bluuebunny/crossref_metadata_2025 huggingface dataset:
P010 GSDMB-mediated pyroptosis exacerbates intestinal inflammation by destroying intestinal epithelium in Crohn’s disease
Authors: Gong W , Liu P , Ren J
Published: May 2021

Background

Intestinal epithelial injury acts an essential role in the pathogenesis and development of Crohn’s disease (CD). Recent studies indicated that gasdermin D (GSDMD) mediated pyroptosis in intestinal epithelial cell (IEC) contributes to the epithelial injury during intestinal inflammation. However, how gasdermin B (GSDMB) mediated pyroptosis regulates intestinal epithelial injury in CD remains unknown.

Methods

We studied the characteristics of GSDMB mediated pyroptosis in CD patients and intestinal epithelial cells (Caco-2, HT-29 and primary IECs). The CD8+ T cells were extracted from intestinal mucosa of CD patients and health controls, and then co cultured with normal primary IECs to observe the pyroptosis of IECs. We further analyzed the CD8+ T cell subsets that promote pyroptosis in intestinal biopsies of CD patients. In addition, we screened out four single nucleotide polymorphism (SNP) of GSDMB that related to disease risk of CD in the public IBD exomes database (https://ibd.broadinstitute.org/), and investigated their effects on pyroptosis.

Results

GSDMB mediated pyroptosis was notably increased in intestinal mucosa of active human CD, and only existed in intestinal epithelial cells (Figure 1). Granzyme A (GrzA) initiated the killing results by the cleavage of GSDMB in intestinal epithelial cells, and interferon gamma (IFN-γ) up-regulated GSDMB expression in intestinal epithelial cells and promoted pyroptosis (Figure 2). GSDMB in primary IECs was significantly cleaved when co cultured with CD8+ T cells from active CD patients, while the phenomenon weakened a lot when GrzA in CD8+ T cells or GSDMB in epithelial cells was knocked down (Figure 3). We also found that IL26 possive CD8+ T cells were the main CD8+ T cells subsets secreting GrzA (Figure 3). We screened out two SNP of GSDMB related to increased disease risk of CD (rs2305480 and rs11078928) and two related to decreased disease risk (rs35104165 and rs143933205), and constructed these four mutant plasmids. Compared with wild type of GSDMB, rs2305480 promoted the cleavage while rs35104165 blocked the cleavage (Figure 4).

Conclusion

GSDMB-mediated pyroptosis results in intestinal epithelial injury, which will exacerbate intestinal inflammation. Modulation of the GSDMB-mediated pyroptosis emerges as a potential therapeutic strategy to target epithelium damage and treat CD.
P030 SUCNR1 mediates inflammasome activation: Relevance in Ulcerative Colitis
Authors: Bauset C , Lis-López L , Ortiz-Masia D , Gisbert-Ferrándiz L , Coll S , Calatayud S , Barrachina M D , Cosín-Roger J
Published: May 2021

Background

Ulcerative colitis (UC) is characterized by a diffuse, continuous, and chronic inflammation of mucosa and submucosa layers in the colon1. Inflammasome complex is involved in the intestinal homeostasis regulation, but its role in UC has not been established yet. We have recently reported that SUCNR1 mediates intestinal inflammation and fibrosis2. We aim to analyze the role of SUCNR1 in inflammasome activation and UC.

Methods

Intestinal resections from UC and non-IBD patients were obtained. HT29 cells were treated with succinate 1mM and an inflammasome activator cocktail (TNF-α 25ng/ml, IFN-γ 20 ng/ml and LPS 1µg/ml) for 24 hours and transfected with SUCNR1 siRNA. Chronic DSS-colitis was induced in wild-type (WT) and SUNCR1-/- (KO) mice with 4 cycles of DSS. Gene expression and protein levels of SUCNR1 and inflammasome markers were analyzed by qPCR, WesternBlot and ELISA. Histology of murine tissue was analyzed by Hematoxylin-Eosin staining. Results were expressed as fold induction (mean±SEM, n≥5). Statistical analysis was performed with one-way ANOVA followed by Newman-Keuls test. Correlations were analyzed with the Spearman coefficient.

Results

In UC patients, gene expression of SUCNR1 (4.47±1.70), Nlrp3 (1.97±0.38), Caspase-1 (2.08±0.33) and IL-1β (6.90±2.02) were significantly increased vs non-IBD. SUCNR1 positively correlates with the expression of Caspase-1 (r=0.46) and ASC (r=0.45). Protein levels of SUCNR1 (151.00±8.29), Nlrp3 (215.20±53.35) and Caspase-1 (518.30±231.50) were increased in UC vs non-IBD. HT29 cells treated with succinate and inflammasome cocktail showed an increased gene expression of SUCNR1 (4.45±1.17), Nlrp3 (3.13±0.29), Caspase-1 (70.40±16.14), ASC (2.38±0.37), IL-18 (2.52±0.31) and IL-1β (2.32±0.18). Of interest, siSUCNR1 cells treated with the cocktail and succinate showed a significant reduction in the expression of Nlrp3 (1.00±0.15), IL-1β (0.98±0.21), and ASC (1.19±0.14). In parallel, protein levels of Caspase-1 in siSUCNR1 cells treated with cocktail and succinate were significantly reduced (609.00±116.20) vs non-transfected cells (1095.00±148.30). IL-1β levels were also significantly reduced in siSUCNR1 cells (148.60±16.13) vs non-transfected cells (744.70±94.06). Finally, WT-DSS mice exhibited a worse colon histology and an increased protein expression of Caspase-1 (170.60±32.20), compared with KO-DSS (61.39±4.59).

Conclusion

SUCNR1 is increased and positively correlates with the expression of inflammasome components in UC patients. Moreover, SUCNR1 mediates inflammasome activation and its absence ameliorates chronic DSS-colitis. Hence, SUCNR1 might be a potential pharmacological target for UC treatment.

Reference
P041 CDKN2B-AS1 (ANRIL) expression is decreased in Inflammatory Bowel Disease epithelia and in Celiac, and its reduction is linked with induced cells proliferation
Authors: Benshoshan M , Sosnovski K E , Braun T , Amir A , Anikster Y , Haberman Ziv Y
Published: May 2021

Background

Long non-coding RNAs (lncRNAs) have attenuated expression in several immune-mediated disorders. Using mRNAseq of intestinal biopsies, we identified a widespread dysregulation of 459 lncRNAs in the ileum of treatment-naïve pediatric Crohn Disease (CD) patients. We noted that large fraction of downregulated lncRNAs were correlated with epithelial functions. CDKN2B-AS1 (ANRIL) is one of the top most down-regulated lncRNA in CD, and showed decreased expression in Ulcerative Colitis (UC) colon tissues in recent studies.

Methods

Transcriptomics data is used to evaluate CDKN2B-AS1 expression in mucosal biopsies datasets and in gut epithelia. siRNA oligonucleotides targeting most CDKN2B-AS1 transcripts using Lipofectamine RNAiMAX is used to modulate CDKN2B-AS1 function, and RT-PCR to evaluate mRNA expression. xCELLigence system with gold microelectrodes in plate base is used to measure the impedance as an indicator for cell index.

Results

CDKN2B-AS1 is down-regulated in bulk mucosal biopsies obtained from CD ileum [fold change (FC) -8, corrected p=1.6E-5], in UC rectum (FC -9.4, corrected p=3.9E-18), and in celiac duodenum (FC -2.3, corrected p=0.03) in comparison to controls. CDKN2B-AS1 is detected under basal conditions in HT-29 cells. Two sets of CDKN2B-AS1 siRNA oligonucleotides (targeting most transcripts) achieved up to 60% reduction in CDKN2B-AS1 expression in HT-29 cells (p=1E-04) as confirmed by RT-PCR using two sets of primers. CDKN2B-AS1 reduction significantly increased cell index as measured by xCELLigence (doubled the index, p=1.7E-03). mRNAseq of the CDKN2B-AS1 reduced HT-29, showed reduction of the tumor suppressor gene APC in CDKN2B-AS1 siRNA treated cells (FC=-1.75, p=0.04) and of TGFBR2 (FC=-1.75, p=0.04). In contrast, reduction of CDKN2B-AS1 resulted in increase in WNT11 (FC=2.1, p=0.02) and TGFB1 (FC=1.9, p=0.04), and induction of the replication associated topoisomerase TOP1MT (FC=2.7, p=0.001). We confirmed these mRNAseq results using RT-PCR. Finally, mimicking inflammation by treating HT-29 with IL1β and LPS, reduced CDKN2B-AS1 expression (by 70%, p=6.3E-04) and doubled the cell index (p=1.8E-03).

Conclusion

We detected reduced CDKN2B-AS1 expression in three inflammatory disease affecting the gut in different location along the GI tract. Using HT-29 model system we were able to show, as was previously shown, an increase in cell index in CDKN2B-AS1 siRNA treated cells. We supplement those showing effect on down-stream genes that may be relevant in controlling cell proliferation. We further show that upon inflammatory triggering of HT-29 cells, CDKN2B-AS1 expression is reduced and cell index is increased, which may suggest a potential role in epithelial renewal in inflammation.
P064 3-oxo-C12:2, a Quorum Sensing molecule from the gut, exerts anti-inflammatory effects through a bitter taste receptor
Authors: Coquant G , Aguanno D , Peyrottes A , Brot L , Belloir C , Briand L , Grill J P , Thenet S , De Sordi L , Seksik P
Published: May 2021

Background

Acyl-Homoserine Lactones (AHLs) are Quorum Sensing molecules involved in the communication network of bacteria and can also have an impact on the host’s cells. We recently showed, in the gut ecosystems, the presence AHLs and among them we identified one that has never been described: 3-oxo-C12:2. This molecule was decreased in Inflammatory Bowel Disease (IBD) patients, especially during flare, and its presence was correlated to normobiosis. Interestingly, 3-oxo-C12:2 is structurally close to an AHL well described and synthesized by P. aeruginosa, 3-oxo-C12. We intent to describe 3-oxo-C12:2 effects on gut inflammation and to identified which signalling pathways are involved. Given its analogous structure to 3-oxo-C12, we hypothesized that 3-oxo-C12:2 can interact with the same cellular partners, in particular a bitter taste receptor (BTR), called T2R138, which is a GPCR expressed by immune and epithelial gut cells.

Methods

To test our hypothesis, we used murine macrophages cell line RAW264.7, stimulated by interferon-ɣ (IFN-g, 20U/mL) and lipopolysaccharide (LPS, 10ng/mL). We performed a transcriptome analysis using RNAseq to identify inflammatory pathways involved in the effects. Inflammatory response was monitored by measuring cytokine secretion TFNα via ELISA. Probenecid, a known allosteric inhibitor for T2R138, was used to study T2R138 role in AHL signalling. BTR screening assay was performed to extend search for 3-oxo-C12:2 receptors. Cytotoxicity was measured via Lactate Dehydrogenase release.

Results

After LPS/IFN-γ activation, we observed a decrease of secreted TNFα when cells are exposed to 3-oxo-C12:2, in a dose dependent manner: 15μM (-30%, p<0.05), 25μM (-50%, p<0.001) et 50μM (-65%, p<0.0001), no change were observed in steady state. Itreflects an anti-inflammatory effect, without increasing cytotoxicity. To identify mechanisms behind those effects, we analysed the transcriptome of RAW264.7 cells exposed to AHL. JAK-STAT and NF-κB pathways were differentially down-regulated in presence of 3-oxo-C12:2. In addition, the anti-inflammatory effects were lost in presence of Probenecid, a T2R138 inhibitor. In a BTR screening assay, we confirmed that 3-oxo-C12:2 activates T2R38, but also five other BTR (T2R13, T2R8, T2R14, T2R1, T2R10).

Conclusion

3-oxo-C12:2 exerts a dose dependent anti-inflammatory effect on murine immune cells. This response is partly mediated by the bitter taste receptor T2R138. This receptor is a potential target of our AHL of interest and we are currently studying the inflammatory pathways involved behind those effects. Studying the signalling between the receptor and the anti-inflammatory response would allow us to better understand the inter-kingdom dialogue between microbiota involving AHL in IBD.
P073 An increased autophagy and decreased apoptosis is detected in intestinal fibroblasts from Crohn’s Disease patients
Authors: Gisbert-Ferrandiz L , Queralt M , Cosín-Roger J , Coll S , Bauset C , Ortiz-Masia D , Llau J , Navarro-Vicente F , Calatayud S , Barrachina M D
Published: May 2021

Background

Fibrosis is a complication commonly present in Crohn’s disease (CD) patients with a structuring (B2) or penetrating (B3) phenotype, with no effective treatment. This process is characterized by a disequilibrium between the production and degradation of the extracellular matrix (ECM), mainly regulated by myofibroblasts. We aim to analyse here, the expression of markers of autophagy, apoptosis and proliferation in intestinal fibroblasts from CD patients.

Methods

Fibroblasts were isolated from the damaged intestinal mucosa of CD patients with a penetrating and stenotic behaviour. Control cells were obtained from the non-damaged intestine of patients with colorectal cancer. Protein levels of markers of autophagy and apoptosis were determined by Western Blot in isolated fibroblasts. The proliferation marker Ki67 was analysed by immunohistochemistry (IHC) in 5 µm slides of intestinal tissue from control or CD patients. Statistical significance was measured by t-test.

Results

In fibroblasts from CD patients, we detected a significant decrease in the ratio phospho-mTOR / mTOR (Fig. A) in parallel with a non-significant increment in the LC3 II / LC3 I protein ratio (174% ± 46.5), and a decrease in p62 protein levels (84.8% ± 5.5). When compared between CD behaviours, a significant decreased in the phospho-mTOR / mTOR protein ratio was detected in fibroblasts from B2- compared to that obtained in cells from B3-CD patients (Fig. B). The analysis of the expression of an apoptosis marker, Caspase 3, revealed a decreased of cleaved caspase 3 protein levels in CD fibroblasts compared to levels detected in control cells (Fig C). Finally, we observed in the lamina propria of the intestine from CD patients an increased number of Ki67 positive cells, compared to that detected in control tissue.

Conclusion

Our data show an increased autophagy and decreased apoptosis in isolated intestinal fibroblasts from CD patients; the high number of cells proliferating in the lamina propria of the intestinal tissue of these patients, strongly suggests a higher viability of these cells in the fibrotic context.
P082 Assessment of anti-inflammatory effect of high acetate administration in UC patient-derived epithelial monolayer cultures
Authors: Deleu S , Arnauts K , Machiels K , Huys G R B , Thevelein J , Raes J , Vermeire S
Published: May 2021

Background

Human organoid-based intestinal monolayer cultures provide an interesting tool to preclinically assess new therapeutic properties in inflammatory bowel disease (IBD). Recently, short-chain fatty acids (SCFA) such as acetate and butyrate have gained interest for their potential beneficial effects in IBD therapy. Most studies have focused on butyrate, given its beneficial effects on gut microbiome composition, intestinal barrier function and the immune system1. Effects of acetate are less well known, despite its lower toxicity to epithelial cells and its potential to support growth of butyrate-producing bacteria by metabolic cross-feeding2. In fact, a recent report suggested that the probiotic potential of Saccharomyces cerevisiae var. boulardii might be related to its high acetic acid production3. We here studied the effect of acetate on organoid-derived epithelial monolayer cultures from ulcerative colitis (UC) patients.

Methods

Colonic biopsies were obtained from non-inflamed regions in 3 patients with UC. Crypts were isolated, cultured and expanded as 3D-organoids. These organoids were then dissociated and transferred to transwell inserts as monolayer cultures. Upon confluency of the monolayer, evaluated by Transepithelial electrical resistance (TEER), cells were basolaterally stimulated with control medium (CTRL) or an inflammatory mix (INFL) containing 100 ng/ml TNF-α, 20 ng/ml IL-1β and 1 µg/ml Flagellin (Fig. 1). After 24h, cells were apically stimulated with control medium or high acetate (HA) (100mM). TEER was measured at 0, 24 and 48h stimulation. After 48h, cells were subjected to RNA extraction followed by reverse transcriptase qPCR targeting a selection of key diagnostic marker genes. The apical and basolateral media were collected for cytokine determination by Mesoscale (Proinflammatory panel 1). Data were analyzed using GraphPad Prism 9 (D’Agostino & Pearson test for normality followed by a Friedman test).

Results

A protective effect (Fig. 2) of high acetate administration on TEER values (HA vs INFL: p=0˒017) was observed, together with a trend towards decrease in IL8 (p=0˒11), TNFA (INFL vs INFL+HA: p=0˒68) and CLDN2 (CTRL vs HA: p=0˒03). Moreover, this was confirmed by a decrease of most proinflammatory cytokines (Fig. 3) in the apical and basolateral media upon HA stimulation e.g., IFN-γ (INFL vs INFL+HA: p=0˒25) and IL 10 (CTRL vs HA: p=0˒11).

Conclusion

In this patient-derived human epithelial cell culture model, a protective effect of high acetate administration on TEER-values, gene expression and cytokine production was observed. Ongoing experiments are expanding the number of patients to 10.

References
P106 Cromoendoscopy versus second generation Narrow band Imaging for dysplasia detection in IBD. An interim analysis of a prospective randomized control trial
Authors: Martin Arranz E , Suarez Ferrer C , García Ramirez L , Sanchez Azofra M , Rueda García J L , Poza Cordón J , Martín Arranz M D
Published: May 2021

Background

Colonic neoplastic risk is increased in long-standing colitis. Chromoendoscopy (CE) is the recommended screening method. Narrow band imaging (NBI) is potentially a more convenient alternative. Few studies have explored the diagnostic yield of second generation NBI (Olympus 190 series) versus chromoendoscopy.

Methods

NBICromo (NCT04403997) is an ongoing prospective randomized controlled trial in which patients with clinical indication for CE (>8 years of disease, left-side or extensive colitis, colonic Crohn′s disease with >2 colonic segments affected or associated primary esclerosing cholangitis) are randomized on 1:1 ratio to CE with methylene blue 0,1% or NBI. All procedures are done with Olympus HQ190 endoscopes by endoscopists with experience in IBD. Biopsies are taken from all visible lesions. Primary objective is to compare the total number of neoplastic lesions detected in each group. Secondary objectives are to compare the procedure time, the number of biopsies taken,and the accuracy of optical characterization of the lesions. The study has been approved by the Hospital Ethics Committee and patient informed consents were obtained.

Estimated sample size for the study is 175 patients, and recruitment is currently ongoing. An interim analysis was conducted with the first 75 randomized patients to exclude futility due to slowed recruitment caused by covid-19 pandemic.

Results

75 patients were randomized, 34 to CE and 41 to NBI. 10 patients were excluded due to presence of inflammation or poor bowel preparation in the colonoscopy. 65 patients were analyzed per protocol, 31 in the CE arm and 34 in the NBI arm. Mean age was 57±13 years, 46.15% were male and 53.85% female. Mean disease duration was 17.1 ± 8.3 years. No significant differences were found between groups in basal characteristics.

123 lesions were detected. 77 with CE and 46 with NBI, of these 34 (27,6%) were neoplastic (14 neoplastic lesions were found in NBI group and 19 in CE group p=0.1. Neoplastic lesions were found in 13 patients in CE group (41,9%) and 7 patients with NBI (20,5%) p=0.06. Total withdrawal time (including staining and/or therapeutics) was significantly shorter in the NBI group (17.6 ±9.8 vs 30.5 ± 16.5 min p<0.001). No differences were found in biopsies numbers (2.5 ± 2.5 CE vs 1.7 ±1.6 NBI p=0.16).

AE were 1 mild post resection bleeding and 1 mild fever, both in the CE group p=0.07.

Conclusion

In this interim analysis there are no significant differences in dysplasia detection between CE and NBI, although more sample size is needed. NBI could be a more convenient alternative to CE, with significant shorter and more simple procedures. The ongoing clinical trial will be completed.
P123 Type I collagen degradation fragments and type IV collagen formation/degradation ratio are serological biomarkers for stricturing (Montreal B2) Crohn’s disease
Authors: Bourgonje A R , Alexdottir M , Loveikyte R , Bay-Jensen A C , van Dullemen H M , Visschedijk M C , Festen E A M , Weersma R K , Karsdal M A , Faber K N , Mortensen J H , Dijkstra G
Published: May 2021

Background

Crohn’s disease (CD) is characterized by increased extracellular matrix (ECM) remodeling, which is a key pathophysiological mechanism underlying intestinal stricture formation and other fibrotic disease complications. Alterations in intestinal ECM turnover may be reflected by products of collagen formation and degradation that are released into the systemic circulation. In this study, we aimed to investigate associations between serological biomarkers of collagen turnover and disease behavior subtypes according to the Montreal classification in patients with CD.

Methods

Serological biomarkers of collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP)-mediated collagen degradation (reC1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope solid-phase competitive enzyme-linked immunosorbent assay (ELISA) technology in 101 patients with CD (Montreal B1: n=47; B2: n=28; B3: n=26) who were characterized according to the Montreal classification. Logistic regression modelling and receiver operating characteristics (ROC) statistics were used to assess discriminative power.

Results

Specific fragments of MMP-2,9,13-mediated degradation of type I collagen (reC1M) were significantly reduced in patients with stricturing (Montreal B2) disease compared to other disease phenotypes (B1 and B3) (P<0.001). Ratios of type IV collagen formation and degradation (PRO-C4/C4M) were significantly elevated in Montreal B2 patients (P<0.001). No differences in remaining serological biomarkers were observed between the different Montreal subtypes. Both reC1M and PRO-C4/C4M ratios demonstrated high discriminative power to distinguish inflammatory CD (B1) from stricturing (B2) CD, also after adjustment for confounding factors (area under the curve [AUC] 0.85 and 0.84, respectively).

Conclusion

Elevated degradation of type I collagen and excessive (relative) formation of type IV collagen strongly associate with stricturing CD (Montreal B2) and accurately discriminate it from inflammatory CD (Montreal B1). Therefore, reC1M and PRO-C4/C4M ratios could serve as serological biomarkers for stricturing CD. Our results should be validated in additional prospective, larger patient cohorts to corroborate these findings.
P146 The Toronto IBD global endoscopic reporting (TIGER) score demonstrates significant correlation with fecal calprotectin, CRP and IBD Disk in Crohn’s disease patients
Authors: Zittan E , Steinhart A H , Aran H , Milgrom R , Koifman E , Gralnek I M , Zelber-Sagi S , Silverberg M S
Published: May 2021

Background

Commonly used endoscopic indices in IBD lack ability to provide overall disease burden and severity, generate low inter-observer agreement, and demonstrate incomplete validation of some scores. We developed an endoscopic reporting tool, the Toronto IBD Global Endoscopic Reporting (TIGER) score for Crohn’s disease (CD) and ulcerative colitis (UC) patients. The aim of our study was to compare the usability and validity of the TIGER score against fecal calprotectin (FC), C-reactive protein (CRP) and IBD DISK score in CD patients.

Methods

A cohort of 60 CD patients participated in the study. Blinded IBD experts reviewed and graded ileocolonoscopy videos. In the validation phase, the TIGER score was compared to: (1) the Simple endoscopic Score for Crohn’s disease (SES-CD) as a reference standard and: (2) inflammatory biomarkers FC and CRP and (3) IBD Disk score.

Results

Inter-observer reliability per segment between reviewers was excellent: Interclass Correlation Coefficient (ICC)=0.94; [95%CI: 0.92–0.96]. For categorized TIGER score, lowest overall agreement was 96.6% [95%CI: 93.5–98.6] and lowest kappa 0.91 [95%CI: 0.84–0.98], reflecting excellent agreement. Overall agreement per segment between SES-CD and TIGER was 91% [95%CI: 84–95] with kappa coefficient 0.77 [95%CI: 0.63–0.91]. Per subject analysis for CD yielded overall agreement of 80% [95%CI: 64–91] and kappa coefficient 0.44 [95%CI: 0.14–0.75]. There was a significant correlation between TIGER and CRP (r s = .689, p < .0083), and TIGER and FC (r s = .687, p < .0001). In addition, there was significant correlation between TIGER and IBD Disk (r s = .613, p < .0001).

Conclusion

The TIGER score demonstrates significant correlation with FC, CRP and IBD disk score in Crohn’s disease patients and thus can be used as a reliable and simple endoscopic score for CD patients to capture overall endoscopic disease burden.
P167 Sexual dysfunction and associated factors in young patients with Crohn’s disease
Authors: Rodríguez A , Herreros B , Muñoz R , Sempere L , Bernal L , Hurtado A , Orts B , Zapater P , Moreno O , Gutiérrez A
Published: May 2021

Background

The prevalence of sexual dysfunction (SD) in general population has been estimated up to 30% in women and 5% in men, and 50% and 25% in IBD patients, respectively. We aimed to compare the rates of SD in young patients with Crohn’s disease (CD) with healthy controls (HC), as well as to identify SD associated factors in CD patients.

Methods

This was a cross-sectional, case-control, observational study, including CD out-patients, aged 18–40 years-old, and HC paired by gender and age. Sociodemographic and disease features were recorded. SD was measured by the Index of Female Sexual Function(IFSF) in women, and by International Index of Erectile Function(IIFE-15) in men. Psychological functioning was evaluated using the Hospital Anxiety and Depression Scale [HAD], and quality of life in IBD by SIBDQ-9. Differences between groups were statistically compared.

Results

A total of 122 subjects were included:73 men(48 CD, 25 HC) and 49 women(21 CD, 28 HC). Nineteen percent of CD women and 8.3% of men had active disease according to Harvey-Bradshaw Index. Nineteen percent of CD women and 6.3% of men were receiving steroids, 23.8% and 14.6% immunosuppressants, and 71.4% and 72.9% biologics, respectively. CD women had more sedentary lifestyle than HC(38.1% vs 3.6%, p=0.005). In women SD rates were 35% in CD vs 12% in HC(p < 0.08). Mean IFSF values were lower in CD women(27 CD vs 30 HC, p=0.02), as well as in the desire item(3.5 CD vs 4.3 HC, p=0.005). SD in men did not show significant difference between groups. Mean IIFE values differed between CD and HC(53.6 vs 67.2, p=0.001), as well as erectile disfunction, orgasm and global satisfaction(p< 0.05)(Table 1). Main factors associated with an abnormal SD in CD women were high fecal calprotectine, current use of steroids, lower SIBDQ score and higher depression score(p<0.05). Although disease features or current treatments did not correlate to SD in CD men, both perianal disease and surgery were associated with lower values of orgasm domain (p<0.05).

Conclusion

In our serie SD was numerically higher in CD patients compared to HS. SD in CD women, but not in men, was driven by disease activity, current steroid treatment and depression.
P241 Gastrointestinal ultrasound instead of magnetic resonance enterography: Large potential cost savings with limited clinical downsides
Authors: Luber R , Petri B , Griffin N , Irving P
Published: May 2021

Background

Gastrointestinal ultrasound (GIUS) is a non-invasive imaging modality capable of detecting intestinal inflammation & associated complications. It has comparable sensitivity & specificity to magnetic resonance enterography (MRE) in detecting ileocolonic disease, however it is less expensive (£24 vs £180) & can be performed at point of care.

We aimed to establish the proportion of MREs that could have been performed as GIUS at a tertiary inflammatory bowel disease (IBD) unit, the potential cost savings, & the predicted pathology miss-rates.

Methods

All MREs performed in January 2018 were retrospectively reviewed. Demographics, scan indication, IBD characteristics, surgical history, & gastrointestinal & non-gastrointestinal findings were collected. Indications deemed suitable for GIUS included: assessment of disease activity of known small bowel (SB) Crohn’s disease; first assessment for presence of SB disease in IBD; & investigation for SB disease in patients without a known diagnosis of IBD. Obesity, complicated surgical history (>1 resection or strictureplasty involving different segments, or stoma), & known proximal SB disease were deemed unsuitable.

Results

105 MREs were performed in January 2018. 59 (56%) were deemed suitable for GIUS instead of MRE. Most common reasons for unsuitability included complex surgical history (n=17, 37%), obesity (n=14, 30%), non-appropriate indication (n=12, 26%) & known upper gastrointestinal disease (n=10, 22%).

Of suitable cases, 32/59 (54%) had active inflammation detected including 17 (53%) isolated ileal, 8 (25%) ileocolonic, & 6 (19%) isolated colonic. In one case performed as first assessment for SB disease, both ileal & jejunal disease were found, the latter likely to be missed with GIUS. No cases of isolated upper gastrointestinal inflammation were found. Regarding non-gastrointestinal findings in potential GIUS patients, there were two cases of pancreatic cysts necessitating further investigation with serial MRIs & endoscopic ultrasound, yielding a side branch intraductal papillary mucinous neoplasm & a benign serous cyst adenoma. One case of multiple high T2 skeletal lesions was deemed clinically insignificant following further investigations. No other significant extra-intestinal findings not expected to be seen on GIUS were identified.

Conclusion

Over 50% of MREs could have been performed as GIUS instead, with a potential annual cost saving of over £110,000. No instances of inflammation would have been missed based on distribution, although in one case the full extent of disease may not have been identified on GIUS. Incidental non-gastrointestinal findings resulted in multiple investigations but were of limited clinical significance.
P246 Development of a new Inflammatory Bowel Disease Patient Identifier shortens time to clinic review and initiation of treatment
Authors: Chee D , Hamilton B , Cairnes V , Lin S , Chanchlani N , Ahmad T , Goodhand J , Kennedy N
Published: May 2021

Background

Timely diagnosis of inflammatory bowel disease (IBD) is important because earlier use of biologic therapies leads to mucosal healing, a reduction in hospitalisations and surgeries and improvements in quality of life. In the United Kingdom, general practitioners refer patients with symptoms suggestive of IBD to colorectal surgeons, emergency department physicians, gastroenterologists or directly for a lower gastrointestinal endoscopy. Consequently, there is variation in the time from endoscopic diagnosis of IBD to specialist review. We created an electronic tool that screens all endoscopy reports for a new diagnosis of IBD. These cases are then reviewed in our weekly complex multidisciplinary team (MDT) meeting and new patients are allocated an IBD specialist. We sought to determine whether our new patient identifier reduced the time to clinical review by an IBD specialist and initiation of IBD treatment.

Methods

We designed a retrospective observational cohort study comparing time from endoscopic diagnosis of IBD to initiation of treatment and IBD specialist review. Outcomes were compared in the 18 months before and after the introduction, in January 2018, of our new IBD patient identifier. Demographic, endoscopic and treatment outcome data were recorded from our electronic patient record. Categorical and continuous variables were summarised as frequencies (%) and median [IQR] and compared with Fisher’s exact and Mann Whitney U tests respectively.

Results

Between the 1st January 2018 and 30th June 2019, 116 new patients diagnosed with IBD were identified and reviewed in our MDT meeting. In the preceding 18 months, 111 patients were diagnosed with IBD. There were no significant differences between groups according to sex, age, age at diagnosis, disease type, or phenotype according to the Montreal classification (Table 1). Both the median time from endoscopic diagnosis to treatment initiation (0 days [IQR 0 – 14.2] vs 14 days [IQR 0 – 31.6], p=0.007) and specialist clinic review (21 days [IQR 7 - 25] vs 48 days [IQR 34 – 63], p<0.0001) were shorter following the introduction of the new IBD patient identifier screening tool (Figure 1).

Conclusion

Systematic electronic screening of endoscopic reports linked to MDT review reduces the time to first treatment and specialist review in newly diagnosed patients with IBD.
P262 Effectiveness and safety of ustekinumab in elderly patients: Real world evidence from ENEIDA registry
Authors: Casas Deza D , Lamuela Calvo L J , Arbonés Mainar J M , Ricart E , Gisbert J P , Rivero Tirado M , Sanchez Rodríguez E , Sicilia B , Gutierrez Casbas A , Merino Ochoa O , Márquez L , Laredo de la Torre V , Martin Arranz M D , Lopez Serrano P , Riestra Menéndez S , Gonzalez Muñoza C , de Castro Parga L , Calvo Moya M , Garcia Alonso J , Esteve M , Iborra Colomino M , Dura Gil M , Barreiro de Acosta M , Lorente Poyatos R , Manceñido N , Caballo B , Calafat M , Rodríguez Lago I , Guardiola Capo J , Morales Alvarado V J , Tardillo C , Bujanda L , Muñoz Nuñez J F , Ber Nieto Y , Bermejo F , Chaparro M , Almela P , Navarro M , Domènech E , García López S
Published: May 2021

Background

Clinical trials and real-life studies with Ustekinumab in Crohn’s disease show its good efficacy and safety profile. However, there are hardly any data on elderly patients, who are excluded from these clinical trials. Our aim is to evaluate these variables in real-life practice.

Methods

Retrospective analysis of patients from the prospectively maintained ENEIDA registry treated with Ustekinumab for Crohn’s disease. Elderly patients were selected as those over 60 years old at the start of treatment. They were compared with 2 randomised controls from the same centre, aged less than 60 years, matched for smoking habit. The degree of comorbidity was assessed using the Charlson’s index. Clinical and biochemical activity and effectiveness were defined based on Harvey-Bradshaw index and calprotectin and CRP levels at weeks 16, 32 and 54, when available.

Results

A total of 648 patients were analysed, 212 elderly (mean age 67 [63.6;72.8] years) and 436 young (mean age 41.6 [32.6;50.0] years). No differences were observed between both groups in baseline variables except for the degree of comorbidity, higher in elderly patients (1.00 [0.00;2.00] vs 0.00 [0.00;0.00], p<0.001) and previous anti-TNF use, lower in the elderly (3.44% vs 15.2%, p<0.001). Baseline clinical and biochemical activity was similar in both groups.

Clinical response rate was similar in both groups at week 16 (70.5% vs 76.6%, p=0.199), week 32 (67.6% vs 70.2% p=0.104) and week 54 (74% vs 74.9%, p=0.326). Steroid-free remission and biochemical response also showed no differences throughout follow-up.

The rate of adverse effects was similar in both groups (14.2% vs 11.2%, p=0.350) except for the occurrence of de novo neoplasms, which was higher in the elderly group (0.69% vs 4.25%, p=0.003). The rate of severe infections (7.08 vs 7.34, p=1.000), the need for surgery (16.5% vs 20.0%, p=0.345) and the need for hospital admission (21.7% vs 19.0%, p=0.489) did not differ.

Persistence of UST treatment was similar in both groups (log Rank test p=0.91).

Conclusion

Ustekinumab achieved clinical response in almost three-quarters of elderly patients, similar to the younger population, with no increase in the rate of infections or other adverse effects, with the exception of de novo neoplasms.
P316 Human neutrophil elastase derived fragment of calprotectin (S100a9) is a serum biomarker (CPa9-HNE) for monitoring of anti-TNFα treatment response in Crohn’s disease
Authors: Mortensen J , Karsdal M A , Grønbæk H , Hvas C L , Dige A , Bay-Jensen A C
Published: May 2021

Background

In patients with inflammatory bowel disease (IBD), up to 30% do not achieve response, 66% do not achieve remission, and 40% experience loss of response to anti-TNFα treatment. In Crohn’s disease (CD), fecal calprotectin is the most widely used fecal biomarker for diagnosis and monitoring of disease activity. Fecal sampling and processing are tedious compared to serum sampling, and biomarker quantification in serum is more efficient, convenient, and also more acceptable for patients. Therefore, there is a need for a robust and reliable serum calprotectin biomarker that performs better than conventional serum biomarkers. The aim of this study was to investigate the performance of a novel serum calprotectin assay, which quantifies a specific human neutrophil elastase (HNE) generated calprotectin (S100a9) fragment (CPa9-HNE), as a measure of true neutrophil granulocyte activity, for monitoring treatment responses in patients with CD.

Methods

We included 30 CD patients with clinically active (Harvey-Bradshaw Index (HBI)≥5) luminal inflammation scheduled for anti-TNF treatment (adalimumab or infliximab). Serum samples where obtained at baseline (n=30), week 1 (n=29), week 8 (n=28), week 26 (n=15), and week 56 (n=7). CPa9-HNE (Calprotectin, S100a9, specific fragment generated by human neutrophil elastase), CRP and fecal calprotectin were quantified. Remitters (n=11) were defined as patients in clinical remission (HBI<5) at week 8 with no flares at week 26 or week 56. Non-remitters (n=19) were defined by having clinical active disease (HBI≥5) at week 8 or having a flare at week 26 or week 56.

Results

Patients with severe disease activity (HBI>16) had significantly elevated serum levels of CPa9-HNE compared with patients in remission (p<0.05), with mild (p<0.05) or moderate (p<0.01) disease activity. CPa9-HNE serum levels were significantly suppressed in remitters compared with non-remitters at week 8 (p<0.001), week 26 (p<0.01) and week 56 (p<0.05) (Figure 1). Fecal calprotectin and CRP were significantly suppressed at week 8, week 26 and week 56 compared with baseline levels for remitters and non-remitters, but there was no significant difference between remitters and non-remitters (Figure 1). Non-remitters were more likely to have high levels of CPa9-HNE at baseline (tertile 1,2 vs tertile 3; OR: 6.8 (CI:1.22-36.5), p=0.027) and week 8 (tertile 1,2 vs tertile 3; OR: 24 (CI:2.56-279), p=0.0014).

Conclusion

CPa9-HNE is a novel non-invasive biomarker for monitoring treatment response to anti-TNFα for CD patients and may be used as a surrogate marker for assessing disease activity and to predict outcome of anti-TNFα treatment.
P326 An exploratory analysis of the impact of COVID-19 on colonoscopy procedures and new biologic treatment initiation among patients with Inflammatory Bowel Disease in the United States
Authors: Ungaro R , Chou B , Mo J , Ursos L , Twardowski R , Candela N , Colombel J F
Published: May 2021

Background

Patients with inflammatory bowel disease (IBD) require frequent colonoscopies to optimize disease management and treatment strategies. At the onset of the COVID-19 pandemic, many routine procedures were postponed to reduce the overall burden on healthcare systems. We characterized the impact of COVID-19 on IBD care by conducting an exploratory analysis of real-world US healthcare claims data to identify changes in treatment patterns and the number of colonoscopy procedures performed in patients with IBD during the first wave of the pandemic.

Methods

De-identified, open-source health insurance claims data, from Jan 2019 to Oct 2020, were obtained from the Symphony Health Integrated Dataverse® for US adults aged 18–80 years with IBD. Four outcome measures were used: number of colonoscopies performed; number of new biologic treatment initiations or treatment switches; number of new biologic treatment initiations or treatment switches in patients who had a colonoscopy within the previous 60 days; and rate of telehealth consultations per 1000 patients per month.

Results

During Jan–Dec 2019 and Jan–Oct 2020, 1.54 million and 1.29 million patients with IBD, respectively, were included. The bimonthly number of colonoscopies remained stable throughout 2019, with a maximum change of +5.4% in Jul–Aug (N = 49947) vs Jan–Feb 2019 (N = 47399). Colonoscopy use decreased by 4.7% in Jan–Feb 2020 (N = 45167) vs the same period in 2019. In Mar–Apr 2020, colonoscopy numbers decreased by 55.3% (N = 20191) vs Jan–Feb 2020 (Figure 1a); a reduction of 59.4% vs Mar–Apr 2019 (N = 49780). In May–Jun 2020 (−23.8%) and Jul–Aug 2020 (+2.0%) the difference vs Jan–Feb 2020 gradually decreased (Figure 1a). Bimonthly numbers of new treatment initiations or treatment switches in 2019 varied by up to 6.9% vs Jan–Feb 2019. In May–Jun 2020, numbers of new treatment initiations or treatment switches decreased by 17.0% (N = 10072) vs Jan–Feb 2020 (N = 12133) (Figure 1b); a decrease of 19.3% vs May–Jun 2019 (N = 12488). The number of new treatment initiations or treatment switches in patients who had a colonoscopy within the previous 60 days decreased by 42.5% (N = 892) in Mar–Apr 2020 vs Jan–Feb 2020 (N = 1551) (Figure 1c); a decrease of 44.2% vs Mar–Apr 2019 (N = 1599). Telehealth utilization increased in March 2020 and remained higher than in 2019 up to October 2020 (Figure 2).

Conclusion

Reduction in colonoscopies and subsequent initiation/switching of treatments during the COVID-19 pandemic first wave suggests lost opportunities for therapy optimization that may have an impact on longer-term patient outcomes. Increased utilization of telehealth services may have helped address gaps in routine clinical care.
P340 Real-world treatment patterns and recurrence rates of rectovaginal fistulas in patients with Crohn’s disease: A retrospective cohort database analysis
Authors: Karki C , Latremouille-Viau D , Gilaberte I , Hantsbarger G , Romdhani H , Lightner A
Published: May 2021

Background

Rectovaginal fistulas (RVF) are a difficult to treat perianal complication of Crohn’s disease (CD) with a significant impact on quality of life. Management of RVF includes both medical and surgical interventions. Few studies have assessed real-world treatment patterns for CD-related RVF. This retrospective US cohort database analysis aimed to assess the rate of, and time to RVF episodes of care in CD, and describe treatment patterns.

Methods

IBM Truven Health MarketScan® databases (Commercial and Medicare supplemental administrative claims [01/01/01 to 31/12/19]) were used. Adult females with a diagnosis code for CD, ≥1 medical claim with a RVF-specific diagnosis/procedure ICD-9/10 code on or after the date of first observed CD diagnosis, and ≥180 and ≥720 days of continuous health plan enrolment before and after index (date of first RVF-related code after first CD diagnosis date), respectively, were included. Treatment patterns were assessed during the 6 months pre-index (baseline period) and any time post-index. The first RVF episode of care (episode) started on the date of the first RVF-related code after CD diagnosis. RVF-related codes ≤90 days apart were considered as the same episode. Time to subsequent episodes was assessed by Kaplan–Meier (KM) analysis. Only descriptive statistics were reported for the proportion of patients with episodes and subsequent treatment patterns.

Results

Of 274 096 adult females diagnosed with CD during a continuous eligibility period, 2540 (0.9%) had a RVF-specific code. Overall, 963 patients met the inclusion criteria (median age: 46.0 years). The median follow-up (time between the index date and end of continuous health plan enrolment or data availability) was 48.5 months. During the follow-up period, 963 (100%), 430 (44.7%) and 217 (22.5%) patients had at least one, two or three episodes, respectively. KM analysis showed the probability of having a subsequent episode within 1, 2 and 5 years of their first or second episode (Figure). During the baseline period, 775 (80.5%) and 287 (29.8%) patients received non-biologic or biologic therapies, respectively, and 929 (96.5%) and 494 (51.3%) at any time post-index. At any time post-index, 587 (61.0%) patients had ≥1 RVF-related surgery.

Conclusion

This study showed patients with CD-related RVF required recurrent episodes of medical and surgical care in a US real-world setting. In addition, post-index, an important proportion of patients were observed with biologics use (>50%) and nearly two-thirds of patients had RVF-related surgery. Patients with CD-related RVF had varied treatment patterns and more studies are needed to inform the standard of care for patients with RVF.

Sponsor: Takeda Pharmaceuticals, Inc.
P366 Vedolizumab maintenance therapy reduced use of corticosteroids in patients with Crohn’s disease in the GEMINI 2 trial
Authors: D’Haens G , Candela N , Uddin S , Peterson T , Dubinsky M , Colombel J F
Published: May 2021

Background

Corticosteroids (CSs) can induce clinical remission of Crohn’s disease (CD), but long-term use is associated with serious side effects. In the GEMINI 2 trial, a greater proportion of patients with moderately to severely active CD treated with vedolizumab (VDZ) maintenance therapy achieved CS-free remission at week 52 compared with placebo (PBO).1 Response to VDZ is influenced by prior exposure to anti-TNF therapy. In this post hoc exploratory analysis of GEMINI 2, we investigated the impact of VDZ maintenance therapy on use of CSs stratified by prior anti-TNF therapy failure status and baseline disease activity (moderate or severe).

Methods

In GEMINI 2, patients who responded to VDZ induction therapy at week 6 were re-randomized to receive VDZ or PBO every 4 or 8 weeks and began a prespecified CS tapering regimen (Figure 1).1 In patients receiving CSs at baseline, we measured change in CS dose from baseline to week 52 , proportion of patients with CS dose ≤ 7.5 mg/day, and proportion of patients with ≥ 90 or ≥ 180 consecutive CS-free days at week 52. Analyses were conducted overall and stratified by prior anti-TNF therapy failure status, baseline Crohn’s Disease Activity Index (CDAI) score (moderate: ≤ 330, severe: > 330), and the composite of both measures.

Results

In the overall population, a greater proportion of patients treated with VDZ (67.7%) vs PBO (61.5%) had their CS dose reduced from baseline. This trend was also observed among patients with no prior anti-TNF therapy failure, with a baseline CDAI score ≤ 330, and with no prior anti-TNF therapy failure and a baseline CDAI score ≤ 330 (Figure 2). Similarly, numerically higher proportions of patients treated with VDZ vs PBO received a CS dose of ≤ 7.5 mg/day in the overall population and in subgroups with no prior anti-TNF therapy failure, with baseline CDAI score ≤ 330, and with no prior anti-TNF therapy failure and a baseline CDAI score ≤ 330 (Figure 3). Overall, 35.2% and 32.7% of patients receiving VDZ had ≥ 90 and ≥ 180 consecutive CS-free days, respectively, compared with 28.0% and 22.0% of those receiving PBO. The proportion of patients with ≥ 180 consecutive CS-free days was numerically higher for the VDZ group vs the PBO group, regardless of prior anti-TNF therapy failure status or baseline CDAI score.

Conclusion

VDZ maintenance therapy was associated with more successful CS withdrawal than PBO, particularly in patients with no prior anti-TNF therapy failure and moderate disease activity. Interpretation of these results is limited by the exploratory nature of the analyses, small sample sizes and different initiation weeks for CS tapering per patient.

Reference