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ObjectiveOur aim was to explore the risk of infection with all classes of inflammatory bowel disease (IBD) medications and the impact of these medications on the disease course in a nationwide cohort of patients with IBD.DesignThis was a retrospective national cohort study of patients with IBD in the Veterans Affairs Healthcare System. We categorised IBD medication use immediately prior to the COVID-19 pandemic and used survival analysis methods to study associations with SARS-CoV-2 infection, as well as a combined secondary outcome of COVID-19 hospitalisation or COVID-19-related mortality.ResultsThe analytical cohort of 30 911 patients was primarily male (90.9%), white (78.6%) and with ulcerative colitis (58.8%). Over a median follow-up of 10.7 months, 649 patients (2.1%) were diagnosed with SARS-CoV-2 infection and 149 (0.5%) met the combined secondary outcome. In adjusted models, vedolizumab (VDZ) use was significantly associated with infection relative to mesalazine alone (HR 1.70, 95% CI 1.16 to 2.48, p=0.006). Patients on no IBD medications had increased risk of the combined secondary outcome relative to mesalazine alone (sub-HR 1.64, 95% CI 1.12 to 2.42, p=0.01), however, no other IBD medication categories were significantly associated with this outcome, relative to mesalazine alone (each p>0.05). Corticosteroid use was independently associated with both SARS-CoV-2 infection (HR 1.60, 95% CI 1.23 to 2.09, p=0.001) and the combined secondary outcome (sub-HR 1.90, 95% CI 1.14 to 3.17, p=0.01).ConclusionVDZ and corticosteroid were associated with an increased risk of SARS-CoV-2 infection. Except for corticosteroids no medications including mesalazine were associated with an increased risk of severe COVID-19.

Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.

The current coronavirus pandemic is an ongoing global health crisis due to covid-19, caused by severe acute respiratory syndrome coronavirus 2. Although covid-19 leads to little or mild flu-like symptoms in the majority of affected patients, the disease may cause severe, frequently lethal complications such as progressive pneumonia, acute respiratory distress syndrome and organ failure driven by hyperinflammation and a cytokine storm syndrome. This situation causes various major challenges for gastroenterology. In the context of IBD, several key questions arise. For instance, it is an important question to understand whether patients with IBD (eg, due to intestinal ACE2 expression) might be particularly susceptible to covid-19 and the cytokine release syndrome associated with lung injury and fatal outcomes. Another highly relevant question is how to deal with immunosuppression and immunomodulation during the current pandemic in patients with IBD and whether immunosuppression affects the progress of covid-19. Here, the current understanding of the pathophysiology of covid-19 is reviewed with special reference to immune cell activation. Moreover, the potential implications of these new insights for immunomodulation and biological therapy in IBD are discussed.

Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, that display heterogeneity in inflammatory and symptomatic burden between patients, and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients.This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK).A systematic review of 88,247 publications, and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence and expert opinion based-recommendations for pharmacological, nonpharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive, up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and post-operative management, as well as structure and function of the multidisciplinary team, and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2,379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.

Thiopurines have been considered the reference treatment for patients with steroid-dependent moderate to severe IBD for many years. This has been based on evidence describing the efficacy and safety of azathioprine and mercaptopurine in Crohn's disease (CD) and UC. In CD, efficacy has been established through controlled trials, meta-analyses, cohort studies and data on mucosal healing, as well as in withdrawal studies. A Cochrane meta-analysis concluded that azathioprine and mercaptopurine effectively maintained remission in CD with an OR between 2 and 3 compared to placebo.1 Mucosal healing was initially studied in patients on azathioprine with longstanding steroid-free remission.2 In this setting, full mucosal healing was achieved in 54% of patients with ileitis and 70% with colitis. The majority of the remaining patients had at least partial healing, and only a small minority experienced no healing at all. This healing potential was confirmed in a controlled study showing the superiority of azathioprine over budesonide.3 When patients achieve sustained steroid-free remission under azathioprine, it is usually stable and longstanding. A controlled withdrawal study from the GETAID indicated sustained remission over more than 5 years in 80% of patients when the treatment was continued, compared to 40% of patients when it was stopped.4 The evidence base in UC is weaker. Nevertheless, a controlled trial comparing azathioprine to mesalazine in steroid-dependent UC clearly showed the superiority of azathioprine with an OR of 4.8 (95% CI 1.6 to 14.5).5 This benefit was confirmed in a meta-analysis.6 Additionally, a withdrawal study, although not controlled, showed around 60% of patients with UC relapse over 5 years after azathioprine withdrawal.7 In CD, these data have also been reinforced by cohort studies suggesting a beneficial effect of thiopurines on long-term outcome, including a decrease in the rate of surgery in adult and paediatric patients. …

The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohn's disease (CD) with moderate or severe endoscopic recurrence.This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6-24 months without subsequent clinical recurrence and with a Crohn's disease activity index (CDAI) score200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0-2.5 mg/kg/day or mesalazine 4 g/day over 1 year. The primary end point was therapeutic failure during 1 year, defined as a CDAI scoreor = 200 and an increase ofor = 60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction.Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI -5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showingor = 1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023).In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure.

Objectives: To determine the therapeutic equivalence and safety of once daily (OD) versus three times daily (TID) dosing of a total daily dose of 3 g Salofalk (mesalazine) granules in patients with active ulcerative colitis. Design: A randomised, double-blind, double-dummy, parallel group, multicentre, international, phase III non-inferiority study. Setting: 54 centres in 13 countries. Patients: 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis (clinical activity index (CAI)>4 and endoscopic index ⩾4 at baseline) were randomised and treated. Interventions: 8-week treatment with either 3 g OD or 1 g TID mesalazine granules. Main outcome measures: Clinical remission (CAI⩽4) at study end. Results: 380 patients were evaluable for efficacy and safety by intention-to-treat (ITT); 345 for per protocol (PP) analysis. In the ITT population, 79.1% in the OD group (n = 191) and 75.7% in the TID group (n = 189) achieved clinical remission (p

Aim: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. Methods: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2×1.2 g tablet) or divided dose (1×1.2 g tablet twice daily) for 12 months. Results: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). Conclusions: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. Trial registration number: NCT00151944.

Introduction Immune activation has been reported in the mucosa of IBS patients with diarrhoea (IBS-D), and some small studies have suggested that mesalazine may reduce symptoms. We performed a double-blind, randomised placebo-controlled trial of 2 g mesalazine twice daily versus placebo for 3 months in patients with Rome III criteria IBS-D. Primary outcome was daily average stool frequency during weeks 11–12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of ‘satisfactory relief of IBS symptoms’. Results 136 patients with IBS-D (82 women, 54 men) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in mesalazine and 2.7 (1.9) in the placebo group with no significant group difference, (95% CI) 0.1 (−0.33 to 0.53), p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared with placebo during the last two-weeks follow-up. Conclusions This study does not support any clinically meaningful benefit or harm of mesalazine compared with placebo in unselected patients with IBS-D. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. Trial registration number NCT01316718.

BACKGROUND AND AIMS: The widespread use of anti-tumour necrosis factor alpha antibody (Infliximab) in Crohn's disease (CD) raises concerns about a possible cancer risk in the long term. In a matched pair study, we assessed whether Infliximab is associated with an increased risk of neoplasia. METHODS: In a multicentre matched pair study, 404 CD patients treated with Infliximab (CD-IFX) were matched with 404 CD patients who had never received Infliximab (CD-C). Cases and controls were matched for sex, age (+/-5 years), site of CD, age at diagnosis (+/-5 years), immunosuppressant use, and follow up. New diagnoses of neoplasia from April 1999 to October 2004 were recorded. RESULTS: Among the 404 CD-IFX, neoplasia was diagnosed in nine patients (2.22%) while among the 404 CD-C, seven patients developed neoplasia (1.73%) (odds ratio 1.33 (95% confidence interval 0.46-3.84); p=0.40). The survival curve adjusted for patient year of follow up showed no differences between CD-IFX and CD-C (p=0.90; log rank test). In the CD-IFX group, there was one cholangiocarcinoma, three breast cancers, one skin cancer, one leukaemia, one laryngeal cancer, and two anal carcinomas. Among the 7/404 (1.73%) CD-C, there were three intestinal adenocarcinomas (two caecum, one rectum), one basalioma, one spinalioma, one non-Hodgkin's lymphoma, and one breast cancer. Age at diagnosis of neoplasia did not differ between groups (CD-IFX v CD-C: median 50 (range 40-70 years) v 45 (27-72); p=0.50). CONCLUSION: In our multicentre matched pair study, the frequency of a new diagnosis of neoplasia in CD patients treated with Infliximab was comparable with CD patients who had never received Infliximab.

Background and aim: There are limited evidence based data concerning the use of azathioprine in ulcerative colitis. We aimed to compare the efficacy of azathioprine and oral 5-aminosalicylic acid in inducing remission of steroid dependent ulcerative colitis. Methods: Seventy two patients with steroid dependent ulcerative colitis were admitted to this investigator-blind study. Steroid dependence was defined as a requirement for steroid therapy ⩾10 mg/day during the preceding six months, with at least two attempts to discontinue the medication. The disease had to be clinically and endoscopically active at study entry, and all patients were taking systemic prednisolone (40 mg/day). Patients were randomised to receive azathioprine 2 mg/kg/day or oral 5-aminosalicylic acid 3.2 g/day, for a six month follow up period. The outcome of the treatment was defined as (1) success, indicating induction of clinical and endoscopic remission and steroid discontinuation, or (2) failure, indicating the absence of clinical and endoscopic remission and therefore the need for at least one further cycle of systemic steroids to control symptoms, apart from the initial one, or colectomy. Results: Significantly more patients in the azathioprine than in the 5-aminosalicylic acid group had clinical and endoscopic remission, and discontinued steroid therapy, both in the intention to treat (azathioprine v 5-aminosalicylic acid: 19/36 patients (53%) v 7/36 (21%); odds ratio (OR) 4.78 (95% confidence interval (CI) 1.57–14.5)) and per protocol (azathioprine v 5-aminosalicylic acid: 19/33 patients (58%) v 7/34 (21%); OR 5.26 (95% CI 1.59–18.1)) analysis. Conclusions: Azathioprine is significantly more effective than 5-aminosalicylic acid in inducing clinical and endoscopic remission and avoiding steroid requirement in the treatment of steroid dependent ulcerative colitis.

Background and aims: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. Methods: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. Results: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). Conclusion: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Background and aim: Evidence exists for the pathogenic role of the enteric flora in inflammatory bowel disease. Probiotics contain living microorganisms which exert health effects on the host. We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis. Patients and methods: In total, 327 patients were recruited and assigned to a double blind, double dummy trial to receive either the probiotic drug 200 mg once daily (n = 162) or mesalazine 500 mg three times daily (n = 165). The study lasted for 12 months and patients were assessed by clinical and endoscopic activity indices (Rachmilewitz) as well as by histology. The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses. Results: The per protocol analysis revealed relapses in 40/110 (36.4%) patients in the E coli Nissle 1917 group and 38/112 (33.9%) in the mesalazine group (significant equivalence p = 0.003). Subgroup analyses showed no differences between the treatment groups in terms of duration and localisation of disease or pretrial treatment. Safety profile and tolerability were very good for both groups and were not different. Conclusions: The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora.

It is well accepted that patients with ulcerative colitis (UC) are at increased risk of developing colorectal carcinoma. Since 1992, several studies have examined the hypothesis that patients with concomitant primary sclerosing cholangitis (PSC) are at significantly increased risk of developing colorectal cancer or dysplasia. The size, design, end points, and populations involved in these studies have varied but critical review suggests that colorectal cancer is more common in the setting of PSC. Although the data do not allow exact quantification of the increased relative risk, there are nevertheless implications, both for understanding disease pathogenesis and for clinical practice. An increased risk of developing colorectal carcinoma in patients with UC was first recognised in the 1920s.1 The magnitude of this risk varies in different studies with a range in cumulative risk after diagnosis in patients with pancolitis of between 1% and 3% at 10 years, 10% at 20 years, and 25% at 35 years.2-5It is now widely accepted that risk factors for malignant transformation are duration of disease and extent of colitis. The presence of graded dysplasia6 or DNA aneuploidy within the colorectal mucosa, and an early age at onset have been described as additional risk factors.4 It has also been suggested that pharmacological therapy of colitis with sulphasalazine or mesalazine may be associated with a reduced incidence of neoplastic transformation.7 8 PSC is a disease of unknown aetiology characterised by cholestasis associated with diffuse inflammation and fibrosis of the entire biliary tract.9 PSC has a variable clinical course, progressing eventually to cirrhosis and premature death from hepatic failure. Furthermore, PSC is accompanied by a risk of developing carcinoma of the bile ducts.10 Although PSC may occur in isolation, it is closely associated with inflammatory bowel disease, in particular UC. Up to …

BACKGROUND—Butyrate oxidation within the colonocyte is selectively inhibited by hydrogen sulphide, reproducing the metabolic lesion observed in active ulcerative colitis. AIMS—To study generation of hydrogen sulphide by sulphate reducing bacteria (SRB) and the effects of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis in order to identify a role of this noxious agent in pathogenesis. PATIENTS—Fresh faeces were obtained from 37 patients with ulcerative colitis (23 with active disease) and 16 healthy controls. METHODS—SRB were enumerated from fresh faecal slurries and measurements made of sulphate reducing activity, and sulphate and hydrogen sulphide concentrations. The effect of 5-ASA on hydrogen sulphide production was studied in vitro. RESULTS—All controls and patients with active ulcerative colitis carried SRB and total viable counts were significantly related to the clinical severity grade. SRB were of two distinct types: rapidly growing strains (desulfovibrios) which showed high sulphate reduction rates, present in 30% of patients with ulcerative colitis and 44% of controls; and slow growing strains which had little activity. In vitro, 5-ASA inhibited sulphide production in a dose dependent manner; in patients with ulcerative colitis not on these drugs faecal sulphide was significantly higher than in controls (0.55 versus 0.25 mM, p=0.027). CONCLUSIONS—Counts and carriage rates of SRB in faeces of patients with ulcerative colitis are not significantly different from those in controls. SRB metabolism is not uniform between strains and alternative sources of hydrogen sulphide production exist in the colonic lumen which may be similarly inhibited by 5-ASA. The evidence for hydrogen sulphide as a metabolic toxin in ulcerative colitis remains circumstantial. Keywords: colitis; sulphate; sulphide; bacteria; fermentation; salicylate

Introduction Over the past decade, there has been an increasing uptake of immunomodulator therapy in the treatment of Inflammatory Bowel Disease (IBD). The current British Society of Gastroenterology (BSG) and European Crohn’s and Colitis Organisation (ECCO) guidelines highlight the importance of influenza, pneumococcal, human papilloma virus, varicella and hepatitis B vaccination. Our previous audit in 2014 described 75% uptake of any vaccination in these patients. Here we present the re-audit after an intervention, where a letter was sent to general practitioners (GPs) to promote immunisation awareness. Methods 100 consecutive IBD patients attending the general gastroenterology outpatient clinic were asked to complete a questionnaire. All forms of IBD were included. Information regarding medication, infections and immunisation status were recorded. Results were analysed using the statistical package for the social sciences (SPSS). Results Of the 100 questionnaires returned, 3 were excluded due to incomplete completion. Median age was 46 (19–84). Of the IBD subtypes, 48 (49%) patients had Crohn’s, 34 (35%) had ulcerative colitis and 15 (16%) had colitis of unknown aetiology (CUTE); male to female ration was 48:52%. 92% of patients with IBD had medication prescribed in the past 6 months. Within this group, 59% had been on mesalazine, 38% on thiopurines, 36% on steroids and 12% on anti tumour necrosis factor (anti-TNF) agents. Overall, 68% of immunosuppressed patients received some form of immunisation in the preceding 6 months and, of these, 28% had some form of infection reported. In total, 44% of patients had immunosuppressant advice given and 29% of patients had vaccination advice. There was no statistical difference in the baseline characteristics of patients and prescribed medication compared to 2014. Despite engagement with primary care, there was no significant difference in the uptake of immunisation in the IBD population. In fact, there were statistically lower rates of Influenza and Pneumovax vaccination in the 2015 cohort (P see table ). Conclusion Current guidelines state that influenza, pneumococcal and HPV vaccination be considered for all IBD patients. Despite the results of our previous audit there does not appear to be an improvement in vaccination rates. A weakness in the current approach is that information is received by GPs at differing intervals to when a patient is seen. It may be that a targeted, patient-specific letter is sent to GPs with an attached acknowledgement receipt to improve vaccination rates. Disclosure of Interest None Declared

Introduction Once remission is induced, the majority of patients with mild to moderate UC are managed in primary care on long term 5 ASA maintenance therapy. Lack of adherence to therapy has significant implications for patients with an impact on the use of NHS resources. The aim was to assess the management of patients with mild to moderate UC on 5 ASA maintenance therapy in primary care. Methods All UC patients on 5 ASA therapy from 31 practices covering three CCGs in were identified and invited to attend a clinic at their practice. Disease location, activity (Walmsley Index), 5 ASA dose and frequency and adherence to therapy were recorded. Results 481 UC patients were identified, 212 reviewed and 158 patients (M:F = 99:59) fully assessed. Age (mean [range]; 60.6 [22–88 yrs.] yrs.). UC subclass (No [%]): proctitis 23 [14%]; distal colitis: 59 [39%]; pan colitis: 38 [24%]; UC unspecified:38 [23%]. 58% on Asacol; 30% on Pentasa and 9% on Mezavant respectively. Maintenance dose range 1–6.4 g/day; 29% were on lower than the recommended dose for their specific 5 ASA. 48 (31%) received other therapies (azathioprine, steroids or mesalazine enemas). Walmsley Index (mean 2.3) was ­ ≥4 in 27 patients (17%) indicating flare. 27 patients (17%) had symptoms and 39 (29%) had adherence issues. Several patients missed routine surveillance colonoscopy and blood tests. Conclusion UC is inadequately managed in primary care Disclosure of Interest D. Aldulaimi: None Declared, D. Farmer: None Declared, H. Prasher: None Declared, R. Jazrawi Conflict with: Dr R Jazrawi is medical Director of Dr Falk Pharma UK

An enema that contained a complex of bismuth citrate and polyacrylate was compared with 5-aminosalicylic acid (5-ASA) enemas for treatment of distal ulcerative colitis. The multicentre trial involving 63 patients was randomised and double blind with enemas given over four weeks; clinical, sigmoidoscopic, and histological assessments were made. Improvements were seen in both treatment groups. Clinical remission was seen in 18 of 32 patients treated with 5-ASA and 12 of 31 patients treated with bismuth citrate-carbomer (chi 2 1.94; p = 0.16). Sigmoidoscopic remission occurred in 20 of 32 patients in the 5-ASA group and 15 of 31 patients given bismuth (chi 2 1.27; p = 0.26). Improvement of rectal biopsy histology by at least one grade was seen in 16 of 32 patients in the 5-ASA group and 14 of 31 patients with bismuth (chi 2 0.15; p = 0.70). Analysis of covariance gave no significant difference between groups, although there was a trend favouring 5-ASA. There was no evidence of bismuth accumulation during the trial. Bismuth enemas may offer a new therapeutic option in distal ulcerative colitis.

BACKGROUNDTreatment of ulcerative colitis or Crohn’s disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported.CASE REPORTA 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration.CONCLUSIONContrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis.

A 49-year-old male patient with distal ulcerative colitis diagnosed in 2004 was treated with mesalazine. He was hospitalised in May 2005 with a serious flare up of his colitis (C-reactive protein (CRP) = 330 mg/l, 20 …

To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.

Introduction Data on mesalazine (5-aminosalicylic acid; 5-ASA) use in cases of paediatric ulcerative colitis (UC) are limited. In this phase 1, randomised, open-label, multicentre study ([NCT01130844][1]), pharmacokinetic (PK) and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) were examined in youth with UC diagnoses after once-daily (QD) multimatrix mesalazine administration. Method Upon enrolment, patients (pts; aged 5–17 y with diagnosis of UC ≥3 mo, stratified by body weight) were given 30, 60, or 100 mg/kg multimatrix mesalazine QD for 1 wk. The existing, approved, 1200 mg tablet was supplemented with newly developed, smaller-sized 300 and 600 mg multimatrix mesalazine tablets in order to achieve the appropriate study doses in children. Mesalazine was administered at home (Days 1–4) and at the clinic (Days 5–7); onsite, safety evaluations were performed, and blood and urine samples obtained for PK analyses. A validated LC/MS/MS assay was used to determine plasma and urine concentrations of 5-ASA and Ac-5-ASA. Key PK parameters assessed included maximum concentration (Cmax, ss), time of Cmax, ss (tmax), area under the curve for 1 dose interval (AUCss), renal clearance (CLR), and% dose absorbed. Results In total, 52 pts (21, 22, and 9 pts at 30, 60, and 100 mg/kg, respectively) were randomised and treated. Mean (standard deviation) age was 13.3 (3.1) y, and median (range) time since UC diagnosis was 1.8 (0.2–9.6) y. By Day 5, 5-ASA and Ac-5-ASA plasma concentrations reached steady state for all dose groups. On Day 7, for both 5-ASA and Ac-5-ASA, mean Cmax, ss and AUCssshowed dose proportional increases from 30 to 60 mg/kg cohorts. Mean% 5-ASA absorbed for 30, 60, and 100 mg/kg doses were 29.4%, 27.0%, and 22.1%, respectively. Mean CLR ranges were 5.0–6.5 L/h for 5-ASA and 10.0–16.2 L/h for Ac-5-ASA. Treatment-emergent adverse events (TEAEs) were reported by 19.2% of pts; no new safety signals were identified. Events were similar among age and dose groups, and no TEAEs led to premature discontinuation. Conclusion The PK profiles of 5-ASA and Ac-5-ASA in children and adolescents with UC receiving multimatrix mesalazine across all dose levels were similar to those from historical adult data with respect to absorption, clearance, and intersubject variability. Overall, multimatrix mesalazine was well tolerated with no new safety concerns identified. Disclosure of interest C. Cuffari Consultant for: Shire, Prometheus, Abbott Nutrition, D. Pierce Shareholder of: Shire, GlaxoSmithKline, Employee of: Former employee of Shire, B. Korczowski Grant/Research Support from: Shire, K. Fyderek Grant/ Research Support from: Shire, H. Van Heusen Shareholder of: Shire, Employee of: Shire, S. Hossack Employee of: Covance, which received funding from Shire, P. Martin Shareholder of: Shire, Employee of: Shire. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01130844&atom=%2Fgutjnl%2F64%2FSuppl_1%2FA101.1.atom

Introduction From January 2014 the Department of Gastroenterology at York Hospital introduced evidence based guidelines for the use of faecal calprotectin (FC) in monitoring patients with Crohn’s disease (CD) established on a management plan. These are summarised: FC FC 100–250: likely mild or quiescent disease. Manage patient expectantly in the first place and re-test at 6 months. FC >250: likely active disease. Repeat FC and if >250 again consider treatment escalation or re-investigation. Repeat FC 3 monthly after re-establishing management plan. Method An audit of these guidelines was registered with the Clinical Audit and Effectiveness Team. The negative and positive predictive values (NPV and PPV) of these guidelines at 1 year has been determined. Results Demographics: 106 patients have been entered into the audit. Compliance is 87%. Disease location (%): ileal 20, colonic 20, ileocolonic 60, perianal 8, upper GI 4. Previous surgery: 48%. Established therapy (%): none 20, mesalazine 15, azathioprine/6-mercaptopurine 35, methotrexate 5, infliximab 12, adalimumab 12, dual immunomodulation 13. 76% patients were clinically asymptomatic. With a FC cut off set >250: NPV for active CD was: 0.89 (0.77–0.95) and PPV: 0.91 (0.79–0.97). FC FC100–250: of 15 evaluated 4 patients became symptomatic within 6 months. For the asymptomatic remainder FC was stable in 15%, reduced in 15% and increased in 70% at 6 months. FC >250: of 43 evaluated the repeat FC remained >250 in 35 patients. 28 were investigated of whom 24 had active CD. 28 patients had treatment escalation but only 1 required bridging steroid. 2 patients had resections. 73% of those re-evaluated now have a repeat FC Conclusion This interim analysis confirms the applicability of these guidelines. Such a model is ideally suited to a nurse specialist service, identifying those patients that can be managed expectantly without recourse to invasive or expensive investigation and those that require proactive intervention before becoming symptomatic. The key elements to these guidelines are: a traffic light system of risk assessment, the confidence interval between repeat FC assessments, repeating the FC before acting if >250 and recognising that FC monitoring does not replace clinical decision making. In conclusion such a model of FC monitoring has the potential to be safe, clinically- and cost-effective in those with CD established on a management plan. Disclosure of interest None Declared.

Editor, We read the papers by Barbara et al 1 and Lam et al 2 with interest. The authors reported the results of two randomised controlled trials (RCTs) of mesalazine in IBS. These are the largest studies examining the efficacy of this drug in IBS, to date, and the authors are to be applauded for conducting them. The efficacy of mesalazine in UC is undisputed.3–5 However, the observation that a subset of patients with IBS, particularly those with a post-infective aetiology, may demonstrate low-grade colonic mucosal inflammatory changes has led to a renewed interest in the use of the drug for this condition.6 …

A 57 year old Caucasian man presented with an eight week history of loose bowel motions 10 times daily, with blood, slime, and mucus. Sigmoidoscopy showed an abnormal vascular pattern and a granular mucosa. Rectal biopsy was reported histologically to show inflammatory bowel disease, and treatment was initiated with oral Asacol (mesalazine) 800 mg three times daily and Predfoam (prednisolone metasulphobenzoate sodium) enema twice daily. This treatment was continued over a period of about eight weeks, initially with some improvement but latterly relapsing to the pretreatment state. Fibreoptic colonoscopy was then performed, revealing inflammatory changes up to the distal sigmoid colon. Biopsies were suggestive of Crohn’s disease. Treatment was continued for a further three months without improvement. The patient decided on his own initiative to stop …

Introduction Mesalazine has traditionally been administered in divided doses, but there is emerging evidence that once daily dosing is no less effective and may improve treatment adherence. Methods The Colitis Once Daily Asacol® (CODA) study was designed to assess the efficacy and safety of once daily dosing with Asacol® 2.4 g given as 3 × 800 mg tablets (OD) in comparison with three times daily dosing (one 800 mg tablet three times daily) (TDS). Adult UC patients taking mesalazine or sulphasalazine in remission for >4 weeks and Results 213 patients were recruited in 32 UK centres. Groups were well matched. There was no difference in adverse events between OD and TDS groups. Primary analysis confirmed non-inferiority of once-daily dosing. In a secondary analysis, (table 1) both ITT and per protocol (PP) populations demonstrated superiority of OD versus TDS dosing which was statistically significant. A multivariable analysis of baseline factors predicting relapse will be presented. Self-reported adherence at 12 months or relapse was >90% in 97% of patients (OD group) and 85% (TDS group). When asked how easy it was to remember to take tablets, it was reported to be very or fairly easy in 98% (OD group) versus 73% (TDS group). Conclusion Once daily dosing with Asacol ™ 2.4 g is as safe and effective as three times daily dosing, and secondary analysis confirmed significantly reduced relapse rates. The benefit was, however, clinically borderline and may relate to ease of adherence.

We thank Dr Ford for his comments1 on our recent paper in Gut entitled ‘Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy multi-centre trial’.2 With regard to our power calculation assuming a difference in treatment effect of 35% in favour of azathioprine, although two previous …

Introduction Disease flare in ulcerative colitis (UC) can result in substantial cost implications to the NHS. While the costs associated with treatment and management of UC are well-documented, estimates of the cost of flare are lacking. A cost analysis was performed to construct a model to estimate the costs associated with managing a flare across variable pathways. Methods A decision tree model was developed in Excel to estimate the direct medical costs of flares of various clinical severity. Within the model, the baseline UC patient cohort was maintained on Asacol ® (mesalazine) at a maximum dose of 2.4 g/day. Simplified care pathways were mapped, assuming that patients would either be treated and managed in primary care, or as an outpatient, or admitted to hospital. Taking a conservative approach, costs for surgery and other procedures e.g., stoma care were excluded as these outcomes are rare and inclusion would significantly increase average flare cost estimates. Treatment and management strategies were based on best practice guidelines, published data sources and clinical expert opinion. Drug costs were calculated using the British National Formulary (BNF) and healthcare management costs were based on published unit costs. The relative proportions of patients likely to follow each route of the treatment pathway were estimated and weightings were applied to enable calculation of an average cost of flare. Results The estimated annual cost to manage a patient with UC in remission was £955. The estimated cost to control a flare in primary care was £175 and for secondary care outpatient management was £578. For secondary care inpatient management, the estimated cost was £3488. If a biologic/ciclosporin was needed, the estimated cost rose to £4272. All costs were inclusive of clinical investigations and treatment reviews. The proportions of patients managed via each pathway were applied to calculations resulting in an estimated average cost of flare of £984. Conclusion A model was developed, based on simplified decision tree pathways to enable estimation of the cost of flare in UC. Depending on the severity of the flare episode, costs ranged from £175 to £4272. In the future, this model can be used for economic evaluations of interventions to reduce the risk of flare in UC and to help understand the costly aspects of managing ulcerative colitis. Disclosure of Interest A. Bassi Speaker bureau with: Warner Chilcott (UK) Ltd, K. Tolley Consultant for: Warner Chilcott (UK) Ltd, G. Wiseman Employee of: Warner Chilcott (UK) Ltd, S. Shaw Consultant for: Warner Chilcott (UK) Ltd.

Introduction The rising incidence of IBD, young age of onset and chronic nature mean that IBD has significant cost implications with the National IBD Audit estimating that cost to the National Health Service (NHS) exceeded £1 billion in 2010. The recent introduction of Clinical Commissioning Groups has also changed the way in which healthcare is paid for. This model is designed to be used by both commissioners and individual gastroenterology units to calculate the annual cost per patient of treating Ulcerative Colitis (UC) and Crohns Disease (CD) and to enable areas of potential cost savings to be explored. Methods The cost of care for IBD was calculated by summing the costs of treatment, treatment side effects and disease-related complications, accounting for the proportions of patients incurring these costs. Default input values for costs, the percentage of patients receiving each treatment, and the percentage of patients experiencing side effects or complications were determined from sources such as the British National Formulary (BNF), National Institute for Clinical Excellence (NICE), NHS trusts and published literature. However, an important feature of the model was its customisability allowing users to input local data, thereby generating costs which were unique and precise for that unit. Results Using default input values, the annual cost of treating any UC patient was estimated to be £3,084. For a UC patient in remission, in relapse with mild-to-moderate UC or in relapse with severe UC, annual cost per patient was estimated to be £1,693, £2,903 and £10,760, respectively. The annual cost for any CD patient was estimated to be £6,156 (£1,800 for patients in remission; £10,513 for patients in relapse). However, inputting local data would show some variability in the costs from trust to trust. Annually £743.65 was spent per UC patient on mesalazines. The model allows exploration of the cost savings if the percentage of patients on each brand of mesalazine was altered. When the percentage of relapsing CD patients on adalimumab was increased from 5% to 10%, the annual cost per relapsing CD patient rose from £10,513 to £11,032. The overall annual cost for any CD patient rose from £6,156 to £6,416. Increasing the percentage of mild-to-moderate UC patients on leukapheresis from 0.5 to 8% increased the annual cost per mild-to-moderate patient from £2,903 to £3,352, and the annual cost for any UC patient from £3,083 to £3,263. However, assuming that increased use of leukapheresis would cause a decrease from 20% to 15% in the annual proportion of patients experiencing acute severe flares, the annual cost for any UC patient fell to £3,078. Conclusion This model facilitates calculation of local annual costs per UC and CD patient, and allows areas to be identified where savings could be made. Disclosure of Interest: None Declared.

Introduction “Immune activation” has been described in the mucosa of IBS-D patients which Mesalazine (M) could suppress. Our main aim was to compare the effect of M versus placebo (P) on stool frequency. Secondary endpoints were abdominal pain, stool consistency and satisfactory relief of IBS symptoms. Methods All patients were required to have daily stool frequency of ≥3/day for more than 2 days/week for 2 weeks and stool consistency of ≥25% type 5–7 and ≤25% type 1–2 according to the Bristol Stool Form Scale. Subjects were randomised to either 2g M/ P for a week, to increase to 2 g twice/day for remaining 11 weeks if tolerated. All participants completed a 12-week stool diary. Since we expected M would require >2 months exert its effect, all primary and secondary outcomes were based on the stool diary completed during week 11–12. Satisfactory relief of IBS symptoms was defined as answering ‘yes’ to weeks 11 and 12 of the stool diary Results 136 subjects with IBS-D, meeting the Rome III criteria, were randomised to the 2 groups. Mean (SD) age was 47.1 (13.5) years in P and 42.6 (15.2). Treatment compliance for P and M were similar, 59% and 58% respectively. Analysis by intention to treat showed M did not improve bowel frequency, abdominal pain and stool consistency compared to P during week 11–12. Treatment did not affect satisfactory relief of IBS symptoms, HAD, PHQ15 and EQ-5D VAS scores compared to P. See table below for results. Conclusion This study did not show any clinically meaningful benefit or harm of M compared to P in this group of IBS-D patients. We need better phenotyping/ biomarkers for IBS patients to allow targeting of effective treatments. Disclosure of Interest C. Lam: None Declared, W. Tan: None Declared, M. Leighton: None Declared, J. Williams: None Declared, A. Agrawal: None Declared, S. Sen: None Declared, S. Foley: None Declared, M. Rutter: None Declared, A. Ramadas: None Declared, P. Whorwell Grant/research support from: Danone, Almirall, Shire, Boehringer Ingelheim UK, Sucampo, Saliz, Chr-Hansen and Norgine, Consultant for: Danone, Almirall, Shire, Boehringer Ingelheim UK, Sucampo, Saliz, Chr-Hansen and Norgine, A. Montgomery: None Declared, R. Spiller Grant/research support from: Lessaffre, Ironwood, Consultant for: Almirall, Astellas, Danone and Sanofi, Conflict with: free drug for clinical trial from Norgine.

Introduction Immunomodulator therapy is commonplace in the management of inflammatory bowel disease, IBD. The European Crohn’s and Colitis Organisation, ECCO, published guidelines in 2009 recommending every patient with IBD be considered for varicella, human papilloma virus, influenza, pneumococcal and hepatitis B vaccination. This study examines current immunisation practices in an IBD population at a District General Hospital. Methods 100 consecutive patients with IBD attending general gastroenterology outpatient clinics were asked to complete a questionnaire. All subtypes of IBD were included. Information regarding IBD related medication, recent infections and immunisation status were collected. The results were analysed using the statistical package for the social sciences, SPSS software. Results 100 questionnaires were collected; 3 were excluded, 2 due to duplication of patients, 1 was submitted blank. The patients’ median age was 52 (17–86), with a male to female ratio of 36:64%. Of IBD subtypes, 52 had Crohn’s disease, CD, 42 ulcerative colitis, UC, and 3 had colitis of undetermined type or aetiology, CUTE. 91 (94%) of patients had been on prescribed medication for IBD in the last 6 months. Of those, a majority (69%) had taken mesalazine, nearly half (42%) thiopurines, a quarter (24%) steroids and 15% anti tumour necrosis factor, anti-TNF. Of the 97 patients, 64% had been on an immunosuppressing medication in the previous 6 months, 29% of which reported having had an infection in the preceding 12 months. Chest and urinary tract infections were the most commonly reported in 33% and 22% of those reporting an infection respectively. 39% of patients on immunosuppressants reported a doctor discussing vaccinations with them. 74% of immunosuppressed patients had received an immunisation of any sort. 92% of these had received influenza vaccine, 40% Pneumovax, 21% hepatitis B vaccination, and 1 (2%) human papilloma virus. Of note, all patients who reported a chest infection had received the influenza vaccine and two thirds had received Pneumovax. Conclusion A significant number of patients diagnosed with IBD will require immunosuppressing medications at some point during their care. Despite ECCO guidelines advising all patients with IBD be considered for a vaccination program at initial diagnosis, only three quarters had received any vaccinations whatsoever. Interestingly, in our small cohort, influenza and pneumococcal vaccinations did not seem to protect against self reported chest infections. Traditionally the role of vaccination has been seen as a function of primary care. Increasing awareness of the need for vaccination in primary care may improve adherence. Ultimately, with the increasing use of immunomodulators and their inherent infection risks, perhaps more responsibility should be taken on by the IBD clinician? Disclosure of Interest None Declared.

BACKGROUND—Balsalazide is a new 5-aminosalicylic acid (5-ASA) containing prodrug. Its efficacy in comparison with standard mesalazine therapy and the optimum dose for maintaining remission of ulcerative colitis are still unclear. AIMS—To compare the relapse preventing effect and safety profile of two doses of balsalazide and a standard dose of Eudragit coated mesalazine. METHODS—A total of 133 patients with ulcerative colitis in remission were recruited to participate in a double blind, multicentre, randomised trial: 49 patients received balsalazide 1.5 g twice daily, 40 received balsalazide 3.0 g twice daily, and 44 received mesalazine 0.5 g three times daily. Efficacy assessments were clinical activity index (CAI) and endoscopic score according to Rachmilewitz, and a histological score. In addition, laboratory tests were performed and urinary excretion of 5-ASA and its metabolite N-Ac-5-ASA was analysed. The study lasted for 26 weeks. RESULTS—Balsalazide 3.0 g twice daily resulted in a significantly higher clinical remission rate (77.5%) than balsalazide 1.5 g twice daily (43.8%) and mesalazine 0.5 g three times daily (56.8%) (p=0.006). The respective times to relapse were 161 days, 131 days (p=0.003), and 144 days (NS). Accordingly, pairwise contrasts of the final endoscopic score demonstrated a significant difference (p=0.005) between the two balsalazide treatment groups while differences between either of these two groups and mesalazine were not statistically significant. Patients treated with balsalazide excreted less 5-ASA and N-Ac-5-ASA than patients receiving mesalazine but these differences were not statistically significant. Discontinuation of the trial because of adverse effects occurred in nine patients: three in the balsalazide 1.5 g twice daily group, two in the balsalazide 3.0 g twice daily group, and four in the mesalazine 0.5 g three times daily group. No clinically important new drug safety related findings were identified in this study. CONCLUSIONS—High dose balsalazide (3.0 g twice daily) was superior in maintaining remission in patients with ulcerative colitis compared with a low dose (1.5 g twice daily) or a standard dose of mesalazine (0.5 g three times daily). All three treatments were safe and well tolerated. Keywords: balsalazide; mesalazine; aminosalicylic acid; ulcerative colitis

The main disadvantage of surgery for Crohn's disease is postoperative recurrence of disease even when all macroscopically involved bowel is removed. Risk factors for early recurrence are ileal or ileocolonic resection with ileocolonic anastomosis, heavy smoking, especially in females, and perforating type of disease. Within weeks to months after resection, new lesions can be visualised endoscopically just proximal to the ileocolonic anastomosis that will later evolve to full blown Crohn's disease. The placebo group in controlled recurrence prevention trials yielded symptomatic recurrence rates of about 20% at one year and 40% at two years. Subsequently there is a 10% increase in symptomatic recurrence per follow up year. Strategies to prevent recurrence of Crohn's disease after ileocolonic resection have been largely unsuccessful to date. The current trial by Loch et al is the largest trial to date using a 5-aminosalicylic acid (5-ASA) formulation for prophylaxis of Crohn's recurrence. All patients entered the study within 10 days after resection and received a high dose (4 g) of the sustained 5-ASA release formulation Pentasa. The overall results show clearly that 5-ASA formulations are not effective in preventing symptomatic recurrence up to 18 months after surgery. The positive results in the subgroup of patients with Crohn's disease involving the small …

I read the study performed by Reinisch and colleagues with interest.1 As the authors state, the optimum strategy for the treatment of Crohn's disease following intestinal resection remains uncertain, with conflicting evidence for use of mesalazine,2 3 and only limited data to suggest that 6-mercaptopurine (6-MP) or azathioprine are more effective than placebo4 5 in terms of the prevention of either clinical or endoscopic relapse of disease activity. Reinisch et al are therefore …

An example of acute pancreatitis developing five weeks after initial treatment with 5-aminosalicylic acid (5-ASA) and methylprednisolone for severe Crohn's disease is reported in a 37 year old female patient. She had undergone cholecystectomy for gall stones some years earlier. There was no evidence of acute or chronic pancreatitis. No morphological changes of the upper gastrointestinal tract were found except for some irregularity of the main pancreatic duct and the secondary ducts on endoscopic retrograde pancreatography. Rechallenge with 5-ASA did not induce recurrent pancreatitis or changes in pancreatic enzymes. This case report supports the concept of an association between acute pancreatitis and Crohn's disease.

Decreased cell mediated cytotoxicity occurs frequently in inflammatory bowel disease, particularly in patients with active disease. It is not clear, however, whether this decrease is caused by the disease or is a consequence of the medical treatment. In this study we evaluated the effect of in vivo treatment with 5-aminosalicylic acid and sulphasalazine on the in vitro natural killer cell activity in five patients with inflammatory bowel disease in remission and in four healthy control subjects in a double blind randomised crossover trial preceded and separated by four weeks of treatment with placebo. The natural killer cell activity was significantly impaired in 67% (six of nine subjects) after four weeks' sulphasalazine treatment and tended to be related to subjects with a slow acetylator phenotype. In contrast, 5-aminosalicylic acid treatment caused only a marginal reaction in the natural killer cell activity in 22% (two of nine subjects). The inhibitory effects were found to be reversible since the decreased natural killer cell activity was completely restored after placebo treatment in all subjects. In conclusion, in vivo treatment with sulphasalazine inhibits the in vitro natural killer cell activity and this seems to be mediated by the sulphapyridine moiety. This phenomenon may contribute to the low natural killer cell activity found in patients with active inflammatory bowel disease.

Background—Daily administration of rectal formulations of mesalazine is effective in preventing relapse of ulcerative proctitis. Maintenance of remission with lower doses would be an advantage.Aim—The efficacy of mesalazine suppositories (Pentasa) 1 g three times a week v placebo to maintain remission in patients with cryptogenetic proctitis was studied.Methods—Ninety five patients with cryptogenetic proctitis were randomised within two weeks of remission to receive for one year or until relapse three suppositories per week of either Pentasa (n=48) or placebo (n=47). In the case of a relapse, the patients received one suppository/day.Results—It was found that 25 of 48 subjectsv 18 of 47 remained in remission in the mesalazine and placebo groups respectively. The relapse rate was lower in the mesalazine group for the following time intervals: 0–90 days (19%v 38%, p=0.035), 0–180 days (29% v 54%, p=0.017), 0–270 days (38% v 60%, p=0.031), and 0–365 days (48% v 62%, p=0.18). Treatment of relapse with one suppository/day induced remission in 11 of 18 and 2 of 26 patients in the mesalazine and placebo groups respectively (p=0.001). Overall, 61%v 28% patients remained in the protocol and were in remission at one year (p=0.001). Tolerance was good.Conclusion—Mesalazine suppositories 1 g three times a week are effective for preventing relapses of cryptogenetic proctitis. Increasing the dose to 1 g/day is effective in a high proportion of subjects who relapsed.

A 55 year old man with chronic hepatitis C presented with diarrhoea and bloody stools in July 2003. Colonoscopic examination showed redness and oedematous mucosa in the rectum and ulcerative colitis was suspected. Biopsy of the lesion confirmed the diagnosis and treatment was initiated with mesalazine (5-ASA 2250 mg/day). However, he showed short term improvement and mesalazine was discontinued. He was treated with percutaneous radiofrequency ablation therapy (RFA)(Cool-tip) for adenomatous hyperplasia in S5 of the liver in December 2004. After providing consent to treatment with interferon (IFN), the patient underwent combination therapy with PEG-IFNα-2b (100 mg/week) and ribavirin (800 mg/day) for chronic hepatitis C. Liver biopsy and blood biochemistry revealed chronic active hepatitis C virus (HCV) F3/A2, genotype 1b, liver injury associated with HCV, aspartate aminotransferase (AST) 109 IU/l, alanine aminotransferase (ALT) 126 IU/l, and HCV RNA 3400.0 KIU/ml (by reverse transcription nested polymerase chain reaction, high range method). One …

Introduction Clostridium difficile (CD) colitis is a major complication of antibiotic therapy. The most widely used test for diagnosing C. difficile colitis is a test that detects toxins produced by CD in a stool sample. Flexible sigmoidoscopy (FS) or colonoscopy can show the characteristic pseudomembrane plaque appearance in about half of affected patients. It is usually performed if rapid diagnosis is needed or in a patient who has ileus. However, some patients with CD colitis will have pseudomembranes only in the right colon. Our aim was to assess whether patients, with confirmed CDAD, had their management altered following FS. Methods A single centre, retrospective analysis of patients who had a FS with stool culture confirmed CDAD admitted to our CD ward (CDW) over 7 years (March 2005–2012) was performed at a district general hospital in North London. The medical notes, endoscopy database and electronic results of patients on CDW undergoing FS was scrutinised. Results 18 patients on CDW had a FS during the study period. 2 patients were excluded as they were found to be CD negative. 16 of the 1535 (1.04%) patients diagnosed with CDAD at our hospital during this period had a FS. The mean age was 74.1 (range 37–93) with 6 males. FS was requested 27 days (range 1 – 100) and the procedure was performed 40 days (range 10–110) after the diagnosis of CD was made. The indications were persistent diarrhoea in 82% (13/16), bleeding PR 6% (1/16), abnormal CT scan 6% (1/16) and previous CMV colitis 6% (1/16). 8(50%) patients had a normal FS, 2(13%) had pseudomembranous colitis, and 1 (6%) patient each had adenocarcinoma, colonic polyps, diverticulosis and infective colitis. 2 (13%) patients were newly diagnosed to have ulcerative colitis and were started on mesalazine and steroids along with CD treatment. Conclusion In this study only a small proportion of patients (1.04%) with CDAD underwent FS. However, when FS is performed in patients with CDAD with persistent symptoms it aids in clarification of the diagnosis with an abnormal FS noted in 50% of patients. From our observation we would recommend FS in CDAD if symptoms persist despite treatment due to the high positive findings at FS. Disclosure of Interest None Declared

Introduction The aetiology of microscopic colitis remains unknown. We have previously reported our experience of microscopic colitis diagnosed in our region between 1999 – 2004(1). Although data continue to emerge, the natural history of microscopic colitis remains unclear. Furthermore, there are reports of macroscopic changes in the mucosa at endoscopy. Methods Cases from 2004–2011 were identified from pathology records. Case notes were retrospectively reviewed and data extracted including subtype of microscopic colitis and clinical details where possible. Results 82 case notes were obtained and reviewed. 8 cases did not have a clear diagnosis and were excluded. Of the remaining 74 cases, 56 were collagenous colitis, 18 lymphocytic colitis. 17 patients had macroscopic abnormalities (excluding diverticulosis) at endoscopy; 16 of these in the collagenous colitis group, representing 28% of this subgroup. The mean age was 46.1 (range 33–87), female: male ratio of 4.3:1. 18 reported an autoimmune condition including 2 coeliac disease and 7 hypothyroidism. 30(40%) were on a proton pump inhibitor at the time of diagnosis and 15(24%) were on non-steroidal anti-inflammatories. Follow up data was available for 66 patients. Of these 47(71%) reported complete resolution of symptoms and 15(22%) partial resolution. 5(7%) did not respond in the follow up period. Therapeutic strategies included either alone or a combination of stopping/switching PPI, loperamide, mesalazine and steroids. 24/47(65%) of complete responders required simple intervention (PPI withdrawal, switch in brand of PPI, loperamide or even spontaneous resolution) whereas 10/47(21%) required steroids. 7/15(47%) partial responders received steroids. Conclusion Since microscopic colitis was last studied in our region, the female predominance has increased, the mean age has dropped by almost 20yrs, and the ratio of collagenous : lymphocytic colitis has increased from 2:1 to 3:1. This could represent a change in the number of younger people investigated or missing data in our cohort. A significant number of patients with a diagnosis of collagenous colitis had endoscopic abnormalities in comparison to the lymphocytic colitis group, which does raise the question of the nomenclature. The majority of patients have complete resolution of symptoms with simple intervention. Disclosure of Interest None Declared. Reference Microscopic Colitis in Tayside: Clinical features, associations and behaviour. Mowat C, Heron T, Walsh S. Gastroenterology 2005: 128 (4); A331

Introduction Faecal calprotectin (FC) has become a useful marker of mucosal healing, with studies showing raised levels predictive of relapse 1,2,3 . These studies did not assess mucosal healing however, so did not compare calprotectin with mucosal appearance as predictors of relapse. Methods In the CODA (Colitis Once Daily Asacol®) trial of once daily (OD) Asacol® (three 800 mg tablets) vs one 800mg tablet taken three times daily (TDS), 213 UC patients in remission for >4 weeks, but relapse in the past 2 years, were recruited. Baseline FC (Phical ELISA kit) was collected and rectal sigmoidoscopy (sig) score at baseline, and relapse or 1 year (using the modified Baron score: 0 = normal; 1 = erythema, decreased vascular pattern; 2 = marked erythema, absent vascular pattern, friability, erosions; 3 = spontaneous bleeding, ulceration). At entry patients had no symptoms of active disease, with a sig score of 0 or 1. Follow-up was for 1 year or until relapse (symptoms of active disease with a sig score of 2 or 3). Demographic factors, concomitant drugs, FC, sig score, CRP, and adherence were evaluated in a Cox regression model of time to relapse. Results (Shown as median[IQR] unless stated otherwise). Remission duration prior to entry was 6.0 [3–12] months. Disease extent was extensive (30.0%), Lt. sided (54.9%), proctitis (13.6%). At entry FC was 78mg/kg stool [23.3–159.4], sigmoidoscopy score 0 (70.9%), 1 (29.1%). All were taking mesalazine, and 11.7% thiopurines. Baseline FC was higher if sig score was 1 (109[38–335]) than if 0 (62[21–120], p = 0.001, but did not differ according to disease extent or medication (including aspirin (n = 18) and occasional NSAIDs (n = 6). Remission rates at one year were 62% overall (68.9% in OD and 55.5% in TDS group). Factors associated with time to relapse were explored in a Cox proportional hazards model, with baseline FC dichotomised at 150mg/kg stool (as by Costa et al . Relapse risk was 2.5 times higher in those with baseline sig score 1 compared to score 0 (95% CI 1.32–4.76, p = 0.005). Age, concomitant medication, previous duration of remission, disease extent, smoking, trial medication adherence and baseline FC (cut off at 150 mg/kg stool or as a continuous variable) did not remain in the final model. Conclusion In this study, sigmoidoscopy appearance at baseline was the sole factor predicting relapse over 1 year of maintenance mesalazine 2.4g, whereas calprotectin level was not a predictor, perhaps because of wide variability in this group of patients. FC may have more value in measuring relative change in individual patients. Disclosure of Interest A. Hawthorne Grant/Research Support from: CODA study supported by unrestricted grant from Warner Chilcott, D. Gillespie: None Declared, C. Probert: None Declared References Gisbert IBD 2009; 15:1190. Tibble Gastroenterol 2000; 119:15. Costa Gut 2005; 54:364.

BACKGROUND: Data on collagenous colitis have been based on a limited number of patients. AIMS: To obtain more information on this disease from a register set up at Orebro Medical Center Hospital. PATIENTS AND METHODS: Twenty five Swedish hospitals have contributed to this patient register, which comprises 163 histopathologically verified cases. Clinical data were retrospectively analysed. RESULTS: Collagenous colitis followed a chronic intermittent course in most cases (85%) with a sudden onset in 42%. Symptoms were chronic watery diarrhoea, often nocturnal (27%), abdominal pain (41%), and weight loss (42%). Sixty six patients (40%) had one or more associated diseases. Routine laboratory data were mostly normal. The median age at diagnosis was 55 (range 16-86) years, but 25% of the patients were younger than 45 years. Seven patients died of unrelated diseases. The response rate for sulphasalazine was 59%, and 50% and 40% for mesalazine and olsalazine. Prednisolone was most effective with a response rate of 82%, but the required dose was often high and the effect was not sustained after withdrawal. Antibiotics were efficient in 63%. Cholestyramine and loperamide had response rates of 59% and 71% respectively. CONCLUSIONS: Collagenous colitis follows a chronic continuous course. Symptoms can be socially disabling, but the disease does not seem to have a malignant potential. A plan for the treatment of a newly diagnosed patient with collagenous colitis is proposed.

To determine the incidence and severity of drug induced acute pancreatitis, data from 45 German centres of gastroenterology were evaluated. Among 1613 patients treated for acute pancreatitis in 1993, drug induced acute pancreatitis was diagnosed in 22 patients (incidence 1.4%). Drugs held responsible were azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine (ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin. Pancreatic necrosis not exceeding 33% of the organ was found on ultrasonography or computed tomography, or both, in three patients (14%). Pancreatic pseudocysts did not occur. A decrease of arterial PO2 reflecting respiratory insufficiency, and an increase of serum creatinine, reflecting renal insufficiency as complications of acute pancreatitis were seen in two (9%) and four (18%) patients, respectively. Artificial ventilation was not needed, and dialysis was necessary in only one (5%) case. Two patients (9%) died of AIDS and tuberculosis, respectively; pancreatitis did not seem to have contributed materially to their death. In conclusion, drugs rarely cause acute pancreatitis, and drug induced acute pancreatitis usually runs a benign course.

Introduction Colonic DUOX2 expression produces hydrogen peroxide, a reactive oxygen species (ROS), which is up-regulated in active ulcerative colitis (UC). Overproduction of hydrogen peroxide amplifies ROS-induced genetic damage and causes cellular transformation which may explain the increased colorectal cancer (CRC) risk associated with chronic UC. Mesalazine (5-ASA) has been shown to be chemo-preventative for UC associated CRC and scavenges ROS. Here, we aimed to identify and investigate the effect of 5-ASA on DUOX2 expression using human rectal cancer cell lines and mucosal tissue biopsies. Methods Mucosal biopsies were taken from 35 patients with UC and 24 patients with normal colons for in vivo experiments, and 24 patients with UC and 14 patients with normal colons for ex vivo experiments. Total RNA was extracted and quantitative real-time PCR used to calculate expression of DUOX2. Cytometric bead array technology was used on ex vivo culture supernatants to measure cytokine profiles. In situ hybridisation for DUOX2 expression was performed on sections from eight matched pairs of non-inflamed/inflamed biopsies and five matched pairs of non-inflamed/inflamed/dysplasia biopsies from UC patients. Human rectal cancer cells were used for quantitative real-time PCR, with multiparameter flow cytometry utilised to measure hydrogen peroxide levels, apoptosis, DNA damage and cell proliferation. Results DUOX2 is expressed throughout the colonic epithelium, is upregulated in active compared to quiescent ulcerative colitis and also in areas of UC associated dysplasia. In the setting of intestinal inflammation, but not in quiescent disease, 5-ASA enhances DUOX2 expression in vivo and ex vivo. As expected, 5-ASA was found to suppress cytokine (IL-6 and IL-8) production during an inflammatory flare and to maintain low cytokine levels during remission. The addition of 5-ASA in vitro led to upregulation of DUOX2 and elevated levels of hydrogen peroxide, DNA damage and apoptosis. These effects were further enhanced in a setting of hypoxia. Conclusion We have shown that 5-ASA over stimulates DUOX2 expression in the setting of inflammation and hypoxia, but not in quiescent disease. Importantly, this suggests that during a flare 5-ASA could act as a carcinogen rather than a chemo-preventative drug. Further investigations to confirm the functional relevance of DUOX2 up-regulation in the colonic mucosa of patients with active UC is indicated. Competing interests T Macfie Grant/Research Support from: SHIRE, A Parker: None declared, A Nijhuis: None declared, T Boitsova: None declared, N Suraweera: None declared, R Jeffery: None declared, R Poulsom: None declared, J Lindsay Grant/Research Support from: SHIRE, A Silver: None declared.

Introduction Painful symptomatic diverticular disease (SDD) is a common but poorly understood condition. Approximately 20% of patients with diverticulosis complain of pain, but there are currently no effective treatments. We have previously reported peripheral immune activation and alteration in colonic nerve function in SDD. Aims To test the significance of this immune activation by performing the first parallel design, double blind, randomised placebo controlled trial of an anti-inflammatory drug, mesalazine in SDD. Methods Patients with confirmed SDD underwent an unprepared flexible sigmoidoscopy and biopsies at baseline and after 12 weeks treatment, completing diaries of pain and bowel habit. They were randomised to receive 3 g per day of mesalazine (M) or identical placebo (P) for 12 weeks with follow-up visits at 2 & 4 weeks. RNA from sigmoid biopsies was analysed using a custom made gene card. Gene expression and changes in symptoms were assessed between baseline and final visits using Wilcoxon signed-rank test. Results 43 volunteers were recruited (F:M; 24:19), but 11 withdrew during the study resulting in 18 and 14 participants in the P and M groups respectively. M significantly reduced important inflammatory and pain genes including those involved in response to bacterial ligands (Abstract OC-119 table 1), changes not seen with P. M but not P significantly reduced the duration of abdominal pain (Median (range) (hrs/day) P group Pre 1.0 (0–5), Post 0.65 (0–4) p0.1919; M Group Pre 3.0 (0–20), Post 0.125 (0–5.5) p0.0413). Conclusion This pilot study suggests that mesalazine significantly alters many of the pathways mediating immune activation by bacteria thought to contribute to pain in SDD and may provide benefit for patients. However further larger studies are required to confirm these mechanisms and efficacy of mesalazine in this group. Competing interests J Smith grant/research support from: Wellcome Trust Training Fellowship, Conflict with: £17 000 Gift from Dr Falk Pharma for manufacture of medication for the study, D Humes: None declared, K Garsed: None declared, C Lam: None declared, A Zaitoun: None declared, A Bennett: None declared, J Scholefield: None declared, R Spiller: None declared.

Introduction Calcineurin inhibitors (CI), most commonly ciclosporin, may be used as salvage therapy in patients with refractory moderate-severe ulcerative procto-colitis (UC), who would otherwise require surgery. 1 However, use of CI may be limited by drug toxicity. For patients who have a good clinical response to ciclosporin but experience side effects, tacrolimus may be used as an alternative. 2 We report our experience with CI in patients with moderate-severe UC whom either failed, or were intolerant of, thiopurines and as an alternative to surgery. Methods NICE (January 2008) did not support the use of infliximab in patients with moderate-severe UC. 3 Our patients were offered the choice of surgery or treatment with CI. Clinical response was assessed by AWH in clinic. If ciclosporin (4–6 mg/kg/day in two divided doses) led to a clinical response but caused intolerable side effects, tacrolimus (0.1 mg/kg/day in two divided doses) was offered as an alternative. Failure of therapy prompted referral for surgery. Results 14 patients (8 female; mean age 38 [range 22–56] years) were treated with CI (13 ciclosporin, 1 tacrolimus). Ten of 14 (71%) patients had an initial clinical response to CI. Adverse effects were common (57%): nausea, paraesthesia, menstrual disturbance, maculopapular rash, hypertension (two patients) and renal dysfunction (one patient). Of the four patients who failed to respond to CI, three were referred for surgery and one patient is managed on mesalazine suppositories. A further four patients stopped treatment with CI due to adverse effects: two were referred for surgery and two were offered treatment with methotrexate. 6 (43%) of 14 patients responded successfully to CI and without side effects. 4 (30%) of these remain on CI: 3 on ciclosporin (mean duration of treatment 39 [range 19–71] months) and one patient on tacrolimus (duration of treatment 24 months); two patients stopped treatment with CI for reasons unrelated to efficacy or adverse effects (one to start a family and the other out of choice). Conclusion CI should be considered as an alternative therapy for patients with refractory moderate-severely active UC who would otherwise require surgery. CI can be used safely and effectively in the presence of an established evidence-based protocol to ensure safe prescribing and monitoring for adverse side effects. Competing interests None declared. References 1. Lichtiger S , Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Eng J Med 1994; 330 :1841–5. 2. Ogata H , Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006; 55 :1255–62. 3. Ulcerative colitis (subacute manifestations)–Infliximab (TA140) NICE.