Margaret Hastings

Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα

Objectives The postinfectious irritable bowel syndrome (PI-IBS) suggests that impaired resolution of inflammation could cause IBS symptoms. The authors hypothesised that polymorphisms in genes whose expression were altered by gastroenteritis might be linked to IBS with diarrhoea (IBS-D) which closely resembles PI-IBS. Design Part 1: 25 healthy volunteers (HVs), 21 patients 6 months after Campylobacter jejuni infection, 37 IBS-D and 19 IBS with constipation (IBS-C) underwent rectal biopsy for gene expression analysis and peripheral blood mononuclear cell cytokine production assessment. Part 2: Polymorphisms in genes whose expression was altered in Part 1 were assessed in 179 HV, 179 IBS-D, 122 IBS-C and 41 PI-IBS. Results Part 1: Mucosal expression of seven genes was altered in IBS: CCL11, CCL13, Calpain 8 and TNFSF15 increased while NR1D1, GPR161 and GABRE decreased with similar patterns after infection with C jejuni. Part 2: The authors assessed 21 known single nucleotide polymorphisms (SNPs) in these seven genes and one SNP in each of the TNFα and IL-10 genes. Three out of five TNFSF15 SNPs (rs6478108, rs6478109 and rs7848647) showed reduced minor allele frequency (MAF) (0.28, 0.27 and 0.27) in subjects with IBS-D compared with HV (0.38, 0.36 and 0.37; p=0.007, 0.015 and 0.007, respectively) confirming others recent findings. The authors also replicated the previously reported association of the TNFα SNP rs1800629 with PI-IBS which showed an increase in the MAF at 0.30 versus 0.19 for HV (p=0.04). Conclusion IBS-D and PI-IBS patients are associated with TNFSF15 and TNFα genetic polymorphisms which also predispose to Crohns disease suggesting possible common underlying pathogenesis.

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea

Background Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D. Methods 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment. Results Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001. Conclusions Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease

Background  Anxiety, depression and nongastrointestinal symptoms are often prominent in irritable bowel syndrome (IBS), but their relative value in patient management has not been quantitatively assessed. We modified the Patient Health Questionnaire 15 (PHQ‐15) by excluding three gastrointestinal items to create the PHQ‐12 Somatic Symptom (PHQ‐12 SS) scale.

A mechanistic multicentre, parallel group, randomised placebo-controlled trial of mesalazine for the treatment of IBS with diarrhoea (IBS-D)

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.

A mechanistic multi-centre, parallel group, randomised placebo controlled trial of Mesalazine for treatment of irritable bowel syndrome with diarrhoea (IBS-D)

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.

OC-091 Ondansetron slows transit and improves stool consistency in patients with diarrhoea predominant irritable bowel syndrome

Introduction 5-Hydroxytryptamine three receptor antagonists (5HT3RA) are effective in diarrhoea predominant irritable bowel syndrome (IBS-D), with a number needed to treat (NNT) for Alosetron of 7.1 Due to safety concerns (constipation [25%] and ischaemic colitis [0.1%]) Alosetron is not licensed in the UK. Ondansetron (OND) is a 5HT3 RA, widely and safely used for nausea, with constipation as a side effect. Methods We recruited 125 patients meeting the Rome III criteria from primary and secondary care to a two centre randomised, double-blind, placebo-controlled, crossover trial. Screening comprised of blood tests, rectal biopsy and a 1-week baseline Bristol stool form diary before randomisation to placebo (PLA) or OND for 5 weeks. Efficacy was optimised by dose titration during weeks 1–3 starting at 4 mg daily, increasing (max 8 mg three time a day) or decreasing as required. A 2-week washout preceded 5 weeks of the opposite therapy to that received in treatment 1. Symptom diaries including stool form, frequency, pain, bloating and urgency were completed daily. Transit using the Metcalf method was measured after each treatment period.2 The primary endpoint was the difference in average stool form between baseline and the last 2 weeks of each treatment. Stool consistency “responders” were defined as experiencing >50% reduction in the days/week with stool form 6 or 7. Analysis is presented by intention to treat. Results 80 women and 28 men completed the study (mean age 40.8, range 18–72, and 41.5, range 25–60). The mode dose of OND was <4 mg a day. Stool form improved significantly in the OND arm, mean change 1.4 (95% CI 1.2 to 1.6), vs 0.5 (95% CI 0.3 to 0.7) compared to PLA, p=<0.0001. Stool frequency improved on OND, mean 0.86 (95% CI 0.8 to 1.4), vs 0.44 (95% CI 0.4 to 0.89) on PLA, p=<0.01, as did urgency score 0.6 (95% CI 0.8 to 0.4) vs 0.3 (95% CI 0.5 to 0.2) p=<0.001. There were no significant improvements in pain or bloating. 74% of patients preferred OND while 26% preferred PLA or had no preference, χ2 p=<0.0001. 70% were “stool consistency responders” while taking OND compared with 33% taking PLA giving a NNT of 2.7. Whole gut transit slowed significantly while taking OND, 25 (13.5–47.5) h compared to 16 (7–29) h with PLA p=<0.001. 9% receiving OND complained of constipation compared to 2% on PLA, all but one responded to dose reduction alone. 2% withdrew because of constipation. There was no case of ischaemic colitis. Conclusion Using dose titration Ondansetron acts to slow whole gut transit and is highly effective in IBS-D with a low incidence of constipation. Competing interests None declared. References 1. Cremonini F. Neurogastroenterol Motil 2003. 2. Metcalf A. Gastroenterology 1987.