Association Between Ex Vivo Human Ulcerative Colitis Explant Protein Secretion Profiles and Disease Behaviour.

BACKGROUND: The clinical course of ulcerative colitis (UC) is variable. There is an unmet clinical need for biomarkers of UC disease behaviour. We aimed to evaluate the association between ex vivo human UC explant conditioned media (explant-CM) secreted protein profiles and UC disease behaviour. METHODS: UC patients undergoing endoscopy were prospectively recruited. Endoscopic biopsies were collected and explant-CM generated. Association between explant-CM protein secretion profiles and disease progression was evaluated. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent. Association between explant-CM secreted protein profiles and anti-TNF failure status was also evaluated. p values < 0.05 were considered significant in analyses. RESULTS: Twenty-four UC patients were included (age [median, range]) 55 [21-72] years; 50% female. Disease progression during follow-up occurred in twelve (50%) patients. Multivariate analysis, including endoscopic remission status, demonstrated reduced IL-2 secretion to be independently associated with UC disease progression, p = 0.01. In univariate analysis, anti-TNF failure status was associated with significantly increased IL-17A/F (p = 0.015) and IL-12 / IL-23p40 (p = 0.044) concentrations. In multivariate analysis, there was a trend towards an association between IL-17A/F and anti-TNF failure status (p = 0.069); FLT-1 was demonstrated to be independently associated with anti-TNF failure status (p = 0.016). CONCLUSION: Reduced explant-CM secreted IL-2 is associated with UC disease progression. Increased secretion of IL-23 pathway-associated cytokines was observed in anti-TNF failure status consistent with previous reports. Ex vivo human UC explants, generated from endoscopic biopsies, have potential as precision medicine tools in inflammatory bowel disease.

Characteristics and outcomes of acute colitis diagnosed on cross-sectional imaging presenting via the emergency department in an Irish academic medical centre.

BACKGROUND AND AIMS: A significant proportion of patients presenting to the Emergency Department with gastrointestinal symptoms that result in cross-sectional imaging receive a radiological diagnosis of colitis. We aimed to review the characteristics, outcomes, and final diagnoses of new emergency department presentations with colitis diagnosed on cross-sectional imaging. METHODS: A radiology database was interrogated to identify patients admitted from the Emergency Department of St James's Hospital whose cross-sectional imaging demonstrated colitis. Baseline demographic data, information on inpatient investigations, final diagnoses, and outcomes were recorded. Adverse outcomes were defined as a requirement for surgery, intensive care unit (ICU) stay, or mortality RESULTS: A total of 118 patients, 67% female, were identified with a median age of 64 years (range 16.9-101.2). Median (range) admission duration was 10 days (1-241). Final colitis diagnoses were infectious (28%), undefined (27%), reactive (18%), inflammatory bowel disease (11%), ischaemic (9%), chemotherapy-associated (3%), diverticular (3%), and medication-associated (1%). Colonic perforation, colectomy, and mortality occurred in 1%, 5%, and 13% of the cohort respectively. On univariate analysis, low haemoglobin, low albumin, high lactate, and male gender were associated with adverse outcomes with the following odds ratios (OR) and 95% confidence intervals (95%CI) were low haemoglobin 1.49 [1.15-1.92] P = 0.002, low albumin 1.16 [1.07-1.25] P = 0.0002, lactate 1.65 [1.13-2.42] P = 0.009, and male gender 3.09 [1.23-7.77] P = 0.019. On multivariate analysis, male gender was associated with adverse outcomes. CONCLUSION: Patients presenting to the Emergency Department with a colitis, requiring an abdominal CT are a heterogenous group with a proportion having concomitant intra-abdominal pathology resulting in critical illness. Hence their is a significant morbidity and mortality observed in this cohort which should not be extrapolated to a general population of patients presenting with colitis. In this cohort of patients, anaemia, hypoalbuminaemia, and elevated lactate in patients presenting to the ED with acute colitis are significantly associated with adverse outcomes. Early recognition of these prognostic factors may identify the cohort of patients who are best managed in a high-dependency setting.

Point Prevalence of Adult Intestinal Failure in Republic Of Ireland.

Parenteral Nutrition (PN) is a life-saving treatment used for patients with Intestinal Failure (IF). PN is complex and demands highly specialised care to avoid serious complications in the home setting. All tertiary centres in the Republic of Ireland (ROI) were contacted to assess the prevalence of IF requiring PN and complications, over a one year period. Sixty-seven patients were treated across 15 centres: a period prevalence of 14.6 and 9.6 patients per million for long-term PN and home PN respectively. Three-quarters of patients experienced at least one major complication with 18% mortality rate over the study period. There were 2.86 admissions per HPN patient, each lasting mean 13.4 days. One-third experienced catheter-related infections. There was a reduced length of stay during emergency re-admissions in high volume centres (mean 31 v 43 days, p=0.17). The establishment of a National Centre for IF/HPN in ROI is integral to reducing PN-associated complications.

Treatment of Clostridium difficile infection: a national survey of clinician recommendations and the use of faecal microbiota transplantation.

Adherence to Clostridium difficile infection treatment guidelines is associated with lower recurrence rates and mortality as well as cost savings. This survey of Irish clinicians indicates that patients are managed using a variety of approaches. Faecal microbiota transplantation is potentially underused despite its recommendation in national and European guidelines.

Characterization of Intestinal Microbiota in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis.

BACKGROUND AND AIMS: There is an unexplained association between ulcerative colitis [UC] and primary sclerosing cholangitis [PSC], with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. METHODS: UC patients with PSC [PSC-UC] and without PSC [UC] were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units [OTUs] using Quantitative Insights Into Microbial Ecology [QIIME]. Microbial alpha diversity, beta diversity, and relative abundance were compared between PSC-UC and UC phenotypes. RESULTS: In all, 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis [PCoA] demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort, Chao 1 index was modestly decreased in PSC-UC compared with UC [p = 0.04] but did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, but results were not robust to false-discovery rate correction. CONCLUSIONS: No strong PSC-specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment centre had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors.

Is there a therapeutic window of opportunity in early inflammatory bowel disease? Early stage inflammatory bowel disease: the actual management.

Traditionally therapy for inflammatory bowel disease (IBD) encompassed a sequential approach with subjects treated with 5-ASA products and/or corticosteroids initially, and only where failing such treatment, moving on to immunomodulator or biologic therapy. In the rheumatologic literature the importance of the early introduction of immunosuppressive therapies for inflammatory arthropathies has been increasingly recognized, however this concept remains much debated in IBD with no clear consensus on the optimal therapeutic approach. In this review we discuss how the natural history of IBD provides a rationale for the early introduction of the most effective therapy. We outline how the experience of early immunosuppressive therapy in rheumatoid arthritis informs therapeutic decision making in IBD. We review the evolving treatment strategies in IBD and the current evidence supporting the introduction of immunosuppressive treatment soon after IBD diagnosis. Finally we discuss the importance of selecting appropriate therapeutic endpoints in IBD and review the potential risks and benefits of early immunosuppressive treatment strategies in IBD.

Haematological support during peg-interferon therapy for HCV-infected haemophiliacs improves virological outcomes.

Hepatitis C virus-infected haemophiliacs are traditionally under represented in international treatment studies thus data assessing response to pegylated-interferon (peg-IFN) and ribavirin (RBV) in HCV mono-infected or HCV/HIV co-infected haemophiliacs are few. Since 2001, 37 haemophiliac patients have received peg-IFN and RBV according to centre-based investigator initiated protocols. Primary end points were: early virological response (EVR); end of treatment response (EOTR) and sustained virological response (SVR). An intention-to-treat analysis was used. Secondary end points were adverse events, haemopoietic stem cell growth factor use, therapy discontinuations and dose reductions. Hepatitis C virus mono-infection group (Mono-I) numbered 20 (60% genotype 1). HCV/HIV co-infected group (Co-I) numbered 17 (59% genotype 1/4). Primary end points were: EVR 76%, EOTR 70% and SVR 43%. Comparison of Mono-I to Co-I demonstrated: EVR rates of 70% and 82%, respectively; EOTR rates of 65% and 76%, respectively, and SVR rates of 35% and 53%, respectively. SVR rates genotype 1/4 group - 17% (Mono-I) vs. 30% (Co-I); SVR rates genotype 2/3 group - 63% (Mono-I) vs. 86% (Co-I). Therapy discontinuations: six of 20 (30%) Mono-I vs. three of 17 (18%) Co-I. Dose reductions: two of 20 (10%) Mono-I vs. zero of 17 Co-I. Haematological support factor use: one of 20 (5%) Mono-I vs. four of 17 (23.5%) Co-I. Virological outcomes to peg-IFN and RBV in HCV-infected haemophiliacs are comparable to published data relating to other HCV-infected cohorts. Good virological outcomes can be achieved in HIV co-infected haemophiliacs particularly when growth factors are used to facilitate full dosing of peg-IFN and RBV.

Infliximab therapy in Crohn's disease: a pragmatic approach?

BACKGROUND: Infliximab is recognized as an effective therapy in unresponsive luminal and fistulating Crohn's disease. The use of maintenance or 'on demand' therapy thereafter is controversial. AIM: To assess the need for maintenance infliximab therapy in a clinical setting where immunomodulatory agents are widely used and where episodic therapy is used in preference to maintenance therapy. METHODS: Ninety-three patients with Crohn's disease receiving infliximab; 72 with unresponsive luminal disease and 21 with fistulous disease. Data collected included disease site and duration, surgical and smoking history, initial response rates, duration of response maintenance and concomitant medications. RESULTS: Fifty-six of 72 (78%) patients with luminal disease and 11 of 21 (52%) with fistulous disease achieved an initial response. Ten of 67 responders required conversion to maintenance infliximab infusions, while 31 remain in remission. Patients with luminal disease and those who had not taken previous surgery had higher response rates to infliximab. Younger patients and those with small bowel disease had higher relapse rates following initial response. Three patients developed allergic reactions to infliximab and one patient died of progressive pulmonary disease 6 weeks after their first infusion. CONCLUSIONS: Many patients with Crohn's disease can be maintained successfully with an episodic infliximab regimen.