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Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80.4% [95% CI 66.1-90.6]) of 46 patients in the infliximab-continued group and 25 (54.3% [39.0-69.1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26.1% (95% CI 7.7-44.5; p=0.0076) before adjustment and 27.3% (95% CI 8.0-44.1; p=0.0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3.9% [95% CI -10.3 to 18.1]; p=0.59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66.7%, 95% CI 34.9-90.1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.Background Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab.Methods We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092. Findings Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80.4% [95% CI 66.1-90.6]) of 46 patients in the infliximab-continued group and 25 (54.3% [39.0-69.1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26.1% (95% CI 7.7-44.5; p=0.0076) before adjustment and 27.3% (95% CI 8.0-44.1; p=0.0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3.9% [95% CI & minus;10.3 to 18.1]; p=0.59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66.7%, 95% CI 34.9-90.1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.Interpretation Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account.Funding Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan.Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Background Despite widespread adoption of potent acid suppression treatment with proton pump inhibitors (PPI) for reflux-like symptoms, persistent symptoms are commonly reported in primary care and community studies. Aims This multidisciplinary review critically evaluates how the management of reflux-like symptoms could better reflect their multifactorial pathophysiology. Methods A panel of experts (from general practice, gastroenterology and gastropsychology) attended a series of workshops to review current management and propose a framework for the provision of more individualised care. Results It was agreed that the perceptual (as well as the physiological) causes of reflux-like symptoms should be considered at the start of management, not as a last resort when all else has failed. A short course of PPI is a pragmatic approach to address reflux-like symptoms, but equally important is counselling about the gut-brain axis and provision of symptom-specific behavioural interventions for those who show signs of somatisation, hypervigilance or co-existing disorders of gut-brain interaction. Other low-harm interventions such as lifestyle and dietary advice, should also be better integrated into care at an early stage. Multidisciplinary care management programmes (including dietary, weight loss, exercise and behavioural intervention) should be developed to promote greater self-management and take advantage of the general shift toward the use of remotely accessed health care resources. Conclusions Management of reflux-like symptoms should be adapted to reflect the advances in knowledge about the multifactorial aetiology of these symptoms, addressing both acid-related and behavioural components early in management. The time has come to treat the patient, not the "disease".

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder which represents a major cost to healthcare services. IBS-D patients represent about one-third of the IBS population and are currently treated with antispasmodics, loperamide, bile acid sequestrants and antidepressants. Alosetron and rifaximin are also available in USA, ramosetron in Japan, Korea and Thailand and ondansetron as an off-label treatment.Areas covered: This article focuses on eluxadoline, a novel pharmacological agent that has recently been approved by both the FDA and EMA for treatment of patients with IBS-D.Expert commentary: The efficacy and safety of eluxadoline in treating bowel habit alterations and pain, both in the short and long-term, make the drug a welcome addition to our therapeutic alternatives in IBS-D. Its positioning in any IBS algorithm will depend on the ‘real world’ prevalence of the small risk of sphincter of Oddi spasm and mild pancreatitis.

Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders., This Consensus Statement provides a conceptual and methodological framework to expand research on colonic motility in experimental animals and humans. The work is intended to facilitate the development of new drugs for common colonic motility disorders and of appropriate diagnostic and therapeutic algorithms for the management of paediatric and adult patients.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder, which represents a major cost to healthcare services. Current pharmacological treatment includes fibre supplements, antispasmodics, laxatives, loperamide and antidepressants. This article reviews the novel pharmacological treatments already or recently approved for patients with IBS-C (lubiprostone, linaclotide) and IBS-D (alosetron, ramosetron, rifaximin, eluxadoline). Furthermore, results for drugs in development (plecanatide, ibudutant and ebastine) or used in chronic constipation or for other indications, with potential application in IBS (prucalopride, elobixibat, mesalazine, ondansetron and colesevelam) are also reviewed.

Background An altered anorectal function is reported after chemoradiotherapy (CRT) and surgery for rectal cancer. Aim The aim of this study was to clarify the relative contribution of neoadjuvant chemoradiation and surgical resection on the impairment of anorectal function as evaluated by anorectal manometry. Methods Thirty-nine patients with rectal cancer, who underwent neoadjuvant CRT and laparoscopic rectal resection, were evaluated with the Pescatori Faecal Incontinence score, and with anorectal manometry: before neoadjuvant therapy (T0), after neoadjuvant therapy and before surgery (T1), 12 months after stoma closure (T2). Results Resting and/or maximum squeeze pressure and/or volume thresholds for urgency were below the normal values in 12 (30%) patients at baseline. After CRT the mean resting pressure significantly decreased (p = 0.007). Surgery determined a significantly decrease of the resting pressure (p = 0.001), of the maximum squeeze pressure (p = 0.001) and of the volume threshold for urgency (p = 0.001). Impairment of continence was reported by 5, 11 and 18 patients at T0, T1 and T2, with a mean incontinence score of 3, 3.8 and 3.9 respectively. Conclusions CRT is detrimental to the function of the internal anal sphincter. Rectal resection significantly affects both internal and external anal sphincter function and the maximum tolerated volume of the neo-rectum, particularly in patients with low rectal cancer, significantly impairing anal continence.

Background: Only few studies have applied high-resolution manometry (HRM) to the study of colonic motility in adults and none of them have concurrently evaluated colonic and anal motor activity. Aims: To evaluate colonic and anal motor activity by means of HRM in healthy subjects. As the present study revealed the presence of a new colonic motor pattern (pan-colonic pressurizations) in healthy subjects, three additional studies were conducted: the first and the second to exclude that this motor event results from an artefact due to abdominal wall contraction and to confirm its modulation by cholinergic stimulation and the third, as pilot study, to test the hypothesis that this colonic pattern is defective in patients with chronic constipation refractory to current pharmacological treatments. Methods: In both volunteers and patients the HRM catheter was advanced proximally during colonoscopy. Results: In all subjects, pressure increases of 15±3 mmHg and 24±4s simultaneously occurring in all colonic sensors (pan-colonic pressurizations), associated with anal sphincter relaxation were identified. Subjects had 85±38 pan-colonic pressurizations which increased significantly during meal (p=0.007) and decreased afterward (p=0.01), and were correlated with feelings of and desire to evacuate gas. The mean number of propagating sequences was 47±39, and only retrograde increased significantly postprandially (p=0.01). Pan-colonic pressurizations differed from strain artifacts and significantly increased after prostigmine. In patients pan-colonic pressurizations were significantly reduced as compared to volunteers. Conclusions: Pan-colonic pressurizations associated with relaxations of the anal sphincter represent a new colonic motor pattern which seems to be defective in patients with treatment-refractory chronic constipation and may play a role in the transport of colonic gas and in the facilitation of the propagating sequences-induced colonic transport.

Background & Aims: Rectal motor hyperreactivity to distention may be involved in the pathophysiological course of defecatory symptoms in patients with irritable bowel syndrome (IBS), but results of patient studies are conflicting, possibly because of differences in the applied distention rate. Because a fast rate of distention increases the rectal motor response in healthy subjects, it also may show hyperreactivity in patients with IBS. The aim of this study is to compare the effects of 2 distention rates on rectal motor responses and sensations in 16 patients with IBS and 12 healthy subjects. Methods: Rectal distensibility and the frequency of rectal contractions and sensations were recorded during volume-controlled rectal distentions at 2 distention rates (10 and 100 mL/min). Results: Recta of patients with IBS were significantly less distensible than those of healthy subjects during fast distention ( P = 0.0006), but this difference was not statistically significant during slow distention ( P = 0.07). The frequency of rectal contractions and sensations, the majority of which were sensations of gas and a desire to defecate, were significantly greater in patients with IBS during both slow and fast distentions (both P Conclusions: Recta of patients with IBS are hyperreactive to distention, and fast distention magnifies this abnormal motor response. A greater frequency of sensations during a fixed-time distention period may help to characterize the patients.

With increasing chronic opioid use, opioid-induced constipation (OIC) is a rapidly increasing clinical challenge. Naloxegol, an orally administered, peripherally-acting, µ-opioid receptor antagonist, was developed for the treatment of OIC. This drug profile summarizes published information and presentations at meetings on the effects of naloxegol in OIC. In animal studies, naloxegol was able to inhibit gastrointestinal opioid effects while preserving central analgesic actions and human pharmacodynamic studies were in agreement with such mode of action. Phase II and Phase III studies in patients with non-cancer OIC confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. There were no signs of opioid withdrawal in these studies. Side effects were mainly gastrointestinal in origin, and usually transient and mild. A long-term safety study showed no new adverse events. The US FDA and EMA are currently evaluating the use of naloxegol in OIC.

Based on improvements of abdominal pain during treatment, more recently introduced drug treatments for constipation, tegaserod, lubiprotsone and linaclotide, sought and obtained approval for irritable bowel syndrome with constipation (IBS-C) as well. The aim of the current study was to determine whether the observed decreases in pain level were unique effects or a consequence of their laxative properties, which can also be seen in other agents. METHODS: The pubmed databank was searched for clinical trials in constipation and IBSC to identify publications that provided detailed data on changes in bowel movement frequency and pain intensity for time points before and after a therapeutic intervention. The results were abstracted and subjected to a meta-regression analysis. RESULTS: A total of 23 fully reported trials (9 IBS-C) met entry criteria. When normalized to a 5 point scale, pain ratings were higher in IBS-C 2.50 [2.32-2.68] compared to data obtained in studies on constipation (2.15 [1.96-2.33]; P=0.008), while weekly bowel movement frequency were lower in constipation with 1.95 [1.68-2.28] versus 2.75 [2.40-3.11] in IBS-C (P=0.006). Using changes in pain intensity as dependent variable, the meta-regression demonstrated a significant correlation between treatment-induced increases in bowel frequency and decreased pain ratings. CONCLUSION: This analysis of composite data suggests that the effective treatment of constipation decreases discomfort independent of specific drug mechanisms, thus arguing against an additional benefit of newer and often more costly medications.

G A A b st ra ct s overlapping (PD and ED) had the lowest scores in the 5 components of PAGI-QOL (P

Summary Background It is unclear whether decreased serotonin transporter function contributes to sensorimotor abnormalities in irritable bowel syndrome. Aim To study the influence of acute serotonin transporter inhibition on colonic sensorimotor function in man. Methods Ten healthy subjects (five men, aged 20–29 years) underwent a combined manometry/barostat study of the descending colon on two occasions. Stepwise distentions by 2 mmHg increments were performed until discomfort. Subsequently, placebo or citalopram 20 mg were administered i.v. over 20 min and distentions were repeated. Afterwards, isobaric tone measurements were performed 30 min before and 90 min after ingestion of a meal. High-amplitude propagated contractions, colonic motility index, colonic compliance, sensitivity and colonic response to a meal after placebo or citalopram were compared by t-test and two-way anova. Results Citalopram induced a significant increase in colonic motility index (5.6 ± 0.9 to 0.8 ± 1.9 mL*min, P

Background & Aims: Studies in health have shown that tension-sensitive mechanoreceptors mediate sensitivity to gastric distention. A role for these mechanoreceptors in perception or symptoms in hypersensitive functional dyspepsia (FD) has not been established. Tension-sensitive mechanoreceptors are activated during phasic contractions and inactivated during gastric relaxation. The aim of the present study was to investigate whether hypersensitive FD patients perceive spontaneous changes in fundic wall tension and whether fundus-relaxing drugs decrease sensitivity to gastric distention and meal-related symptoms. Methods: Fifty patients were selected after a barostat study established gastric hypersensitivity. In 12 patients, an intragastric balloon was inflated with a fixed volume just below perception thresholds and patients were asked to indicate changes in perception on a keypad, and the relationship between perception and contractions was analyzed. In 20 patients, we studied the influence of the fundus-relaxing drug sumatriptan on sensitivity to gastric distention. In, respectively, 10 and 8 patients, we studied the influence of the fundus-relaxing drugs sumatriptan and clonidine on meal-related symptoms. Results: The majority of patients had a statistically significant association between perception and phasic isovolumetric contractions. Pretreatment with sumatriptan increased both pressures and volumes needed to induce first perception and discomfort. Pretreatment with sumatriptan and clonidine both significantly decreased meal-induced symptoms. Conclusions: Patients with hypersensitivity to gastric distention perceive isovolumetric phasic contractions of the proximal stomach. Fundus-relaxing drugs decrease sensitivity to gastric distention and decrease meal-induced symptoms in these patients. The findings are compatible with involvement of tension mechanoreceptors in symptom generation in hypersensitive FD.

Epidemiological studies suggest considerable overlap between functional dyspepsia (FD) and irritable bowel syndrome (IBS).The aim of the present study was to investigate whether coexisting IBS is also associated with symptom pattern or pathophysiology in FD.In 309 consecutive FD patients (207 women, age 42 +/- 0.8 yr), questionnaires were used to assess the dyspepsia symptom pattern and the Rome II criteria for IBS. The overall symptom severity was calculated adding the severity score (0-3, 0 = absent, 3 = severe) of eight dyspepsia symptoms. All patients underwent Helicobacter pylori testing, gastric barostat to determine sensitivity to distention and accommodation to a meal, and gastric emptying breath test.Fifty-four percent of the patients had FD alone, whereas 46% had FD + IBS. FD + IBS patients were more likely to be female (75%vs 60%, p0.01) and to have a greater weight loss (5.4 +/- 0.6 vs 3.5 +/- 0.4 kg, p0.05). Coexisting IBS did not increase the risk of having any of the dyspeptic symptoms but the overall symptom severity was significantly higher in FD + IBS (12.4 +/- 0.4 vs 9.8 +/- 0.3, p0.01). FD + IBS patients had a lower threshold for first perception (2.9 +/- 0.3 vs 3.8 +/- 0.3 mmHg, p0.05) and for discomfort (7.9 +/- 0.4 vs 9.5 +/- 0.5 mmHg, p0.05) and a greater prevalence of hypersensitivity to gastric distention (44%vs 28%, p0.05). Gastric emptying, accommodation to a meal, and prevalence of H. pylori infection did not differ in the two groups.About half of the FD patients fulfill the Rome II criteria for IBS. FD + IBS is more prevalent in female patients and is associated with a higher weight loss, with greater overall symptom severity, and with hypersensitivity to distention.

Background: Handicapped patients with advanced neurological impairment and dysphagia require gastrostomy feeding and are associated with gastroesophageal reflux disease (GERD). Concurrent fundoplication is often recommended at the time of gastrostomy placement (GP) in those patients because of avoiding long-term anti-reflux medication or preventing future reflux symptoms. Fundoplication has recently been thrown doubts about its indication in those patients because of unignorable complications and the high incidence of recurrence of GERD. It was aimed in this study to conduct a retrospective review of the outcome of handicapped patients with GP alone. Methods: The subjects consisted of 60 profoundly handicapped patients requiring tube feeding, aged 1 yr to 33 yrs (median 9 yrs), who underwent GP alone. The operative criteria included no or medically controllable reflux symptoms. Operative procedure was laparoscopic in 53 and open in 7. They were divided into two groups based on % esophageal total time pH