bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP37 Efficacy and safety of 3 years of continuous ozanimod treatment: an interim analysis of the True North open-label extension study
Authors: Danese S , Abreu M T , Wolf D C , Canavan J B , Jain A , Wu H , Petersen A , Charles L , Panaccione R , Afzali A 
Published: January 2023

Abstract

Background
The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients with moderately to severely active ulcerative colitis (UC). Patients completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented is the interim analysis of the TN OLE in patients with approximately 3 years of continuous ozanimod treatment.

Methods
This analysis evaluated patients who achieved clinical response after receiving 52 weeks of continuous ozanimod 0.92 mg during TN and subsequently entered the TN OLE (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition was available for patients). Patient-reported (rectal bleeding and stool frequency) and clinician-reported (Physician’s Global Assessment) outcomes were collected. Centrally read endoscopy was performed at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively). Efficacy data (clinical remission, clinical response, endoscopic improvement, and corticosteroid-free remission) were evaluated in the intent-to-treat population at OLE Weeks 46 and 94 using observed case (OC) and nonresponder imputation (NRI) analyses. Partial Mayo scores (PMS) were assessed from TN baseline to OLE Week 94. Adverse events were monitored throughout TN and the subsequent OLE.

Results
In all, 131 patients entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN; at data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumour necrosis factor inhibitors. Most patients achieved clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement at OLE Week 46 in the OC (Figure 1A) and NRI (Figure 1B) analyses. At OLE Week 94, 91.4% of patients achieved clinical response in the OC analysis (NRI, 56.5%). Ozanimod was associated with a reduction in mean PMS during TN (PMS=6.2 at Week 0 and 0.9 at Week 52), and this was sustained through OLE Week 94 (PMS=0.9) (Figure 2). No new safety findings emerged from this analysis.

Conclusion
This interim analysis of the TN OLE found that most of the patients who achieved clinical response after 1 year of ozanimod had sustained efficacy for an additional 2 years. No new safety signals were observed with long-term ozanimod use.
DOP41 Achievement of corticosteroid-free clinical endpoints in subjects with ulcerative colitis: an analysis of the phase 3 ELEVATE UC 52 trial
Authors: Sands B E , Rubin D T , Panés J , Gecse K B , Leung Y , Goetsch M , Wang W , Shan K , Woolcott J , Smith C C , Wosik K , Schreiber S W 
Published: January 2023

Abstract

Background
Achievement of corticosteroid (CS)-free remission is an important long-term outcome in ulcerative colitis (UC). Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active UC. This analysis of the ELEVATE UC 52 trial reports on the achievement of CS-free clinical endpoints.

Methods
In ELEVATE UC 52 (NCT03945188), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. At study entry, subjects were permitted to receive concomitant treatment with CS (prednisone [≤20 mg/day], budesonide [≤9 mg/day], or equivalent]) provided they were on a stable dose 4 weeks prior to the screening endoscopy. Tapering of CS begun after the induction period. This analysis reports on achievement of CS-free (defined as no CS exposure in the 12 weeks immediately prior to week 52) clinical remission, CS-free endoscopic improvement, and CS-free symptomatic remission at week 52 in the ELEVATE UC 52 population, as well as CS-free clinical remission in pre-specified subgroups.

Results
In ELEVATE UC 52 a significantly greater proportion of etrasimod-treated subjects had CS-free clinical remission (32.1% [88/274] vs 6.7% [9/135]; P&lt;0.001), CS-free endoscopic improvement (36.9% [101/274] vs 10.4% [14/135]; P&lt;0.001), and CS-free symptomatic remission (43.4% [119/274] vs 18.5% [25/135]; P&lt;0.001) at week 52 vs PBO (Figure 1). Subgroup analyses of CS-free clinical remission demonstrated efficacy across subgroups including previous exposure to a biologic/JAKi, number of previous biologics/JAKis (0, 1, or &gt;1), disease severity at baseline (MMS 4-6 or 7-9), and extent of disease (proctitis, left-sided colitis/proctosigmoiditis, or pancolitis) (Figure 2A-D). There was a trend towards greater benefit in subjects who were biologic/JAKi naive and subjects who had been exposed to 0 or 1 vs &gt;1 prior biologic/JAKi.

Conclusion: In ELEVATE UC 52, a greater proportion of etrasimod-treated subjects achieved CS-free clinical remission, CS-free endoscopic improvement, and CS-free symptomatic remission at week 52 vs PBO. These results were also consistent for multiple disease-specific subgroups, including those with and without prior exposure to biologics/JAKis. Notably, all ELEVATE UC 52 subjects who were in clinical and symptomatic remission at week 52 were also in CS-free clinical and CS-free symptomatic remission.1
Reference:
1. Sandborn WJ, et al. Presented at: DDW 2022; May 24, 2022. Abstract 968a.
DOP46 Mucosal host-microbe interactions associate with clinical phenotypes in Inflammatory Bowel Disease
Authors: Bourgonje A , Hu S , Gacesa R , Jansen B H , Björk J R , Bangma A , Hidding I J , van Dullemen H M , Visschedijk M C , Faber K N , Dijkstra G , Harmsen H J M , Festen E A M , Vich Vila A , Spekhorst L M , Weersma R K 
Published: January 2023

Abstract

Background
Host intestinal immune gene signatures and microbial dysregulations expose potential mechanisms in the pathogenesis of inflammatory bowel diseases (IBD). Profiling of mucosa-attached microbiota allows the understanding of locally present microbial communities and their immediate impact on the host. This study aimed to comprehensively examine interactions between host mucosal gene expression and mucosal microbiota in patients with IBD.

Methods
Intestinal mucosal RNA-sequencing data was combined with mucosal 16S rRNA gene sequencing data from 696 intestinal biopsies derived from 337 patients with IBD (181 with Crohn’s disease [CD] and 156 with ulcerative colitis [UC]) and 16 non-IBD controls (Fig. 1). Mucosal gene expression and bacterial abundances were systematically analyzed in relation to the presence of inflammation, Montreal disease classification, medication use (e.g. TNF-α-antagonists) and dysbiotic status. Pathway-based clustering and network analysis (Sparse-CCA and centrLCC analysis) and individual pairwise gene–taxa associations were investigated to identify host–microbiota interactions in different clinical contexts. Subsequently, the contribution of microbiota to variation in intestinal cell type–enrichment was analyzed. To confirm the key findings, we used publicly available mucosal 16S and RNA-seq datasets for external validation.

Results
In total, 1,141 inflammation-specific genes and 131 microbial taxa were identified, which were further classified by sparse-CCA into six hubs of molecular pathways associated with specific bacterial groups (FDR&lt;0.05) (Fig. 2), findings we could partially validate in an independent cohort. An increased abundance of Bifidobacterium was associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides was associated with increased metallothionein signaling. Fibrostenotic CD was characterized by a transcriptional network dominated by immunoregulatory genes associated with Lachnoclostridium bacteria in non-stenotic tissue (Fig. 3). In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes associated with Ruminococcaceae. Mucosal microbiota composition was associated with enrichment of distinct intestinal cell types, particularly intestinal epithelial cells, macrophages, and NK-cells (Fig. 4).

Conclusion
This study is the largest of its kind demonstrating the diversity and versatility of host-microbe interactions in IBD. Furthermore, it highlights the strong effects of patient traits on these interactions, providing important pathophysiological insights. Overall, we identify multiple host–microbe interactions that may guide microbiota-directed personalized medicine in IBD.
DOP49 Metagenomic Characterisation of The Colonic Mucosa-Associated Microbiota Reveals Novel Microbes and Communities in Health and Crohn’s disease. The ENIGMA study.
Authors: Kang S , Teh J J , Zhang J , Hu J , Hamilton A L , Wilson-O'Brien A , Trakman G L , Lin W , Ching J , Sung J J Y , Yu J , Ng S C , Kamm M A , Morrison M 
Published: January 2023

Abstract

Background
Deep functional understanding of the mucosa-associated microbiota (MAM) in Crohn’s disease and health by DNA sequencing approaches is restricted by the dominance of human DNA in samples. We established an ex vivo combination of tissue preservation, microbe culture, and metagenomic sequencing to overcome this knowledge gap1 and applied this approach to characterise the colonic MAM from two populations with different Crohn’s disease epidemiology (Hong Kong and Australia) and in comparison to healthy subjects.

Methods
Biopsies (right colon) were cryopreserved from 100 participants in the Eastern IBD Gut Microbiota (ENIGMA) study, with 59 Crohn’s disease (29 from Australia) and 41 healthy subjects (20 from Australia). The MAM were recovered from these samples1 and taxonomic and functional assessments of their metagenomes was performed using the HUMANn3 pipeline. Metagenome-assembled genomes (MAG) were produced using the MetaWRAP pipeline, and their taxonomy determined via the Genome Taxonomy Database-Tool kit (GTDB-Tk).

Results
Our approach supported the recovery of ~1300 high-quality, phylogenetically diverse MAG across 8 bacterial phyla, including 35 “new” species, representing novel pathogenic and protective bacteria. The colonic MAM from healthy subjects possessed greater taxonomic diversity and a larger number of functional genes than the Crohn’s disease subjects from both countries, but fewer of these genes could be assigned to reference taxa. As such, the colonic MAM from healthy subjects possesses novel forms of microbial “dark matter”. There were 27 and 25 species unique to the Australian and Hong Kong Crohn’s disease subjects, respectively, and another 14 species shared by both. Many of the functional gene classifiers differentiating Crohn’s disease from healthy subjects were assigned to low prevalence taxa including Proteus, Acidaminococcus, and Fusobacterium. The dissimilarity scores of the colonic MAM were larger among the Crohn’s disease subjects from both countries, suggesting more heterogeneity in Crohn’s disease than in health.

Conclusion
Here we use two populations with very different rates of Crohn’s disease incidence to show the colonic MAM of healthy subjects in both countries are more diverse, less heterogenous, and contain a greater amount of functional and taxonomic “dark matter” than Crohn’s disease subjects. Novel microbes have been identified and cultured, bringing genomes to life as microbial consortia and novel axenic isolates, to fully define their role in Crohn’s disease pathogenesis or abrogation.
1Teh JJ, Berendsen EM, et al., ISME J 2021;15:3326-3338.
The ENIGMA study is supported by a grant from the Leona M. and Harry B. Helmsley Charitable Trust
DOP54 Time to effect of biologics and small molecules for patients with moderately to severely active luminal Crohn’s disease – a systematic review and network meta-analysis
Authors: Attauabi M , Steenholdt C , Burisch J , Gubatan J , Nielsen O H , Seidelin J B 
Published: January 2023

Abstract

Background
Patients with moderately to severely active luminal Crohn’s disease (CD) have a high inflammatory burden, which can result in irreversible complications and therefore require urgent treatment. However, the speed of onset of efficacy of advanced agents is unclear. Therefore, we aimed to assess the onset of efficacy of biological therapies and small molecules for this adult patient population.

Methods
For this systematic review and network meta-analysis, we searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and Sep 10, 2022. We included original data from randomized clinical trials and open-label interventional studies. The co-primary outcomes were clinical response, defined as i) ≥70-point or ii) ≥100-point reduction in Crohn’s Disease Activity Index (CDAI-70 and CDAI-100) from baseline, and clinical remission, defined as CDAI ≤ 150 at week 2. Network meta-analysis was conducted under the Bayesian framework. This study is registered with PROSPERO: CRD42022368509.

Results
Of 10,129 and 19,281 studies from databases and congress proceedings, 61 studies comprising 17,436 patients were eligible for this study. Adalimumab 160/80 mg, adalimumab 80/40 mg, and certolizumab 400 mg were evaluated for the induction of a CDAI-70 and CDAI-100 response at week 2 and were all superior to placebo. Further, data on upadacitinib 45 mg once daily, vedolizumab 300 mg, and ustekinumab 6 mg/kg were reported for CDAI-100 response at week 2, with the former ranking highest and the latter ranking lowest. Of note, vedolizumab 300 mg did not achieve statistical superiority compared to placebo. However, no statistically significant difference between the agents was found (Figure 1).
Further, the biosimilar BI 69550 160/80 mg and adalimumab 160/80 mg ranked highest and were superior to filgotinib 200 mg for achieving CDAI remission at week 2 (Figure 2). The latter ranked lowest and was, along with vedolizumab 300 mg, not superior to placebo for achieving CDAI remission at week 2 (Figure 2). Findings were consistent in the sensitivity analysis for bio-naïve and bio-exposed patients. However, in the sensitivity analysis of efficacy at week 4 in bio-exposed patients, ustekinumab 6 mg/kg ranked highest for both CDAI-70 and CDAI-100 responses (Figure 3). Sensitivity analysis on modes of action did not yield statistically significant differences.

Conclusion
In this network meta-analysis, we found adalimumab 160/80 mg and upadacitinib 45 mg to be the preferred agents for rapid induction of clinical response and clinical remission at week 2, while vedolizumab 300 mg, filgotinib 200 mg, and ustekinumab 6 mg/kg might have a relatively slower onset of effect in this patient population.
DOP55 The increasing burden of direct and indirect costs of IBD
Authors: Burisch J 
Published: January 2023

Abstract

Background
The cost of care for inflammatory bowel disease (IBD) has nearly doubled over the last two decades. With an increasing number of patients and evolving treatment paradigms utilizing costly but efficacious biologic agents earlier and more often, the cost burden is only expected to worsen. Furthermore, IBD carries significant indirect costs to lost productivity of patients and their caregivers and out-of-pocket healthcare expenses borne directly by patients.

Methods
This talk will explore the current landscape and drivers of IBD direct costs and indirect costs as well as discuss challenges in assessing and comparing such data across countries

Results
Direct costs of IBD management have shifted substantially in recent years, primarily due to the emergence and penetrance of biologic therapy into clinical practice. Despite the increased use of biologic agents in IBD treatment, the expenditure on hospitalization and surgery has had a relatively small impact on reductions in cost, and the mean per capita costs spent on biologics in recent years is higher than what was saved on hospitalization per capita. In fact, direct health care costs associated with IBD treatment have dramatically increased over the last decade. New biologics and small molecules are also expected to be approved in the coming years, which is only likely to further increase the economic burden of IBD. These drivers of increasing costs may be offset by the recent loss of patent exclusivity for infliximab and adalimumab in much of the Western world, which has allowed for increased competition in the form of biosimilar agents and a reduction in prices.
The greatest burden of indirect costs in this population relates to absenteeism and presenteeism among working individuals and premature retirement. However, costs related to reduced professional development and personal achievement due to illness—as well as caregiver costs—are largely unknown.

Conclusion
IBD is an expensive chronic disease with payments only expected to rise. Treating CD remains more expensive than treating UC and biologics escalate treatment costs and these are not offset by possible reductions of hospitalization and other costs. Direct costs differ substantially between countries and health care systems. Indirect cost constitute a significant burden on society
DOP57 GLP-1 based therapies and risk of Inflammatory Bowel Disease: real world evidence from a nationwide cohort study
Authors: Christensen H S , Andersen D , Jess T , Allin K H 
Published: January 2023

Abstract

Background
Glucagon-like peptide-1 (GLP-1) based therapies, including GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP4i), are incretin therapies used to treat type 2 diabetes. In addition to incretin effects, GLP-1 based therapies exhibit anti-inflammatory effects. Nevertheless, a previous study reported increased risk of inflammatory bowel disease (IBD) associated with DPP4i use, while two other studies reported no altered risk. No previous studies have investigated the use of GLP-1RA and risk of IBD. In this study we investigated whether use of GLP-1 based therapies alters the risk of developing IBD among individuals with type 2 diabetes.

Methods
In the setting of a prospective Danish nationwide cohort study (January 1, 2007 - December 31, 2018), we applied a new user active comparator design to compare the risk of IBD in users of GLP-1 based therapies with users of other glucose-lowering drugs. Considering exposure to GLP-1 based therapies as a time-varying covariate, we used a Cox proportional hazards model adjusted for sex, age, socio-economic status, urbanisation, and metformin use to estimate hazard ratios (HRs) of IBD.

Results
Among 177,950 new users of glucose-lowering drugs, 412 individuals developed IBD during a median follow-up period of 4.84 (95% CI 4.82 to 4.87) years. We found no altered risk of IBD associated with the use of GLP-1 based therapies with an adjusted HR of 0.96 (95% CI 0.72 to 1.27). Adjusted HRs of IBD were 1.30 (95% CI 0.86 to 1.96) for new users of GLP-1RA and 0.84 (95% CI 0.59 to 1.19) for new users of DPP4i compared to new users of other glucose lowering drugs. Findings were consistent in all analyses, including separate analyses of Crohn’s disease and ulcerative colitis.

Conclusion
In a population-based cohort of individuals with type 2 diabetes, we did not find an altered risk of IBD associated with the overall use of GLP-1 based therapies. Specifically, we did not confirm the previously reported increased risk of IBD associated with DPP4i. The influence of GLP-1RA on IBD needs further examination.
DOP58 predictors of complicated disease course in CD in an administrative database: a nationwide study from the epi-IIRN
Authors: Lujan R , Atia O , Gili F , Greenfeld S , Kariv R , Loewenberg Weisband Y , Lederman N , Matz E , Dotan I , Turner D 
Published: January 2023

Abstract

Background
Several studies have proposed models to predict disease outcomes in Crohn’s disease (CD), but with limited accuracy, often due to small sample size. We aimed to use a large nationwide cohort to explore predictors of disease course in CD.

Methods
Data of patients diagnosed with CD in the epi-IIRN cohort 2005-2020 were retrieved from the four Israeli Health-Maintenance-Organizations covering 98% of the population. The following potential predictors were explored: demographic data, laboratory results, induction medications, change in medications during the induction period, extra-intestinal manifestations, perianal disease, and diagnostic delay. The primary outcome was complicated disease course defined as CD-related surgery, steroid-dependency, or need for more than one biologic class. Hierarchical clustering categorized disease severity at diagnosis based on available laboratory results into five groups of disease severity (minimal, mild, moderate, severe, and extreme). A Cox proportional hazard model with Bonferroni correction to adjust for multiple comparisons was sought to assess the relationship between predictors and time to complicated outcome. A nomogram was created by conversion of the hazard ratios from the model to points on a scale between 0 to 100.

Results
A total of 19,263 patients with 140,354 person-years of follow-up were included, of whom 6,874 (36%) had complicated disease course. In a Cox multivariable regression model, complicated disease course was predicted by diagnostic delay (HR 1.2 [95%CI 1.09-1.33]), induction therapy with biologics (HR 2.8 [2.21-3.64]), severity of laboratory tests prior to diagnosis (HR 1.6 [1.28-1.99]) and perianal disease (HR 1.5 [95%CI 1.4-1.6]; Figure 1). Specifically in the laboratory tests, there was a gradual increase in rates of patients who had complicated disease course amongst the disease severity clusters (p&lt;0.001; Figure 2). These variables formed a model to predict time to complicated disease, with fair accuracy during the first year from diagnosis (AUC 0.69 [95%CI 0.65-0.73]; Figure 3).

Conclusion
In this nationwide cohort, complicated disease course was apparent in a third of patients and predicted by diagnostic delay, serum laboratory tests, perianal disease and type of induction therapy. Our results also highlight the ability of clustering analyses to define clinically meaningful categories in administrative database of CD.