bluuebunny/crossref_metadata_2025 huggingface dataset:
P098 Novel drug candidate for the treatment of Inflammatory Bowel Disease with unique mechanisms of action
Authors: Lee J , Kim G , Kim J C , Park J H , Han C , Kim M
Published: January 2023

Background

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation and severe dysfunction of the gastrointestinal tract. Despite significant improvements in therapeutic agents targeting IBD, many subjects with IBD fail to achieve recovery or do not respond to current medication. Moreover, current therapy has been limited to the management of inflammation, while almost no progress has been made in the development of anti-fibrotic therapies for IBD. NEXEL’s novel protein NP-011, targeting αVβ3 and αVβ5 integrins and phosphatidylserine, has shown anti-inflammatory and anti-fibrotic effects in various in vivo models with fibrosis. This study was designed to evaluate the therapeutic potential of NP-011 for the treatment of IBD using mice models.

Methods

Acute ulcerative colitis was induced by exposure to 2% dextran sodium sulfate (DSS)-treated drinking water from Day 1 to Day 7; Normal control animals did not receive DSS. Animals were then dosed with vehicle (NP-011 storage buffer, n=10), comparative protein, MFG-E8 (n=10), or NP-011 (n=10) daily for five days (IV) from Day 7 to Day 11. All animals were sacrificed on Day 14. The chronic colitis model was induced by exposure to 2% DSS-treated drinking water (initial three consecutive days of each week) and recovered by providing normal water (four days each from Day 3 and Day 10). Animals were dosed with the vehicle, three commercial drugs (n=10, 1.03 mg/kg, on Day 3), and NP-011 (n=10, 320, and 640 ug/kg, on Day 3 and Day 10) by intravenous injection. All animals were sacrificed on Day 18. Colon length and histological changes (inflammation and crypt damage) were analyzed.

Results

The induction of colitis was characterized by weight loss. Treatment with comparative protein or NP-011 improved body weight gain during recovery. Both proteins suppressed the shortening of the colon and reduced histological score, including intestinal inflammation and crypt damage. Notably, the administration of NP-011 showed higher efficiency than the same dose of the comparative protein in improving these pathologic parameters. NP-011 was also effective in the chronic model of colitis. Colon shortening, inflammation reactions, and crypt damage were markedly attenuated in NP-011-administered mice with comparable efficacy to commercial drugs.

Conclusion

Treatment with NP-011 demonstrated substantial improvement in histological characteristics of bowel pathology and suppression of colon shortening in the IBD mice model. Taken together, this novel protein, NP-011, could be a promising drug candidate for the treatment of IBD with unique mechanisms of action, including anti-inflammation and anti-fibrosis

*JL, GK, and JCK have equally contributed to this study.
P100 Atypical Anti-Neutrophil Cytoplasmatic Antibodies Are Antibodies Against Neutrophil Extracellular Traps: A Novel Pathophysiological Mechanism In Ulcerative Colitis
Authors: Mendieta Escalante E A , Parada-Venegas D , Bourgonje A , Roozendaal C , Hermoso Ramello M , Faber K N , Dijkstra G
Published: January 2023

Background

The number of mucosal neutrophils, as well as the presence of neutrophil extracellular traps (NETs), correlate with disease activity in Ulcerative colitis (UC), an inflammatory bowel disease. Most (~80%) UC patients present atypical Anti-Neutrophil Cytoplasmatic Antibodies (a-ANCAs) to a yet unknown antigen, which shows a different immunofluorescence staining pattern when compared to cytoplasmatic (c-ANCA) and perinuclear (p-ANCA) that target proteinase (PR3) and myeloperoxidase (MPO), respectively. Here, we analyzed whether a-ANCAs specifically bind to NETs.

Methods

Blood neutrophils were treated to form non-lytic NETs using LPS-treated platelets with and without DNAse and Trypsin. Patient biopsies and in vitro-formed non-lytic NETs were incubated with p-ANCA, c-ANCA and a-ANCA positive patient and ANCA negative control serum and processed for immunofluorescence microscopy. Macrophage-mediated clearance of serum-pretreated NETs was analyzed in real-time using Incucyte microscopy.

Results

Ethanol-fixed neutrophils displayed c-ANCA, p-ANCA patterns, and a-ANCA web-like staining. Only c- and p-ANCA react to DNAse-treated ethanol-fixed neutrophils (Fig 1). Serum containing a-ANCA’s bound to non-lytic NETs that disappeared upon treatment with DNAse and Trypsin whereas c- and p- ANCA binding did not disappear upon DNAse treatment (Fig 2) indicating that both DNA and proteins are needed for a-ANCAs to bind to non-lytic NETs. In inflamed colonic tissue of UC patients, a-ANCA co-stained with extracellular DNA and neutrophil elastase covering the intestinal epithelium (Fig 3). In vitro, NETs were efficiently cleared by macrophages, which was strongly inhibited after pre-incubating with a-ANCAs (Fig 4). Macrophages exposed to a-ANCA-incubated NETs expressed higher CXCL-8 and IFN-B levels than the NETs exposed to control serum (both p<0.05).

Figure 1

Figure 2

Figure 3

Figure 4

Conclusion

a-ANCAs specifically bind to de novo DNA-protein antigens in non-lytic NETs, which prevents efficient macrophage-mediated clearance and induces a pro-inflammatory (M1) phenotype. This inflammatory milieu may contribute to the pathophysiology of UC.
P101 Circulating MicroRNA-16 in Inflammatory Bowel Disease Patients - Potential Biomarker to Assess Inflammation
Authors: Atanassova A , Georgieva A C
Published: January 2023

Background

miR-16 is important for the inflammatory processes and the signal pathways that participate in the immune system regulation. As there is an immune mucosal inflammation in IBD, miR-16 could also serve as a potential biomarker to assess inflammation.

Methods

The study aims to assess the expression of serum miR-16 in IBD patients and to correlate its expression with clinical parameters such as disease extent, activity and severity.

35 patients with UC and 35 patients with CD were included in the study. Serum miR-16 expression was assessed with reverse transcriptase quantitative real time PCR (RT-qPCR), and was then correlated with the miR-16 levels in a group of 30 healthy subjects.

Results

miR-16 expression is increased in patients with CD, localized in the small intestine (3.54±2.33) and in pancolitis Е3 of UC (2.01±1.54). There is a significant difference in miR-16 expression in inflammatory (B1), stenotic (B2) and penetrating (B3) form of CD (р=0.010) with higher expression levels in the more severe B2 and B3 forms. There is no significant difference in miR-16 expression according to the forms of evolution in patients with UC. In patients with CD, there is a moderate direct correlation between the expression of miR-16 and the Crohn’s disease activity index CDAI (r=0.424; p=0.015). miR-16 expression levels increase progressively in correlation with the activity of CD. Patients with moderate activity of their CD have significantly higher miR-16 expression (4.27±3.00) as compared to patients with mild activity (2.38±1.06) or in remission (2.41±1.23) of the disease (р=0.048). The increased expression levels of miR-16 are a risk factor for CDAI > 150 levels (OR=4.80 (0.506-45.495); p=0.015). In patients with UC, there is no correlation between the miR-16 expression levels and the severity (S) index, measured as per the Montreal classification or the endoscopic activity, measured as per the Partial Mayo score. In patients with severe disease, measured by both S index (1.38±0.89) and Partial Mayo score (1.80±1.12), there is a decrease in miR-16, close to normal controls. MiR-16 expression levels do not correlate with any treatment that was given in patients with either CD or UC.

Conclusion

The increased miR-16 serum expression corelates with the localization of CD in the small intestine and the stenotic and penetrating form of the disease. Increased miR-16 levels are also found in extensive UC. In patients with CD there is a positive correlation between the expression of miR-16 and the activity of the disease as measured by the CDAI.
P103 Colitis-associated faecal miRNAs are mediators of host-microbiota interactions and key regulators of intestinal permeability and inflammation
Authors: Casado-Bedmar M , Roy M , Hugot J P , Le Gall M , Chassaing B , Viennois E
Published: January 2023

Background

Like in other chronic pathologies, evidence has shown disruption of host immune-microbial interactions and intestinal dysbiosis in the pathogenesis of Inflammatory Bowel Diseases (IBD), also characterized by chronic inflammation and increased intestinal permeability. Faecal microRNAs (miRNAs) have recently emerged as potential inter-kingdom mediators between the host and its microbiota, but the influence of its interaction on chronic intestinal disorders remains unclear. Here, we aimed to study the impact of colitis-associated miRNAs on intestinal inflammation, permeability and microbiota.

Methods

A panel of faecal miRNAs was profiled in IL10-/- mice, known as a model of spontaneous colitis. Faecal miRNAs and microbiota composition were compared between IBD and healthy controls. Identified colitis-associated miRNAs were then administered with/out antibiotics ad libitum to C57BL6 mice. Parameters of inflammation, intestinal epithelial barrier function, as well as microbiota composition, were analysed. Ex vivo and in silico studies were performed to comprehend the direct effects of the miRNAs on the gut microbiota and the host. Lastly, endogenous miRNAs were inhibited in IL10-/- mice administering miRNA-inhibitors through oral gavage.

Results

We identified in mice two colitis-associated miRNAs that were also increased in faecal samples of IBD compared to healthy controls (Graphic 1). Notably, the exogenous administration of these two miRNAs was sufficient to drive intestinal inflammation (Graphic 2) and alter the intestinal barrier function in mice. Such effects were directly impacted by the microbiota presence and composition. In humans, the measurement of faecal lipopolysaccharides and the 16S microbiota sequencing further showed strong associations between miRNAs and bacterial species, such as Faecalibacterium prausnitzii and Parabacteroides distasonis. In mice, the treatment with colitis-associated miRNAs altered the microbiota composition with a significant increase of Cyanobacteria and Verrucomicrobiota. Importantly, the inhibition of endogenous miRNAs through anti-miRNA administration prevented the emergence of severe colitis in IL10-/- mice (Graphic 3).

Conclusion

Overall, our findings identify an inflammatory role played by faecal miRNAs in the gastrointestinal environment, which pathogenic potential appears closely related to dysbiosis. Hence, our data suggest that miRNAs or miRNA inhibitors might be considered therapeutic agents to beneficially alter the microbiota and intestinal inflammation in IBD and other dysbiosis-associated conditions.
P104 Exploring the transcriptomic miRNA signatures of Egyptian Inflammatory Bowel Disease patients
Authors: Khaled M , Hamdy K , Abou-Aisha K , Mansour M
Published: January 2023

Background

Inflammatory Bowel Disease (IBD) is a chronic autoimmune gastrointestinal disease, sub-classified into Crohn’s disease (CD) and ulcerative colitis (UC). The two subclasses are characterized by a relapsing-remitting course with an increasingly high incidence and prevalence worldwide. Molecular mechanisms guarding the pathogenesis of these diseases remain, to the present day, ambiguous to researchers. MicroRNAs are 22 nucleotides long small noncoding RNAs that have been recently described as essential participants in immune cell development and the immune response to pathogens. During the past decade, genetic and epigenetic studies in IBD have been labeled as essential; since endoscopic assessment and biopsies provide limited data concerning early disease activity, factors for relapse, and response to treatment. To the best of our knowledge, IBD research has never addressed miRNA profiles in Egyptian CD and UC patients as compared to unaffected controls.

Methods

Therefore, this study aims to profile miRNAs in Egyptian patients suffering from UC and CD, using RNA-seq of total RNA extracted from colonoscopically obtained tissue pinch biopsies.

Results

The sequencing results showed that 30 miRNAs were uniquely expressed in tissue biopsies obtained from the CD patients, as compared to only 14 uniquely expressed in UC patients. Further web-based functional enrichment analysis showed that the miRNAs- in both disease groups- are mainly involved in six interlinked molecular pathways; including the JAK/STAT, WNT, PI3K/AKT, FOXO, MAPK, and NF-κB signaling pathways. One of the most interesting findings of the current study is the fact that the downregulation of the miR-204-5p in UC patients (log2 FC= 5.05)-as compared to CD patients- may be caused by the sponging effect of the MALAT1 long non-coding RNA (lncRNA); affecting related signaling pathways such as the Wnt/β-catenin signaling. This suggests an essential interplay between miRNAs and lncRNAs in shaping the molecular pathogenesis of UC vs. CD.

Conclusion

The results of the current study revealed explicit-previously undetermined- differences in the miRNA profiles of patients suffering from UC and CD. Such results are expected to impact the understanding of the difference in the molecular pathogenesis of IBD subtypes affecting patients’ response to treatment.
P105 Epithelial microRNA signatures as potential biomarkers in Crohn’s disease related to clinical and endoscopic activity
Authors: Moon J M , Kim K U , Shin S Y , Joo H J , Min H , Choi C H
Published: January 2023

Background

Emerging evidence suggests that epithelial cell-derived microRNAs (miRNA) are involved in the pathogenesis of inflammatory bowel disease; however, as of now specific implications in the real clinical practice, especially in relation to biologics use are yet far-fetched. Therefore, we tried to investigate specific epithelial cell derived miRNA signatures related to clinical and endoscopic activity in Crohn’s disease (CD) patients.

Methods

We prospectively collected terminal ileum tissue samples via ileocolonoscopy from healthy control (n=12), CD patients in remission (n=32) and active CD patients (n=36). CD remission was defined as clinical remission of Crohn's disease activity index (CDAI) <150 and achievement of endoscopic mucosal healing. Both inflamed and non-inflamed lesions were sampled in the active CD patients. Clinical information, medication use, chemistry data were measured within a week from the tissue sample date. miRNA levels were measured by small-RNA sequencing and qRT-PCR. Diagnostic ability of specific miRNA found were evaluated by receiver operating characteristic (ROC) curve analysis.

Results

The study cohort was followed up until January 2022. Mean follow-up period of the prospective CD cohort was 13.06 months. In comparing to the healthy control, CD patients in remission and active state revealed specific miRNA profiles in small-RNA sequencing. Through RT-PCR validation, we found that the expression levels of miR-141-3p, miR-338-3p, miR-378a-3p, and miR-200b-3p were significantly decreased, while miR-125b-5p, miR-29b-3p and miR-155-5p were significantly increased in the inflamed tissue of active CD patients. Moreover, in case of active CD patients, expressions of miR-150-5p, miR-200b-3p and miR-155-5p were significantly down-regulated in those using biologics, compared with biologics naïve patients. This may suggest that these miRNAs were not only as biomarkers of CD patients, but also as biomarkers related to inflammation and biologics response. ROC curve analysis suggested miRNAs with different diagnostic activity related to both clinical disease activity and endoscopic inflammation status. MiR-338-3p, miR-141-3p and miR-378a-3p demonstrated area under curve of greater than 0.9 in predicting active CD patients.

Conclusion

We report specific miRNA biomarkers identifying CD and its disease inflammation activity with relation to biologics use, suggesting potential treatment target in CD pathogenesis. These miRNA signatures could also be of potential clinical use in positioning biologics, which we intend to explore in the near future.
P110 activation protein is strongly expressed in intestinal fibrosis in inflammatory bowel disease patients
Authors: Lartey D , van Roest M , Verhoeff J , Grootjans J , Buskens C , van der Bilt J , Wildenberg M , D'Haens G , Löwenberg M
Published: January 2023

Background

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) with limited diagnostic modalities to detect and determine the degree of fibrosis. Fibroblast activation protein alpha (FAP) is a protein with both dipeptidyl peptidase and endopeptidase properties which is virtually absent in healthy tissues and has increased expression in chronic inflammatory and fibrotic diseases. In this study, we investigated the presence of FAP in intestinal fibrosis caused by Crohn’s disease (CD) and ulcerative colitis (UC).

Methods

For this study, transmural surgical resection specimens were retrieved from the Tytgat institute IBD biobank located at Amsterdam University Medical Center. IBD patients undergoing an ileocecal resection for stricturing CD or a subtotal colectomy for therapy-refractory disease, and patients undergoing a right-sided hemicolectomy or ileocecal resection for dysplasia or non-metastasized colorectal cancer (CRC), were included. All patients had an established diagnosis of (CD, UC, dysplasia or CRC) by previous endoscopy and biopsies and had provided informed consent prior to surgery.

FAP protein and gene expression levels were determined using immunohistochemistry staining and quantitative polymerase chain reaction (qPCR). Mass cytometry was used to identify FAP–expressing cells.

Results

In total, 59 ileal and 35 colonic samples were stained and quantified to asses FAP expression (figure 1). A 1.7-fold and 1.9-fold increase of FAP protein expression was seen in inflamed (mean 22.3, p=0.0069); and stenotic (mean 25.5 p=0.0002) CD ileum compared to healthy non-IBD tissue (mean 13.1). Inflamed UC colon (mean 26.8, p = 0.0406) showed a 1.4-fold increase compared to healthy colon (mean 19.2).

For the gene expression, 66 ileal and 42 colonic samples were processed and used for qPCR analysis. A 5-fold and 6.4-fold increase of FAP was found in inflamed (mean 0.011, p=0.0475) and stenotic (mean 0.014, p=0.0042) CD ileum, and a 1.7-fold increase was seen in inflamed UC colon (mean 0.278, p=0.0195) compared to controls (means: ileum 0.002; colon 0.165).

Conclusion

This is the first study reporting the potential of FAP as a fibrotic biomarker not only in stricturing CD, but also in therapy-refractory UC. Significantly increased FAP protein and gene expression is found in inflamed and stenotic ileum in CD and inflamed colon in UC. Additionally, CD90+GP38+ cells have been identified as the most present FAP expressing cells.
P113 Protein fingerprint biomarkers of collagen remodeling can evaluate fibrogenesis in an in vitro colonic scar-in-a-jar model
Authors: Pehrsson M , Sorokina Alexdottir M , Asser Karsdal M , Høg Mortensen J
Published: January 2023

Background

Intestinal fibrosis affects most inflammatory bowel disease (IBD) patients, resulting in severe clinical complications and reduced treatment response. With no treatments approved for intestinal fibrosis, there is a need for preclinical models to investigate the pathobiology and novel treatments. Myofibroblasts are the main drivers of intestinal fibrosis and the excessive accumulation of extracellular matrix in IBD patients. We investigated a prolonged scar-in-a-jar model of colonic fibrogenesis to validate protein fingerprint (PF) biomarkers of collagen formation for clinical use and the in vitro model as a screening tool.

Methods

Human colonic fibroblasts (CCD-18co) purchased from ATCC were grown in EMEM supplemented with 10% FBS and 1% P/S in culture flasks with 200 µg/cm3 gelatin to reduce cell activation. At 80% confluency, the cells were seeded at 30,000 cells/well in a 48-well plate noted as day -2. The cells were either unstimulated or stimulated with a 2-fold dilution of TGF-β starting at 800 pM to 50 pM starting at day 0 and then every fourth day, terminating at day 12. At termination, the wells were decellularized and the collagen matrix was stained with Sirius Red for visual confirmation of collagen formation. Imaging was done using light microscopy at X20 magnification using similar settings for all images. Fibrogenesis was quantitatively determined by measuring the biomarkers PRO-C1, PRO-C3, and PRO-C6 in the supernatants. The biomarkers reflect type I, type III, and type VI collagen formation, respectively. We applied Šídák’s multiple comparisons test for differences in the collagen formation biomarker levels by comparing stimulated with unstimulated cells.

Results

Stimulation with TGF-β significantly increased type I and type III collagen formation at days 4, 8, and 12 compared to unstimulated cells, with the stimulation inducing a 297.4% increase of type III collagen at day 12 (table 1 + fig.1). Irrespective of the TGF-β concentration, a 426.8% spike in the fibrotic hormone endotrophin (PRO-C6) was observed on day 4, which declined to unstimulated levels at days 8 and 12 (table 1 + fig.1). All concentrations of TGF-β induced a significant release of the collagen formation biomarkers to the supernatant (fig. 1). Collagen deposition was confirmed by Sirius Red (fig. 2). No significant increase was observed in the unstimulated cells determined by biomarker measurements and Sirius Red (fig. 1 + 2).

Conclusion

PF biomarkers can be applied in vitro to objectively quantify fibrogenesis, demonstrating a significant increase following TGF-β stimulation of colonic fibroblasts. The model may be combined with the biomarkers to evaluate drug targets of intestinal fibrosis.
P124 Risk of surgery in inflammatory bowel disease: A systematic review and meta-analysis of sex-based differences
Authors: Rasmussen N F , Gregersen L H K , Hikmat Z , Moos C M , Green A , Andersen V , Madsen G I , Jess T , Kjeldsen L J
Published: January 2023

Background

Inflammatory bowel diseases (IBDs) are chronic diseases that require routine hospital visits and long-term medical treatment for control of disease activity. Factors such as gender may impact the use and need for healthcare. This systematic review aimed to summarize what is known about sex differences in the risk of bowel surgery in patients with IBD.

Methods

Embase, Medline, CINAHL, and Web of Science abstracts (January 2012 to January 2022) were searched systematically for observational studies examining associations between sex and risk of bowel surgery. Screening and data extraction were performed independently by two reviewers using Covidence. Study data were analysed and reported in accordance with the PRISMA guidelines. Quality assessment of included studies was conducted using the Newcastle-Ottawa Scale for cohort studies. Pooled hazard ratios (HRs) were calculated using random effects model meta-analysis for the risk of surgery. In addition, meta-analysis was undertaken to assess the risk of surgery by IBD subtype. The between-study heterogeneity was assessed by calculating the tau-squared and the I-squared statistics.

Results

Of 9,902 screened articles, 36 studies were included in the review. Most studies were retrospective by design (74.6%). In total, 21 of 36 studies found statistically significant sex-based differences in the risk of bowel surgery for IBD patients. A pooled estimate of HRs for the 13 studies eligible for meta-analysis showed a statistically significant increased risk of bowel surgery among male patients (HR: 1.43 [95% confidence interval (CI): 1.09;1.86]) compared to female patients. The between-study heterogeneity was high (I2=88.60 [60.60;96.33] and tau2=0.17 [0.03;0.58]) indicating that the pooled estimate should be interpreted with caution. These findings were consistent with the subgroup analysis for ulcerative colitis (HR: 1.78 [1.16;2.72]), but no statistically significant sex difference in the risk of surgery in Crohn’s disease patients was found (HR: 1.26 [0.82;1.93]).

Conclusion

Sex differences exist in the risk of bowel surgery in IBD patients, and further research is needed to address the underlying causes and consequences of these disparities. It is unclear whether differences are due to underlying biologic mechanisms or are associated with healthcare system related factors such as differential access to care. Surgical procedures or the lack or delay thereof, will have consequences for the further disease trajectory.
P128 The role of small bowel capsule endoscopy as a diagnostic tool in isolated complex perianal disease
Authors: Avni Biron I , Ollech J E , Toth E , Nemet A , Wurm Johansson G , Schweinstein H , Kopylov U , Margalit Yehuda R , Dotan I , Yanai H
Published: January 2023

Background

Isolated complicated perianal disease (cPD) might be the sole representation of Crohn’s disease (CD). We aimed to evaluate the impact of small bowel capsule endoscopy (SBCE) as a diagnostic tool for CD in this population.

Methods

A multicenter, retrospective cohort study from three tertiary centers. Patients with cPD who had a negative workup for CD (Ileocolonoscopy and cross-sectional imaging) and underwent evaluation with SBCE were included. Demographics, biomarkers, and the Lewis inflammatory score (LS) were recorded and analyzed. A LS≥135 was considered a positive SBCE.

Results

Ninety-one patients were included: 65 males (71.4%), mean age 40 (14) years, median duration of cPD 25.13 months (12.53-66.1). SBCE was positive in 24 patients (26.37%). Median LS was 675 (222-1518). Fecal calprotectin (FC) positively correlated with LS (r=0.81; p<0.0001): patients with a positive vs. negative SBCE had a significantly higher mean FC level (255 [389] vs 97[180], p=0.02), Figure 1. Correspondingly, a FC level ≥ 300 mg/kg had a specificity of 90% for a positive SBCE, while a cutoff of FC level <100 mg/kg or <50 mg/kg had a sensitivity of only 40% or 50% to rule out small bowel CD, respectively.

Conclusion

SBCE was positive in over a quarter of patients with cPD and a negative workup for CD. FC levels correlated with the degree of inflammation defined by the LS. However, the sensitivity of low FC to rule out CD was low. These results suggest that SBCE is an essential diagnostic tool for patients with cPD even after negative workup.
P136 Multidimensional assessment of visceral hypervigilance in patients with IBD
Authors: Atanasova K , knoedler L L , Schmitteckert S , Ebert M , Reindl W , Thomann A
Published: January 2023

Background

Persons with inflammatory bowel diseases (IBD) can suffer from irritable bowel syndrome (IBS-like) symptoms in the absence of inflammation. Also, the prevalence of anxiety symptoms and disorders is increased in IBD. Both IBS-like and anxiety symptoms impair quality of life and are challenging to treat as well as poorly understood in IBD. Visceral hypervigilance (VH) as a specific form of anxiety and a common feature of disorders of gut-brain interaction may be a relevant symptom in IBD and could relate to IBS-like symptoms. This study aimed at investigating clinical, psychological and biological factors associated with VH in persons with IBD.

Methods

We used the visceral sensitivity index (VSI) to investigate VH in 308 patients with different states of IBD disease activity (as determined by Harvey Bradshaw Index or partial Mayo Score). We further assessed demographic (age, sex), clinical (disease duration, CRP levels) and psychological (anxiety and depression, HADS) characteristics. Genetic and metabolic parameters related to serotonin metabolism were analyzed in subsamples with active disease (single nucleotide polymorphisms in genes related to serotonin signaling (n=83) and serum tryptophan metabolites (n=70)). We used multiple regression analyses to examine which factors could predict patients’ VH levels and to explore genetic and metabolic predictors of VH.

Results

The strongest predictors for VH were anxiety, depression and disease activity (all p < .001, Fig.1, left). Explorative analyses revealed polymorphisms in the HTR3A (p = .028) and SERT gene (p = .030) to predict VH (Fig.1, middle). While clinical disease activity was related to VH, there was no association between VH and inflammatory biomarkers or tryptophan metabolites (Fig.1, left and right).

Conclusion

VH as a specific type of anxiety strongly relates to psychopathology in persons with IBD. Anxiety was found to be the strongest predictor of VH, contributing to a greater extent to VH than disease activity. Possible genetic predispositions of VH should be investigated in larger studies. Screening patients for VH could help to detect disturbances in gut-brain-interactions and improve individualized treatment.
P137 The prevalence and severity of sexual dysfunction in male IBD patients: an observational single-center study
Authors: Dal Buono A , Gabbiadini R , Alfarone L , Brunetti A , Solitano V , D'Amico F , Vena W , Pizzocaro A , Armuzzi A
Published: January 2023

Background

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are lifelong disabling disorders with a significant impact on the quality of life. Previous studies reported sexual dysfunction (SD) could have a remarkable prevalence of about 25-45% in male IBD population, compared to 10-20% in the general population of the same age. However, this topic has not attracted widespread attention, and thus research studies are scarce. The aim of the study was to determine the rate and the severity of SD in a cohort of male IBD patients and to identify the associated risk factors.

Methods

This is an observational single-center study. From July 2021 to June 2022, IBD patients, who were attending scheduled visits, were invited to fill the International Index of Erectile Function (IIEF) questionnaire. Clinical data, including disease behaviour, treatment history and previous surgery, were collected. Both descriptive and inferential statistical analyses were carried out.

Results

A total of 61 male IBD patients, encompassing 33 with CD and 28 UC, were enrolled. Overall, the median age was 33.8 years (range, 19.7 – 63.7); the median body mass index (BMI) was 26.5 kg/m2 (range, 17.6 – 31.9). Almost half of the subjects were active or former smokers (49.1%). The great majority (81.9%) were receiving biological therapies, less than half had an history of IBD-related surgery (42.6%). The median total IIEF score was 64 (range, 18-75). Totally, 25.4% of the included patients reported having erectile dysfunction (ED), according to erectile function subscore. Univariate analysis showed age (p = 0.001), calprotectin levels (p<0.05) and biological therapy duration (p<0.05) as variables significantly associated with total IIEF score; age (p = 0.003) and calprotectin levels (p<0.05) were also significantly correlated with erectile function subscore. At multivariate level, age and calprotectin levels were confirmed to significantly influence both total IIEF score (p = 0.003 and p = 0.002, respectively) and erectile function subscore (p = 0.001 and p = 0.01, respectively).

Conclusion

Nearly a quarter of included IBD patients were found having ED, while rates of 5-15% in healthy subjects of the same age has been previously reported in literature. Based on our results, gastroenterologists should assess the sexual function of IBD patients and, when indicated, prompt referral for andrological investigation should be considered to improve their quality of life.
P139 Inflammatory bowel disease and impairment of working life
Authors: Mtir M , Kchir H , Mechergui N , Cherif D , Debbabi H , Yacoub H , Hassine H , Maamouri N
Published: January 2023

Background

Inflammatory bowel disease(IBD) is a lifelong illness that mainly affects patients of working age with a significant impact on their professional life. In fact, the maintenance and promotion of employees is one of the important social goals and can be considered as a determinants of health for IBD patients.

The aim of the study was to analyze the impact of disease on the working life among IBD patients and to characterize the breadth of challenges they experience in their workplace.

Methods

We conducted a cross-sectional study including working patients followed for IBD, over a 9-months period. We collected sociodemographic, clinico-biological and evolutionary data. We performed a survey among these patients using a self-report questionnairy on employment status, IBD-related difficulties at work and sick leave.

Results

We included 45 patients: 80% Crohn disease and 20% ulcerative colitis. The mean age was 44 years [20-72], the sex-ratio M/F was 0.7 and the average of follow-up was 9 years [1-18]. Civil servants represented 33% of the total population, those in the private sector 47%, and those in the liberal profession 20%. The most important socio-professional category was manual workers with 51%. Thirty-seven patients(82%) developed their disease after being employed with a mean delay of 142 months[2-648]. The average number of working hours per week was 38.84 [9-60]. The majority of the employees worked full time(84%), only seven subjects worked part-time, two of them because of their IBD. One in three patients claimed to have been exposed to at least one harmful agent during their professional career. The main complaint reported by the patients during the daily work was about physical fatigue (69%). The digestive symptoms were mainly abdominal pain(53%) evaluated according to VAS with a mean intensity of 2.8 [0 - 10], subocclusive syndrome(40%), presence of diarrhea(38%), incontinence and fecal impaction(22%) which was worsened by the absence of accessible restrooms(33%). Psychological repercussions such as anxiety and depression were mentioned in 27% of cases. The average absenteeism during the last twelve months was 49.6 days [0-240] and the average number of hospitalization days was 30.7 [0-150]. Twenty patients(44%) claimed that they were subject to a salary restriction because of their illness. Only five people had alreadỳ benefited from a contact with the occupational medicine and health service.

Conclusion

IBD has a negative impact on the working life of patients, due to uncomfortable symptoms, days of absenteeism, and unadapted workplaces, which can affect career plans, professional achievement, and income. Appropriate supports and accommodations to the workplace are needed in order to improve their working experience.
P144 Impact of major medication discontinuation during the first wave of COVID-19 pandemic on the risk of early relapse in patients with inflammatory bowel disease: a French observational retrospective study
Authors: Meunier C , Monte C , Hadjisavvas H , Rozieres A , Roblin X , Venturin C , Gay C , Flourie B , Boschetti G , Danion P , Mathieu N , Charlois A L , Faure M , Nancey S
Published: January 2023

Background

The prevalence of nonadherence to major treatments and the subsequent adverse outcomes in IBD patients during the first wave of COVID-19 pandemic remain scarce.

Aim

to investigate the risk of early disease relapse in a cohort of IBD patients under immunosuppressants and/or biologics who decided themselves to discontinue their IBD-related major treatments without previous medical advice during the first wave of COVID-19 pandemic.

Methods

All consecutive patients with inactive IBD under immunosuppressants and/or biologics who acknowledged having withdrawn their major therapy for IBD without previous medical advice during the first wave of COVID-19 (from March 2020 to December 2020) were enrolled. The primary endpoint was the survival rate without disease relapse. Kaplan-Meier curves were plotted for time from inclusion to IBD relapse and a logistic regression model with uni- and multivariate analyses was performed to identify predictors of relapse after drug discontinuation.

Results

During the study period, among the 862 IBD patients followed as outpatients either treated with infliximab or vedolizumab (outpatient clinics n= 368) or treated with oral azathioprine, adalimumab, golimumab or ustekinumab alone or in combination (n= 494), 54 patients (6.2 %) (42 CD, 12 UC, 28 F, median age 36 years) who had discontinued themselves their IBD-related major therapy without previous medical advice were included. The median duration of drug withdrawal was 7.0 weeks (range 2-24) and the median time to relapse was 9.0 weeks (range 4-20). The most treatments withdrawn were adalimumab (n=19), ustekinumab (n=19), azathioprine (n= 12), golimumab (n=1) and a lesser degree infliximab (n=7) eand vedolizumab (n=6). During the median follow-up period of 24 weeks (range 5-42), 22 out of 54 patients (40.7 %) who discontinued their IBD treatment experienced a relapse in whom 6 requiring administration of oral steroids, 4 hospitalization and 2 IBD-related surgery. By univariate analysis, past IBD related surgery was identified as the only predictor of disease relapse after drug withdrawal (OR=3.3 CI 95 % [1.08-10.38].

Conclusion

In IBD patients, major treatment discontinuation by the patients themselves without medical advices during the first wave of pandemic Covid-19 including the lockdown was associated with a substantial risk of disease relapse occurring in around 4 out of 10 patients and subsequent further risk of need for steroids, hospitalization and surgery. Strategies targeting the adherence to therapy and patient’s informations about the real risks leading to drug discontinuation are of paramount interest, especially during health crisis to minimize such issues.
P146 Stigmatization and resilience in inflammatory bowel disease patients at one-year follow-up
Authors: Broglio G , Lenti M V , Mengoli C , Borrelli De Andreis F , Vernero M , Pitotti L , Padovini L , Delliponti M , Klersy C , Corazza G R , Di Sabatino A
Published: January 2023

Background

Inflammatory bowel disease (IBD), namely ulcerative colitis and Crohn’s disease, is a chronic relapsing immune-mediated condition that may cause an impairment of social functions due to stigmatisation. Resilience instead is associated with an improvement in coping with adversities and thus may counteract the detrimental effects of stigmatisation. We here sought to determine the fluctuation of stigmatisation and resilience in a cohort of patients with IBD at 1-year follow-up.

Methods

This is a prospective, monocentric study conducted in a tertiary referral centre. All patients with IBD were assessed at enrolment and at one-year follow-up. Several clinical and demographic variables were collected. Stigmatisation was assessed through a validated Italian version of the Perceived Stigma Scale for IBD (PSS-IBD), while resilience was assessed through the 25-item Connor Davidson Resilience Scale (CD-RISC25). Also, self-efficacy scale (SEF), and self-esteem scale (SES) were assessed.

Results

In this study, 105 patients were enrolled (46 Crohn’s disease, 59 ulcerative colitis; mean age 47 years ±11, M:F ratio 1:1.2). None of the 4 scales showed a significant variation at one year compared to baseline (median CD-RISC25 64 at baseline vs 61 at follow-up; SEF 31 vs 30; SES 32.5 vs 32; PSS-IBD 0.45 vs 0.45). A statistically significant and inverse correlation was found between CD-RISC25 and PSS-IBD (rho -0.222, p=0.01), SEF and PSS-IBD (rho -0.219, p= 0.01), SES and PSS-IBD (-0.316, p=0.003). CD-RISC25 was found to be positively associated with inactive IBD (p=0.05).

Conclusion

Patients with IBD may perceive stigmatisation due to their disease, and this variable is stable on a long term. Interventions aimed at improving resilience, self-esteem, and self-efficacy may potentially counteract stigmatisation.
P149 Novel capillary blood point-of-care test for adalimumab and infliximab trough levels: Effects of abnormal blood conditions on the test result
Authors: Brosi L , Reinhard C , Anchling L , Afonso J , Schuster T , Gerhold C B , Ricken B
Published: January 2023

Background

Patients suffering from inflammatory bowel disease can be treated with the biologics adalimumab (ADL) or infliximab (IFX). Previous studies demonstrated the usefulness of therapeutic drug monitoring (TDM) to adjust the patient’s biologic concentration individually. Commercially available rapid assays support laboratories in the fast and easy detection of ADL and IFX concentrations but the assays’ dependency on serum as analyte matrix is a general hindrance for TDM, as serum preparation from whole blood is time-consuming and requires laboratory equipment. Patients and clinicians would thus benefit from rapid point-of-care (POC) and easy to use assays that are independent of laboratory equipment. The objective of this project was to expand existing serum lateral flow assays for the analysis of ADL or IFX in capillary blood and investigate potential interactions resulting from the blood matrix.

Methods

ADL and IFX lateral flow serum kits were optimized in such a way that both, capillary blood and EDTA whole blood can be used as analyte matrix by using disposable capillaries for blood collection and for its transfer into dropper bottles that are prefilled with chase buffer. To measure ADL or IFX levels with a POC lateral flow test cassette reader (BÜHLMANN Quantum Blue® Reader) the mixture is then applied on an ADL or IFX lateral flow test cassette. Matrix agreement studies were performed to compare spiked EDTA whole blood and capillary blood samples with serum as reference. Additionally, spiked EDTA whole blood samples were treated to obtain three abnormal blood conditions: Icteric, hemolytic and lipemic blood. Bias in results exceeding 30% relative difference to the untreated sample was considered as an interference.

Results

Spiked blood samples showed good agreement with reference serum samples. A bias of less than 15% at the clinical decision points for ADL (5 µg/mL and 12 µg/mL) and IFX (3 µg/mL and 7 µg/mL) was revealed. Observed relative differences between all tested abnormal blood conditions ranged between -20% and +26% for IFX and -16% and +5% for ADL.

Conclusion

Two POC assays for the determination of ADL or IFX in capillary blood or EDTA whole blood samples were successfully developed and can be used by healthcare professionals with time to results of only 15 minutes and without the need for additional laboratory equipment. No systematic interferences were detected with treated EDTA whole blood samples, which could appear when using blood as analyte matrix. The excellent agreement to serum trough levels shows that the POC adalimumab/infliximab capillary blood assays are ideal for therapeutic drug monitoring analysis at a clinician’s office or an infusion site.
P152 The prevalence of Thiopurine-methyltransferase and NUTD15 in patient with ulcerative colitis: a hospital-based study in central Taiwan
Authors: Wu Y H , Chou J W , Po J H , Wang C P , Cheng K S
Published: January 2023

Background

Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of these thiopurine drugs. Methylation of thiopurine drugs by TPMT competes with the formation of their active 6-thioguanine nucleotide metabolite, thereby potentially modulating the therapeutic and toxic effects of these drugs. Polymorphisms in TPMT and Nudix hydrolase-15 (NUDT15) have been implicated as the predominant cause of thiopurine-induced leukopenia in the Western and East Asian countries, but the frequency of the risk alleles is lower in Asians. Recently, a variant in the NUDT15 was reported to be associated with early severe leukopenia in Asians. The exact role of these polymorphisms in patients with ulcerative colitis (UC) in Taiwan is uncertain.

The aim of this study was to investigate the prevalence of TPMT and NUDT 15 variants and other characteristics in patients with UC in central Taiwan.

Methods

From January 1980 to November 2022, a total of 172 consecutive patients with UC at the China Medical University Hospital, a tertiary referral center in central Taiwan, were enrolled in this study. Clinical characteristics of patients with UC, including gender, age at diagnosis, disease phenotype and behavior, were collected. We used polymerase chain reaction-restriction fragment length polymorphism method to determine the allelic frequencies of TPMT and NUD15 variants in our UC patients.

Results

A total of 172 patients with UC was enrolled into our current study. The mean diagnostic age of these enrolled patients was 46.1 years (ranging from 21 years to 75 years old). Male accounted for the majority of all patients in our present study (64.5%). Among these 172 patients with UC, TPMT variants were tested in 138 patients, which showed the allelic frequencies of TPMT*1 were 98.5% (136/138) for patients with UC. The allelic frequencies of TPMT*3C were 1.5% (2/138) for patients with UC. No TPMT*2, 3A, 3B, 3D and 4-8 were found in these populations. In addition, NUD15 was tested in 123 patients with UC, which showed normal metabolizer in 109 patients (88.6%, 109/123), intermediate metabolizer in 14 patients (11.4%, 14/123), and poor metabolizer in 0 patient (0%, 0/123).

Conclusion

NUDT15 mutation rate was significantly higher than TPMT polymorphism and reached 11.4%. NUDT15 mutation was associated with thiopurine-induced leukopenia. The measurement of NUDT15 polymorphism can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of UC. Phenotypic TPMT and NUDT15 analysis could be useful to better manage UC therapy with thiopurine.
P156 Submucosa hypertrophy of active UC patients suggests transmural involvement in UC-associated inflammation
Authors: Kucharzik T , Helwig U , Strobel D , Fischer I , Hammer L , Rath S , Maaser C ,   TRUST&UC
Published: January 2023

Background

Transmural response and healing assessed by intestinal ultrasound (IUS) have gained relevance as outcome measures with the ability to guide treatment decisions in inflammatory bowel diseases (IBD). Bowel wall thickness (BWT) is the most widely used IUS parameter and encompasses the thickness of mucosa, muscularis mucosae, and submucosa [1]. Recently, the ratio between submucosa/BWT to estimate endoscopic remission was suggested [2] and de Voogd et al. have shown that the submucosa is the most responsive wall layer [3]. However, little is known about the association between submucosa hypertrophy and clinical as well as lab parameters.

Methods

TRUST&UC was a prospective, observational study including 224 UC patients with increased BWT at baseline and active disease (SCCAI ≥ 5) with up to 4 visits (baseline, optional visit at week 2 (W2), W6 and W12). At baseline, patients received therapy intensification according to standard of care. In this post-hoc analysis, 171 patients with a W12 visit ± 4 weeks were included. Overall BWT, mucosa and submucosa thickness were evaluated for the sigmoid colon and stratified for SCCAI, CRP, fecal calprotectin (fCal), and Mayo endoscopic subscore (MES).

Results

Active UC patients in our cohort had a median age and disease duration of 37.1 years (28.9 –50.2) and 3.55 years (0.54 – 10.18), more were male (56.6%, n = 95). At baseline, UC patients presented with a high disease activity reflected by a median SCCAI of 9.00 (7.0-10.0). Mean values for BWT, mucosa, and submucosa were 5.54 mm, 1.7 mm, and 2.32 mm, respectively. Over the study course, mucosa and submucosa thickness were significantly reduced with the most pronounced reduction happening within the first 2 weeks (figure 1). Patients with SCCAI ≤ 2 tended to have a more reduced mucosa and submucosa thickness than patients with SCCAI > 2 (fig 2A, A1). Whilst a similar trend was observed for fCal values (not shown), this effect was found neither for CRP (not shown) nor for MES.

Conclusion

We found that both mucosa and submucosa thickness of active UC patients were reduced as a consequence of therapy intensification. The lack of difference in thickness of both mucosa and submucosa in patients with and without MES improvement might indicate fibrotic alterations in these patients which needs further evaluation. Based on these and previous results of our group, we suggest measuring BWT in conjunction with other established IUS parameters such as colour Doppler signal to assess disease activity in UC.

1-Ilvermark et al. JCC 2022

2-Miyoshi et al. J Gastroenterol 2022

3-de Voogd et al. Gastroenterol 2022