia, nausea, fatigue and dizziness AEs, respectively. All were non-serious and did not lead to treatment discontinuation, apart from one case of pyrexia in which early termination visits were incomplete. Proportions and IRs (per 100 PY) for headache and dizziness AEs were higher with etrasimod (any dose) vs placebo (IRs: 13.45 vs 8.63 and 6.52 vs 1.69, respectively); IRs for other non-serious AEs were similar in etrasimod (any dose) and placebo groups (Table). Onset of AEs varied over time and most AEs were short in duration (Figure shows onset and duration for headache and dizziness AEs). Most AEs were deemed not related to study treatment by the site investigator. Pts with dizziness on Days 1–3 had similar changes in heart rate vs those with dizziness after Day 3. No consistent trend in heart rate was observed in pts receiving etrasimod with early dizziness. Conclusion Among pts in the etrasimod UC clinical programme, all headache, pyrexia, nausea, fatigue and dizziness events were non-serious. IRs were similar for most non-serious AEs across treatment groups, excluding headache and dizziness. Most non-serious AEs were short in duration and judged as not related to study treatment, suggesting they may not impact on the overall tolerability of etrasimod.

OP39 Vedolizumab response in ulcerative colitis associates with reduced IgG+ plasma cells and FcγR signaling

Abstract Background Vedolizumab (VDZ) targets the gut-homing receptor α4β7. Despite its widespread use as a frontline therapy for ulcerative colitis (UC), its mode of action (MOA) remains unclear. Previously, we documented that response to VDZ is associated with size loss of gut-associated lymphoid tissues (GALT). To further understand drug MOA, here we aimed at defining the relationship between GALT attrition and resolution of inflammation. Methods Tissue immunofluorescence (IF) was performed on two independent UC cohorts (n=60, n=21) studied longitudinally pre- and post-VDZ. Peripheral blood mononuclear cells from UC patients (n=56) were examined at week 0 (pre-VDZ) and 14 (post-VDZ) by flow cytometry, while intestinal biopsies were analyzed in a subset of patients. Transcriptomic analyses were performed in a third cohort of 401 UC patients and 243 controls where bulk RNA-sequencing was performed on intestinal biopsies. Finally, data from a fourth validation cohort (n=31) was examined pre- and post-VDZ. Results Using IF, we examined follicular naïve B (FB) cells (IgD+), germinal center (GC) B cells (BCL6+CD3-) and total T cells (CD3+), and identified three GALT types: organized aggregates (demarcated B/T cell zones) with GC, organized aggregates without GC, and poorly organized aggregates (Fig1A). When comparing pre- and post-VDZ, Responders (R) had a significant reduction in GALT organization, while no change was seen in Non-Responders (NR). The number of FB cells was significantly reduced post-VDZ in R but not in NR (Fig1B), with no change in T cells (Fig1C). The reduction in FB was validated using transcriptomic data (Fig1D). To explore potential consequences of GALT attrition, we analyzed circulating β7+ (GALT-generated) and β7- plasmablasts (PB). The frequencies of β7+IgG+ and β7+IgA+ PB were significantly reduced post-VDZ in R, but not in NR (Fig1E). No change was observed in β7- PB post-VDZ (Fig1F). Among β7+ PB, there was a greater reduction in IgG+ compared to IgA+ (Fig1G). Furthermore, colonic IgG+ plasma cells (PC) were significantly reduced post-VDZ in R but not in NR (Fig1H). To evaluate IgG-mediated proinflammatory function, we studied the expression of FcγR-pathway genes in colonic biopsies. Importantly, the FcγR-pathway was enhanced in inflamed tissues of UC patients (Fig1I-J) and was significantly reduced in R (but not in NR) post-VDZ (Fig1K). Conclusion Our work demonstrates a novel effect of anti-α4β7 blockade that results in intestinal lymphoid aggregate attrition through impaired recruitment of naïve B cells, leading to the suppression of IgG-driven immune responses and proinflammatory FcγR signaling. These data highlight the targeting of GALT as a novel therapeutic paradigm in IBD.

P870 Effectiveness and safety of adalimumab as first line biological treatment in Ulcerative Colitis

Abstract Background The increase in licensed therapies for ulcerative colitis (UC) is revolutionizing its treatment but making first line choice more challenging. Adalimumab (ADA) is inexpensive but, anecdotally, is sometimes regarded as less effective than other first line advanced therapies. We aimed to evaluate the results of first line ADA in UC. Methods We performed a single centre retrospective analysis of UC patients started on ADA between January 15 and March 2022 in an IBD referral hospital. Clinical remission was defined as SCCAI &amp;lt;2 points, endoscopic remission as a UCEIS &amp;lt;2 points and treatment failure as the need for colectomy or second biological line Results A total of 79 patients were included (Table 1). Median follow-up was 19 months (2-91); 78.5% were followed &amp;gt;6 months. At 6 months, 80.3% (61/76) and 37.3% (22/59) of the patients were in clinical and endoscopic remission, respectively. 54.3% received combination treatment with immunomodulators (50.6% thiopurines, 3.7% methotrexate). Dose intensification to weekly treatment occurred in 27.8% after median 9 months (4-48 months). During follow-up 51% received corticosteroids at some point (26% topically-acting oral corticosteroids, 10% oral corticosteroids, 15% both). Of patients who received steroids, 55% (22/40) were able to continue adalimumab therapy. 2.5% of patients were hospitalised for a disease flare. 5.1% had an infection recorded during follow up, none discontinued the treatment. No other major adverse events were recorded. In 22.8% (18/79) of patients, ADA was stopped due to treatment failure, mean 15 months after starting the drug (4-56 months), (Figure 1). None of these patients underwent colectomy at the time of stopping the drug; in 17/18 a second biological therapy was started (10 tofacitinib, 1 filgotinib, 1 upadacitinib, 2 ustekinumab, 2 vedolizumab, 1 golimumab). TDM was performed using a drug-sensitive ELISA, which is only able to detect antidrug antibodies when drug levels are low or absent. Drug levels at the time of stopping the drug were &amp;lt;5 µg/mL in 22% of patients (in 2 antibodies were detected), 5-8 µg/mL in 11% and &amp;gt;8 µg/mL in 67%. Conclusion In a real-world UC cohort, ADA appears to be an effective well tolerated first-line advanced therapy with the vast majority of patients reaching clinical remission and a significant proportion achieving mucosal healing. Table 1. Cohort characteristics (N 79, frequency and %). Figure 1: Kaplan-Meier survival analysis of time to ADA discontinuation.

P1187 Persistence of Advanced Therapies in Patients with Inflammatory Bowel Disease: Retrospective cohort study using large healthcare claims database in Japan

Abstract Background Inflammatory bowel disease (IBD) is a lifelong disease and strategically utilizing advanced therapies is essential. Few studies exist to inform the drug utilization of biologics or JAK inhibitors in Japan. The objective is to describe persistence of index and subsequently used biologics or JAK inhibitors in patients with Crohn’s disease (CD) or ulcerative colitis (UC) in Japan. Methods This retrospective cohort study used the Japan Medical Data Center database, which contains claims data from 14 million individuals in Japan. Patients who were diagnosed with CD or UC, and received advanced therapy, including biologics and JAK inhibitors, between January 1, 2010 and September 30, 2022 were included. Patients aged at least 15 years old were required to have no treatment with advanced therapies within 6-month prior to the initiation of index treatments of interest: adalimumab, infliximab, vedolizumab, golimumab, ustekinumab and tofacitinib for CD and UC in Japan. Persistence was defined as having continuous treatment with each therapy over a specified follow-up period (i.e., 6 months, 12 months, 18 months, or 24 months since the index date), without the presence of a pre-defined treatment gap, i.e., 1.5 times the number of days covered by the prior day’s supply. Results The numbers of eligible patients with CD and UC during the study period were 1,115 and 1,942, respectively. Among patients with CD, the distribution of index treatment for adalimumab, infliximab, ustekinumab and vedolizumab was 41.4%, 37.4%, 18.2%, and 3.0%, respectively. Among patients with UC, the distribution of index treatment for infliximab, adalimumab, vedolizumab, golimumab, tofacitinib and ustekinumab was 33.6%, 24.8%, 17.5%, 11.2%, 7.3% and 5.6%, respectively. For CD cohort, persistence of ustekinumab was numerically highest in all periods (94.7% at 6 months, 91.3% at 12 months, 88.2% at 18 months and 80.4% at 24 months), followed by infliximab (94.1%, 87.7%, 82.0% and 76.8%, respectively). For UC cohort, highest persistence was observed in ustekinumab through all periods (95.1% at 6 months, 84.0% at 12 months, 81.6% at 18 months and 75.0% at 24 months), followed by vedolizumab (82.0%, 69.7%, 64.2% and 59.4%, respectively). As subsequent treatments, persistence of ustekinumab and infliximab were comparable for CD while the highest persistence was observed for ustekinumab through all periods for UC. Conclusion Persistence of advanced IBD treatments available in Japan was investigated. As an index treatment, ustekinumab maintained high persistence through 2 years from the index date both in CD and UC. This data provides valuable information on the management of patients living in Japan with IBD under real-world setting.

P046 Real-world data on the treatment with Mirikizumab in a mostly biological-experienced Ulcerative colitis cohort

Abstract Background Mirikizumab was approved for treating Ulcerative colitis (UC) in May 2023. However, real-world data, especially in biological-experienced patients, is scarce. We aimed to determine the treatment efficacy and persistence of Mirikizumab in mostly treatment-experienced UC patients. Methods All patients treated for UC in the Inflammatory Bowel Disease (IBD) outpatient clinic of the University Hospital Frankfurt from 07/23-11/23 were analyzed retrospectively. Data on clinical (Simple Clinical Colitis Activity Index (SCCAI)) and biochemical disease activity (fecal calprotectin (FC)), as well as patient history, were collected. Patients were followed up for at least 12 weeks. Results Seventeen patients with UC were included. Sixteen patients had already received at least one biological agent before starting Mirikizumab. Twelve patients were exposed to ≥ 2 biological agents, and four patients to ≥ 4 biological agents before starting Mirikizumab. One patient received Mirikizumab as a first-line treatment. 4 patients were treated with Ustekinumab before the therapy with Mirikizumab. Nine patients received oral steroids as a concomitant treatment. The median SCCAI at the time of the first infusion/start of induction was 7. We report a reduction in clinical disease activity from 7 to 5 based on the preliminary data of the SCCAI. Biochemical disease activity was assessed with FC levels. The median FC level at the start of the induction was 557.5. At week 8, the median FC level was 513 based on 7 out of 17 patients reached week eight until November 2023. Intravenous induction therapy was extended in 2 of 17 patients. There was no report of adverse events. Conclusion We report preliminary real-world data on the evidence and efficacy of Mirikizumab. In our interim analysis, Mirikizumab is an effective and safe treatment in biological-experienced UC patients.

Identifying Macrophage-Related Genes in Ulcerative Colitis Using Weighted Coexpression Network Analysis and Machine Learning.

Ulcerative colitis (UC) is an inflammatory bowel disease of unknown cause that typically affects the colon and rectum. Innate intestinal immunity, including macrophages, plays a significant role in the pathological development of UC. Using the CIBERSORT algorithm, we observed elevated levels of 22 types of immune cell infiltrates, as well as increased M1 and decreased M2 macrophages in UC compared to normal colonic mucosa. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with macrophages and UC, resulting in the identification of 52 macrophage-related genes (MRGs) that were enriched in macrophages at single-cell resolution. Consensus clustering based on these 52 MRGs divided the integrated UC cohorts into three subtypes. Machine learning algorithms were used to identify ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14), and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the training set, and their diagnostic value was validated in independent validation sets. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed the main biological effects, and that interleukin-17 was one of several signaling pathways enriched by the three genes. We also constructed a competitive endogenous RNA (CeRNA) network reflecting a potential posttranscriptional regulatory mechanism. Expression of diagnostic markers was validated in vivo and in biospecimens, and our immunohistochemistry (IHC) results confirmed that HMGCS2 gradually decreased during the transformation of UC to colorectal cancer. In conclusion, ENPP1, SLC6A14, and HMGCS2 are associated with macrophages and the progression of UC pathogenesis and have good diagnostic value for patients with UC.

Short-term outcomes of bariatric surgery in patients with inflammatory bowel disease: a national analysis

BackgroundWhile considered standard of care for obesity management, bariatric surgery is uncommon in patients with co-morbid inflammatory bowel disease (IBD). ObjectivesThe present study aimed to assess the association of IBD with postoperative outcomes and resource use following bariatric surgery. SettingAcademic, university-affiliated; United States. MethodsAll elective adult hospitalizations for laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) were identified in the 2016–2019 Nationwide Readmissions Database. Patients were classified based on diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD). Multivariable regression models were developed to evaluate the association of IBD with outcomes of interest. ResultsOf an estimated 719,270 eligible patients, 860 and 1214 comprised the UC and CD cohorts, respectively. Compared to non-IBD, UC and CD had a higher Elixhauser comorbidity index (UC: 3.0 ± 1.4; CD: 3.1 ± 1.5; non-IBD: 2.7 ± 1.4, P < .001) and more frequently underwent sleeve gastrectomy (UC: 77.5%; CD: 83.2%; non-IBD: 68.8%, P < .001). All IBD patients survived to discharge. After adjustment, IBD was not associated with significant differences in most clinical outcomes analyzed. UC (adjusted odds ratio: 2.86; 95% confidence interval: 1.14–7.13) and CD (adjusted odds ratio: 4.40; 95% confidence interval: 2.20–8.80) were associated with increased odds of gastric outlet obstruction after RYGB but not sleeve gastrectomy. CD, but not UC, was linked to significantly higher odds of small bowel obstruction following RYGB (adjusted odds ratio: 4.50; 95% confidence interval: 1.76–11.49). There was no difference in index LOS, hospitalization costs, or odds of 30-day readmission based on IBD. ConclusionsPatients with obesity and IBD faced low rates of adverse outcomes following bariatric surgery. There is an increased risk of gastrointestinal obstruction for patients with IBD undergoing RYGB. Given its safety profile, bariatric surgery can be utilized as a weight loss intervention for the growing proportion of patients with obesity and co-morbid IBD.

Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn's disease, and celiac disease.

Ulcerative colitis (UC), Crohn's disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate-induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.

Association between body fat composition and disease duration, clinical activity, and intravenous corticosteroid-induced response in inflammatory bowel disease

BackgroundBody fat composition is believed to be associated with the progression, medical response, and prognosis of inflammatory bowel disease (IBD). Hence, we conducted this study to explore if fat metrics were associated with the disease activity of severe IBD and the response to intravenous corticosteroids (IVCS).MethodsWe included 69 patients with ulcerative colitis (UC) and 72 patients with Crohn's disease (CD) who had previously received IVCS during hospitalization. We quantified individual fat distribution using abdominal computed tomography slices. The correlations between fat parameters and disease activity were available with Spearman correlation analysis. The prediction model was developed using independent risk factors derived from multivariable logistic regression analysis. Model discrimination was evaluated leveraging the receiver operating characteristic curve. 1000 bootstrap resamples internally validated the model's prediction performance.ResultsNotable differences in age, nutritional status, serum cytomegalovirus replication, stool condition, and extraintestinal involvement between UC and CD patients were observed. UC subjects who responded to IVCS had higher subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), and mesorectal adipose tissue index (MATI) than non-responders. IVCS-responding CD individuals had lower VATI and mesenteric fat index (MFI) than non-responders. CD patients with a prolonged disease duration had a decreased SATI and an elevated MFI. VATI and MATI were reduced as UC clinically progressed, while more prominent clinical activity in CD correlated with increased VATI, MATI, and MFI. A high SATI indicated that patients with UC were more prone to be IVCS responders. For patients with CD, levels of VATI and MFI were negatively associated with effective IVCS treatment. The established models showed a discriminative accuracy of 0.834 [95% confidence interval (CI) 0.740–0.928] in the UC cohort and 0.871 (95% CI 0.793–0.949) in the CD cohort. Repeated samples supported the reliability of the developed models (AUCUC = 0.836, 95% CI 0.735–0.919; AUCCD = 0.876, 95% CI 0.785–0.946).ConclusionHuman fat indexes represent novel imaging biomarkers for identifying IBD patients who respond to IVCS, thus building accelerated therapy regimens and avoiding the adverse effects of ineffective IVCS.

Economic and Clinical Burden of Herpes Zoster Among Patients With Inflammatory Bowel Disease in the United States.

Patients with ulcerative colitis (UC) or Crohn's disease (CD) are at increased risk of herpes zoster (HZ); however, relevant cost and healthcare resource utilization (HCRU) data are limited. We estimated HCRU (hospitalization, emergency department [ED], and outpatient visits) and costs in patients with UC or CD, with and without HZ, using administrative claims data (October 2015-February 2020). HCRU and costs (2020 US dollars) were compared at 1 month, 1 quarter, and 1 year after the index date, using propensity score adjustment and generalized linear models. In total, 20 948 patients were included: UC+/HZ+ (n = 431), UC+/HZ- (n = 10 285), CD+/HZ+ (n = 435), and CD+/HZ- (n = 9797). Patients with HZ had higher all-cause HCRU rates and all-cause total healthcare costs relative to those without HZ. In the first month, adjusted incidence rate ratios (aIRRs) for hospitalizations and ED visits for patients with UC and HZ compared with UC alone were 2.87 (95% confidence interval [CI], 1.93-4.27) and 2.66 (95% CI,1.74-4.05), respectively; for those with CD and HZ, aIRRs were 3.34 (95% CI, 2.38-4.70) and 3.31 (95% CI, 2.32-4.71), respectively, compared with CD alone (all P < .001). Adjusted cost differences in UC and CD cohorts with HZ over the first month were $2189 and $3774, respectively, chiefly driven by higher inpatient costs. The incremental impact on HCRU and costs in cohorts with HZ predominantly occurred during the first quarter following diagnosis. HZ is associated with increased HCRU and costs in patients with UC and CD, especially shortly after diagnosis.

Acute idiopathic pancreatitis is associated with more aggressive disease course in Crohn’s disease but not in ulcerative colitis

PurposePatients with inflammatory bowel disease (IBD), whether Crohn’s disease (CD) or ulcerative colitis (UC), have an increased risk of acute pancreatitis. The prognostic value of diagnosing acute idiopathic pancreatitis in patients with IBD is not well understood.MethodsA retrospective review of 56 patients with IBD and acute pancreatitis was conducted in a tertiary center from 2011 to 2020. Aggressive disease course was defined as (i)biologic change, (ii)biologic dose escalation, or (iii)IBD-related surgeries occurring within 1 year of acute pancreatitis diagnosis. Logistic regression modelling identified associations between covariates and an aggressive disease course.ResultsBaseline characteristics between idiopathic pancreatitis and other causes of acute pancreatitis, in both CD and UC cohorts, were similar. Idiopathic pancreatitis was significantly associated with an aggressive disease course in CD (P = 0.04). No confounding factors were associated with an aggressive disease course in CD. Idiopathic pancreatitis, however, was not associated with an aggressive disease course in UC (P = 0.35).ConclusionThe diagnosis of acute idiopathic pancreatitis may provide a prognostic indicator of a more severe disease course in CD. No such association appears to exist with UC. To the best of our knowledge, this is the first study that identifies an association and possible prognostic value between idiopathic pancreatitis and a more severe disease course in CD. More studies with a larger sample size are needed to validate these findings, further define idiopathic pancreatitis as an extraintestinal manifestation of IBD and elucidate a clinical strategy to optimize care in patients with aggressive CD and idiopathic pancreatitis.

1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

Colectomy in patients with ulcerative colitis is not associated to future diagnosis of primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a hepatobiliary disease closely related to ulcerative colitis (UC). In PSC patients, colectomy has been linked to improved prognosis, especially following liver transplantation. This suggests an involvement of the gut-liver axis in PSC etiology. We aimed to investigate the association between colectomy and the risk of future PSC in an epidemiological setting. Through nationwide registers, we identified all adults diagnosed with UC in Sweden 1990-2018 and retrieved information on PSC diagnosis and colectomy. Within the UC cohort (n=61,993 patients), we matched 5577 patients with colectomy to 15,078 without colectomy. Matching criteria were sex, age at UC onset (±5years), year of UC onset (±3years), and proctitis at the time of colectomy. Incidence rates of PSC per 1000-person year were calculated, and the Cox proportional hazard regression model estimated hazard ratios (HRs) for PSC until 31 December 2019. During the follow-up, 190 (3.4%) colectomized UC patients and 450 (3.0%) UC comparators developed PSC, yielding incidence rates of 2.6 and 2.4 per 1000 person-years (HR 1.07 [95% CI 0.90-1.28]). The cumulative incidence of colectomy decreased remarkably over calendar periods, but the cumulative incidence of PSC remained unchanged. The risk of developing PSC in colectomized versus comparators changed over time (HR 0.68 [95% CI; 0.48-0.96] in 1990-97 and HR 2.10 [95% CI; 1.37-3.24] in 2011-18). In UC patients, colectomy was not associated with a decreased risk of subsequent PSC. The observed differences in the risk of PSC development over calendar periods are likely due to changes in PSC-diagnosis and UC-treatment.