bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOP16 Safety of long-term ozanimod treatment for up to 4 years in patients with moderately to severely active Ulcerative Colitis: an interim analysis of the True North open-label extension
Authors: Siegel C , Danese S , Rubin D T , Sabino J , Long M D , Cross R K , Armuzzi A , Blumenstein I , Kobayashi T , Lama S , Charles L , Cetin V , Petersen A , Wu H , Wang D , Jain A , D'Haens G 
Published: January 2024

Abstract

Background
The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of up to 3 y of OZA in the ongoing TN open-label extension (OLE; NCT02531126; from TN baseline to OLE Week [W] 94). This analysis presents the cumulative long-term safety of OZA in TN and the TN OLE for an additional year (up to OLE W142).

Methods
The TN study design has been previously described. This analysis included all TN pts who entered the OLE from TN (clinical nonresponders at W10, lost response during maintenance, or completed maintenance at W52). Safety assessments were reported from the first dose of OZA either in TN or OLE up to OLE W142. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were reported. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for all treatment-emergent adverse events (TEAEs).

Results
A total of 823 pts entered the TN OLE (average age: 41.7 y; 59% male); 62% had left-sided UC disease. Total PY exposure to OZA at OLE W142 was 2536 y. Overall, the cumulative safety assessments did not significantly change with an additional year of OZA exposure from OLE W94 to W142 (Table). A decrease in EAIRs per 100 PY was observed in overall TEAEs (85.5 vs 87.6) and serious TEAEs (7.0 vs 7.4) at OLE W142 vs OLE W94, respectively. Notably, with an additional year of OZA exposure, TEAEs leading to treatment discontinuation remained at 2.5 EAIR/100 PY, and there were no new cases of bradycardia or atrioventricular block. One new TEAE each of herpes zoster, macular oedema, cystoid macular oedema, myocardial ischaemia, pulmonary embolism, and deep vein thrombosis were noted. COVID-19 TEAEs increased at OLE W142 (n=103; EAIR: 4.3/100 PY) from OLE W94 (n=66; EAIR: 3.0/100 PY). Reductions in ALC &lt;500 cells/mm3 were common in the OLE (OLE W94, 54.0%; OLE W142, 56.1%); few pts had ALC &lt;200 cells/mm3 (OLE W94, 5.3%; OLE W142, 6.5%), but these pts had no serious infections. No serious hepatic safety events were observed. One new death due to adenocarcinoma, which was unrelated to OZA, was reported.

Conclusion
The ongoing safety profile of OZA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses. Long-term use of OZA representing 2536 PYs of exposure continues to be well tolerated in pts with moderately to severely active UC.
DOP18 Efficacy of risankizumab versus ustekinumab by baseline Crohn’s Disease location: post-hoc analysis of the SEQUENCE head-to-head trial
Authors: Peyrin-Biroulet L , Colombel J F , D’Haens G , Dubinsky M , Cao Q , Kligys K , Garrison A , Huang X , Neimark E , Anschutz T , Crowley J , Panaccione R 
Published: January 2024

Abstract

Background
In Crohn’s disease (CD), disease location may impact treatment effect. This post-hoc analysis of the SEQUENCE head-to-head trial (NCT04524611) compared the efficacy of risankizumab (RZB), an interleukin (IL)-23 p19 inhibitor, versus ustekinumab (UST), an IL-12/23 p40 inhibitor, by CD location.

Methods
SEQUENCE was an open-label, efficacy assessment-blinded, randomized controlled trial, which enrolled patients (pts) with moderate to severe CD who previously failed ≥1 anti-tumor necrosis factor (TNF) therapy. Pts included in the primary efficacy analysis were randomised 1:1 to receive RZB (selected dosing: intravenous 600 mg induction dose administered at weeks (wks) 0, 4, and 8, followed by subcutaneous 360 mg maintenance dose every 8 wks starting at wk 12) or UST (a single weight-based induction dose administered at wk 0, followed by subcutaneous 90 mg maintenance dose every 8 wks starting at wk 8. A mandatory steroid taper began at wk 2. The primary endpoints were clinical remission (CD Activity Index &lt;150) at wk 24 and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least a 2-point reduction versus baseline and no subscore &gt;1 in any individual variable, as scored by a central reviewer blinded to treatment allocation) at wk 48. In this post-hoc analysis, both endpoints were evaluated in 100% of pts included in the primary efficacy analysis, stratified by baseline CD location subgroups (ileal only, colonic only, ileal-colonic). Nominal P-values were reported for treatment differences within subgroups.

Results
At baseline, majority of pts had either ileal-colonic (225 [43.3%]) or colonic (208 [40%]) CD; 87 (16.7%) pts had isolated ileal disease. At wk 24, numerically greater proportions of pts achieved clinical remission with RZB versus UST, regardless of disease location (treatment difference [95% confidence interval], P-value: ileal only, Δ0.8 [-20.1, 21.7], P=0.941; colonic only, Δ22.4 [9.2, 35.5], P=0.001; ileal-colonic, Δ18.2 [5.3, 31.0], P=0.007) (Figure). Pts randomized to RZB with colonic only disease had numerically higher rates of clinical remission relative to pts with ileal only or ileo-colonic disease. At wk 48, RZB-treated pts demonstrated numerically higher rates of endoscopic remission than UST-treated pts (ileal only, Δ22.5 [4.4, 40.6], P=0.017; colonic only, Δ18.3 [6.6, 30.0], P=0.003; ileal-colonic, Δ10.3 [-0.2, 20.9], P=0.057) (Figure). Endoscopic remission rates in the RZB-treated pts were generally similar between ileal only and colonic only CD.

Conclusion
In pts who have failed ≥1 anti-TNF therapy, RZB demonstrated greater rates of endoscopic remission compared to UST regardless of CD location, and greater rates of clinical remission in ileo-colonic and colonic CD.
DOP44 Melatonin Ameliorates Colitis In DSS-fed Mice Via The SIRT1 Pathway
Authors: Lin B , Mao Q , Zhang W , Zhang Y , Cao Q , Xu M 
Published: January 2024

Abstract

Background
Melatonin is an amine hormone with high content in gastrointestinal tract, which plays a positive role in anti-inflammatory. Intestinal microbiota imbalance and intestinal immune damage caused by colitis are often accompanied by a decrease in endogenous melatonin. However, whether melatonin supplementation improves colitis, and the mechanism is unclear.

Methods
The study focused on melatonin treatment of colitis in dextran sodium sulfate(DSS)-fed mice and analyzed the mechanism multidimensionally by quantitative real-time PCR, western blotting, immunofluorescence, 16s-rDNA, and mRNA-seq.

Results
The weight, colon length, and microscopic structure of the colonic crypts were improved in DSS-fed mice after melatonin supplementation. Tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and IL-6 were significantly elevated in colon tissues of the DSS group, and this result was down-regulated in the melatonin group. Tight junction proteins(ZO-1 and occludin) in the colonic mucosa were significantly decreased in the DSS group, and improved in the melatonin group. In terms of antimicrobial peptides, melatonin supplementation significantly increased levels of defa-3, defa-4, and CRAMP. Surprisingly, our study found increased expression of SIRT1 protein in the intestinal tissues of the melatonin group. After the addition of Ex-527, a SIRT1 inhibitor, the protective effect of melatonin on DDS-fed mice disappeared, and tight junction proteins did not differ from those of the DSS group. In addition, fecal 16s-rRNA results in the control, DSS, and melatonin groups suggested some differences. The DSS group had an increase in α-diversity (Shannon's Diversity Index) and a decrease in β-diversity (PCoA) in comparison to the control group, and all of these changes were reversed in the melatonin group, but there was no significance between the three groups. At the phylum level, Firmicutes were significantly increased in the DSS-fed group, and the melatonin group reversed this change. At the genus level, the abundance of Akkermansia was decreased in the DSS group and increased with melatonin supplementation. While the abundance of Desulfovibrio, a pathogenic genus was increased in the DSS group and decreased with melatonin supplementation. Colon tissue mRNA-seq identified a number of possible pathogenic and therapeutic pathways, such as Slc7a2, a cationic amino acid transporter.

Conclusion
The study suggests that melatonin modulates the intestinal mucosal barrier through the SIRT1 pathway to alleviate colitis.
DOP47 Characterisation of endoscopic improvement in Crohn’s Disease with upadacitinib treatment
Authors: Panaccione R , Melmed G Y , Khanna R , D’Haens G , Danese S , Ford S , Anyanwu S I , Garrison A , Lacerda A P , Vermeire S 
Published: January 2024

Abstract

Background
Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), demonstrated significantly higher rates of endoscopic response and remission compared with placebo (PBO) in the phase 3 induction (U-EXCEL, U-EXCEED) and maintenance (U-ENDURE) trials.1 Improvements in the narrowing component of BL stenoses with UPA have been previously reported.2 This analysis evaluated changes in the individual components of the Simple Endoscopic Score for CD (SES-CD) among patients treated with UPA vs PBO.

Methods
Data were pooled from the two induction phase 3 studies evaluating patients who received PBO or UPA 45 mg (UPA45) once daily (QD) for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 were re-randomised in the U-ENDURE maintenance study to receive PBO, UPA 15 mg (UPA15) QD, or UPA 30 mg (UPA30) QD for 52 weeks. This analysis evaluated the mean changes from baseline (BL) in total SES-CD and four individual components (size of ulcers, ulcerated surface, affected surface, presence of narrowing), as well as improvements by disease location and prior biologic failure (bio-failure) status.

Results
Mean [SD] total SES-CD at BL was similar across treatment groups (induction: PBO 13.9 [7.5], UPA45 14.6 [7.7]). In the overall population, mean [SD] changes from BL in total SES-CD were greater with UPA45 (–6.8 [7.6]) vs PBO (–0.5 [5.7]; P &lt; .0001) at week 12, and at week 52 with UPA15 (–9.9 [8.6]) and UPA30 (–10.3 [8.1]) vs PBO (–2.4 [5.0]; all P &lt; .0001; Figure 1A). Similar results were observed for patients with ileocolonic and colonic disease at week 12 and week 52 (Figure 1A). For patients with prior bio-failure, mean changes from BL in total SES-CD were greater with UPA45 (–6.6 [7.9]) vs PBO (0.0 [5.8]; P &lt; .0001) at week 12, and with UPA15 (–10.4 [9.4]) and UPA30 (–9.7 [7.2]) vs PBO (–2.8 [4.8]; all P &lt; .0001) at week 52; similar findings were reported for patients without prior bio-failure. At week 12 and week 52, treatment with UPA resulted in greater improvements vs PBO in the individual SES-CD components of size of ulcers, ulcerated surface, and affected surface, but not for the presence of narrowing (Figure 1B).

Conclusion
In patients with moderately to severely active CD, UPA induction and maintenance treatment vs PBO improved total SES-CD, irrespective of prior bio-failure. The changes were driven by the SES-CD components of the size of ulcers, ulcerated surface, and affected surface. When evaluated by disease location, appreciable improvements occurred in patients with ileocolonic and colonic CD, as compared to ileal disease.
References:
1. Loftus, E. V. et al. N. Engl. J. Med. 2023;388,1966–80
2. Reinisch, W. et al. UEGW 2023. MP005 [Poster]
DOP83 Intestinal epithelium-specific deletion of the Aryl hydrocarbon Receptor (AhR) reduces intestinal Tight Junction permeability thereby hindering homeostatic antigen sampling and tolerogenic immune responses
Authors: Saha K , Ganapathy A S , Arumugam P , Wang A , Harris L , Yochum G , Koltun W , Nighot M , Nighot P 
Published: January 2024

Abstract

Background
The Aryl Hydrocarbon Receptor (AhR) plays important functions in intestinal stem cell differentiation, intestinal homeostasis, and immune regulation, however, its role in regulating intestinal tight junction (TJ) barrier and immune tolerance remains poorly understood. In this study, we assessed the role of intestinal epithelium-specific AhR deletion on the intestinal paracellular TJ barrier and its role in homeostatic intestinal antigen sampling and immune tolerance.

Methods
Ahr fl/fl , and AhrVil-Cre mice were maintained in a specific pathogen-free area until injected with tamoxifen (i.p) to delete the Ahr gene, and then moved to the normal housing. The AhR deletion was maintained by weekly tamoxifen injections for 3 weeks. We performed physiological assessments of the gut epithelial barrier and used flow cytometry, confocal immunofluorescence imaging, and qRT-PCR analysis were also employed to assess the effects of epithelial AhR deletion.

Results
Conditional gut epithelium-specific knockout of AhR (AhrΔIEC) significantly increased the colonic transepithelial resistance (TER) and reduced the paracellular flux of urea and inulin. Assessment of transcript levels in the mouse colonic tissues, after 3 weeks of AhR deletion, showed that AhrΔIEC colonic tissues had higher transcript abundance of barrier-forming proteins like Claudin-3, -4, and occludin with reduced abundance of the pore-forming claudin-2. Ultrastructural investigation of intestinal TJs of AhrΔIEC mice showed diffused, laterally extended, and collapsed TJ architecture. AhrΔIEC did not alter the baseline levels of TNF-α, IFN-γ, and IL-4 however, the transcript levels of IL-6, IL-1β, and IL-17A showed marked elevation. The AhrΔIEC colonic tissues also showed increased infiltration by CD45+ immune cells under baseline conditions with a high abundance of inflammatory dendritic cells (DCs), macrophages (MΦs), and Th17 cells with a corresponding reduction in their tolerogenic counterparts and Treg cells. The AhrΔIEC also showed reduced colonic transcript levels of IL-10, a key anti-inflammatory cytokine, and Programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), the two key proteins, involved in limiting the pro-inflammatory responses in the gut mucosa. In-vitro, AHR-/- in Caco-2 cells also reduced paracellular TJ permeability, and co-culture assays with human dendritic cells showed reduced basal to apical paracellular podia formation and antigen sampling by DCs.

Conclusion
Our data show that deletion of the AhR gene in the gut epithelial cells reduces the epithelial paracellular TJ permeability in-vitro and in-vivo and also highlights the role of homeostatic paracellular TJ permeability in the development of intestinal immune homeostasis.
P021 Higher TNFα and IL-6 mucosal levels in ulcerative colitis patients with more severe endoscopic activity
Authors: Calviño Suárez C , Martinez-Rodriguez A L , Moreira-Alvarez D , Ardao-Palacios I , Duran-Rubi M , Ferreiro-Iglesias R , Baston-Rey I , Porto-Silva S , Nieto-Garcia L , Varela-Liste M J , Brea-Floriani J M , Dominguez-Munoz J E , Loza-Garcia M , Barreiro-de Acosta M 
Published: January 2024

Abstract

Background
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterised by colonic mucosa inflammation. Its clinical course is marked by alternating periods of relapse and remission that impair patients' quality of life. In the last decades, novel therapies have shown to be effective for UC resulting in lower rates of colectomy. However, there is still a significant proportion of non-responding patients that change from one treatment to another, being exposed to its potential adverse events. Thus, predictive factors of response to available drugs are needed to tailor the best treatment strategy for each patient. The aim of our study was to measure TNFα and IL-6 levels in colonic biopsies from patients with UC with moderate to severe endoscopic activity.

Methods
A prospective, observational single-centre study was designed and it is currently on going. Adult UC patients with moderate to severe endoscopic activity (Mayo Endoscopic Score (MES) &gt; 1) in a routine colonoscopy were included. Biopsies from inflamed (MES&gt;1) and non-inflamed (MES=0) colon of each patient were homogenised and processed by using RIPA buffer and ultrasounds to obtain cell lysates. Human Luminex Discovery Assay (2 plex) was used for the simultaneous detection and quantitation of IL-6 and TNFα. Data are shown as percentage, median, interquartile range (IQR) and mean ± standard deviation (SD) as appropriate.

Results
So far, 21 patients were consecutively included (mean age 53.8 years (SD 17.0), 52.4% female). About 43% of patients had left-sided UC, 28.5% extensive UC and 28.5% proctitis. Regarding endoscopic activity, 61.9% of patients showed MES=2 and 38.1% were MES=3. Fourteen patients (66.6%) were bio-naïve and 7 (33.3%) had been exposed to anti-TNFα. IL-6 was detected in biopsies from colon with MES ≥ 2 of 18 (85.7%) patients, of which 10 (55.6%) patients also TNFα was found. Neither IL-6 nor TNFα were detected in biopsies from non-inflamed colon (p=0.00). Median IL-6 in inflamed colonic samples from patients with MES-2 was 25.6pg/ml (IQR 0.2-74.3) and 92.2pg/ml (IQR 16.9-314.3) in those with MES-3 (p=0.09). Median TNFα in inflamed colonic biopsies from patients with MES-2 was 0.0pg/ml (IQR 0.0-20.0) and 22.2pg/ml (IQR 0.0-34.3) in patients with MES-3 (p=0.12) (Figure 1). No differences were found in TNFα levels between anti-TNFα naïve patients and those patients previously exposed to anti-TNFα (p=0.96).

Conclusion
IL-6 and TNFα are elevated in inflamed colonic mucosa, particularly in those patients with more severe endoscopic activity, while they are not found in non-inflamed colonic mucosa. The correlation between cytokine levels and endoscopic severity suggests their potential as biomarkers for treatment response.
P032 Exploring the genetic sequence of action across the natural history of IBD
Authors: Mateos B , Gaite-Reguero A , Rodríguez-Lago I , Marigorta U M 
Published: January 2024

Abstract

Background
We have been very successful at identifying genetic variants associated with inflammatory bowel disease (IBD). From a single locus by the early 2000s, we now know about over 300 regions involved in IBD susceptibility. However, we face two main gaps of knowledge. First, we ignore the mechanisms by which they lead to disease. Second, we ignore their role through the natural history of the disease (e.g., prognosis). To address these gaps, we must integrate inferences from other omic techniques and characterize the genetic sequence of action that takes place across the distinct stages of the disease.

Methods
We have processed publicly available important studies of the genomics and transcriptomics of IBD to make inferences about the sequence of action of genes involved. In total, we processed the large IBDGC GWAS, five transcriptomics and two proteomic datasets (Table 1). We studied different phases of the disease: preclinical, debut and remission, both in Crohn’s disease and ulcerative colitis. We selected sets of genes associated with stages of IBD by the mentioned omics and looked for the overlaps. Last, we performed transcriptome-wide association studies (TWAS) to study the gene expression levels determined genetically in each individual.

Results
We report three main observations from this omic-wide exploration on the genetic sequence of action in IBD. First, we observed a lack of overlap in the gene lists that are relevant in each stage (Figure 1). For instance, just 6.4% of genes discovered by GWAS are differentially expressed at the time of diagnosis and/or remission e.g., NOD2, C2, CCL2, IL27, CSF2, CCL11 and BACH2. In turn, gene signatures discovered through transcriptomics are not particularly enriched for GWAS signals. Second, the genetic risk of each individual, measured through polygenic risk scores, does not correlate with the clustering of patients detected molecularly using gene expression. Third, TWAS analysis reveals an intriguing twist, since we observe large differences between the genetically determined component and the actual gene expression observed in each stage.

Conclusion
Although the genetic makeup of an individual influences expression of key genes involved in IBD, many other genes not detected in genetic studies (GWAS) conform the backbone of molecular alterations present at the time of diagnosis. This global observation challenges the conventional assumption, implying that different actors play a leading role in each stage. Moreover, genetic predisposition is not a strong determinant of the molecular heterogeneity observed in patients across stages. We conclude that the gene regulation dynamics across the natural history of IBD are more intricate than usually assumed.
P033 Unrevealing new potential key mechanisms implicated in inflammatory bowel disease by multiomic approach
Authors: Baldan-Martin M , Azkargorta M , Aransay A M , Gil-Redondo R , Moreno-Indias I , Iloro I , Soleto I , Orejudo M , Ramírez C , Lucendo A J , Rodríguez Gutiérrez C , Gutiérrez A , Martín Arranz E , Bujanda L , Rodríguez-Lago I , Riestra S , Iglesias-Flores E , Bermejo F , Van Domselaar M , García M J , Fernández Salazar L , Barrio Andrés J , Calvet X , Torrealba L , Bastón Rey I , Pallarés H , Ber Y , Carnerero E L , Casanova M J , Casals F , Mendoza J , Moreno Monteagudo J A , Millet Ó , Elortza F , Mato J M , Tinahones F J , Chaparro M , Gisbert J P 
Published: January 2024

Abstract

Background
Inflammatory bowel diseases (IBD), comprising Crohn´s disease (CD) and ulcerative colitis (UC), are characterised by chronic, relapsing and remitting inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression remains incomplete. This study aimed to clarify IBD pathogenesis using a multiomic approach in serum, urine, intestinal tissue and stool samples.

Methods
We performed a multiomic analysis (transcriptomic, proteomic, metabolomic and metagenomic) in a discovery cohort of 53 patients with active CD, 50 patients with active UC, and 33 healthy controls (HC). Proteomic analysis of intestinal tissue was performed by liquid chromatography-mass spectrometry, serum and urine samples were used for metabolome study using nuclear magnetic resonance spectroscopy, and metagenomic analysis of stool samples was performed by 16rRNA gene sequencing.

Results
Gene expression profiles showed a detailed transcriptome landscape of intestinal tissue in patients with CD and UC. A total of 4,105 proteins were identified in mucosal biopsies, of which 2,128 were differentially expressed (DE) between CD and HC, 2,715 proteins DE in UC compared with HC, and 1,653 proteins DE between CD and UC. Metabolomic analyses revealed metabolites and pathways related to ketone, amino sugar and methyl histidine metabolism, Warburg effect, and ammonia recycling deregulated in IBD patients. Moreover, metagenomic results indicated that CD and UC differ in their microbial populations according to beta diversity. In comparison to HC, the microbial population in CD was different, and its alpha diversity was significantly lower (Figure 1).

Conclusion
The results showed that some analytes identified could play essential roles in the pathogenesis of CD and UC. New potential key mechanisms that could help to understand the information of omics layers that underlies the pathogenesis of IBD have been outlined.