UC Severity Research Articles

MSCT enterography score for prediction of disease severity in patients with active ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic non-specific inflammatory bowel disease (IBD). It is characterized by diffuse inflammatory process of the bowel mucosa with a relapsing course. The precise evaluation of UC severity is pivotal in the therapeutic decision-making. Modified Mayo score is consistently used for the evaluation of the disease activity which depends on the patient’s symptoms as well as the colonoscopic findings. The aim of this study is to assess the role of the CT enterography (CTE) scoring system in the evaluation of the disease severity in ulcerative colitis. From October 2022 to July 2023, 66 patients with known ulcerative colitis patients at time of disease activity were referred from the inflammatory bowel disease unit for radiological assessment by CTE. CT images were analyzed to determine the anatomical location of the affected bowel segments, mucosal thickening and hyperenhancement as well as the extra-enteric involvement. Correlation with the modified Mayo score was established.ResultsOur results showed a statistical significant correlation between modified Mayo score and CTE with a P value of 0.000. The correlation coefficient is r = 0.964. The cut-off value of the optimal CTE score to predict mild and moderate UC was 7.5 with 0.996 area under the ROC curve, 92%sensitivity and 100% specificity. The cut-off value of the optimal CTE score to predict moderate and severe UC was 10.5 with 0.983 area under the ROC curve, 90.6% sensitivity and 100% specificity.ConclusionsCTE is a reliable diagnostic method in the systematic assessment of the disease severity of active ulcerative colitis. CTE score shows a strong proportionate correlation with modified Mayo score. The aggravation of the course of the disease increased the CTE score. CTE scoring system can help plan the therapeutic strategy and predict prognosis.

P146 Latent activation of the extrinsic coagulation pathway in patients with ulcerative colitis

Abstract Background Ulcerative colitis (UC) is associated with an increased risk of venous thromboembolism. We investigated the correlation of UC severity with latent activation of the extrinsic coagulation pathway and colonic stromal tissue factor (TF) expression. Methods Plasma exosomes, microparticles (EM), TF protein, activities of EM-bound TF (EM-TF) and FVIIa, as well as TF mRNA (F3) in primary colonic stromal cells in culture were measured. Disease extent by Montreal classification, medications, UC clinical activity by partial Mayo score (PMS), endoscopic severity by the MS endoscopic component (eMS; loss of response defines as ≥2), quality of life by the short IBD questionnaire- SIBDQ, complete blood count, CRP, ESR and albumin were retrieved. Statistical significance (p) was assessed with the following tests: Student’s t for 2 groups with normally distributed values, Mann-Whitney U if not, Wilcoxon test for paired data. Correlation of continuous against scale variables was assessed with Pearson’s or Spearman’s r and corresponding p values for linear or logarithmic continuous variables, respectively. Results Plasma was obtained from 38 UC patients (31 males, disease duration 151±25 months, 14 with extensive colitis, 5 current smokers) and 28 healthy blood donors (HBD; 20 males) who served as controls. TF mRNA (F3) was measured in primary colonic stromal cells in culture from 12 UC patients (11 males, disease duration 169±53 months, 8 with extensive colitis, 1 current smoker) and from 7 controls undergoing screening colonoscopy. UC patients had 4- and 3.7- times more exosomes and microparticles than controls, respectively (A). TF protein correlated with PMS (r 0.443), albumin (-0.362), ESR (0.353), PLT (0.575) and endoscopic UC severity (0.468; B). EM-TF activity was 1.6-times higher (C) and correlated to disease extent (E3: 1.9 x E2), albumin (-0.624), endoscopic severity (0.422; D) and SIBDQ (-0.64). Downstream, FVIIa activity was 2.2-times higher. Refractory-to-treatment patients had 5.8-, 1.5-, 2.1- times higher TF protein (E), MP-TF, FVIIa activity, respectively. Within responders, the need for steroids or biologics correlated with 2.2-times higher MP-TF activity. Colonic stromal cells from patients with UC maintained a 2.2-times higher F3 (F), which correlated to PMS (0.56), albumin (Spearman’s r -0.543), endoscopic severity (M3: 8.3 x M2). All the aforementioned were statistically significant with a < 0.05. Conclusion The extent of spontaneous activation of the extrinsic coagulation pathway is associated with clinical and endoscopic UC activity and response to treatment. TF in colonic stromal cells mirrors its systemic activity and indicates the possible contribution of such cells to increased TF plasma bioactivity.

P1014 Faecal loss of vedolizumab is associated with UC severity, lower serum vedolizumab levels and rates of clinical response – Results from the FAVOUR study

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

Correlations between the symptoms of insomnia, depression, sleep quality, antitumor necrosis factor therapy, and disrupted circadian clock gene expression in inflammatory bowel disease.

Inflammatory bowel disease (IBD) might be accompanied by emotional disturbances. Circadian rhythm genes, such as brain and muscle ARNT‑Like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), or nuclear receptor subfamily 1 group D member 1 (NR1D1) are related to inflammation and psychiatric symptoms that might modulate their expression. The study aimed to compare the expression of the BMAL1, CLOCK, NPAS2, NR1D1 mRNA in IBD patients and healthy controls (HCs). We evaluated the association between the gene expression and the disease severity, antitumor necrosis factor (TNF) therapy, sleep quality, insomnia, and depression. A total of 81 IBD patients and 44 HCs were recruited and classified according to the disease activity and IBD type (ulcerative colitis [UC] or Crohn disease [CD]). The participants filled out questionnaires assessing their sleep quality, daytime sleepiness, insomnia, and depression. Venous blood samples were collected, and the IBD patients on the anti‑TNF therapy had their blood drawn before and after 14 weeks of the treatment. In comparison with HCs, the IBD group had decreased expression of all studied genes apart from the BMAL1 gene. UC individuals with exacerbation had decreased expression of the CLOCK and the NPAS2 genes, as compared with the remission group. UC severity negatively correlated with the CLOCK, NPAS2, and NR1D1 mRNA levels. The IBD participants with depression symptoms had a decreased expression of the CLOCK and the NR1D1 genes, as compared with those without mood disturbances. Poor sleep quality was associated with a decreased expression of the NR1D1 gene. Biologic treatment decreased the expression of the BMAL1 gene. Disruption of the clock gene expression might constitute a molecular background of sleep disorders and depression in IBD and might contribute to UC exacerbation.

P533 Relation between TL1A expression in intestinal mucosa, and endoscopic severity and clinical course in ulcerative colitis

Abstract Background TL1A is a TNF super family member cytokine encoded by TNFSF15 and reported to be a disease susceptibility gene for IBD. The relationship between TL1A expression and IBD pathophysiology, clinical course, endoscopic findings was not sufficiently clear. The aim of this study was to clarify the correlation between TL1A expression in the intestinal mucosa of UC and endoscopic severity, clinical severity, and clinical course. Methods The subjects were patients with UC who were visiting our hospital. Mucosal samples were biopsied from rectum with lower gastrointestinal endoscopy, and TL1A gene expression was examined by RT-PCR. We analyzed the relationship between patients’ background, clinical symptoms, blood test findings, and mucosal activity and TL1A expression. Results A total of 77 specimens obtained with individual colonoscopy from 61 cases were included. Median age was 43, 36 cases were males, duration of disease was 2 years, the number of pancolitis was 54, median partial mayo score (pMayo) was 3, and the level of CRP was 1.5 mg/L. The number with Mayo endoscopic subscore (MES) of 0, 1, 2, and 3 were 14, 27, 24, and 12, respectively, and the mean TL1A expression was 1.76-, 1.09-, and 1.17-times higher in MES 1, 2, and 3 than in MES 0, respectively. TL1A expression was significantly higher in MES 1 than in MES 0 and MES 2. TL1A expression was significantly lower in the active group (pMayo 4 or higher) compared to the clinically low disease activity group (pMayo 3 or lower). TL1A expression was significantly lower with CRP ≥0.03 compared to CRP <0.03. TL1A expression was significantly higher in those with MES 1 at the initial onset than in those with MES 2 and 3. Eight cases were compared before and after induction therapy, and TL1A expression increased 1.9-fold after induction therapy. No correlation was found between the use of biologics and small molecular compounds and the expression of TL1A. Conclusion Relatively low activity in UC revealed higher mucosal expression of TL1A. TL1A is known to be secreted from various cell types such as macrophages and lymphocytes. It was suggested that the source of cell types and the amount of expression would alter according to the degree of inflammation.

A182 THE LACK OF CHROMOGRANIN A IMPACTS COLONIC EPITHELIAL CELLS MARKERS IN AN EXPERIMENTAL MODEL OF ULCERATIVE COLITIS

BackgroundUlcerative colitis (UC) is a chronic and acute inflammatory disorder of the colon linked to dysregulated gut mucosal immune response and compromised colonic epithelial barrier function and integrity. Chromogranin-A (CHGA), a pro-peptide secreted by enteroendocrine cells, is highly expressed in colonic tissues of patients with UC. Elevated CHGA has been shown to correlate with UC disease activity and severity. Moreover, complete deletion of CHGA was shown to result in a diminution of pro-inflammatory markers known to disrupt the colonic epithelial barrier function and gut mucosal healing process. However, little is known about the effect of the absence of CHGA on colonic epithelial barrier function and gut mucosal integrity.AimsHere, we characterized the impact of the lack of CHGA on the colonic mucosa and epithelial barrier structure and function using CHGA knockout (CHGA-/-) mice treated with dextran sulfate sodium (DSS) to induce colitis.Methods13–17 weeks old male C57BL/6 wild-type (CHGA+/+) and C57BL/6 CHGA-/- mice were treated for 5 days with 5% DSS to induced acute colitis, control mice received regular water. CHGA mRNA expression, disease activity index (DAI), and macroscopic score (MS) were analyzed. Distal colonic tissues were isolated, and mRNA expression of markers associated with regenerative stem cells (fast-cycling stem cells [Lgr5+] and reserve stem cells [HOPX+] and [LY6a+], Goblet cells functions mucus barrier mucin 2 [MUC2], resistin-like molecule β [RELMβ], WAP 4-disulphide core domain 2 [WFDC2]) and trefoil factor 3 (TFF3) was evaluated by qRT-PCR.ResultsWe validated a beneficial effect of the Lack of CHGA on colitis severity, associated with significantly lower DAI and MS. In colitic CHGA+/+ and CHGA-/- mice, Lgr5+ and HOPX+ were both highly down-regulated, although, compared to CHGA+/+, CHGA-/- mice presented a 10.5fold higher expression of HOPX+. Compared to non-colitic states, Ly6a+ expression was significantly elevated in both colitic CHGA+/+ and CHGA-/- mice, however, no differences in Lgr5+ and Ly6a+ expression were noted between CHGA+/+ and CHGA-/- mice in all conditions. In CHGA+/+ mice, inflammatory conditions led to higher MUC2 and RELMB expression, although, compared to CHGA+/+, these markers were significantly lower in CHGA-/- mice. In colitic conditions, compared to CHGA+/+, CHGA-/- had a significant increase of WFDC2. In non-colitic conditions, mRNA expressions of all markers evaluated between CHGA+/+ and CHGA-/- in this study were unaltered. Finally, no differences were observed in TFF3 gene expression.ConclusionsThese results indicate in the absence of CHGA, the colonic epithelial barrier integrity and function are maintained through the modulation of goblet cells functions and elevated gut mucosa regenerative potential, thus enhancing the mucosal protection to colitis damage.Funding AgenciesCIHR

P089 Long ncRNA Landscape in the Rectum of Treatment Naïve Early Onset Ulcerative Colitis Highlights Association with Severity and Early and Late Disease Outcome, with Potential Role in Epithelial Metabolic Functions

Abstract Background Long non-coding RNAs (lncRNAs) are tissue-specific and regulate cellular functions. We previously reported a dramatic inhibition of epithelial metabolic mitochondrial functions in mucosal biopsies from the UC PROTECT cohort. We aimed to define lncRNAs that are dysregulated in UC, linked with attenuated epithelial metabolic functions, and associated with worse outcome. Methods Transcriptomics of pre-treatment rectal biopsies in PROTECT UC [206 UC and 20 controls (Ctl)]. Weighted gene co-expression network analysis (WGCNA) to identify modules and gens associated with UC severity, week 4 remission after 5-ASA/steroids (W4R), week 52 steroid-free remission (W52SFR), and colectomy within 3 years. Epithelial mechanistic data of prioritized lncRNA. Results PROTECT transriptomics included 2,826 lncRNA genes with TPM>1 in 20% of samples. Principal components analysis (PCA, Fig 1) using these lncRNA showed distinct clusters of UC and Ctl, and PC2 values were linked (p<0.01) with endoscopic (Mayo score) and clinical (PUCAI) disease severities. Random forest classifiers using the 2,826 lncRNA trained to distinguish UC from Ctl using PROTECT, predicted the correct diagnosis in PROTECT (AUC=1) and in RISK (AUC=0.88) connecting lncRNA to UC pathogenesis in two independent cohorts. WGCNA on the 2,826 lncRNA resulted in 6 modules (M1-M6) associated with UC (p<0.01, Fig 2). M1, which contained lncRNA reduced in UC, was associated with lessW4R (p=0.01) less W52SFR (p=0.04) and increased colectomy (p=0.02). In contrast, M6, which contained lncRNA elevated in UC, was linked with W4R (p=0.008). The hub genes in the M1 and M6 modules included GATA6-AS1 and LINC01272 lncRNAs, respectively. Re-analysis of single cell datasets supported epithelial expression of GATA6-AS1 and myeloid expression of LINC01272. GATA6-AS1 co-expression with protein-coding genes in PROTECT showed significant enrichment for mitochondrial functions (p<1E-40). Reduction of GATA6-AS1 expression with 2 shRNAs resulted in reduced mitochondrial complex IV MT-CO2 mRNA and protein and reduction of LGR5, linking mitochondrial genes and function with epithelial renewal. We recently showed pronounced reduction of the mitochondrial membrane potential (MMP) by JC-1 staining in UC epithelia. Consistent with this finding, GATA6-AS1 inhibition reduced MMP levels from 0.22 in control to 0.08 (p=0.01), similarly to MMP of cells treated with CCCP that is known to depolarize and reduce MMP. Conclusion LncRNA are significantly linked with UC and disease severity, and the M1 epithelial enriched module shows significant association with worse outcome. GATA6-AS1 within the M1 hub genes show potential role in epithelial metabolic functions and renewal.

The contribution of different permanent tooth types to untreated caries: Implications for public health surveillance and prevention

BackgroundUntreated caries (UC), although highly prevalent, is largely preventable. Information on the contribution of different teeth to UC prevalence and severity could be helpful in evaluating UC surveillance protocols and the relative benefits of caries prevention interventions. MethodsThe authors combined data from 3 cycles (2011-2016) of the National Health and Nutrition Examination Survey for participants aged 6 through 11 years, 12 through 19 years, 20 through 34 years, 35 through 49 years, 50 through 64 years, 65 through 74 years, and 75 years and older. For each age group the authors calculated the contribution of successive permanent tooth types (for example, first molars and second molars) to UC prevalence and severity. ResultsUC prevalence and the percentage of prevalence detected by means of screening molars were, respectively, 5% and 95% among participants aged 6 through 11 years; 16% and 92% among participants aged 12 through 19 years; 29% and 86% among participants aged 20 through 34 years; 26% and 70% among participants aged 35 through 49 years; 21% and 48% among participants aged 50 through 64 years; 16% and 36% among participants aged 65 through 74 years; and 17% and 25% among participants 75 years and older. Among adults aged 50 years and older, no teeth appeared to capture a disproportionate share of UC prevalence. Molars accounted for 87%, 79%, and 56% of severity among participants aged 6 through 11 years, 12 through 19 years, and 20 through 34 years, respectively. After age 34 years, molars accounted for less than 50% of severity. ConclusionsMolars are the tooth type most susceptible to UC well into adulthood. Practical ImplicationsMolars could be used as sentinel teeth for surveillance of UC and adults could benefit from caries prevention that targets molars.

Dilodendron bipinnatum Radlk. extract alleviates ulcerative colitis induced by TNBS in rats by reducing inflammatory cell infiltration, TNF-α and IL-1β concentrations, IL-17 and COX-2 expressions, supporting mucus production and promotes an antioxidant effect

Ethnopharmacological relevanceDilodendron bipinnatum (Sapindaceae) stem bark decoction and macerate were used to treat uterine inflammation, pain in general, dermatitis and bone fractures. These homemade preparations also have diuretic, stimulant, expectorants and sedative effects and are effective in treating worm infections in the Brazilian Pantanal population. Our previous research confirmed the anti-inflammatory activity of the hydroethanolic extract of inner stem bark of D. bipinnatum (HEDb). AimThis work aimed to investigate the efficacy of HEDb in ameliorating experimental colitis in rats and to elucidate the possible mechanisms involved in the anti-ulcerative colitis properties of HEDb in rats and Caco-2 cell line. Materials and methodsThe effects on cell viability, IL-8 and TNF-α in human colon adenocarcinoma (Caco-2) were determined by flow cytometer and ELISA. Wistar rats (n = 6–7) were orally gavaged with, vehicle (0.9% saline), HEDb at doses of 20, 100 or 500 mg/kg, or mesalazine at a dose of 500 mg/kg, at 48, 24 and 1 h prior to the administration of trinitrobenzene sulfonic acid via rectal administration to induce colitis. The anti-inflammatory effects of HEDb were assessed macroscopically, by myeloperoxidase (MPO) activity and for glutathione (GSH) concentration in the colon. Additionally, colonic histopathological analyses of UC severity were conducted by different staining methods (H&E, PAS and toluidine blue). Pro-inflammatory cytokines TNF-α and IL-1β were quantified in colonic tissue by ELISA and colonic expressions of COX-2 and IL-17 were analyzed by western blotting. ResultsHEDb was shown to be non-cytotoxic with mean viability of 80% in Caco-2 cells. HEDb pre-treatments of 1, 5 or 20 μg/mL significantly reduced TNF-α production in Caco-2 cells by 21.8% (p < 0.05), 60.5 and 82.1% (p < 0.001) respectively following LPS treatment compared to LPS alone. However, no change in IL-8 production was observed. HEDb pre-treatment of rats subjected to TNBS significantly (p < 0.001) reduced colonic lesion score. Higher doses (100 and 500 mg/kg) caused a sharp downregulation of haemorrhagic damage, leukocyte infiltration, edema and restoration of mucus production. Moreover, mast cell degranulation was inhibited. Colonic MPO activity was reduced following all doses of HEDb, reaching 51.1% ± 1.51 (p < 0.05) with the highest dose. GSH concentration was restored by 58% and 70% following 100 and 500 mg/kg of HEDb, respectively. The oral treatment of HEDb at doses 20, 100 and 500 mg/kg decreased the concentrations of TNF-α and IL-1β at all doses in comparison to vehicle treated control. In addition, HEDb inhibited the COX-2 and IL-17 expressions with maximal effect at 500 mg/kg (60.3% and 65% respectively; p < 0.001). In all trials, the effect of HEDb at all doses being 20, 100 and 500 mg/kg was statistically comparable to mesalazine (500 mg/kg). ConclusionsHEDb reduces colonic damage in the TNBS colitis model and relieves oxidative and inflammatory events, at least in part, by increasing mucus production, reducing leukocyte migration and reducing TNF-α (in vivo and in vitro), IL-1β, IL-17 and COX-2 expression. Therefore, HEDb requires further investigation as a candidate for treating IBD.

PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation

ABSTRACT NRBF2, a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex, positively regulates macroautophagy/autophagy. In this study, we report that NRBF2 is required for the clearance of apoptotic cells and alleviation of inflammation during colitis in mice. NRBF2-deficient mice displayed much more severe colitis symptoms after the administration of ulcerative colitis inducer, dextran sulfate sodium salt (DSS), accompanied by prominent intestinal inflammation and apoptotic cell accumulation. Interestingly, we found that nrbf2 −/- mice and macrophages displayed impaired apoptotic cell clearance capability, while adoptive transfer of nrbf2 +/+ macrophages to nrbf2 −/- mice alleviated DSS-induced colitis lesions. Mechanistically, NRBF2 is required for the generation of the active form of RAB7 to promote the fusion between phagosomes containing engulfed apoptotic cells and lysosomes via interacting with the MON1-CCZ1 complex and regulating the guanine nucleotide exchange factor (GEF) activity of the complex. Evidence from clinical samples further reveals the physiological role of NRBF2 in maintaining intestinal homeostasis. In biopsies of UC patient colon, we observed upregulated NRBF2 in the colon macrophages and the engulfment of apoptotic cells by NRBF2-positive cells, suggesting a potential protective role for NRBF2 in UC. To confirm the relationship between apoptotic cell clearance and IBD development, we compared TUNEL-stained cell counts in the UC with UC severity (Mayo Score) and observed a strong correlation between the two indexes, indicating that apoptotic cell population in colon tissue correlates with UC severity. The findings of our study reveal a novel role for NRBF2 in regulating apoptotic cell clearance to restrict intestinal inflammation. Abbreviation: ANOVA: analysis of variance; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BMDM: bone marrow-derived macrophage; BSA: bovine serum albumin; CD: Crohn disease; CD68: CD68 molecule; CFP: cyan fluorescent protein; CMFDA: 5-chloromethylfluorescein diacetate; Co-IP, co-immunoprecipitation; CPR: C-reactive protein; Cy7: cyanine 7 maleimide; DAB: diaminobezidine 3; DAI: disease activity indexes; DAPI: 4ʹ6-diamidino-2-phenylindole; DMEM: dulbecco’s modified eagle’s medium; DMSO: dimethyl sulfoxide; DOC: sodium deoxycholate; DSS: dextran sulfate sodium; EDTA: ethylenediaminetetraacetic acid; EGTA: ethylenebis (oxyethylenenitrilo) tetraacetic acid; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; FRET: Förster resonance energy transfer; GDP: guanine dinucleotide phosphate; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; GTP: guanine trinucleotide phosphate; GWAS: genome-wide association studies; HEK293: human embryonic kidney 293 cells; HRP: horseradish peroxidase; IBD: inflammatory bowel disease; IgG: immunoglobin G; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; IRGM: immunity related GTPase M; ITGAM/CD11b: integrin subunit alpha M; KO: knockout; LRRK2: leucine rich repeat kinase 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MPO: myeloperoxidase; NaCl: sodium chloride; NEU: neutrophil; NOD2: nucleotide binding oligomerization domain containing 2; NP40: nonidet-P40; NRBF2: nuclear receptor binding factor 2; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PE: P-phycoerythrin; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3P: phosphatidylinositol-3-phosphate; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SDS-PAGE: sodium dodecylsulphate-polyacrylamide gel electrophoresis; TBST: tris-buffered saline Tween-20; Tris-HCl: trihydroxymethyl aminomethane hydrochloride; TUNEL: TdT-mediated dUTP nick-end labeling; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; WB: western blotting; WT: wild type; YFP: yellow fluorescent protein.

A qualitative study exploring the health-related quality of life and symptomatic experiences of adults and adolescents with ulcerative colitis

BackgroundUlcerative colitis (UC) often first presents during adolescence and early adulthood. Primary symptoms of UC are well known, yet similarities and differences of disease experience in adults and adolescents are not well characterized.MethodsTo understand the health-related quality of life (HRQoL) and symptomatic experience of UC, in-depth interviews were conducted in the US with 21 adults (20–70 years) and 14 adolescents (12–17 years). Eligibility and medical history were confirmed by clinician report. A previously conducted literature review and resultant conceptual model informed the discussion guide to explore symptoms and HRQoL. Age appropriate creative tasks (“animal” task and collage) were employed to facilitate discussion. Transcripts and collages were subjected to thematic analysis using ATLAS.ti software.ResultsClinician-reported UC severity included 24% mild, 38% moderate, 38% severe among adults; and 64% mild, 29% moderate, 7% severe among adolescents. Among adults, 52% were female, 67% were white. Among adolescents, 50% were female, 71% were white. During analysis it was noted that all participants reported stomach/abdominal pain. Other key symptoms identified were frequent bowel movements, diarrhea, blood in stools, sudden need for bowel movement, stomach cramping, bloating, and feeling gassy/passing gas (≥75% of participants). Key impacts identified were embarrassment, dietary limitations, having to plan around UC, worry/fear, anger, low mood/depression, and relationship with others, (≥75% of participants). In creative tasks, animals were chosen to represent their UC and content included in the collages reflected the most commonly discussed themes from the interviews. Only adults discussed feeling dehydrated, while only adolescents discussed the impact of UC on school life.ConclusionsOpen-ended interviews highlighted the HRQoL and symptomatic experiences of UC from the patient’s perspective, which were similar between adult and adolescent UC patients.

Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience.

Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes. This retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models. Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy. This study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

Early endoscopic, laboratory and clinical predictors of poor disease course in paediatric ulcerative colitis

ObjectiveData to support treatment algorithms in ambulatory paediatric UC are scarce. We aimed to explore the 1 year outcome in an inception cohort of paediatric UC patients and to identify...

P572 Changes of the smoking habit after diagnosis of Crohn's disease

visits to hospital and general practice, steroid use and cost of treatment. Results: In total, 363 UC patients were reviewed, change was recommended in 130 patients (36%) and was actioned in 87 (24%). The main reasons for changing to once daily mesalazine were adherence issues (52%), patient preference (36%) and symptoms (12%). In the first pilot study the second review 6 months later demonstrated that 70% of the patients improved their UC severity score (Walmsley Index) and 30 had no change. There was no worsening of the UC score in any patients. In the second pilot study review after 6 months in patients switched to once daily mesalazine maintenance therapy demonstrated: 47% reduction in all hospital visits, 60% reduction in hospital visits due to flare up of UC, 45% reduction in GP visits and 50% reduction in steroid courses used. The majority of patients preferred once daily dosing and 85% of patients admitted no prior knowledge of the availability of alternative dosing regimes. Both pilot studies demonstrated a substantial cost saving. Conclusions: Maintenance therapy of UC in the community is inadequate in more than one third of patients. Optimising maintenance therapy by switching to a once daily mesalazine leads to improved patient and disease outcomes as well as cost saving.

Calcitonin Gene-Related Peptide Is a Promising Marker in Ulcerative Colitis

Assessment of the severity and extent of disease activity continues to present challenges for physicians in the treatment of ulcerative colitis. Standard markers that can objectively reflect disease activity are useful for physicians to both evaluate the course of ulcerative colitis and monitor the effectiveness of therapy for any given patient. We hypothesize that calcitonin gene-related peptide (CGRP) can reflect the activity and severity of ulcerative colitis and be used as a marker to assess the effectiveness of various therapies. We examined the expression levels of CGRP by reverse transcription polymerase chain reaction (RT-PCR) and semi-quantitative immunohistochemisty in mucosal biopsies from 38 patients with UC and 18 controls. Levels of CGRP mRNA and protein expression were compared between patients and controls with the clinical activity index (CAI) and the endoscopic activity index (EAI) for various levels of UC severity. Our results showed that the levels of CGRP mRNA and protein expression were significantly reduced in UC patients compared to controls. This effect was more pronounced in patients with more severe cases of UC. There is a statistically significant negative correlation between levels of CGRP mRNA expression and CAI/EAI scores. A statistically significant negative correlation was also found between levels of CGRP protein expression and CAI/EAI scores. Overall, high CAI and EAI scores were accompanied by low CGRP mRNA and protein expression levels. Levels of CGRP protein and mRNA expression in the colonic mucosa of patients are closely associated with UC severity and corroborate traditional indices used to assess the disease.

New Genetic Associations Detected in an Exome-Wide Association Study for Toxicity Related to Thiopurine Treatments in Inflammatory Bowel Disease

associated with nominal significance (p<10-5); and (2) at a second region on chr.4, ~37 Mb away, with the combined ASCA, I2, CBir1 and Ompc Z-score (rs2995965 plinear= 1.35x10-9, β=0.82; rs1863284 plinear=1.71x10-7, β=0.85; rs2911920 plinear=6.29x10-6, β=0.61). RELL1, a homologue of RELT the TNF receptor that induces epithelial cell apoptosis is located at this locus. Conclusions: These observations suggest that these two loci contribute to the phenotypic difference of UC patients, one for UC severity as typified by ANCA level, the other for the expression of antibodies more characteristic of CD. Studies to assess the phenotypic differences tagged by these SNPs within the UC population are in progress.

Genome-Wide Association Study of CD-Associated Anti-Microbial Antibodies

associated with nominal significance (p<10-5); and (2) at a second region on chr.4, ~37 Mb away, with the combined ASCA, I2, CBir1 and Ompc Z-score (rs2995965 plinear= 1.35x10-9, β=0.82; rs1863284 plinear=1.71x10-7, β=0.85; rs2911920 plinear=6.29x10-6, β=0.61). RELL1, a homologue of RELT the TNF receptor that induces epithelial cell apoptosis is located at this locus. Conclusions: These observations suggest that these two loci contribute to the phenotypic difference of UC patients, one for UC severity as typified by ANCA level, the other for the expression of antibodies more characteristic of CD. Studies to assess the phenotypic differences tagged by these SNPs within the UC population are in progress.