bluuebunny/crossref_metadata_2025 huggingface dataset:
DOP15 Intestinal ultrasound correlates with colonoscopy and biomarkers, and can be used in a tight monitoring approach to assess response to therapy in Crohn’s disease: a multicentre prospective study
Authors: Morão B , Revés J , Nascimento C , Frias Gomes C , Cúrdia Gonçalves T , Freitas M , Castro F , Moreira M J , Cotter J , Pereira F , Caldeira A , Sousa R , Coelho R , Macedo G , Macedo C , Ferreira M , Glória L , Torres J , Palmela C
Published: January 2023

Background

Intestinal ultrasound (IUS) is a non-invasive monitoring tool increasingly being used to assess response to therapy in Crohn’s disease (CD). Herein we describe the longitudinal evolution of IUS parameters, and its correlation with clinical, laboratorial and endoscopic parameters during the first year of infliximab (IFX) therapy.

Methods

Prospective multicentre cohort study of patients with active CD starting IFX. Harvey-Bradshaw index (HBI), C-reactive protein (CRP), fecal calprotectin (FC) and IUS were performed at week (W) 0, 14, 30 and 54. Ileocolonoscopy was performed at W0 and W54. IFX through levels (ITL) were measured at W14, 30 and 54. Clinical remission (CR) was defined as HBI<5 and laboratorial remission (LR) as CRP <0.5mg/dL and FC <150ug/g. IUS response was defined as a reduction >25% in bowel wall thickness (BWT) and IUS remission as normalization of BWT (≤3mm), color doppler sign (CDS≤1), wall stratification and inflammatory fat. The IBUS-SAS score was used to assess disease activity and includes BWT, doppler sign, stratification and inflammatory fat. Endoscopic response was defined as 50% reduction of SES-CD in most affected segment and endoscopic healing as total SES-CD <3.

Results

62 patients with CD (50% male; mean age 36±15y) were included: all with IUS at W0 and W14, 58 (94%) patients with IUS at W30 and 53 (85%) at W54. Following therapy initiation there was a positive evolution of all assessed parameters; IUS response and remission increased gradually from baseline to week 54 (Table 1 and Figure 1). Figure 2 illustrates the reduction of BWT and IBUS-SAS score from baseline to week 54. The reduction of BWT and IBUS-SAS were significantly more pronounced in the first 14 weeks of therapy (BWT: DW0-14 vs DW14-30, p=0.015; IBUS-SAS: DW0-14 vs DW14-30, p=0.004; DW0-14 vs DW30-54, p=0.037). There was a good agreement between IUS and colonoscopy for evaluation of the most affected segment at baseline (kappa 0.788, p<0.001). In all time points, there was a significantly fair to moderate correlation between ultrasonographic parameters (BWT, CDS and IBUS-SAS score) and laboratorial biomarkers (specially fecal calprotectin) (Table 2). After induction (week 14), there were also a fair correlation between IBUS-SAS and ITL (r=-0.277, p=0.034).

Conclusion

We found a significantly fair to moderate correlation between IUS parameters and laboratorial and endoscopic parameters during the first year of infliximab therapy. BWT and IBUS-SAS score reduction was more pronounced during induction therapy. IUS can be reliably used to monitor disease activity longitudinally, in a tight monitoring strategy.
DOP25 Contraceptive method use according to Inflammatory Bowel Disease status among young women in the United States
Authors: Brenner E , Zhang X , Long M , Dubinsky M , Kappelman M
Published: January 2023

Background

Inflammatory bowel disease (IBD) and estrogen-based contraceptives both increase thromboembolism risk, leading gastroenterologists to recommend long-acting reversible contraceptives (LARCs) over estrogen-based methods for women with IBD. No study has evaluated whether young women with IBD follow this guidance, especially as many patients lack awareness of estrogen-related risks, and young women generally prefer estrogen-based methods. We evaluated contraceptive use patterns for young women with versus without IBD, including odds of estrogen-based contraceptive use.

Methods

Using the IQVIA Pharmetrics Plus Database, a United States (US) health insurance claims database, we identified US women ages 15-25 with ≥1 prescription contraceptive and ≥6 months continuous enrollment from enrollment start to first contraceptive code (intake period). We excluded patients with ≥1 hysterectomy/sterilization claim during intake. The independent variable was IBD diagnosis, defined as ≥3 codes for Crohn’s disease (CD) or ulcerative colitis (UC), 2 CD and/or UC codes and 1 IBD medication code, or 1 CD or UC code and 2 IBD medication codes during intake. The dependent variable was estrogen-based contraceptive use (estrogen-based contraceptive pill, patch, and ring) versus non-estrogen-based (progestin-only pill, injectable, implant, and intrauterine device [IUD]), based on the first contraceptive claim. We generated descriptive statistics for contraceptive sub-type and covariates stratified by IBD status and performed bivariate comparisons. Using multivariable logistic regression, we determined adjusted odds ratios (aOR) with 95% confidence intervals (CI) for estrogen-based contraceptive use, adjusting for age, region, year, and insurance.

Results

We identified 802,932 young women on contraceptives, of whom 1,083 had IBD. Demographics were similar across IBD status except more women with IBD had commercial insurance (Table). Use of the estrogen-based pill, patch, and ring was similar or marginally lower for women with IBD versus without IBD (67.6% vs 68.8%, 2.7 vs 3.1%, and 1.5 vs 1.4%). Women with IBD had a slightly higher proportion of implant use and similar IUD use versus those without IBD (16.1% vs 14.2%; 1.8% vs 1.7%,) (Table, Figure). After adjustment, young women with IBD were 0.82 times as likely to use estrogen-based contraceptives compared to those without IBD (aOR 0.82; 95% CI 0.71-0.94).

Conclusion

Young women with IBD on contraceptives are only slightly less likely to use estrogen-based methods as those without IBD, despite the recommendation for LARC over estrogen-based contraceptives in IBD. This finding suggests a need for reproductive health education efforts and contraceptive safety studies specific to young women with IBD.
DOP35 High-fat diet reduces gut microbiota-derived metabolite indole-acetic acid and aggravates colitis
Authors: Li M , Dong Y , Zhang K , Ma J , He L , Wei J , Jiang J , Zhao Q , Zhao Q , Cao H
Published: January 2023

Background

It is widely accepted that high-fat diet (HFD) has been considered as one of the risk factors of inflammatory bowel disease(IBD), while the mechanism is little known. We aimed to examined whether dietary high fat promotes colonic inflammation through modulating gut microbial tryptophan metabolites.

Methods

The C57BL/6 female mice were fed with chow diet (12kcal% fat) or HFD (60kcal% fat) for 2 weeks. Fresh fecal samples were collected before administration of 2% DSS. LC-MS/MS analysis was performed to detect fecal microbial tryptophan metabolites. Next, 8-week-old mice were administrated 3-indoleacetic acid (IAA) for 7 days prior to 2.5% DSS treatment. The severity of colitis was assessed and the colonic sections were collected. RNA sequencing was performed to analyze the differential genes in intestinal tissue of mice fed with IAA or not. Real-time PCR and Western blotting were performed to detect the transcription and protein expression of mucin sulfation-related genes. High iron diamine-alcian blue (HID-AB) staining of colon tissues and LS174T cells was used to detect the abundance of sulfated mucin. Additionally, the Chromatin immunoprecipitation (ChIP) sequencing is performed to confirm the binding of aryl hydrocarbon receptor(AHR) to 3’-phosphoadenosine 5’-phosphosulfate (PAPS) synthase 2 (PAPSS2).

Results

Short-term HFD increased the susceptibility to colitis of mice. Mice fed with HFD have impaired tryptophan metabolism with remarkable lower level of IAA. IAA supplementation resulted in ameliorative colitis symptoms. Mechanistically, the transcriptome sequencing detected that IAA supplementation enriched the the cytosolic sulfonation pathway and significantly increased the expression of PAPSS2 of colon tissue, a rate-limiting enzyme on the mucin sulfation pathway. Next, in vivo and in vitro experiments verified IAA increased the expression of PAPSS2 and its downstream genes and promoted the mucin sulfation in golgi apparatus of colon through AHR. ChIP sequencing and ChIP-PCR verified IAA can enhance the binding of AHR to the promoter region of PAPSS2 , which further promoted the expression of PAPS transporter 2 (PAPST2 or Slc35b3) and ultimately promotes the mucin sulfation.

Conclusion

HFD altered the gut microbial tryptophan metabolites and disrupt the protective effect of IAA on the intestinal barrier. IAA could relief colitis through AHR-PAPSS2-PAPST2-mucin sulfation axis, which may present a potential approach for precise prevention and treatment of IBD.
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

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

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<0.001), CS-free endoscopic improvement (36.9% [101/274] vs 10.4% [14/135]; P<0.001), and CS-free symptomatic remission (43.4% [119/274] vs 18.5% [25/135]; P<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 >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 >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

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<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

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

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

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

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

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<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.
DOP62 Medication use is increased in the decade prior to IBD diagnosis: A nationwide cohort study
Authors: Bonfils L , Karachalia Sandri A , Juul Poulsen G , Agrawal M , Ward D J , Jess T , Colombel J F , Allin K H
Published: January 2023

Background

There is increasing evidence of a pre-clinical phase of inflammatory bowel disease (IBD), but its length and progression with time is not well characterized. We here identified the use of any prescription medications within a decade prior to IBD diagnosis and compared their use in a matched population of individuals without IBD.

Methods

We harnessed the cross-linked nationwide Danish health registers to identify all individuals with incident IBD in Denmark from 2005 to 2018. Individuals with IBD were matched one to ten to individuals without IBD on age, sex, municipality of residence, and year of IBD diagnosis. Next, we examined their use of any prescription medication within the decade leading to IBD diagnosis or matching date. Prescription histories were compared and examined according to the WHO classification of medication by anatomical main group and therapeutical subgroup.

Results

We compared 29,219 individuals with IBD to 292,190 individuals without IBD. Up to a decade prior to IBD diagnosis, the IBD population had a significantly higher use of medications across all organ systems than the matched population. Medication use was more abundant in the IBD population at ten years before diagnosis/matching (p-value <0·0001). This increased use was observed in 12 out of 14 main medication groups, covering most organ systems, and including medications used to treat gastrointestinal, cardiovascular, lung, infectious, neurological, and psychiatric diseases. For these 12 main medication groups, the proportion of users was 1.1- to 1.8-fold higher in the IBD population already ten years prior to IBD diagnosis (p-value <0.0001). The pattern applied across IBD subtypes, sex, and age. The increased use by individuals with IBD became even more pronounced for several medication groups, the closer measurements were to a diagnosis of IBD. The IBD population had a steep increase in use of several medication groups in the two years imminent to diagnosis.

Conclusion

There is an increased use of a broad range of medications a decade before diagnosis of IBD. These findings further suggest a long pre-diagnostic phase of IBD, association of IBD with other immune-mediated diseases, and that IBD could be a multiorgan disease to a much larger extent than hitherto established. The long pre-diagnostic period is a window of opportunity for earlier detection, diagnosis, and intervention of IBD.
DOP67 A transcriptional module associated with neutrophil degranulation is highly conserved across species and is a core molecular pathway of treatment resistance in ulcerative colitis
Authors: Cozzetto D , Lo J , Powell N
Published: January 2023

Background

Advanced therapeutics are changing the treatment landscape in ulcerative colitis (UC), but drug resistance is still common. New strategies are needed to identify the molecular and cellular drivers of treatment resistance and inform the development of novel molecular diagnostics and therapies. In this study we analysed transcriptional modules conserved across species and different colitis models to look for fundamentally important pathways of disease.

Methods

We surveyed the colonic transcriptome in preclinical UC models, including the T-cell transfer, Il10-/-, DSS, DNBS, anti-CD40 mAb and TRUC (Tbx21-/- x Rag2-/- UC) models and multiple cohorts of patients with UC. Gene expression and pathway level changes were defined. Conserved gene and pathway level changes were defined and their relationship to treatment response with anti-TNF, ustekinumab and vedolizumab assessed in independent UC cohorts, including key registration trials.

Results

Principal component analysis showed clear separation between control and experimental colitis samples, which clustered according to the specific model and classification, such as chemically induced (DSS and DNBS), T-cell dependent (T-cell transfer model and Il10-/-, and T-cell independent, innate-mediated models (anti-CD40 mAb and TRUC models). Between 1700 and 8200 genes were differentially expressed (FDR < 0.05) between the experimental models and the corresponding controls; 145 genes had expression levels at least doubled up in all cases. Pathway analysis highlighted significant shared effects (FDR<0.05) on known cytokine-cytokine receptor interactions, signalling by interleukins and neutrophil degranulation. Genes expressed more specifically in the T-cell dependent models were enriched in immune processes such as the complement system, FCERI signalling and downstream activation of MAPK and NFKB, while those more specific to chemically-induced models were enriched in extracellular matrix functions like degradation and remodelling. A set of 21 genes involved in neutrophil degranulation, and over-expressed across all models of colitis, was also significantly enriched in the colon of patients with active UC. Moreover, the magnitude of enrichment of this gene list could differentiate between responders and non-responders to infliximab (difference in median -704.58, p=0.01) and ustekinumab (difference in median -771.08, p=2.19e-08) but not vedolizumab (difference in median 2212.71, p=0.37).

Conclusion

This transcriptional atlas provides a new lens to scrutinize fundamental biological pathways of gut inflammation and new opportunities to understand the core molecular features of the resistome. A set of neutrophil degranulation genes was associated with resistance to anti-cytokine therapies in UC.
DOP68 Autophagy induction in the intestinal epithelium protects against inflammation-induced barrier loss in vivo.
Authors: Saha K , Ganapathy A S , Wang A , Morris N , Yochum G , Koltun W , Ding W , Nighot M , Ma T , Nighot P
Published: January 2023

Background

Loss of the paracellular tight junction (TJ) barrier and defective autophagy in the gut are pathogenic factors for inflammatory bowel disease (IBD). Earlier, we demonstrated the role of autophagy in the degradation of the pore-forming claudin-2 protein and the resultant TJ barrier enhancement. Here, we investigated the role of autophagy in the regulation of the TJ barrier in vivo and in Crohn’s disease (CD) patient-derived tissues and patient-derived organoids.

Methods

Wild type and autophagy-deficient Atg7-/- mice were given intraperitoneal rapamycin injection to induce autophagy along with LPS or TNF-α to induce inflammation. Surgically resected tissues from CD patients were incubated with rapamycin and the paracellular barrier was measured by Ussing chambers. Autophagy was induced in human colonic organoids by incubation with either rapamycin or by nutrient starvation.

Results

Intraperitoneal rapamycin injection in WT mice successfully induced autophagy as evidenced through the degradation of the autophagy substrate p62/SQSTM. Rapamycin injection increased the colonic occludin levels and enhanced the paracellular TJ barrier as evidenced by the decreasing paracellular flux of inulin. Rapamycin prevented LPS and TNF-a induced colonic paracellular barrier loss and reduction in occludin levels in WT mice. Rapamycin reduced the LPS and TNF-a-induced increase in occludin’s association with caveolin-1 thereby preventing its caveolae-mediated endocytosis and degradation. The protective effect of rapamycin was dependent on autophagy. Conditional knockout of Atg7 (cAtg7) in mouse colon decreased baseline occludin levels and increased inulin flux in mouse colon. Furthermore, rapamycin failed to prevent the LPS and TNF-a-induced colonic barrier loss in the cAtg7 mice. Additionally, these mice lacking the ability to undergo autophagy in the colon were more susceptible to Dextran Sodium Sulphate (DSS)-induced colitis. In normal and inflamed colonic tissues from CD patients, incubation with rapamycin induced autophagy, evidenced through the reduction in p62/SQSTM1 protein levels, increased occludin levels and enhanced the paracellular TJ barrier. Autophagy induction by rapamycin or nutrient starvation also increased occludin levels and its membrane localization in patient-derived organoids.

Conclusion

Our data show that rapamycin successfully induced autophagy in WT mice’s colon and protected these mice from the barrier disruptive effect of both LPS and TNF-α, indicating the importance of autophagy in regulating the intestinal TJ barrier. Our data also highlights the application of autophagy induction as a potential therapeutic approach in the treatment of IBD.
DOP70 Crohn’s Disease Like Inflammation of The Pouch is a Distinct Type of Pouchitis
Authors: Kayal M , Tankelevich M , Guo Y , Fischer J , Jimenez D , Canales-Herrerias P , Livanos A , Colombel J F , Dubinsky M , Faith J , Ko H , Mehandru S
Published: January 2023

Background

Pouchitis occurs in up to 80% of patients with ulcerative colitis (UC) after total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA). The pathogenesis of pouchitis is unclear, but is thought to involve a complex interaction between the microbiome and mucosal immune system. To examine the underlying pathophysiological mechanisms of pouchitis, the present study aims to simultaneously define immuno-histological and microbial parameters associated with different pouch phenotypes.

Methods

Endoscopic biopsies from the pre-pouch ileum (PI) and the pouch body (PB) were obtained from 51 subjects age>18 who underwent TPC with IPAA, n=48 for UC and n=3 for familial adenomatous polyposis (FAP). Mucosal mononuclear cells (MMC) were isolated from the intra-epithelial compartment (IEC) and lamina propria (LP) and examined for lymphoid, myeloid and innate immune subsets by multiparameter flow-cytometry (FC). Histological sections were examined by two pathologists, blinded to clinical identifiers and scored for inflammatory parameters that included neutrophilic activity, lymphoplasmacytic infiltration, eosinophilia, villous atrophy and submucosal fibrosis. Metagenomic sequencing of stool was performed and analyzed for microbial beta and alpha diversity.

Results

IPAA subjects were classified into the following phenotypes: normal pouch (NP) n=15 (29.4%), acute pouchitis (AP) n=9 (17.6%), chronic antibiotic dependent pouchitis (CADP) n=9 (17.6%), Crohn’s disease like pouch inflammation (CDLPI) n=15 (29.4%), and FAP NP n=3 (5.9%). Among subjects with NP, the PB had a higher frequency of naïve-CD4+ and CD8+ T cells, central memory- CD4+ T cells, and naïve B cells and a lower frequency of homeostatic IELs relative to the PI (Fig. 1A). Immune remodeling of the PB was further confirmed on histology that demonstrated increased lymphoid aggregates and decreased IELs. Subjects with CDLPI had significantly higher levels of inflammation, chronicity, and lymphoid aggregates but decreased IELs in the PI than NP or AP patients (Fig. 1B and 1C). In contrast to immune parameters, the composition of the microbiota in non-inflamed UC pouches was more similar to inflamed UC pouches than to FAP pouches. Alpha diversity and genus relative abundance differences between UC and FAP pouch stool samples were not statistically significant (Fig. 1D).

Conclusion

CDLPI represents a distinct entity of pouchitis that is associated with heightened levels of chronic inflammation relative to AP despite similarities in microbiota.
DOP71 TREM1, OSM and a co-expressed transcriptional module are core components of the molecular resistome to anti-cytokine therapy in Ulcerative Colitis
Authors: Saifuddin A , Madgwick M , Cozzetto D , Pavlidis P , Verstockt B , Hart A , Korcsmaros T , Powell N
Published: January 2023

Background

Molecular biomarkers are emerging as promising tools to predict response to advanced therapy in IBD. For instance, mucosal expression of Triggering Receptor Expressed on Myeloid cells-1 (TREM1) and oncostatin M (OSM) are associated with anti-TNF non-response in Ulcerative Colitis (UC). The specificity of such transcriptional features is poorly understood. We investigated whether mucosal expression of TREM1 and OSM influences ustekinumab response in UC.

Methods

UNIFI is a landmark, phase III, registration trial that evaluated the efficacy of ustekinumab as induction and maintenance therapy in patients with moderate to severe UC. In a subset of patients (n=358), colonic biopsies were sampled at baseline and gene expression profiled by RNA microarray (Affymetrix HT HG-U133+ PM). Normalised expression levels of TREM1 and OSM for responders and non-responders to induction (week 8 mucosal healing) were compared using Mann-Whitney U test on GraphPad Prism 9.2.0. Co-expressed transcripts were determined with Morpheus matrix visualisation software (Broad Institute, USA). Gene set variation analysis was used to calculate gene set enrichment scores (ES) within the expression data. Multivariable models were developed to construct receiver operating characteristic curve (ROC) analyses. Deeper biological insights of TREM1- and OSM-expressing cells were explored using single cell RNA sequencing and Gene Ontology over-representation analysis (R 4.2.2).

Results

Mucosal expression of TREM1 and OSM in inflamed colonic biopsies correlated highly (r = 0.81, p<0.0001) and TREM1 was the third-highest correlate with OSM across the entire genome. Pathway analysis showed that a 20-gene module (GS1) of transcripts co-expressed with TREM1 and OSM was enriched for immune cell adhesion, migration and differentiation (Fig 1). Expression of TREM1 (median: 6.27 vs 5.55, p<0.001), OSM (5.00 vs 4.72, p=0.002) and GS1 (ES: 0.00221 vs -0.496, p<0.0001) were all significantly increased in ustekinumab non-responders compared to responders (Fig 2). Although key clinical parameters correlated weakly with TREM1 and OSM expression, they improved the performance of multivariate models to predict non-response (Fig 3). TREM1 and OSM were predominantly expressed by the same population of inflammatory monocytes accumulating in inflamed colon tissue (Fig 4).

Conclusion

Colonic expression of TREM1 and OSM is associated with resistance to both anti-TNF therapy and ustekinumab, supporting the notion that they constitute a core molecular resistome in UC patients treated with anti-cytokine agents. Their predominant co-expression in infiltrating, inflammatory monocytes indicates that treatment resistance is likely underpinned by biological pathways regulated by this cell population.