关键词： IBD   Soluble ligands   Cytokines   Biopharmaceutical agents   Target  

摘要： Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification "soluble ligands" that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible than receptors, which are embedded in the cell membrane and have complex tertiary membrane structures. Lastly, certain potential target proteins that are present in membrane-bound forms can become soluble following cleavage, providing further opportunities for intervention in the treatment of IBD. In this review, 49 drugs targeting 25 distinct ligands have been evaluated, including consideration of the characteristics of the ligands and drugs in respect of IBD treatment. In addition to approved drugs targeting soluble ligands, we have also assessed drugs that are in preclinical research and drugs inhibiting ligand-receptor binding. Some new types of targetable soluble ligands/proteins, such as epoxide hydrolase and p-selectin glycoprotein ligand-1, are also introduced. Targeting soluble ligands not only opens a new field of anti-IBD drug development, but the circulating soluble ligands also provide diagnostic insights for early prediction of treatment response. In

摘要： Background Whether long-term effectiveness differs between anti-tumour necrosis factor (anti-TNF) agents is unknown. Aims To examine drug survival of first-line anti-TNF agents and identify predictors of discontinuation. To reduce channelling bias, we also compared drug survival of the second anti-TNF. Methods Biologic-naive patients (N = 955) recorded in the Swedish IBD Quality Register (SWIBREG) were examined. We used propensity score matching, comparing drug survival over up to three years of follow-up. Cox regression estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Results In Crohn's disease, discontinuation because of lack/loss of response was 32% [95%CI = 26%-38%] for infliximab versus 16% [95%CI = 11%-21%] for adalimumab. Infliximab [vs adalimumab;aHR = 1.96;95%CI = 1.20-3.21] and colonic disease (L2) [vs no L2;aHR = 2.17;95% CI = 1.26-3.75] were associated with higher discontinuation rates, whereas normalised CRP at three months [aHR = 0.40;95% CI = 0.19-0.81] with a lower rate. Consistently, patients who switched from adalimumab to infliximab (vs infliximab to adalimumab) had earlier discontinuation (P = 0.04). Concomitant use of immunomodulators was associated with a lower adverse drug reaction-mediated discontinuation rate [aHR = 0.46;95% CI = 0.28-0.77], in part explained by fewer infusion reactions [aHR = 0.27;95% CI = 0.08-0.89]. In ulcerative colitis, the probability of discontinuation because of lack/loss of response was 40% [95% CI = 33%-47%] for infliximab versus 37% [95% CI = 21%-53%] for adalimumab. Disease duration >= 10 years [aHR = 0.25;95% CI = 0.10-0.58] and normalised CRP after three months [aHR = 0.39;95% CI = 0.18-0.84] were associated with lower discontinuation rates. Conclusions Clinical characterisation of patients may aid decision-making on anti-TNF treatment. The consistently shorter drug survival for infliximab (vs adalimumab) in Crohn's disease, suggests a potential difference between the two drugs.

关键词： Hirschsprung disease   Inflammatory bowel disease   Ulcerative colitis   Crohn's disease   Epidemiology   Level of evidence   IV  

摘要： Background/purpose: Hirschsprung disease has previously been reported to be associated with inflammatory bowel disease (IBD). The aim was to clinically confirm the diagnosis and to describe characteristics among individuals with both conditions in a national populationbased cohort. Methods: Nationwide, population-based cohort study, including all individuals with a Hirschsprung disease diagnosis and an IBD diagnosis registered between 1964 and 2016, in which clinical data were collected from the medical records of 18 validated cases with both Hirschsprung disease and IBD. The medical record of each individual in the study cohort was reviewed for age at IBD diagnosis, type of aganglionosis, type of surgical treatment, subtype of IBD, and treatment for IBD. Results: Median age at follow up was 34 years (range 19-66), and 3 of 18 indivduals (17%) were females. Median age at first diagnosis of IBD was 21 years (range 10-46). Six patients had ulcerative colitis, ten had Crohn's disease and two had unclassified IBD. Most of the patients had pharmacological treatment for IBD and 5 (28%) individuals had surgical treatment. Conclusion: Hirschsprung disease and IBD was clinically confirmed in 18 cases. Age at IBD onset and subtype of IBD is similar to IBD patients without Hirschsprung disease. Five individuals had undergone surgical treatment for IBD. (c) 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://***/licenses/by/4.0/ )

关键词： Inflammatory bowel disease   Thiopurine   Pharmacogenomics   Nudix hydrolase 15   Thiopurine methyltransferase   Metabolite monitoring  

摘要： In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.

关键词： Polyphenolic   Grape pomace seeds   Ulcerative colitis   Anti-inflammatory  

摘要： Purpose The global production of agroindustry wastes generate high amounts of wastes that represent an economical and environmental issues. Hence, the objective of this study was to characterize the phenolic composition profile recovered from Vitis vinifera waste and its related in vitro antioxidant and anti-inflammatory activities. Methods In this study, we investigated the effects of different amounts of V. vinifera grape pomace seeds polyphenols (GPEs) on an experimental ulcerative colitis mouse model. We induced colitis using acetic acid and estimated disease activity index (DAI), which included weight loss, stool consistency and bleeding. The colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. Microscopic damage score and changes in weight and length of colon and digestive system segment were analyzed. Results Macroscopic activity of acetic acid-induced colitis was observed, the colon of acetic acid-treated mice showed severe inflammation characterized by marked ulceration, edema and erosions. The severity of acetic acid-induced colitis was assessed by macroscopic score analysis. Treatment with phenolic extract (0.15 and 0.1 mg) significantly (P < 0.001) reduced the disease index and significantly improved the macroscopic score. Histological analysis shows the therapeutic effect of GPEs (0.15 and 0.1 mg), with a decrease in the intensity and distribution of lesions in the duration of treatment. Conclusion In conclusion, grape pomace seeds polyphenols may serve as a natural antioxidant and anti-inflammatory treatment for ulcerative colitis. [GRAPHICS] .

关键词： Vedolizumab levels   Anti-vedolizumab antibodies   Crohn's disease   Ulcerative colitis   Inflammatory bowel diseases   Endoscopic healing index  

摘要： BackgroundThe aim of this study was to assess the relationship between serum vedolizumab (VDZ) concentrations and antibodies to VDZ (ATV) in a large cohort of patients with inflammatory bowel diseases. Furthermore, we evaluated the association between serum VDZ concentrations and a novel serum-based biomarker panel designated as the endoscopic healing index (EHI), developed and validated for identifying mucosal inflammation in patients with Crohn's disease (CD).MethodsRetrospective study where results from patient samples submitted to a commercial clinical laboratory were included. Serum VDZ and ATV levels were analyzed using a drug-tolerant assay. In CD patients for whom both VDZ and EHI were available, VDZ concentrations were correlated with EHI. serum VDZ threshold analysis was performed using ROC curves, and the serum VDZ concentrations that best differentiated EHI<20 (previously associated with endoscopic remission) were *** total of 9356 patients were included in the VDZ/ATV analysis. Detectable ATV was observed in 2.9% patients with significantly lower serum VDZ concentrations when compared to those with undetectable ATV [3.9 g/mL (0-9.0) vs. 11.3 mu g/mL (5.9-20.6), p<0.0001]. Of the patients with serum VDZ result, 287 patients had a concomitant EHI test. An inverse correlation was observed between VDZ concentration and EHI (rho=-0.20, p<0.001). A serum VDZ concentration >= 15.7 mu g/ml was best correlated wi th an EHI<20 [AUROC: 0.67 (95% CI 0.57-0.77)].ConclusionsIncidence of ATVs was low, but significantly associated with lower VDZ levels. A serum VDZ concentration threshold of15.7 mu g/ml was associated with endoscopic remission as defined by an EHI<20.

关键词： acute severe colitis   biologics   corticosteroid   inflammatory bowel disease  

摘要： Background and Aim Despite widespread recommendations and use of intravenous corticosteroids (IVCS) for the treatment of acute flares of ulcerative colitis and Crohn's disease, limited evidence exists comparing outcomes of the two most common regimens, intravenous methylprednisolone (IVMP) and intravenous hydrocortisone (IVHC). IVHC has stronger mineralocorticoid effects compared with IVMP and may cause higher rates of hypokalemia. We aimed to determine differences in clinical outcomes including requirement for inpatient rescue therapy, bowel resection, and rates of hypokalemia. Methods We conducted a multicenter cohort study of all adult patients admitted with an acute flare of inflammatory bowel disease (IBD) to the three tertiary hospitals in Auckland, New Zealand, where the protocol at each institution is either IVMP 60 mg daily or IVHC 100 mg four times daily. All patients requiring IVCS between 20 June 2016 and 30 June 2018 were included. The IVCS protocol was then changed at one hospital, where further data were collected for a further 12 months from 30 January 2019 until 30 December 2019. Results There were 359 patients, including 129 (35.9%) patients receiving IVMP and 230 (64.1%) patients receiving IVHC. IVMP treatment was associated with a greater requirement for rescue therapy than IVHC (36.4% vs 19.6%, P = 0.001;odds ratio [OR] = 2.79;95% confidence interval [CI], 1.64-4.75, P < 0.001), but also reduced rates of hypokalemia (55.8% vs 67.0%, P = 0.04;OR = 0.49;95% CI, 0.30-0.81, P = 0.005). There was no difference between treatment groups for the median length of admission (5 days, interquartile range [IQR] 3-8), median duration of IVCS treatment (3 days, IQR 2-5), or bowel resection within 30 days of admission (12.4% vs 11.7%;OR = 1.04). Conclusion For the treatment of an acute flare of IBD, treatment with IVMP results in significantly more requirement for inpatient rescue biologic or cyclosporin. In addition, it causes statistically significant less hy

关键词： body composition   nutrition   paediatric inflammatory bowel disease  

摘要： Objective: Evaluate accuracy of skinfold thicknesses and body mass index (BMI) for the prediction of fat mass percentage (FM%) in paediatric inflammatory bowel disease (IBD) and to develop population-specific formulae based on anthropometry for estimation of FM%. Methods: IBD children (n = 30) and healthy controls (HCs, n = 144) underwent anthropometric evaluation and dual-energy X-ray absorptiometry (DEXA) scan, as the clinical reference for measurement of body composition. Body FM% estimated with skinfolds thickness was compared with FM% measured with DEXA. By means of 4 prediction models, population specific formulae for estimation of FM% were developed. Results: No significant difference in terms of FM% measured by DEXA was found between IBD population and HCs (FM% 29.6% vs 32.2%, P = 0.108). Triceps skinfold thickness (TSF, Model 2) was better than BMI (Model 1) at predicting FM% (82% vs 68% of variance). The sum of 2 skinfolds (biceps + triceps;SF2, Model 3) showed an improvement in the prediction of FM% as compared with TSF, Model 2 (86% vs 82% of variance). The sum of 4 skinfolds (biceps + triceps + suprailiac + subscapular;Model 4) showed further improvement in the prediction of FM% as compared with SF2 (88% vs 86% of variance). Conclusions: The sum of 4 skinfolds is the most accurate in predicting FM% in paediatric IBD. The sum of 2 skinfolds is less accurate but more feasible and less prone to error. The newly developed population-specific formulae could be a valid tool for estimation of body composition in IBD population and an alternative to DEXA measurement.

关键词： biologic drugs   inflammatory bowel disease   pregnancy  

摘要： Background and Aim Vedolizumab is a novel monoclonal antibody used in patients with inflammatory bowel disease, often affecting women of child-bearing age. We aimed to compare maternal and fetal adverse outcomes in pregnancies of women with inflammatory bowel disease exposed to vedolizumab versus those on other treatment. Methods We performed a systematic literature search through December 2020 looking for studies including outcomes from pregnancies of female inflammatory bowel disease patients treated with vedolizumab. Our primary outcome was a composite of adverse pregnancy-related events in pregnancies of female patients on vedolizumab compared with those of disease-matched controls on other medication regimens. Events of interest included preterm births, early loss of pregnancy, late fetal death, elective termination of pregnancy, and congenital anomalies. Results Four studies were included in our review meeting criteria for our primary analysis. Compared with those with no vedolizumab exposure, pregnancies with vedolizumab exposure had an increase in overall adverse pregnancy-related outcomes (odds ratio [OR] 2.18, 95% confidence interval [CI], 1.52-3.13). The vedolizumab group also had increased preterm births (OR 2.16, 95% CI, 1.28-3.66), and early loss of pregnancies (OR 1.79, 95% CI, 1.06-3.01) but no difference in number of live births (OR 0.60, 95%CI, 0.36-1.00), or congenital malformations (OR 1.56, 95% CI, 0.56-4.37). Conclusions Our systematic review highlights possible concern with the general safety of vedolizumab in pregnancy, as an increase in overall total unfavorable outcomes was observed. Premature births and early loss of pregnancy were also more prevalent in pregnant female patients on vedolizumab. It is possible these findings are confounded by disease activity, and further prospective cohort studies of vedolizumab and pregnancy outcomes are warranted.