Ulcerative Colitis Subgroups Research Articles

Construction of molecular subgroups of ulcerative colitis.

Ulcerative colitis (UC), a chronic inflammatory disease of the colon with unknown etiology, is characterized by remission and recurrence. At present, a considerable number of UC cases are misdiagnosed or delayed in diagnosis and treatment. We aimed to identify UC-related genes to aid the development of drugs for this condition. Transcriptome data of 362 patients with UC and 126 control subjects were obtained from the Gene Expression Omnibus. The 362 patients with UC were subgrouped using unsupervised machine learning. R software was used to analyze the clinical characteristics of the subgroups, screen subgroup-specific genes, assess the relationships between gene modules and clinical characteristics using weighted gene co-expression network analysis, and perform Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the subgroups. Patients with UC were classified into two subgroups. Genes specific to subgroup I included IL21R, ATP8B2, and PLEKHO1. Severe disease tended to be associated with immune cell infiltration; anti-tumor necrosis factor (TNF)-α antibodies and ustekinumab may have been effective in this subgroup. Subgroup II-specific genes included SLC4A4, EPB41L4B, and PLCE1. Patients in this subgroup had mild clinical conditions; however, their disease was more likely to progress to colorectal cancer. Thus, 5-aminosalicylic acid-based drugs may be effective for the treatment of UC in these patients. We divided UC into two molecular subgroups based on transcriptome data, providing molecular evidence for the development of diagnostic methods and individualized treatment strategies for UC.

Identifying anti-TNF response biomarkers in ulcerative colitis using a diffusion-based signalling model.

Resistance to anti-TNF therapy in subgroups of ulcerative colitis (UC) patients is a major challenge and incurs significant treatment costs. Identification of patients at risk of nonresponse to anti-TNF is of major clinical importance. To date, no quantitative computational framework exists to develop a complex biomarker for the prognosis of UC treatment. Modelling patient-wise receptor to transcription factor (TF) network connectivity may enable personalized treatment. We present an approach for quantitative diffusion analysis between receptors and TFs using gene expression data. Key TFs were identified using pandaR. Network connectivities between immune-specific receptor-TF pairs were quantified using network diffusion in UC patients and controls. The patient-specific network could be considered a complex biomarker that separates anti-TNF treatment-resistant and responder patients both in the gene expression dataset used for model development and separate independent test datasets. The model was further validated in rheumatoid arthritis where it successfully discriminated resistant and responder patients to tocilizumab treatment. Our model may contribute to prognostic biomarkers that may identify treatment-resistant and responder subpopulations of UC patients. Software is available at https://github.com/Amy3100/receptor2tfDiffusion. Supplementary data are available at Bioinformatics Advances online.

Work productivity loss is determined by fatigue and reduced quality of life in employed inflammatory bowel disease patients: a prospective multicentre cohort study.

Inflammatory bowel disease (IBD) patients experience problems at work resulting in work productivity loss driving indirect healthcare costs. We aimed to find determinants for work productivity loss in employed IBD patients while correcting for disease severity according to prior and active maintenance treatment. In this longitudinal multicentre cohort study, 510 employed IBD patients completed online questionnaires during 18 months follow-up. Work productivity, fatigue and health-related quality of life (HRQL) were measured using the Work Productivity and Activity Impairment questionnaire, the Multidimensional Fatigue Inventory (score 20-100) and Short-Inflammatory Bowel Disease Questionnaire (score 10-70). Linear mixed model analyses including random, repeated and fixed effects were performed. Fatigue (β 0.22; 95% CI, 0.12-0.32) and reduced HRQL (β -1.15; 95% CI, -1.35 to -0.95) were the strongest determinants for work productivity loss in employed IBD patients. Clinical disease activity (β 9.50, 95% CI 6.48-12.51) and corticosteroid use (β 10.09, 95% CI 5.25-15.84) were associated with work productivity loss in the total IBD group and ulcerative colitis subgroup, but not in Crohn's disease patients. History of IBD-related surgery (β 9.41; 95% CI, 2.62-16.20) and vedolizumab use (β 12.74; 95% CI, 3.63-21.86) were significantly associated with work productivity loss in the ulcerative colitis subgroup. Fatigue and reduced HRQL were the strongest determinants for work productivity loss in employed IBD patients while correcting for disease severity and activity. These results underline the importance of monitoring fatigue and HRQL in routine care to reduce work productivity loss and indirect costs.

Elevated systemic immune inflammation index level is associated with disease activity in ulcerative colitis patients

BackgroundIt has been confirmed that high Systemic immune-inflammation index (SII) levels usually indicate poor outcomes in various diseases, especially on malignancies. However, the clinical significance of the SII in ulcerative colitis (UC) patients is remain unclear. Therefore, the purpose of our paper is to analyze the levels of SII in UC patients and assess the relationship between the SII and disease activity. Materials and methodsWe studied 187 consecutive patients with UC and 185 age- and sex-matched healthy controls retrospectively. The Mayo scoring system was adopted to evaluate disease activity in UC patients. We collected clinical characteristics and laboratory parameters from hospital electronic medical records. ResultsThe SII levels were significantly higher in UC patients than those in healthy subjects (P < 0.001). Higher SII levels were observed in moderate and severe UC subgroups compared to mild or remission subgroups. Correlation analysis displayed that the SII levels were positively relatived with Mayo score (r = 0.469, P < 0.001), C reactive protein (CRP) (r = 0.480, P < 0.001), and erythrocyte sedimentation rate (ESR) (r = 0.336, P < 0.001), but negatively with haemoglobin (Hb) (r = −0.271, P < 0.001). A multiple linear regression analysis suggested that there was an independent correlation between Mayo score and SII (beta = 0.324, t = 4.241, P < 0.001). The receiver operating characteristic (ROC) curve revealed that the maximum area under the curve (AUC) was 0.711 (95% CI, 0.630–0.791, P < 0.001), and the cut-off value for diagnosing active UC was 485.95, the sensitivity was 0.641, and the specificity was 0.75. ConclusionsWe demonstrated that the SII was elevated significantly in UC patients and was closely related to the UC disease activity. In addition, the SII had a high discriminative capacity for active UC.

Patients developing inflammatory bowel disease have iron deficiency and lower plasma ferritin years before diagnosis: a nested case-control study.

Iron deficiency is common among inflammatory bowel disease (IBD) patients, generally reported without comparisons with controls. The aim of this study was to analyse if iron deficiency was more common among those later developing IBD compared to matched controls in a prospective setting. We included 96 healthy subjects later developing IBD and 191 matched controls from the Northern Sweden Health and Disease Study. We analysed iron, ferritin, transferrin, and calculated transferrin saturation in plasma sampled at least 1 year prior to IBD diagnosis. Iron deficiency was defined as plasma ferritin <30 µg/L if C-reactive protein (CRP) was <3 mg/L. When CRP was >3 mg/L, iron deficiency could not be excluded if ferritin was <100 µg/L. Iron deficiency could not be excluded among more male cases vs controls (25.0% vs 2.2%; P < 0.001), whereas with no differences for women (39.6% vs 35.3%; P = 0.538). Ferritin was lower among male IBD cases (P = 0.001) and for ulcerative colitis (P = 0.016 for males and 0.017 for females), but not for Crohn's disease. Ferritin was associated with a lower risk for IBD and in the ulcerative colitis subgroup when using sex-based z-scores. Ferritin quartiles 2-4 had a 65% lower odds ratio for all IBD, ulcerative colitis, and Crohn's disease in multivariable analysis. Lower ferritin was associated with higher risk for developing IBD in a prospective setting. Iron deficiency was more common among healthy males years later developing IBD compared to matched controls, but not among women.

Long-term direct and indirect costs of ulcerative colitis in a privately-insured United States population

Objective: Prior evaluations of ulcerative colitis (UC)-related costs are dated or encompassed limited follow-up. This study assessed the incremental direct and indirect work loss-related costs of privately-insured patients with UC in the United States, overall and in specific subgroups.Methods: In this retrospective matched cohort study, the OptumHealth Care Solutions, Inc (formerly Optum Health Reporting and Insights employer) database (01 January 1999–31 March 2017) was used to identify adult patients with ≥2 claims for UC, who were matched 1:5 to patients with no claims for inflammatory bowel disease (IBD). UC subgroups were identified based on indicators during the observation period (i.e. use of biologics, opioids, or corticosteroids; UC-related surgery; moderate-to-severe disease; UC-related comorbidities). Healthcare resource utilization (HRU), work loss days, and direct and work loss-related costs were compared between matched cohorts. Descriptive analyses of direct and work loss-related costs were conducted within each UC subgroup.Results: Compared to the non-IBD cohort (n = 46,765), the UC cohort (n = 9353) incurred higher HRU, including 128% more inpatients visits, resulting in $11,029 higher direct costs per patient per year (PPPY; $7170 vs. $18,198; p < .001). Patients in the UC cohort also incurred more work loss days, resulting in $2142 higher work loss-related costs PPPY ($3165 vs. $5307; p < .001). Direct and work loss-related costs were particularly high in the UC subgroups, with patients undergoing UC-related surgery incurring the highest costs.Conclusions: Over ∼5 years follow-up, patients with UC had significantly higher all-cause direct healthcare and indirect work loss-related costs compared to matched patients without IBD.

Exhaled Breath Analysis for Assessment of IBD (Inflammatory Bowel Disease) Based on Electronic Nose System

Introduction The diagnosis and differentiation of IBD (Inflammatory Bowel Disease) lacks a single gold standard. IBD commonly suffers from a delay in time from first occurrence of symptoms to diagnosis, especially in young patients with ileal disease, which hinders our ability to alter the progression of disease. Also, once the diagnosis of IBD is made its sub categorization into CD (Crohn’s Disease) or UC (ulcerative colitis) is critical for determining the optimal treatment strategy. It is important to identify at risk population that could benefit from a therapeutic approach [1]. Metabolomics studies have recently enter the field of IBD. A variety of studies have been conducted to be significantly different between CD, UC and heathy controls [2]. Limitation for use of metabolomics markers would be too time-consuming and expensive for assessment of IBD or invasive testing in cases. An ideal approach regarding IBD assessment is that breath metabolome offers great potential with simply, easy to use, non-invasive, cheap, rapid and reproducible [3]. An electronic nose system, which is an instrument comprises an array of chemical sensors with partial specificity and an appropriate pattern recognition system capable of recognition simple or complex odors [4], has been suggested a potential alternative as a novel approach for breath analytic technique.In this presentation, we introduce exhaled breath analysis for assessment of IBD from controls and CD from UC using an electronic nose system incorporating a solid-phase micro extraction (SPME) technique. Method We have been developed an electronic nose system composed one chip type array of chemical sensors, chamber, data acquisition system with microprocessor, and sampling system for SPME fiber operation for non-invasive heath care monitoring. The 2x4 sensor array in the system consisted of three oxides of SnO2, NiO2, and In2O3 using Au, Pt, and Pd as catalyst and fabricated on one chip by glancing angle deposition method [5]. A chamber was used to maintain the stable operating temperature of sensor array, and SPME fiber used transferring of exhaled breath samples for measurement. Figure 1 is shown electronic nose system which has been used for experimental work in the hospital. The collection of exhaled breath for IBD patients (23 CD, 32 UC) and 15 controls was carried out using tedlar bag in connection with mouthpiece having a saliva trap to prevent humidity. The SPME fiber coated 85μm Polyacrylate was inserted into the tedlar bag and exposed to the collected breath at an ambient temperature. The system exposed the fiber to the heated sensor array desorbing the volatile off the fiber directly onto the sensors in the chamber. The collection and measurement of expiration were conducted in a hospital after approval of the IRB (Institutional Review Board) at Dongsan Medical Center, Deagu, Korea. Results and Conclusions The primary result for collected data from electronic nose system is shown at Figure 2 using Linear Discriminant Analysis (LDA) algorithm. As shown in Figure 2, IBD patients and controls are distinguished, especially IBD subgroup between CD and UC is well separated each other. However, some samples from UC subgroup are mixed with controls. In this study, we implemented an electric nose system by fabricating a one chip sensors array incorporating SPME sampling technique. Throughout the experimental result, we investigate the possibility of classification between IBD including 2 subgroup discrimination and controls. However, we need more research to improve discrimination regarding UC and controls following by optimal VOCs markers between UC and control including instrument control.

P083 CREATION OF A PROSPECTIVE, LONGITUDINAL ADULT INFLAMMATORY BOWEL DISEASE COHORT COMBINING HIGH-RESOLUTION PHENOTYPING WITH BIOSAMPLE COLLECTION TO FACILITATE PRECISION MEDICINE: SPARC IBD

Abstract Background Disease location, behavior, and average activity over time vary significantly amongst patients with inflammatory bowel disease (IBD). Despite this heterogeneity patients are often subjected to a “one size fits all” treatment plan. Clinical and multi-omic profiles which predict responsiveness to treatment are needed given the expanding range of therapeutic options for IBD. Methods The Study of Prospective Adult Research Cohort of IBD (SPARC IBD) is a prospective, longitudinal cohort study of patients with IBD ages 18 and older managed according to local standards at 17 academic medical centers in the US. Demographic data, disease-related data, and patient-reported outcomes are collected at baseline, during routine GI office visits, and quarterly by data abstraction from the electronic health record, patient surveys, and highly structured electronic case report forms (eCRF) created with Epic Systems (IBD SmartForm). Biosamples are collected at baseline (blood and stool), at the time colonoscopy (stool and tissue), and after key medication changes (blood and stool). Clinical data is transferred from sites on a periodic basis and stored in the Crohn’s &amp; Colitis Foundation’s exchange platform called IBD Plexus. A portion of the biosamples are analyzed and the rest are banked for future use. Results Between November 2016 and October 2019, 2582 patients have enrolled in SPARC IBD (66% Crohn’s disease [CD], 33% ulcerative colitis (UC), and 1% IBD-U). Females comprise 52.5% of the cohort. Median age at enrollment is 37 years (range18-85). The majority of patients are white (80.5%) and non-Hispanic or Latino (84.5%). Median disease duration is 12 years (range 0–53). Distribution of disease location in the CD sub-group is 44% with small bowel and colonic disease, 28% with isolated small bowel disease, and 15% with isolated colonic disease. In the UC sub-group, 50.5% of patients have extensive colitis, followed by 23.5% with left-sided colitis, and 8.8% with proctitis. Among CD patients, 17.6% have stricturing disease, 12.5% have penetrating disease, 5.8% have both stricturing and penetrating disease and 16.2% have perianal involvement. At time of study enrollment 60% of CD patients, 41% of UC patients and 37% of IBD-U patients were on a biologic. The majority of patients with CD (88%) and UC (89%) were in remission. Conclusions SPARC IBD is a prospective cohort study of adult IBD patients which combines high-resolution phenotyping with biosample collection at multiple points in time. The unique aspects of this study including the multiple modalities for clinical data collection, the geographic diversity of patients enrolled, as well as the biosample procurement at multiple time points position SPARC IBD to aid in the discovery of novel biomarkers which can predict therapeutic responsiveness.

Serum galectin 3, galectin 9 and galectin 3-binding proteins in patients with active and inactive inflammatory bowel disease.

Galectins are lectins involved in physiological processes such as cell proliferation, apoptosis and migration, immune responses, inflammation, signalling, and angiogenesis. This study assessed the serum levels of galectin-3 (Gal-3) and galectin-3 (Gal-9) and galectin 3 binding protein (Gal-3BP), and evaluated their associations with the clinical characteristics and levels of inflammatory markers in patients with inflammatory bowel disease (IBD). A total of 48 patients with ulcerative colitis (UC), 77 with Crohn's disease (CD), and 30 healthy volunteers participated in the study. Complete blood counts, C-reactive protein, fibrinogen, albumin, glucose, creatinine, Gal-3, Gal-9, and Gal-3BP were measured. The median Gal-3 and Gal-9 levels did not differ between patients and controls. The median level of Gal-3BP was significantly higher in patients with CD than in controls (8084.6 (5637.8 - 11494.4) ng/ml versus 5962.2 (5280.15 - 7247.92) ng/ml, P = 0.02). No significant differences in Gal-3, Gal-9, and Gal-3BP between active and inactive CD and UC subgroups were found. The median Gal-3BP was higher in subgroups with active CD than in controls (8175.9 (5736.4 - 12871.62) ng/ml versus 5962.2 (5280.15 - 7247.92) ng/ml, P = 0.004). Our results showed that serum Gal-3 and Gal-9 should not be considered biomarkers of IBD. Despite not being a specific marker for CD, serum Gal-3BP might be used as an adjuvant biomarker for disease activity. However, further studies using a larger cohort are required to confirm its clinical usefulness.

Hospital Mortality Trends of Inflammatory Bowel Disease

Introduction: Recent studies have indicated the increasing rates of hospitalization among the Inflammatory bowel disease(IBD) patients. With rapidly improving treatment regimens for Inflammatory Bowel Disease(IBD), patients are expected to live longer. We sought to determine whether the mortality has improved over the last ten years. We also aim to determine the factors associated with mortality. Methods: National Inpatient Sample data from 2005 to 2014 was used to assess the trends. Logistic regression analysis was used to assess the various factors association with mortality. Results: 1.IBD as one of the Diagnosis: 8860 (1.6%) of 552887 IBD hospitalizations ended in death. Age-adjusted mortality increased from 608 deaths per 100,000 admissions in 2005 to 816 in 2014, peaked to 915 in 2008. Similar trends were seen in both Ulcerative colitis(UC) and Crohn's disease(CD). Mortality was high for UC than the CD (1071 vs 619 per 100,000 admissions, OR 1.71,95% CI 1.5 to 1.9, P < 0.001). On Logistic regression, Mortality is associated with Advanced age, longer Length of stay, septicemia, higher Deyo modified Charlson Comorbidity Index score, Clostridium Difficile infection, UC. Race and Sex have no effect on mortality, Obesity appears to be protective. A similar association was observed in both the UC and CD subgroups, except Female sex appears to be protective in CD. Clostridium difficile infection is associated with higher mortality in UC than Crohn's. 2.IBD as primary Diagnosis: 862 (0.5%) of 181224 admissions ended in death. The age-adjusted mortality decreased from 553 per 100,000 admissions in 2005 to 232 in 2014. Similar trends were seen in the both UC and Crohn's groups. Mortality in UC subgroup is higher than the Crohn's, OR 1.98, P < 0.001 On logistic regression, Septicemia, advanced age, longer Length of stay, higher Deyo Modified Charlson Index, Clostridium difficile infection, UC is associated with higher mortality. Obesity and Calendar year appears to be protective. The most common primary Diagnosis for IBD patient's admission is IBD followed by Intestinal obstruction without Hernia, Septicemia, for the patient with mortality is Septicemia, IBD, Respiratory Failure, Intestinal Infection, Pneumonia. Conclusion: The hospital mortality rates have improved in patients with IBD as the primary diagnosis but not in the patients with any primary diagnosis in this large national hospital database.Figure: Mortality trends Total IBD admissions vs admission with IBD as primary Diagnosis.Figure: Ulcerative Colitis and Crohns mortality trends.Figure

5-ASA and Chemoprevention in Inflammatory Bowel Disease: A Population-Based Analysis

Introduction: Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing and remitting inflammatory disease of the gastrointestinal tract. Colorectal cancer (CRC) is a well-documented complication of IBD and is associated with IBD severity, extent and duration. Treatment with 5-aminosalicylic acid (5-ASA) reduces the risk of CRC in IBD. Our objective was to test the association of cumulative exposure to 5-ASA on CRC risk. Methods: A retrospective cohort study was performed using a population-based IBD cohort derived from administrative health data in Saskatchewan, Canada. Data were from 1979 to 2011. Exposure to 5-ASA and CRC diagnosis during the study period were examined. CRC rates were compared between 5-ASA exposed and non-exposed groups using chi-square tests. Exposure to 5-ASA was evaluated using survival analysis. To account for differences in 5-ASA exposure, propensity scores (PS) based on IBD duration, immunomodulator (IM) and anti-TNF exposure, number of endoscopies, and decade of IBD diagnosis were used to match non-exposed to exposed patients. The Kaplan-Meier estimator was used to describe the time-to-event data and Cox proportional hazards regression models were used to test the association of exposure with CRC diagnosis. Analyses were stratified by type of IBD (UC, CD). Results: A total of 8821 IBD patients were included in the study, of which 289 (3.3%) developed CRC. In the CRC-free group, 73.9% (n = 6307) of patients had exposure to 5-ASA, whereas 61.9% (n = 179) had exposure in the CRC group. Figure 1 contains a Kaplan Meier curve for time-to-diagnosis of CRC for the exposure groups. In the PS-matched cohort, the hazard ratio (HR) was 2.56 (95% CI: [1.9, 3.5]) while controlling for gender, location (urban/sub-urban/rural), diagnosis and previous corticosteroid use. The risk of CRC diagnosis was higher in the UC sub-group (HR=3.54, 95% CI: [2.3, 5.5]) when compared to the CD sub-group (1.73, 95% CI: [1.1, 2.6]), controlling for gender, location and decade of diagnosis. A dose response survival model was developed to attempt to control for the duration of 5-ASA exposure on CRC rates, and the HRs were similar.Figure 1Conclusion: This population-based cohort study suggests a chemoprotective effect of 5-ASA exposure for CRC diagnosis amongst patients with IBD. A larger protective effect was observed amongst UC patients than CD patients.

Clinical Pattern of Early-Onset Inflammatory Bowel Disease in Saudi Arabia: A Multicenter National Study.

The objectives of this multicenter national study were to compare the clinical phenotype of early-onset inflammatory bowel disease (IBD) (EO-IBD) with IBD in older children and to examine whether there is any variability in consanguinity rate and familial aggregation in EO-IBD compared with later onset IBD. A retrospective analysis was performed on children aged 0 to 14 years with IBD in 17 centers located in geographically distinct regions in Saudi Arabia, from 2003 to 2012. Data of patients with EO-IBD (0 to <6 yrs) were compared with those with later onset IBD (6-14 yrs). Moreover, we evaluated differences in clinical pattern of infantile or toddler onset IBD subgroup (0-3 yr) as compared with those presenting in older children. Of 352 IBD patients identified during the 10-year study period, 76 children (21.6%) younger than 6 years were diagnosed with IBD. Among the Crohn's disease (CD) group, infantile or toddler onset CD subgroup showed a more frequent isolated colonic involvement (L2) than later-onset group (57% versus 20%; P = 0.002). Positive family history was significantly more common in the infantile or toddler onset ulcerative colitis subgroup (29.4% versus 4.2% in later onset ulcerative colitis; P < 0.0001). The consanguinity rate was significantly higher in the infantile or toddler onset CD subgroup as compared with later onset CD group (57.1% versus 25.3%; P = 0.04). In conclusion, EO-IBD exhibits a unique clinical phenotype with a strikingly higher familial aggregation in early-onset ulcerative colitis. Our data suggest a significant genetic impact on the onset of CD in the very young children.

AN EPIDEMIOLOGICAL STUDY OF THIOPURINEMETHYLTRANSFERASE VARIANTS IN A CROATIAN INFLAMMATORY BOWEL DISEASE PATIENT COHORT

Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. Over 20 variant TPMT-encoding alleles, which cause reduced enzymatic activity, have been discovered so far. Our aim was to investigate the frequencies of variant alleles, i.e. genotypes in inflammatory bowel disease (IBD) patients and healthy individuals and to compare these frequencies with selected world populations. The most common variant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C were analyzed with polymerase chain reaction-based assays and allele-specific polymerase chain reaction-based assays in 685 participants including 459 IBD patients and 226 healthy volunteers. Study results revealed 434/459 (94.55%) IBD patients and 213/226 (94.25%) healthy subjects to be homozygous for the wild-type allele (TPMT*1/*1). TPMT*1/*2 and TPMT *1/*3C genotypes were found in 4/459 (0.87%) and 7/459 (1.53%) IBD patients, respectively; in healthy volunteers they were not found. TPMT*1/*3A genotype was found in 14/459 (3.05%) IBD patients and 13/226 (5.75%) healthy subjects. Variant genotypes were statistically significantly more common in Crohn's disease subgroup than in ulcerative colitis subgroup. The prevalence of variant genotypes was 23/338 (6.80%) in Crohn's disease subgroup as compared with 2/121 (1.65%) in ulcerative colitis subgroup (χ2 = 4.59; p = 0.032). In conclusion, the most frequently occurring nonfunctional TPMT allele in Croatian population is TPMT*3A. The overall frequency of mutant alleles in our population is statistically nonsignificantly lower when compared with other populations of Caucasian origin. The Crohn's disease group had more mutant alleles than the ulcerative colitis group.

NLRP3 gene is associated with ulcerative colitis (UC), but not Crohn's disease (CD), in Chinese Han population.

This study aimed to investigate whether NLRP3 is associated with IBD in Chinese Han population. Three SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients [232 Crohn's disease (CD) patients, 56 ulcerative colitis (UC) patients] and 274 controls. In IBD group, the results showed no significant association. When subdivided to CD and UC, it showed in CD subgroup, there was no significant association. However, in UC subgroup, rs10754558 (P allele=0.015272, P genotype=0.029776, OR [95% CI]=0.604190[0.401200-0.909886]) and rs10925019 (P allele=0.013042, P genotype=0.037045, OR [95% CI]=2.022613[1.149854-3.557812]) have significant associations with UC. The G and T alleles were risk factors of the susceptibility of UC, the GG and TT genotypes may increase risk of this disease. Rs4925648 has no association with UC. The haplotypes analysis results showed as follow: for rs4925648-rs10925019, CC and TT are risk factors for UC (for CC, χ2=3.605, P=0.057613, OR [95% CI]=1.645 [0.980-2.761], for TT, χ2=5.522, P=0.018804, OR [95% CI]=0.426[0.205-0.884]), and for rs10754558-rs10925019, CT and GC haplotypes are risk factors for UC (for CT, χ2=3.545, P=0.059739, OR [95% CI]=0.571[0.317-1.029], for GC, χ2=9.359, P=0.002228, OR [95% CI]=1.904 [1.255-2.887]). We first demonstrated that rs10754558 and rs10925019 are significantly associated with the susceptibility of UC, but not CD in Chinese Han population, suggesting that NLRP3 may play an important role in the pathogenesis of UC.

Circulating leptin and adiponectin and their relation to glucose metabolism in children with Crohn’s disease and ulcerative colitis

Crohn's disease (CD) and ulcerative colitis (UC) result in metabolic consequences. We assessed circulating leptin and adiponectin concentrations and examined their relations to glucose metabolism in children with CD and UC. Circulating morning fasting concentrations of leptin, adiponectin, glucose, and insulin were measured in 32 children with CD and 18 children with UC. Insulin resistance (IR) and β-cell function were evaluated by the updated homeostatic model assessments (HOMA2-IR and HOMA2-B). Leptin was positively related to BMI z-scores overall and in the CD and the UC subgroups (P < 0.001). A negative correlation between leptin and disease activity was observed in the entire population (P = 0.034) and in the UC (P = 0.03) group. None of the assessed parameters was related to adiponectin. Fourteen percent of the participants were insulin resistant (15.6% in the CD group and 11.1% in the UC group), significantly more than expected (P < 0.001). Leptin was associated with HOMA2-IR (overall: r = 0.29, P = 0.045). Pathway analysis suggested that, overall, disease activity and BMI significantly affect leptin, which in turn is the only correlate of HOMA2-IR. Disease activity was significantly and inversely related to leptin in children with inflammatory bowel disease (IBD). A significant proportion of the patients had increased IR, which is positively related to circulating leptin.

CLOSTRIDIUM DIFFICILE IN IBD: AN UNDER DIAGNOSED CAUSE OF DISEASE RELAPSE?

IntroductionClostridium difficile (CDI) is the leading cause of infectious nosocomial diarrhoea in industrialised countries. Patients with IBD, both Crohn's Disease (2-fold increase) and Ulcerative Colitis (3-fold increase) have an increased...

CD4+ immune response as a potential biomarker of patient reported inflammatory bowel disease (IBD) activity

BackgroundCrohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) which are characterized by dysfunctional regulation of the immune system. A number of immune modifying drugs are used to treat CD and UC. Therapy is adjusted largely on the bases of subjective reports of disease activity and non-specific laboratory tests.Identification of a single or combination of immune markers of disease activity could be useful to select and monitor therapeutic responses. However, to date no reliable quantitative associations between IBD activity and laboratory measures of immune function have been identified.This study was designed to evaluate the usefulness of a commercially available laboratory measure of CD4+ immune function, the Cylex® ImmuKnow®, as a surrogate marker of IBD activity. MethodsAdult IBD patients with either CD (N=55, 27 males, mean, SD age=38.5, 11.5years) or UC (N=45, 24 males, mean, SD age=41.7, 15.4years) were enrolled. Patients both in clinical remission and with active disease provided responses to structured, validated questionnaires (CDAI and HBI for CD patients and SCCAI for UC patients) used to monitor IBD activity. Whole blood and plasma samples were collected to quantify various markers of disease status including routine cell counts and differentials (CBCs), CRP, and albumin (Alb), as well as CD4+ immune response (Cylex® ImmuKnow®, N=98). Results were compared between all IBD patients as well as between CD and UC subgroups. ResultsThere was a good correlation between the results of CDAI and HBI scores (r=0.811, p<0.01, Spearman-Rho) but HBI scores correlated slightly better (r=0.575, p<0.001) than the CDAI's (r=0.449, p=0.001) with CD patients' reported perception of their general condition. CDAI and HBI scores categorized 12/55 versus 36/55 of CD patients respectively as having active disease. SCCAI scores indicated that 25/45 of UC patients had active disease. Cylex® results (in ng/mL of ATP) were increased in 74/98 IBD subjects (≥525ng/mL) but were influenced by the use of systemic corticosteroids (SCS) and infliximab. There were weak but statistically significant Spearman-Rho correlations between Alb concentrations and both CDAI (r=0.413, p=0.002) and HBI (r=0.325, p=0.017) scores as well as between CRP values and HBI scores (r=0.331, p=0.016). Correlations between CRP and both CDAI and SCCAI scores and between Alb and SCCAI scores were not significant and there were no significant positive associations between any of the three clinical scores and Cylex® results. ConclusionsCD4+ immune responses were significantly elevated in IBD patients whether or not they were in clinical remission but were influenced by treatment. There were some significant correlations between the clinical scores and CRP or Alb but not with the CD4+ results. Both other clinical scoring systems, other measures of immune function, and CD4+ immune response changes over time should be examined to see if this or other laboratory measures of immune response are predictive of actual disease activity or symptoms in CD or UC patients.

Colonic expression of leukotriene-pathway enzymes in inflammatory bowel diseases

Leukotrienes derived from the 5-lipoxygenase pathway are proinflammatory lipid mediators that possibly play a role in inflammatory bowel diseases. The expression of 5-lipoxygenase pathway proteins has not previously been examined in colonic mucosa in inflammatory bowel disease. Quantitative immunohistochemical analyses showed that, compared to those of the control subjects (n = 9), colonic biopsies from patients with active inflammatory bowel disease (n = 17) had 3- to 7-fold higher mean counts of cells expressing 5-lipoxygenase (P = 0.03), 5-lipoxygenase-activating protein (P = 0.005), and the leukotriene A(4) hydrolase (P = 0.004), which make up the biosynthetic pathway of the potent neutrophil chemotaxin leukotriene B(4). Immunoexpression of the leukotriene C(4) synthase was unaltered (P > 0.2). The increased representation of leukotriene B(4)-pathway enzymes was associated with higher counts of neutrophils (P = 0.0001), macrophages (P = 0.03), eosinophils (P = 0.0004), CD8(+) T cells (P < 0.001), activated T cells (P < 0.05), and B cells (P < 0.05) but not of mast cells (P > 0.9). These eicosanoid and cellular changes were most marked in the subgroup of patients with ulcerative colitis (n = 9), and were absent in patients with quiescent disease (n = 6). The anomalies in the 5-lipoxygenase pathway were accompanied as expected by more cells immunostaining for cytokine-inducible COX-2 (P = 0.004, n = 17), but this study also revealed a greater number of cells expressing COX-1 in the samples from the patients in the ulcerative colitis subgroup (P = 0.03, n = 9). The 5-lipoxygenase data provide a cellular basis for increased tissue synthesis of the leukotriene B(4), as reflected in the colonic mucosa and rectal dialysates of patients with active inflammatory bowel disease, which contributes to neutrophil influx and colonic injury. The COX-1/COX-2 data highlight the ambiguous functional role of prostanoid pathways in inflammatory bowel diseases.

Repeat planar white cell scanning to monitor short-term therapy of active inflammatory bowel disease: a methodological study and comparison with clinical scores and novel inflammatory markers

Radiolabelled white cell scans provide non-invasive quantification of inflammatory activity. Clinical activity scores measure severity of disease but are partly subjective. White cell scans may provide a suitable method of monitoring the treatment response of active inflammatory bowel disease. Ten subjects with active ulcerative colitis and 13 subjects with active Crohn's disease were recruited. White cell scans were carried out before and 2 weeks after treatment. Prior to each scan, activity scores for ulcerative colitis or Crohn's disease were calculated and serum and faecal tumour necrosis factor-alpha and calprotectin measured. White cell scan activity at 1 h was calculated by using a validated visual grading system. Following anti-inflammatory treatment, 70% of white cell scans improved, 17% remained unchanged and 13% deteriorated. In the ulcerative colitis subgroup subjects there was modest agreement for change in scan score and activity scores. In the Crohn's disease subjects there was better agreement between change of white cell scan score and clinical scores. Planar white cell scans correlated with the van Hees activity index (r=0.68, P=0.002) and faecal calprotectin (r=0.58, P=0.0003). Changes in planar white cell scans correlated with changes in serum calprotectin (r=0.45, P=0.05). Non-invasive white cell scanning is a feasible and objective method to monitor the anti-inflammatory efficacy of treatments for active inflammatory bowel disease.

Polymorphism of HLA‐DRB1 gene shows no strong association with ulcerative colitis in Chinese patients

The genetic factors predisposing to ulcerative colitis (UC) have remained totally unclear to date. This study aimed to investigate the role of HLA-DRB1 genetic polymorphism in the susceptibility to develop UC in Chinese patients. HLA-DRB1 genotyping was carried out in 72 unrelated patients with UC and 314 healthy controls by using polymerase chain reaction-sequence-specific primers (PCR-SSP). All of the patients and healthy controls are Han people in China. The frequency of DRB1*07 allele was increased in UC patients compared with healthy controls (19.4% vs. 9.2%, P = 0.0229, OR = 2.372, 95%CI: 1.181-4.766), but the significance disappeared when given Bonferroni correction (P(C) = 0.2977). Furthermore, compared with healthy controls, although HLA-DRB1*07, DRB1*16/DRB1*09 and DRB1*07/DRB1*12 genotypes were increased in frequency in the patients with extensive colitis, and the patients without extraintestinal manifestations (EIMs) carried an increased frequency of HLA-DRB1*07 and DRB1*07/DRB1*12 genotypes, these differences did not reach statistical significance after Bonferroni correction. HLA-DRB1 alleles showed no strong association with UC, and no HLA-DRB1 alleles or genotypes were strongly associated with clinical subgroups of UC in Chinese patients.