bluuebunny/crossref_metadata_2025_split huggingface dataset:
OP39 Safety of ustekinumab in IBD: Final pooled long-term safety analysis through 5 years in CD and 4 years in UC
Authors: Ghosh S , Feagan B , Ott E , Gasink C , Marano C , Miao Y , Sandborn W , Danese S , Abreu M , Sands B 
Published: January 2023

Abstract

Background
Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC.

Methods
Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI).

Results
In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1).
The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent).

Conclusion
The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications.
References:
1. Sandborn WJ, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4.
2. Afif W, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results from The UNIFI Long-term Extension. UEGW 2023.
3. Sandborn WJ, et al. 129 Safety of Ustekinumab In IBD: Pooled Safety Analysis through 5 years in CD and 2 Years in UC. Gastroenterology. 2021;Supplement:S-35-S-36.
DOP01 The effect of vedolizumab on CD8 T cell repertoire homogeneity and blood-gut trafficking in patients with inflammatory bowel disease
Authors: Williams K , Shows D , Kongala R , Clarke A , Lord J 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) causes T cell to infiltrate intestinal mucosa, but the heterogeneity of these cells is not understood at a clonal level. The anti-integrin α4β7 agent vedolizumab is believed to treat IBD by blocking this T cell infiltration from blood.

Methods
To understand the clonal distribution of T cells in IBD and how this is affected by vedolizumab, we studyined the T cell receptor (TCR) repertoire in CD8+ T cell subsets sorted from blood samples and colon mucosal biopsies via FACS. Inflamed or uninflamed colon segments from 15 ulcerative colitis and 13 Crohn’s disease patients were compared to colon biopsies from 11 people without IBD. In peripheral blood, we profiled purified α4β7+, α4β7- effector/memory, CD45RA+ terminal effector/memory (TEMRA) CD8 T cells, and mucosal-associated invariant T (MAIT) cells. In a separate cohort of 13 IBD patients, samples were obtained before and during vedolizumab therapy to determine its effect on the diversity and overlap of the TCR repertoires of blood and colon CD8+ T cells.

Results
CD8 TCR diversity in the mucosa and peripheral blood did not correlate with inflammation. CD8 TCR repertoire overlap between any two anatomically distinct locations of a person’s colon was consistently high, though often lower between inflamed and uninflamed sites. Repertoire overlap was also seen between the colon and each peripheral blood subpopulation studied, with the highest overlap seen for integrin α4β7+ T cells and the lowest for MAIT cells. Inflamed tissue overlapped more than uninflamed with each blood subpopulation. Vedolizumab did not affect the overlap between colon CD8+ T cells and circulating α4β7+ CD8 T cells, nor their TCR diversity, regardless of treatment efficacy. Indeed, flow cytometry revealed no relative depletion of effector/memory T cells in the colons of vedolizumab recipients. Instead, vedolizumab caused the depletion of rare naïve mucosal T cells and dendritic cells (DC) from the colonic mucosa.

Conclusion
CD8 T cell clones are spread homogenously throughout the colon. Although TCR repertoire overlap is greater within than between inflamed and uninflamed colon segments, a similar diversity of TCRs in both argues against local clonal expansion being the main source of excess T cells in inflamed mucosa. Rather, our data reveal increased TCR overlap between blood and inflamed mucosa to support the significance of T cell trafficking in IBD pathogenesis, particularly concerning experienced α4β7+ T cell populations. However, we surprisingly found neither gross nor clonal evidence that blockade of this trafficking is the mechanism by which vedolizumab treats IBD, instead finding only naïve T cells and DC to be depleted from the colonic mucosa in response to vedolizumab.
DOP06 Deep characterization of IL-23 pathway in different gut segments and associated plasma biomarkers in inflammatory bowel disease
Authors: Cairns J , Monkley S , Tian S , Angermann B , Liu Z , Öberg L , Muthas D , Cabrera C , Rapsomaniki E , Fernández Llaneza D , Olsson M , Paraskos J , Ellison G , Khan E , Duncan E A , Neisen J , Gehrmann U , Chamberlain C 
Published: January 2023

Abstract

Background
The role of Interleukin 23 (IL-23) in the pathogenesis of both Crohn’s disease (CD) and ulcerative colitis (UC) is well documented. However, more than half of patients do not respond or lose response to current anti-IL-23 treatments. Thus, we aimed to identify patients with IL-23-driven disease using gut segment-specific transcriptome analysis and quantification of IL-23 pathway cytokines in plasma to enable patient stratification in inflammatory bowel disease (IBD).

Methods
Analyses of real-world data from the Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) obtained from the IBD Plexus program of the Crohn’s & Colitis Foundation including clinical, plasma biomarker (IL-22, IL-23, INF-γ, and IL-17A), and mucosal ileum and colon transcriptome data.

Results
To differentiate IL-23 from TNF-driven disease, we performed gene set variation analysis (GSVA) using IL-23 and TNF gene sets and ileal and colonic transcriptome data from 1230 CD and 664 UC patients. An IL-23, but not TNF, transcriptional module was enriched in ileal compared to colonic biopsies in CD (p &lt; 0.001​). IL-23 pathway activity was significantly higher in uninflamed Ileal compared to colonic biopsies from CD patients (p &lt; 0.001)​). Importantly, IL-23 pathway activity was increased in intestinal biopsies from macroscopically inflamed compared to uninflamed regions, from all gut segments in both CD and UC and correlated with the endoscopic score for both diseases (Fig 1). We also observed higher plasma IL-22 levels in both CD and UC patients with moderate to severely active disease compared with patients in remission (Fig 2). We found that tissue IL-23 pathway activity was linked to plasma biomarker levels in general. The subgroup of CD patients with elevated plasma IL-22 levels showed higher IL-23 pathway activity in the ileum (p=0.003) and colon (p=0.013). In UC, patients with elevated plasma IL-22 levels showed higher IL-23 pathway activity in the sigmoid colon (p=0.001), but not the cecum (p=0.141) (Fig 3).

Conclusion
IL-23 pathway activity in different segments of the gut may contribute differently to pathogenesis in CD, while IL-23 pathway activity is similar across colonic segments in UC. The association between plasma biomarker levels and gut tissue IL-23 pathway activity suggests that quantifying plasma IL-22 levels could be a valuable tool to assess the efficacy of anti-IL-23 therapy in IBD.
DOP07 Targeting the canonical WNT signalling pathway as a potential novel therapy in Crohn′s associated fibrosis
Authors: Buck A , Weber M C , Friess H , Neumann P A 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) is characterized by chronic recurrent intestinal inflammation that leads to progressive fibrotic remodelling of the intestinal wall. Despite advances in medical therapy for CD, 50% of patients still require surgical treatment after 10 years of disease mainly due to fibrosis-associated intestinal stenosis formation. A specific anti-fibrotic therapy does not yet exist, underlining the medical need for further research in this area. The exact mechanism of fibrosis development in CD fibrosis is not yet understood, but WNT signalling has been shown to play a critical role in fibrosis in other organs. However, the role of WNT-signalling in intestinal fibrosis and its potential druggability is not well characterized.

Methods
Bulk RNA sequencing was performed to uncover important mechanistic pathways participating in fibrosis development in surgical specimens from patients with fibrostenosing CD. Non fibrotic non-inflamed areas of the same patients served as controls. To elucidate the functional role of matrix producing fibroblasts, primary cells were isolated from both areas. Their fibrotic potential was further characterized by flow cytometry, immunofluorescence, and RNA sequencing. Protein levels of fibrosis markers as well as WNT target genes were assessed using immunofluorescence imaging techniques.

Results
Gene set enrichment (GAGE) revealed highly upregulated WNT-pathway (p adj &lt; 0.0029) in CD fibrosis compared to matched normal tissue. Flow cytometry revealed an increased population of PDPN+, PDGFRa+ mesenchymal cells in fibrotic segments compared to non-fibrotic tissue. These cells preserve their fibrotic phenotype in vitro showing elevated expression of aSMA and COL1 in FACS. Functional and gene analysis showed upregulated migratory potential of fibrotic fibroblasts, as well as matrix production capabilities (VIM, COL1A1, FN1). RNA sequencing of tissue as well as fibroblasts revealed markedly elevated expression the Wnt1 effector WISP1, which is upregulated in fibrotic cells and tissue. In turn, WISP1 treatment of primary fibroblasts led to activation of the canonical WNT pathway, its target transcription factors and genes (LEF1, MMP7).

Conclusion
Fibrosis formation in CD patients is associated with activated WNT signalling. One druggable protein, a downstream target gene of WNT-signalling could be WISP1. This will be further investigated in our in vitro as well as in our in vivo model, to propose a novel therapy for reducing surgical intervention in CD patients.
DOP08 Cellular and molecular interaction of MAIT in mucosal tissue and their role in inflammatory bowel disease
Authors: Bosáková V , Frič J 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) manifests as chronic inflammation of the gastrointestinal tract and is characterized by a deregulated immune response targeting the gut microflora. Mucosal-associated invariant T (MAIT) cells have been identified as a possible key player in IBD. Activated MAIT cells produce cytokines including IL-26, a newly discovered cytokine involved in the pathology of IBD. Interestingly, IL-26 is not expressed in mice and therefore its effect on the course of inflammation has not been yet fully investigated. Similarly, studies employing human cell cultures often provide limited results as they cannot fully mimic the complex three-dimensional structure of the intestinal tissue. A great hope is placed in the development of models of human diseases using organoids - 3D structures that better recapitulate the architecture and functionality of tissues.

Methods
Our laboratory recently described a model of intestinal inflammation based on human iPSCs-derived intestinal organoids (IOs). Taking advantage of this model, we investigate the influence of the cytokine IL-26 on the course of IBD. Moreover, we elucidate the influence of MAIT cells on the pathogenesis of IBD by studying their pathways of activation in vitro, and subsequently their interaction with inflamed tissues through the co-culture with IOs.

Results
After stimulation, IOs mimic the pro-inflammatory microenvironment and express various cytokines and chemokines. Moreover, IOs express MR1 which is recognised by the invariant TCR receptor of the MAIT cells. IOs express functional IL-26 receptor and respond to this cytokine.
MAIT cells isolated from human blood show production cytokines including IL-26 and effector molecules upon in vitro activation. Their response differs depending on the origin of the stimuli.

Conclusion
IOs form complex structures and immunocompetent environment allowing to study of intestinal inflammation. IOs consist of various cell types, but not immune cells. Taken together with MR1 and cytokines expression we show that IOs can activate MAIT cells, and they serve as a relevant model for in vitro study of their biology. Moreover, IOs respond to IL-26, so they also provide a relevant model to elucidate the role of this cytokine. We expect that this study will contribute to our understanding of the processes underlying the progression of IBD, and lead to the design of new therapeutic targets for the treatment of idiopathic intestinal inflammation.
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

Abstract

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&lt;5 and laboratorial remission (LR) as CRP &lt;0.5mg/dL and FC &lt;150ug/g. IUS response was defined as a reduction &gt;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 &lt;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&lt;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

Abstract

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

Abstract

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.