Sara McCartney

Endothelin in human inflammatory bowel disease: comparison to rat trinitrobenzenesulphonic acid-induced colitis

There have been suggestions that endothelins (ET-1, ET-2, ET-3) are involved in the pathogenesis of human inflammatory bowel disease (IBD). Furthermore, the non-selective endothelin receptor antagonist, bosentan, ameliorates colonic inflammation in TNBS colitis in rats. However, no studies have measured the tissue expression and release of endothelins in human IBD in direct comparison to experimental TNBS colitis. Mucosal biopsies were obtained from 114 patients (42 Crohns colitis, 35 ulcerative colitis and 37 normal) and compared to whole colonic segments from rats with TNBS colitis. ET-1/2 levels were reduced in human IBD but greatly increased in experimental TNBS colitis. RT-PCR indicated ET-2 was the predominant endothelin isoform in human IBD whereas ET-1 prevailed in the TNBS model. No associations were found between human IBD and tissue expression, content or release of ET-1/2. Our study shows, therefore, that unlike TNBS colitis in rats, in which ET-1/2 levels are greatly elevated and ET receptor antagonists are efficacious, there is no significant link between endothelins and human IBD.

Henoch-Schönlein purpura complicating adalimumab therapy for Crohn's disease.

Anti-tumour necrosis factor-α (TNF) therapy has revolutionised the management of chronic inflammatory conditions. With ever increasing numbers of patients being treated with these agents, uncommon adverse reactions will inevitably occur more frequently. Cutaneous manifestations are associated with many of these chronic conditions and can complicate anti-TNF therapy in about 20% of cases. Vasculitic complications are rarely associated with anti-TNF therapy. Henoch-Schönlein purpura (HSP), a small vessel vasculitis, has been described following infliximab and etanercept therapy but never with adalimumab, a fully humanized TNF antibody. The risk of such immune-mediated reactions is theoretically less with adalimumab compared to infliximab but can still occur. Here we report the first case in the literature of HSP that can be attributed to the use of adalimumab in a 19-year-old male with recalcitrant Crohns disease.

NOS inhibitors in colitis: a suitable case for treatment?

See article on page 180 Nitric oxide (NO) is now well characterised as a physiologically important molecule, acting most notably as an intra- and intercellular messenger within the cardiovascular and nervous systems.1 To fulfil these functions NO is produced in a tightly controlled manner by calcium dependent, constitutively expressed nitric oxide synthases (cNOS) present within endothelial and neural cells. Under pathological conditions, however, NO acts very differently from a benign signalling molecule. In these circumstances NO is produced in large, apparently tissue damaging amounts by inducible, calcium unregulated nitric oxide synthases (iNOS). For example, in inflammatory bowel disease the presence of high local concentrations of pro-inflammatory cytokines, such as interleukin 8, is associated with the induction of iNOS and so the continuous local generation of NO,2 3 possibly in very great amounts.4 Notably, this difference in NO production between cNOS and iNOS enzymes is not due, as is often remarked, to the inducible isoform of NO synthase being capable of producing more NO than the constitutive forms. Indeed, cNOS and iNOS enzymes function with very similar kinetics, co-factor requirements and substrate affinities. The important characteristic of …

Endothelin Content, Expression, and Receptor Type in Normal and Diseased Human Gallbladder

The aims of this study were to characterize the endothelin (ET) system in human gallbladder by determining (1) the tissue content of ET-1 and ET-2 by ELISA; (2) the expression of mRNA of the ET precursors preproendothelin-1, -2, and -3; and (3) mRNA expression for the ETA and ETB receptors. Median content of ET-1/2 was significantly reduced in severely inflamed gallbladders compared to gallbladders with mild inflammation. There was an inverse correlation between content of ET-1/2 and inflammation score. mRNA for preproendothelin-2 was highly expressed in all samples, whereas mRNA for preproendothelin-1 was present in negligible quantities and mRNA for preproendothelin-3 was undetectable. mRNA for ETA receptors was expressed in all samples analyzed, whereas mRNA for ETB receptors was expressed at a much lower level. This study demonstrates the presence of ET-1/2 in human gallbladder. ET-1/2 content is decreased with increasing degrees of histological inflammation. ET-2 is likely to be the physiologically significant endothelin isopeptide expressed and ETA receptors appear to predominate in the human gallbladder.

Advances in the Medical Treatment of Crohn’s Disease

Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract arising in genetically susceptible individuals as a result of either an appropriate immunological response to a luminal antigen or an inappropriate or prolonged immunological response to the normal microflora of the gut. Specific targeting of this response with immunomodulatory regimens is likely to prove the way forward in the management of Crohn’s disease, rather than relying on blanket immunosuppression with its associated side effects (Table 4.1). There is little doubt that further development of treatment strategies is necessary. The incidence of Crohn’s disease has risen steadily in most of the regions where repeated studies have been carried out. Annual incidence figures from both Europe and North America lie mostly between 2 and 6 per 100,000 [1–3]. Interestingly, over the last 2 decades the incidence figures in the under-16 age group have shown a more dramatic increase, from a mean of 1.3 cases per 100,000 from 1983 to 1988, to a mean of 3.1 per 100,000 between 1989 and 1993 [4]. As disease prevalence and chronicity increase, so does the awareness of the inadequacy of current therapy. This inadequacy drives forward the search for new approaches to treatment.This is particularly important because standard therapies fail to induce remission in approximately 30% of patients and there is a lack of efficacious maintenance regimens. In this chapter we discuss both the current role and the new developments in the use of established treatments such as 5-aminosalicylate (5ASA) drugs and corticosteroids that remain the mainstay of management of Crohn’s disease. In addition, we will explore when and how to use the newer immunomodulatory drugs and biological therapies for steroidefractory or steroid-dependent disease or when surgery is inappropriate (Table 4.2). Early trials, however, indicate spontaneous remission rates of up to 30% in Crohn’s disease.

Mo1955 A Significant Proportion of Patients Still Require Colonoscopy After CT Colonography Within the United Kingdom Bowel Cancer Screening Programme

Background: Several European countries are implementing organized programs for colorectal cancer (CRC) screening, due to their superiority on opportunistic interventions. High-quality studies have already clarified the efficacy of the involved faecal and endoscopic tests. However, their cost-effectiveness within this context are unclear. Methods: A Markov model was constructed comparing the strategies of single sigmoidoscopy (FS) at age 58, fecal immunochemical test (FIT) every 2 years, and a sequential strategy (FS+FIT) in 100,000 subjects, based on the policy and data collected from the organized CRC screening program in the Piedmont region. In FS+FIT strategy subjects non-adherent to FS were re-invited to FIT every 2 years until age 69. Ageand sex-specific CRC incidence and mortality rates were extracted from the Piedmont cancer registry. The expected protective effect of screening on CRC incidence and mortality was derived from the literature. Direct cost analysis was carried out separately for FS and for FIT at first and subsequent rounds. All relevant resources consumed by the program were calculated for each strategy. Incremental cost-effectiveness ratios (ICER) between the different strategies were calculated. Sensitivity and probabilistic analysis were also performed. Results: Direct costs for FS and FIT at 1° and >2° rounds were estimated as ¤160, ¤33 and ¤21, respectively. Assuming the observed participation rates in the Piedmont program (FS: 30%; FIT: 42%), all the simulated strategies appeared to be effective (10-17% of CRC incidence reduction) and cost-effective, compared to the no screening scenario, with an ICER lower than ¤1,000 per life-year saved. However, FS and FS+FIT were the only strategies to be cost-saving or cost-neutral, FS being the least expensive (¤14 saving per person). FS+FIT and FS were the only non-dominated strategies, with FS+FIT being more effective and cost-effective than FS (ICER, ¤945-3,151 per lifeyear saved). At probabilistic analysis, FS+FIT strategy was the most cost-effective strategy in 83% of the scenarios. The residual uncertainty appeared to be mainly related with parameters inherent to efficacy of FIT and adherence, whilst costs did not play any significant role. Conclusions: Organized programs of CRC screening appear to be highly cost-effective, irrespectively of the endoscopic or faecal test selected. However, a sequential approach with sigmoidoscopy and FIT would appear the most cost-effective option. In the case of limited resources, a single sigmoidoscopy would appear the least expensive, but still convenient, approach.

Tu1022 Do Patients With a Previous Normal Colonoscopy Within the United Kingdom Bowel Cancer Screening Program Who Subsequently Have a Positive FOBT Require Repeat Colonoscopy

Introduction Patients within the UK Bowel Cancer Screening Programme (BCSP) who have a normal colonoscopy are re-invited invited for Faecal Occult Blood test (FOBt) on a 2-yearly interval. If FOBt is positive, they are invited to have a repeat colonoscopy. The general polyp ‘miss rate’ is up to 22% in colonoscopy. Factors contributing to this include poor bowel preparation, rapid withdrawal time and endoscopist inexperience. However, endoscopists within the BCSP are highly skilled and selected following a rigid assessment process and poor bowel preparation is rare. Therefore, we hypothesised that patients who have previously had a normal colonoscopy within the BCSP who subsequently have a positive FOBt are unlikely to have a high-risk polyp or bowel cancer. Excluding these patients may avoid unnecessary invasive investigations and reduce the burden on an ever-stretching BCSP waiting list. We aimed to assess the detection of pathology in patients who have had a previous normal colonoscopy within the BCSP who subsequently have a positive FOBt and attend for repeat colonoscopy. Methods Patients with a previous normal colonoscopy between 2007–2010 who re-attended within the BCSP for colonoscopy after repeat positive FOBt were identified from the UCLH ‘in-house’ BCSP database. The results of the colonoscopy and outcomes were then scrutinised. Results A total of 1137 patients have had a normal colonoscopy to date within the BCSP and have subsequently been invited to have a repeat FOBt in 2 years time. From the patients who decided to participate in the second round of recruitment, 77 (6.7%) tested positive on FOBt and were invited for repeat colonoscopy. 8 declined another procedure. 6 patients (8%) had low risk adenomas (range 3–6 mm in size, 4 in right colon, 1 in sigmoid and 1 in left colon), all of who were discharged back to 2-yearly FOBt. 3 patients (4%) had hyperplastic polyps, 2 (3%) had inflammatory bowel disease and 58 (85%) had normal examinations. No patients had bowel cancer identified on repeat colonoscopy. Conclusion No cases of bowel cancer were detected in FOBt positive patients who have previously undergone a normal colonoscopy within the BCSP. Only 8% of patients undergoing repeat colonoscopy had a low-risk adenoma detected mainly from the right colon. Discharging patients with a normal colonoscopy in the BCSP from further screening would reduce pressure on endoscopy screening units and any potential morbidity associated with the procedure. From this study, excluding such patients could have avoided 20 colonoscopy screening lists (approximately 80 procedures) over 3 years in our unit. If findings are similar in other centres, current national guidelines should be changed. Disclosure of Interest None Declared.

150 Siblings of Crohn's Disease Patients Exhibit a Pathologically Relevant Dysbiosis: Examination of Mucosal Microbiota Communities Using 16S rRNA Gene Pyrosequencing

Background Reduced mucosal concentrations of Faecalibacterium prausnitzii predict disease recurrence in patients with Crohns disease (CD). Siblings of CD patients have elevated risk of developing CD and share aspects of disease phenotype compared with healthy controls (HC), including dysbiosis in the faecal microbiota.[1] No study has compared the mucosal microbiota of CD siblings with unrelated healthy controls. Aim: to determine whether dysbiosis is present in the mucosal microbiota of siblings of CD patients with reference to HC, and to apply 16S rRNA gene pyrosequencing in order to accomplish a more comprehensive characterisation of that dysbiosis. Methods Rectal biopsies were taken from 21 patients with quiescent CD, 17 of their healthy siblings and 19 unrelated HC. Total DNA was extracted using phenol/chloroform based method. The V1 to V3 region of the bacterial 16S ribosomal RNA gene was amplified using PCR, and microbiota composition resolved by 454 pyrosequencing. Sequence processing and analyses were performed using the open source Mothur software package (www.mothur.org). Results For each group the resulting species in the microbiota were classified into core (common and abundant among similar subjects) versus infrequent and rare.[2] In terms of both microbial diversity (measured by both the ShannonWiener and Simpsons indexes of diversity) and species richness, the core mucosal microbiota of both siblings and CD patients were significantly less diverse than HC. Although the diversity of the rare microbiota was lower in CD compared with HC, there was no difference in diversity of rare microbiota between siblings and HC. Metacommunity profiling using the Bray-Curtis (SBC) index of similarity with unweighted pair group averages showed that the core microbial metacommunity of siblings was more similar to CD (SBC=0.70) than to HC, whereas the rare microbial metacommunity of siblings was more similar to HC (SBC= 0.42). As in CD patients, the species that contributed most to the dissimilarity between healthy siblings and HC was F. prausnitzii, Table 1. Conclusions This is the first in depth case-control study of the mucosal microbiota in the siblings of CD patients. We report a dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. Given that siblings of CD patients have elevated risk of developing CD, this dysbiosis in otherwise healthy people implicates microbiological processes in CD pathogenesis and risk.

Tu1280 Screening Using the European Crohn's and Colitis Organisation (ECCO) Guidelines Demonstrates High Strongyloides Sero-Prevalence in Migrants With Inflammatory Bowel Disease

Introduction Strongyloidiasis can persist and cause hyperinfection years after acquisition when host immunity is impaired. European Crohn9s and Colitis Organisation guidelines 1 on opportunisitc infections recommend that Inflammatory Bowel Disease (IBD) patients returning from endemic areas be screened. However, prevalence of intestinal helminths in migrant IBD patients is unknown. We investigated the sero-prevalence of Strongyloidiasis and factors associated with infection. Methods Migrant patients attending IBD clinic over a 10-month period, with a diagnosis of Crohn9s disease (CD) or Ulcerative colitis (UC), were tested for Strongyloides serology. Eosinophil count and inflammatory markers were measured. Ethnicity was used as a proxy for migrant status. Sero-positive patients were followed-up with a Strongyloides charcoal culture before treatment with Ivermectin. Repeat eosinophil count and inflammatory markers were performed 3 months later. T test and χ 2 analysis (p Results 97 migrant patients (54 CD vs 43 UC) were tested. 13/97 patients were sero-positive. In both groups, over 70% of patients were from Asia. Mean eosinophil counts (×10 9 /l) were not different between the two groups (0.29 vs 0.22, p>0.05). No significant change was seen in eosinophil count or in inflammatory markers post treatment. In the sero-positive group 23% had past and current eosinophilia, but this was not statistically different from sero-negative patients. 9/13 reportable charcoal stool cultures were negative. No patients with Strongyloides were taking steroids, compared to 23% of sero-negative patients. In both groups, >40% were on two or more immunosuppressants. Conclusion There is a high sero-prevalence of Strongyloides in migrant IBD patients. Patients from Asia demonstrated the highest prevalence. Eosinophilia and raised inflammatory markers were not predictive of positive serology, most likely due to the high rate of immunosuppression. We cannot confirm all sero-positive patients were infected; published data 2 supports the specificity of Strongyloides serology for current infection. We recommend ECCO guidelines and current British Society of Gastroenterology guidelines are adapted to include targetting IBD patients who originate from endemic areas and serological testing be first line. Follow-up of patients is required to assess the impact of treatment on IBD activity. Competing interests None declared. References 1. Rahier JF , et al. J Crohn9s Colitis 2009; 3 :47–91. 2. Loutfy MR , et al. Am J Trop Med Hyg 2002; 66 :749–52.