Golimumab induction and maintenance for moderate to severe ulcerative colitis: results from GO-COLITIS (Golimumab: a Phase 4, UK, open label, single arm study on its utilization and impact in ulcerative Colitis)

Objective GO-COLITIS aimed to measure the effectiveness of subcutaneous golimumab in tumour necrosis factor-α antagonist–naive patients with moderate to severe ulcerative colitis (UC) despite conventional treatment. Design GO-COLITIS was an open label, single arm, phase 4 study with a pragmatic design which reflected UK clinical practice. Adult patients were eligible if diagnosed with UC ≥3 months, partial Mayo score (PMS) 4–9. Patients received subcutaneous golimumab induction (200 mg initially and 100 mg at week 2) followed at week 6 by 50 mg or 100 mg (depending on weight) every 4 weeks until week 54 with a 12-week follow-up. Efficacy was measured by PMS at baseline, week 6, 30, 54 and 66. Health-related quality of life (HRQoL; Inflammatory Bowel Disease Questionnaire (IBDQ) and EuroQol Group 5 Dimensions Health Questionnaire (EQ-5D)) was assessed at baseline, week 6 and week 54. All safety adverse events (AEs) were recorded. Results 207 patients were enrolled and 205 received golimumab (full analysis set (FAS)205). At week 6, 68.8% (95% CI 62.0% to 75.1%) and 38.5% (95% CI 31.8% to 45.6%) of patients were in response and remission, respectively, using PMS. At the end of the induction phase, 140/141 patients in clinical response continued into the maintenance phase (Maintenance FAS). Sustained clinical response through week 54 was achieved in 51/205 (24.9%) of the FAS205 population and 51/140 (36.4%) of the Maintenance FAS population. Statistically significant improvements from baseline to week 6 were observed for the IBDQ total score and for each IBDQ domain score (bowel symptoms, emotional function, systemic symptoms and social function), as well as the EQ-5D index score and associated visual analogue scale score (p<0.0001). Improvement of HRQoL was sustained through week 54. Serious AEs leading to treatment discontinuation occurred in 8.8% of patients. Conclusion In this study measuring patient-reported outcomes in patients with moderate to severe UC, golimumab induced and maintained response as measured by PMS and significantly improved quality of life measures. Trial registration number NCT02092285; 2013-004583-56

Irritable bowel syndrome and active inflammatory bowel disease diagnosed by faecal gas analysis

Background Inflammatory bowel disease and irritable bowel syndrome may present in a similar manner. Measuring faecal calprotectin concentration is often recommended to rule out inflammatory bowel disease, however, there are no tests to positively diagnose irritable bowel syndrome and invasive tests are still used to rule out other pathologies. Aim To investigate a platform technology for diagnosing inflammatory bowel disease and irritable bowel syndrome based on faecal gas. Methods The platform technology is composed of a gas chromatography column coupled to a metal oxide gas sensor (OdoReader) and a computer algorithm. The OdoReader separates the volatile compounds from faecal gas and the computer algorithm identifies resistance patterns associated with specific medical conditions and builds classification models. This platform was applied to faecal samples from 152 patients: 33 patients with active inflammatory bowel disease; 50 patients with inactive inflammatory bowel disease; 28 patients with irritable bowel syndrome and 41 healthy donors (Control). Results The platform classified samples with accuracies from 75% to 100% using rigorous validation schemes: namely leave‐one‐out cross‐validation, 10‐fold cross‐validation, double cross‐validation and their Monte Carlo variations. The most clinically important findings, after double cross‐validation, were the accuracy of active Crohn's disease vs. irritable bowel syndrome (87%; CI 84–89%) and irritable bowel syndrome vs. controls (78%; CI 76–80%). These schemes provide an estimate of out‐of‐sample predictive accuracy for similar populations. Conclusions This is the first description of an investigation for the positive diagnosis of irritable bowel syndrome, and for diagnosing inflammatory bowel disease

Use of the analysis of the volatile faecal metabolome in screening for colorectal cancer

Diagnosis of colorectal cancer is an invasive and expensive colonoscopy, which is usually carried out after a positive screening test. Unfortunately, existing screening tests lack specificity and sensitivity, hence many unnecessary colonoscopies are performed. Here we report on a potential new screening test for colorectal cancer based on the analysis of volatile organic compounds (VOCs) in the headspace of faecal samples. Faecal samples were obtained from subjects who had a positive faecal occult blood sample (FOBT). Subjects subsequently had colonoscopies performed to classify them into low risk (non-cancer) and high risk (colorectal cancer) groups. Volatile organic compounds were analysed by selected ion flow tube mass spectrometry (SIFT-MS) and then data were analysed using both univariate and multivariate statistical methods. Ions most likely from hydrogen sulphide, dimethyl sulphide and dimethyl disulphide are statistically significantly higher in samples from high risk rather than low risk subjects. Results using multivariate methods show that the test gives a correct classification of 75% with 78% specificity and 72% sensitivity on FOBT positive samples, offering a potentially effective alternative to FOBT

Neonatal Colonisation Expands a Specific Intestinal Antigen-Presenting Cell Subset Prior to CD4 T-Cell Expansion, without Altering T-Cell Repertoire

Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein α-positive (SIRPα+) antigen-presenting cell subset, whilst SIRPα−CD11R1+ antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPα+ antigen-presenting cells as orchestrators of early-life mucosal immune development

Mechanisms of activation of innate-like intraepithelial T lymphocytes

Intraepithelial T lymphocytes (T-IEL) contain subsets of innate-like T cells that evoke innate and adaptive immune responses to provide rapid protection at epithelial barrier sites. In the intestine, T-IEL express variable T cell antigen receptors (TCR), with unknown antigen specificities. Intriguingly, they also express multiple inhibitory receptors, many of which are normally found on exhausted or antigen-experienced T cells. This pattern suggests that T-IEL are antigen-experienced, yet it is not clear where, and in what context, T-IEL encounter TCR ligands. We review recent evidence indicating TCR antigens for intestinal innate-like T-IEL are found on thymic or intestinal epithelium, driving agonist selection of T-IEL. We explore the contributions of the TCR and various co-stimulatory and co-inhibitory receptors in activating T-IEL effector functions. The balance between inhibitory and activating signals may be key to keeping these highly cytotoxic, rapidly activated cells in check, and key to harnessing their immune surveillance potential

Intestinal transit time in the population calculated from self made observations of defecation

STUDY OBJECTIVES--To assess the feasibility of estimating intestinal transit time in the general population using self recorded data on stool form, frequency of defecation, and the interdefecatory time interval. DESIGN--Prospective measurement of bowel function. SETTING--Bristol, Avon, UK between 1987 and 1989. SUBJECTS--Subjects were drawn from 1897 people who comprised 72.2% of a stratified random sample of all men aged 40-69 years and women aged 25-69 years on the lists of 19 general medical practitioners. Altogether 1561 subjects (59.4%) recorded bowel function and a subsample of 98 (50 women and 48 men) had intestinal transit time measured. MEASUREMENTS AND MAIN RESULTS--The interdefecatory time interval and stool form (on a validated 1-6 scale sensitive to transit time) were recorded prospectively from three consecutive defecations. In the subsample the mean intestinal transit time was measured simultaneously using a four marker, two stool x ray technique. Multiple regression analysis was used to assess the extent to which intestinal transit time could be predicted from the defecatory data. The formulas obtained were then applied to the whole study population. In women, intestinal transit time was best predicted by the formula 103-1.23 (DF)--4.69 (SFS)+0.638 (IDTI), where DF is the stated defecation frequency per week, IDTI is the interdefecatory time interval, and SFS is the sum of the three stool form scores, for which the correlation coefficient r = 0.736. For men the intestinal transit time = 79-1.33 (DF)--1.88 (SFS)+0.329 (IDTI), for which the correlation coefficient r = 0.541. The predicted intestinal transit time was longer in women than men at equivalent ages. Women of childbearing age had longer transit times than older women. CONCLUSIONS--Observations made by untrained subjects can be used to estimate intestinal transit time in epidemiological studies. A gender related difference in transit time exists

Incidence of inflammatory bowel disease is rising and abdominal tuberculosis is falling in Bangaldeshis in East London, United Kingdon

OBJECTIVES: Ulcerative colitis (UC) and Crohn's disease (CD) were previously thought to be uncommon and abdominal tuberculosis (TB) common in patients from Bangladesh. We have reevaluated their incidence in Bangladeshis resident in East London. METHODS: Bangladeshis resident in Tower Hamlets presenting between 1997 and 2001 were identified from pathology, endoscopy, and medical records. Demographic, clinical, and management details were recorded. Incidences were calculated and compared with those from 1981 to 1989. RESULTS: Sixteen Bangladeshi patients with UC, 19 with CD, and 5 with abdominal TB were identified. Between 1997 and 2001, the age-standardized incidence of UC was 8.2/10(5)/yr (95% CI 2.5-13.9) compared with 2.4 (95% CI 0.8-3.8) in 1981-1989, and that of CD was 7.3/10(5)/yr (95% CI 2.0-12.6) (2.3, 95% CI 0.7-3.7 in 1981-1989). The standardized ratios for the incidences of UC and CD in recent periods compared with previous periods were 2.1 (95% CI 0.9-3.9) and 2.5 (1.2-4.6), respectively. There was a significant increase in the number of Bangladeshis developing CD by age &lt;20 yr between the earlier and more recent periods (p &lt; 0.02). The standardized incidence of abdominal TB was 2.5/10(5)/yr (95% CI 0.2-4.8) in 1997-2001, and 7.4 (95% CI 2.1-12.7) in 1985-1989 (p &lt; 0.05). The standardized ratio for the incidence of TB in the two periods was 0.22 (95% CI 0.07-0.53). CONCLUSIONS: In Bangladeshis in East London, the incidence of IBD has increased and of abdominal TB has fallen over the last decade; CD has become a more likely diagnosis than abdominal TB. Clinicians in the Western world need to be aware of the changing incidences of IBD and abdominal TB in South Asians