Sean A. Weaver

Differential regulation of prostaglandin E biosynthesis by interferon-γ in colonic epithelial cells

Cyclooxygenase (COX)‐2 expression and activity in response to pro‐inflammatory cytokines TNFα and IFNγ was evaluated in the colonic epithelial cell line HT29 and the airway epithelial cell line A549. TNFα induced concentration‐ and time‐dependent upregulation of COX‐2 mRNA, protein and prostaglandin (PG)E2 synthesis. Co‐stimulation of TNFα with IFNγ resulted in reduced COX‐2 mRNA and protein expression. IFNγ had no effect on the stability of TNFα‐induced COX‐2 mRNA. TNFα‐induced PGE2 biosynthesis was significantly enhanced by the simultaneous addition of IFNγ and was COX‐2 dependent. The combination of IFNγ and TNFα induced the microsomal prostaglandin E synthase (mPGES), comensurate with the enhanced PGE2 synthesis. These results suggest that, in terms of PGE2 biosynthesis, IFNγ plays a negative regulatory role at the level of COX‐2 expression and a positive regulatory role at the level of mPGES expression. This may have important implications for the clinical use of IFNγ in inflammatory diseases.

Phosphoinositide 3-kinases in the gut: a link between inflammation and cancer?

Carcinoma of the gastrointestinal tract is the most common internal malignancy affecting men and women in Western countries. Chronic intestinal inflammation, especially of the colon, is also a Western disease and correlates with a significantly increased risk of developing cancer. This has suggested that the immune processes involved in both conditions might share some common pathways. Indeed, there is increasing evidence that phosphatidylinositol 3-kinases (PI 3-kinases) are involved in both the pathogenesis of colorectal carcinoma and intestinal inflammation. Here, we discuss this rapidly progressing area of research, presenting evidence for a pivotal role of PI 3-kinase(s) in intestinal pathophysiology.

Tu1157 Low-Dose Thiopurine and Allopurinol Co-Therapy Results in Significant Cost Savings At a District General Hospital

Introduction Thiopurines are used for maintenance of remission in IBD. In England and Wales biologics are approved by NICE (National institute for health and clinical excellence) for Crohn’s disease (CD) but not ulcerative colitis. Adalimumab is recommended in preference to infliximab in patients over 65kg due to cost. Published data report > 50% of patients stop thiopurines due to theraputic failure, hepatitis or side effects. In this situation most UK clinicians start biologics in CD patients. This has significant cost implications. An alternative treatment strategy is low dose thiopurine and allopurinol (LDTA) co-therapy which is effective in most patients who fail standard dose thiopurines. Some patients require liquid thiopurine to achieve the correct (low) dose -this formulation is significantly more costly than tablets. We report the annual cost savings from adopting this strategy at our centre. Methods We maintain a prospective IBD database. Patients with CD treated with LDTA in preference to biologic therapy were identified. The annual drug costs of their treatment with LDTA compared with biologic therapy (adalimumab for patients over 65kg, infliximab for patients Results 17 CD patients who failed standard thiopurine and were eligible for biologics were identified over a 1 year period (Sept 2011-Sept 2012). Of these 4 (24%) failed LDTA and progressed to biologics, 13 (76%) entered a sustained clinical remission. Mean weight of patients = 77.3kg (range: 53.5–105), 6 (46%) patients required a liquid thiopurine. Mean calculated costs were: thiopurine £451.95 (range: £48.48-£1345.44). biologic: £11,331 (range: £10,560-£16,081). Mean cost saving per patient: £10,879 (range: £9,215-£15,146). Total cost saving: £141,427. Conclusion We have previously reported that low dose thiopurine and allopurinol co-therapy is safe and effective. In the present study we have identified significant annual cost savings can be made when this treatment strategy is used to prevent escalation to biologics. These cost savings are likely to be even more significant in the long term since a significant proportion of patients treated with biologic therapy require dose escalation. We believe adopting this strategy more widely could lead to significant health-care savings. Disclosure of Interest None Declared

Su1296 Diagnostic Benefit of MRE Following CT

BACKGROUND AND AIM: recent studies have documented an increased rate of cardiovascular events in IBD patients. Studies on surrogate markers for early ATS have led to conflicting results. Our aim was to investigate the prevalence of increased intima-media thickness (IMT) of the carotid arteries and of arterial stiffness in a homogeneous cohort of young patients with IBD. METHODS: we recruited 68 consecutive IBD patients (35 males), and 38 sex and age matched HC. Median age was 31.6 ± 8.1 years. Data on clinical and demographic features, cardiovascular risk factors, personal and familial history of cardiovascular events, concomitant therapies were registered on a dedicated database. Forty-five out of IBD patients had Crohn disease (CD) and 23 had Ulcerative Colitis (UC). Twenty-two CD patients had a disease duration greater than 5 years and 9 showed a clinically active disease. In the UC group 8 patients had a disease duration greater than 5 years and 3 clinically active disease. Sixteen out of 68 IBD patients were smokers, 9 ex-smokers; 29 had a family history of cardiovascular events, 3 were hypertensive and 2 patients had diabetes mellitus, 21 had a BMI greater than 25. Left and right carotid IMT was evaluated using high resolution Bmode ultrasonography. Arterial stiffness was assessed by measurement of carotid-femoral Pulse Wave Velocity (PWV) and Augmentation Index (AI). RESULTS: there was a statistically significant difference between IBD patients and HC for total cholesterol values (P <0.013) and LDL-cholesterol (P <0.019). There was no difference in lipid profile between CD and UC. There was a trend toward significance in the distribution of BMI values between patients and HC (P 0.082). Right carotid IMT was higher in IBD group than in controls (P <0.047), but there was no statistically significant difference between subjects with CD and UC. Moreover, PWV average and AORTIC AIX (AIx) were significantly higher in patients than in controls (P <0.006 and P <0.004 respectively). CONCLUSION: in our study we have found increased expression of surrogate markers for early onset ATS in young Mediterranean patients with IBD. This seems not to be related to traditional risk factors for ATS. Clinical follow-up of IBD patients should include assessment at diagnosis and monitoring of IMT of the carotid arteries and of arterial elastic properties, in order to reduce the risk of cardiovascular events.

71 Push Enteroscopy Leads to a Change in Diagnosis in the Majority of Patients With Positive Celiac Serology and Negative Duodenal Biopsy

Introduction Coeliac disease is associated with significant morbidity, and is an underdiagnosed condition with an estimated prevalence of 1% in the UK population. Current British Society of Gastroenterology Society guidelines classify individuals with positive coeliac serology and negative duodenal biopsy to latent coeliac disease and do not recommend further investigation or the initiation of a gluten free diet. In our recent practise patients at our institution with a strong clinical suspicion of coeliac disease and negative duodenal biopsies following a gluten containing diet undergo a push enteroscopy with biopsies of the jejunum and duodenum and histological reassessment of the original duodenal biopsies before a diagnosis of latent coeliac disease is made. We aimed to investigate whether push enteroscopy and histological reassessment increased the diagnostic yield of coeliac disease. Methods We searched our prospective endoscopy database for all patients with positive EMA or TTG results but negative D2 biopsies, who had undergone enteroscopy for a possible diagnosis of coeliac disease since 2007. Data including serology, result of histological reassessment of duodenal biopsies and assessment of jejunal biopsies were recorded. Results 13 patients were identified; 4 (31%) were male, the median age was 45 (range 19–78). In all 13, EMA testing had been performed, of which 9 were positive (69%). In 9, TTG results were available, of which 9 were positive (100%). Following review of the original duodenal biopsies by a second pathologist, 7 (54%) of the 13 patients were re-classified to active coeliac disease; median Marsh grade of 1 (range 0–2) Of the remaining 6 patients, 5 (83%) had evidence of active coeliac disease on jejunal biopsy; median Marsh grade of 2 (range 0–3b). Review of the jejunal biopsies alone, without review of original duodenal biopsies, would have led to active coeliac disease being diagnosed in 12 (92%) of 13 patients. Conclusion In this small retrospective series of patients with positive coeliac serology and negative duodenal biopsies, repeat histological assessment and jejunal biopsy led to a change in diagnosis in 92% of patients. These findings are unlikely to be limited to our institution. Our findings support the recommendation that a diagnosis of latent coeliac disease should only be made following repeat histological assessment and enteroscopy with jejunal biopsy. Disclosure of Interest None Declared.