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Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.
Choy, MC, Seah, D, Faleck, DM, Shah, SC, Chao, CY, An, YK, Radford-Smith, G, Bessissow, T, Dubinsky, MC, Ford, AC, et al
Inflammatory bowel diseases. 2019;(7):1169-1186
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Abstract
BACKGROUND Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. METHODS Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. RESULTS Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. CONCLUSIONS In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.
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Acotiamide affects antral motility, but has no effect on fundic motility, gastric emptying or symptom perception in healthy participants.
Masuy, I, Tack, J, Verbeke, K, Carbone, F
Neurogastroenterology and motility. 2019;(4):e13540
Abstract
BACKGROUND Acotiamide, a prokinetic agent was shown to be efficacious in the treatment of functional dyspepsia (FD). The exact mechanism of action is incompletely elucidated. METHODS This randomized, placebo-controlled, cross-over study aimed to examine the effect of acotiamide on gastric motility, measured as intragastric pressure, gastric emptying (GE) rate and gastrointestinal (GI) symptom perception in healthy volunteers (HVs). Participants were treated with acotiamide (100 mg tid) and placebo for 3 weeks, separated by a 1-week washout period. A daily symptom diary was collected during both treatments. At the end of each treatment period, GE rate and gastric motility were assessed with a 13 C-octanoic acid breath test and high-resolution manometry during nutrient infusion, respectively. GI symptom levels were scored during high-resolution manometry. Data were analyzed using mixed models. The study was registered as NCT03402984. KEY RESULTS Twenty HVs (10 female, 25 ± 4.1 years, 22.58 ± 2.73 kg/m2 ) participated in the study. There was no difference in GE half time between both treatments (P = 0.92). Acotiamide had no effect on fundic pressures before and after nutrient infusion (P = 0.91). However, postprandial antral pressures remained significantly lower compared to placebo (P = 0.015). There was no significant difference in hunger, satiation and GI symptoms scores assessed during IGP measurement and by the daily diary (P > 0.12 for all). CONCLUSION Acotiamide is associated with lower antral pressures after nutrient intake, whereas it has no effect on fundic pressures, GE rate and symptom perceptions in HVs. Studies in FD need to elucidate whether lower antral pressures induced by acotiamide underlie postprandial symptom improvement in FD.
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Therapeutic drug monitoring with vedolizumab in inflammatory bowel disease.
Pugliese, D, Privitera, G, Pizzolante, F, Gasbarrini, A, Guidi, L, Armuzzi, A
Minerva gastroenterologica e dietologica. 2019;(4):280-290
Abstract
Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations <20 µg/mL at week 6 and >12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.
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Irritable bowel syndrome and colonic diverticular disease: overlapping symptoms and overlapping therapeutic approaches.
Alamo, RZ, Quigley, EMM
Current opinion in gastroenterology. 2019;(1):27-33
Abstract
PURPOSE OF REVIEW Irritable bowel syndrome (IBS) is a common symptomatic disorder in the Western world and colonic diverticula are also prevalent; however, relationships between IBS-type symptoms and diverticula have been a source of much debate. Our goal was to reassess these relationships in the light of new data. RECENT FINDINGS On removing from consideration clinical scenarios which are directly related to diverticula (i.e., diverticulitis, diverticular hemorrhage, and complications of diverticulitis, such as stricture and fistula), relationships between IBS and diverticula can be seen to revolve around a number of questions. First, are IBS and symptomatic uncomplicated diverticular disease (SUDD) the same condition? Or, in other words is SUDD no more than IBS in an individual who just happens to have diverticula? Although coincident IBS and diverticula inevitably do occur there is some evidence to indicate that SUDD may be somewhat distinctive with SUDD being characterized by more frequent and severe pain. Second, and analogous to interactions between IBS and inflammatory bowel disease or celiac disease, can an episode of acute diverticulitis lead to the de novo development of IBS? There is now epidemiological and pathophysiological evidence to support this occurrence. SUMMARY Although relationships between uncomplicated diverticular disease and IBS have been reexamined their status remains unclear. As yet, however, none of the newer concepts related to this relationship have led to new therapeutic approaches in IBS or diverticular disease.
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Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.
Banerjee, I, Salomon-Estebanez, M, Shah, P, Nicholson, J, Cosgrove, KE, Dunne, MJ
Diabetic medicine : a journal of the British Diabetic Association. 2019;(1):9-21
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Abstract
Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.
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Vedolizumab Therapy is Ineffective for Primary Sclerosing Cholangitis in Patients With Inflammatory Bowel Disease: A GETAID Multicentre Cohort Study.
Caron, B, Peyrin-Biroulet, L, Pariente, B, Bouhnik, Y, Seksik, P, Bouguen, G, Caillo, L, Laharie, D, Carbonnel, F, Altwegg, R, et al
Journal of Crohn's & colitis. 2019;(10):1239-1247
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Abstract
BACKGROUND Whether vedolizumab may be effective as a treatment for primary sclerosing cholangitis [PSC] in patients with inflammatory bowel disease [IBD] remains controversial. METHODS We performed a retrospective observational study of consecutive patients with IBD and PSC, treated with vedolizumab for at least 30 weeks in 22 centres of GETAID from January 2015 to June 2016. The outcomes included a decrease in the serum alkaline phosphatase [ALP] concentration of at least 50% from baseline to Week 30 or 54, a change in any serum liver enzymes concentrations, and an assessment of the efficacy and safety of vedolizumab in IBD. RESULTS Among 75 patients with active IBD and PSC treated with vedolizumab, 21 patients discontinued vedolizumab before Week 30 [due to lack of efficacy in 19 and malignancy in two patients]. In the remaining 54 patients, a decrease in the serum ALP concentration of at least 50% from baseline to Weeks 30 and 54 was observed in four [7%] and four [11%] patients, respectively. No significant change was observed in serum liver enzyme concentrations at week 30 or 54. After a median follow-up period of 19.4 [14.0-29.9] months, nine cases of digestive neoplasia [colorectal neoplasia in seven and cholangiocarcinoma in two] were reported. CONCLUSIONS In patients with IBD and PSC, vedolizumab did not improve serum liver enzyme concentrations at week 30 or 54. Nine cases of digestive cancer occurred during the follow-up period, confirming the need for a tight surveillance programme in this population.
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Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.
Naimi, RM, Hvistendahl, M, Enevoldsen, LH, Madsen, JL, Fuglsang, S, Poulsen, SS, Kissow, H, Pedersen, J, Nerup, N, Ambrus, R, et al
The lancet. Gastroenterology & hepatology. 2019;(5):354-363
Abstract
BACKGROUND Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. METHODS In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. FINDINGS Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. INTERPRETATION Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. FUNDING Zealand Pharma.
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Updates on the pathophysiology and therapeutic targets for hepatic encephalopathy.
Alsahhar, JS, Rahimi, RS
Current opinion in gastroenterology. 2019;(3):145-154
Abstract
PURPOSE OF REVIEW Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin). RECENT FINDINGS Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation). SUMMARY This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.
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Hepatic Encephalopathy Challenges, Burden, and Diagnostic and Therapeutic Approach.
Yanny, B, Winters, A, Boutros, S, Saab, S
Clinics in liver disease. 2019;(4):607-623
Abstract
Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with cirrhosis. The impact of HE on the health care system is similarly profound. The number of hospital admissions for HE has increased in the last 10-year period. HE is a huge burden to the patients, care givers, and the health care system. HE represents a "revolving door" with readmission, severely affects care givers, and has effects on cognition that can persists after liver transplant. This article reviews the current literature to discuss the challenges and diagnostic and therapeutic approaches to HE.
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Pharmacological and non-pharmacological treatments for irritable bowel syndrome: Protocol for a systematic review and network meta-analysis.
Zhou, S, Liu, X, Wang, X, Xi, F, Luo, X, Yao, L, Tang, H
Medicine. 2019;(30):e16446
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Abstract
BACKGROUND The global prevalence of Irritable bowel syndrome (IBS) is estimated to be as high as 15% and a number of different non-pharmacological and pharmacological treatments have been used to manage IBS in clinical practice, which poses great challenges for clinicians to make appropriate decisions. Hence, a systematic review and network meta-analysis on all available pharmacological and non-pharmacological treatments for IBS is needed to provide reliable evidence. METHODS We will search the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane IBD Group Specialized Trials Register, MEDLINE, EMBASE, and Chinese Biomedical medicine (CBM) from inception to 31, May 2019. Randomized controlled trials of pharmacological and nonpharmacological interventions for IBS will be included. Study quality will be assessed on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Primary outcomes are global or clinical improvement and quality of life. A Bayesian network meta-analysis would be performed, and relative ranking of agents would be assessed. A node splitting method will be used to examine the inconsistency between direct and indirect comparisons when a loop connecting 3 arms exists. RESULTS Researchers will rank the effectiveness and safety of the potentials interventions for IBS according the characteristics of patients by conducting an advanced network meta-analysis based on Bayesian statistical model, and interpret the results by using GRADE approach. CONCLUSION The conclusion of our study will provide updated evidence to rank the effectiveness and safety of pharmacological and non-pharmacological interventions for IBS. ETHICS AND DISSEMINATION Ethical approval is not applicable since this study is a network meta-analysis based on published trials. PROTOCOL REGISTRATION NUMBER CRD42018083844.