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1.
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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Efficacy of intestinal microbiota transplantation in ulcerative colitis: a review of current literature and knowledge.
Newman, KM, Vaughn, BP
Minerva gastroenterologica e dietologica. 2019;(4):268-279
Abstract
Inflammatory bowel disease (IBD) results in chronic inflammation in the intestine and is thought to arise from an abnormal immune response to host commensal bacteria. The current treatment paradigm for IBD is focused on suppression of the immune system. However, intestinal microbiota transplant (IMT) may present an avenue to treat IBD by altering the target of inflammation without necessitating immune suppression. Presently, reports of the greatest success with IMT in IBD have been with ulcerative colitis (UC). Four randomized controlled trials have evaluated the efficacy of IMT in UC and reported a pooled rate of combined clinical and endoscopic remission of 28% (95% CI: 4-10). For clinical remission alone, the pooled rate was as high as 42% with a number needed to treat of 5 (95% CI: 3-17). While promising, many questions remain which include elucidating the optimal microbiota enrichment, exacting donor profiling, and identifying the optimal IMT route and frequency. Longer follow-up is needed to determine the ability to achieve stable engraftment for maintenance of remission as well as safety of IMT therapeutics. This review will critically appraise the current literature for IMT in UC and identify key knowledge gaps.
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Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial.
Sharifi, A, Vahedi, H, Nedjat, S, Rafiei, H, Hosseinzadeh-Attar, MJ
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2019;(10):681-687
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon. It has been proposed that the UC pathogenesis may be related to vitamin D deficiency and/or vitamin D administration in UC patients may have an ameliorating effect on the intestinal inflammation. The aim of this study was to assess the effect of vitamin D on the serum levels of immune cytokines in UC patients. In this double-blind randomized controlled trial, 90 mild-to-moderate UC patients were assigned to get either a single muscular injection of 7.5 mg vitamin D3 or 1 mL normal saline as placebo. Three months later serum levels of IL-4, IL-10, IL-12p70, IFN-γ, and TNF-α were measured. Two group variables were compared using independent t-test and analysis of covariance (ANCOVA). There was a significant increase in vitamin D only in the vitamin D group. Compared to placebo, vitamin D had significant decreasing effects on serum TNF-α, IFN-γ, and IL12p70 levels, but it had no significant effect on serum levels of IL4 and IL10. Vitamin D seems to inhibit Th1 immune responses and have no effect on Th2 responses. The findings of this study support several in vitro studies, which suggest a therapeutic immunomodulatory potential of vitamin D.
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Probiotics combined with aminosalicylic acid affiliates remission of ulcerative colitis: a meta-analysis of randomized controlled trial.
Peng, L, Zhong, Y, Wang, A, Jiang, Z
Bioscience reports. 2019;(1)
Abstract
We conducted a meta-analysis to evaluate the effect of probiotic combined with aminosalicylic on induction remission maintenance treatment of ulcerative colitis (UC). We conducted systematic searches in several Chinese and English databases from inception to June 2018, screening randomized controlled trials about effect of probiotics combined with aminosalicylic acid on UC. The evaluation indicator was the rate of remission. The relative risk (RR) and 95% confidence interval (CI) were calculated. A total of 27 studies with 1942 patients were included. The results indicated that the remission rate was significantly higher in the group using probiotics combined with aminosalicylic acid than that in the group using aminosalicylic acid alone (RR = 1.40, 95% CI: 1.27-1.53, P=0.000). The subgroup analysis indicated that probiotics combined with aminosalicylic acid can significantly elevate the remission rate in both mild to moderate (RR = 1.33, 95% CI: 1.16-1.54, P=0.000) and active stage (RR = 1.40, 95% CI: 1.27-1.64, P=0.000) UC. In different number of bacterium, drug types and treatment periods, the combination with probiotics can significantly increase the remission rate UC. The funnel plot shows slight publication bias. Probiotics in conjunction with aminosalicylic can obviously increase the clinical remission rate of activity UC than drug alone. There was no significant difference between combined with mesalazine group and salicylazosulfapyridine group.
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Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics.
Chang, JY, Cheon, JH
Digestive diseases and sciences. 2019;(9):2395-2403
Abstract
Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.
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Vitamin D Decreases Beck Depression Inventory Score in Patients with Mild to Moderate Ulcerative Colitis: A Double-Blind Randomized Placebo-Controlled Trial.
Sharifi, A, Vahedi, H, Nedjat, S, Mohamadkhani, A, Hosseinzadeh Attar, MJ
Journal of dietary supplements. 2019;(5):541-549
Abstract
The prevalence of depression in inflammatory bowel disease (IBD) is significantly more than in controls. Some studies assessed the link between vitamin D and depression. The aim of this study was to assess the effect of vitamin D on Beck Depression Inventory (BDI) score in ulcerative colitis (UC) patients. In this double-blind randomized controlled trial, 90 mild to moderate UC patients were assigned to receive a single injection of 300,000 IU vitamin D3 or 1 ml normal saline as placebo. At baseline and 3 months later, measurements of BDI score and serum 25-OH-vitamin D3 were done. Data were compared by independent sample t test, Mann-Whitney U test, and analysis of covariance (ANCOVA). Baseline BDI scores were not statistically different between the two groups (p = .4); scores decreased in the vitamin D group after the intervention (p = .023). Further subgroup analysis regarding baseline serum vitamin D levels and adjusted for baseline BDIs revealed lowering effect of vitamin D on BDI scores only in subgroup with baseline serum vitamin D levels equal to or higher than 30 ng/ml (p < .001). In this study, there was a statistically significant reduction in BDI score in mild to moderate UC patients 3 months after 300,000 IU vitamin D3 injection. Subgroup analysis showed that patients with sufficient baseline vitamin D may benefit from supplementation more than vitamin D-deficient patients, which indicates that higher serum vitamin D levels may be needed for its antidepressant effect.
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7.
Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.
Nguyen, N, Zhang, B, Holubar, SD, Pardi, DS, Singh, S
The Cochrane database of systematic reviews. 2019;(11):CD001176
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Abstract
BACKGROUND Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear. Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence). Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation (a probiotic formulation) participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.
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N-Terminomics/TAILS Profiling of Proteases and Their Substrates in Ulcerative Colitis.
Gordon, MH, Anowai, A, Young, D, Das, N, Campden, RI, Sekhon, H, Myers, Z, Mainoli, B, Chopra, S, Thuy-Boun, PS, et al
ACS chemical biology. 2019;(11):2471-2483
Abstract
Dysregulated protease activity is often implicated in the initiation of inflammation and immune cell recruitment in gastrointestinal inflammatory diseases. Using N-terminomics/TAILS (terminal amine isotopic labeling of substrates), we compared proteases, along with their substrates and inhibitors, between colonic mucosal biopsies of healthy patients and those with ulcerative colitis (UC). Among the 1642 N-termini enriched using TAILS, increased endogenous processing of proteins was identified in UC compared to healthy patients. Changes in the reactome pathways for proteins associated with metabolism, adherens junction proteins (E-cadherin, liver-intestinal cadherin, catenin alpha-1, and catenin delta-1), and neutrophil degranulation were identified between the two groups. Increased neutrophil infiltration and distinct proteases observed in ulcerative colitis may result in extensive break down, altered processing, or increased remodeling of adherens junctions and other cellular functions. Analysis of the preferred proteolytic cleavage sites indicated that the majority of proteolytic activity and processing comes from host proteases, but that key microbial proteases may also play a role in maintaining homeostasis. Thus, the identification of distinct proteases and processing of their substrates improves the understanding of dysregulated proteolysis in normal intestinal physiology and ulcerative colitis.
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Contemporary Medical Management of Acute Severe Ulcerative Colitis.
Whaley, KG, Rosen, MJ
Inflammatory bowel diseases. 2019;(1):56-66
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Abstract
Acute severe ulcerative colitis is a medical emergency that requires prompt recognition, evaluation, and intervention. Patients require hospital admission with laboratory, radiographic, and endoscopic evaluation with initiation of corticosteroid treatment. Despite early intervention, many patients require salvage medical therapy, with some progressing to colectomy. Here we review important concepts and recent advances in the evaluation and medical management of adult and pediatric patients with acute severe ulcerative colitis.
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10.
Curcuminoids from Curcuma Longa: New adjuvants for the treatment of crohn's disease and ulcerative colitis?
Cunha Neto, F, Marton, LT, de Marqui, SV, Lima, TA, Barbalho, SM
Critical reviews in food science and nutrition. 2019;(13):2136-2143
Abstract
Crohn's Disease (CD) and Ulcerative Colitis (UC) result from an overreaction of the bowel to multifactorial stimuli leading to discomfort, pain, and it is associated with high morbidity and lethality. The medications commonly used are expensive and associated with multiple side effects. Curcuma longa exerts anti-inflammatory and antioxidant actions and has shown positive effects on CD and UC treatment, possibly due to the presence of curcuminoids. The objective of this review was to evaluate the role of curcuminoids in the treatment of IBD. A search for articles associating curcuminoids and CD and UC was performed using MEDLINE-PubMed. It has been found that curcumin can reduce oxidative stress and inhibit the migration of neutrophils and inducible nitric oxide synthase in the intestine. It may also improve micro and macroscopic lesions, prevent apoptosis of intestinal cells and also induce the restoration of the mitogen-activated protein kinase immune reaction. As the incidence of CD and UC is growing in many populations, there is an urgency to find an appropriate and accessible therapeutic approach to improve quality of life of patients. The use of curcumin is cheap, efficient and associated with no side effects, and may become an alternative to the IBD treatment.