Use of methotrexate in inflammatory bowel disease in 2014: A User\u27s Guide

Methotrexate has been used an immunomodulator in many autoimmune diseases, including inflammatory bowel disease. However, many physicians are unfamiliar or uncomfortable with its use in the management of inflammatory bowel disease. We summarize the data for use of methotrexate in common clinical scenarios: (1) steroid dependant Crohn\u27s disease (CD); (2) maintenance of remission in steroid free CD; (3) azathioprine failures in CD; (4) in combination therapy with Anti-TNF agents in CD; (5) decreasing antibody formation to Anti-TNF therapy in CD; (6) management of fistulizing disease in CD; and (7) as well as induction and maintenance of remission in ulcerative colitis. An easy to use algorithm is provided for the busy clinician to access and safely prescribe methotrexate for their inflammatory bowel disease patients

Spatial Structure of the Mormon Cricket Gut Microbiome and Its Predicted Contribution to Nutrition and Immune Function

The gut microbiome of insects plays an important role in their ecology and evolution, participating in nutrient acquisition, immunity, and behavior. Microbial community structure within the gut is heavily influenced by differences among gut regions in morphology and physiology, which determine the niches available for microbes to colonize. We present a high-resolution analysis of the structure of the gut microbiome in the Mormon cricket Anabrus simplex, an insect known for its periodic outbreaks in the western United States and nutrition-dependent mating system. The Mormon cricket microbiome was dominated by eleven taxa from the Lactobacillaceae, Enterobacteriaceae, and Streptococcaeae. While most of these were represented in all gut regions, there were marked differences in their relative abundance, with lactic-acid bacteria (Lactobacillaceae) more common in the foregut and midgut and enteric (Enterobacteriaceae) bacteria more common in the hindgut. Differences in community structure were driven by variation in the relative prevalence of three groups: a Lactobacillus in the foregut, Pediococcus lactic-acid bacteria in the midgut, and Pantoea agglomerans, an enteric bacterium, in the hindgut. These taxa have been shown to have beneficial effects on their hosts in insects and other animals by improving nutrition, increasing resistance to pathogens, and modulating social behavior. Using PICRUSt to predict gene content from our 16S rRNA sequences, we found enzymes that participate in carbohydrate metabolism and pathogen defense in other orthopterans. These were predominately represented in the hindgut and midgut, the most important sites for nutrition and pathogen defense. Phylogenetic analysis of 16S rRNA sequences from cultured isolates indicated low levels of divergence from sequences derived from plants and other insects, suggesting that these bacteria are likely to be exchanged between Mormon crickets and the environment. Our study shows strong spatial variation in microbiome community structure, which influences predicted gene content and thus the potential of the microbiome to influence host function

Presentation and outcomes among inflammatory bowel disease patients with concurrent pneumatosis intestinalis: A case series and systematic review

© 2020 Korean Association for the Study of Intestinal Diseases. Background/Aims: Inflammatory bowel disease (IBD) involves chronic inflammation of the colon with ulcerative colitis (UC), and the colon and/or small intestine with Crohn\u27s disease (CD). Pneumatosis intestinalis (PI), characterized by compromise of the intestinal wall with gas-filled cysts, has rarely been reported with IBD. The presentation, best management and outcomes of PI with IBD are poorly defined. Methods: We conducted a search for PI in all abdominal computed tomography (CT) reports at 2 large tertiary care hospitals from January 1, 2010 to December 31, 2017, cross referenced to ICD codes for IBD. CT and chart review was performed to confirm PI and IBD respectively. A systematic review excluding case reports was performed for PI with IBD for comparison. Results: Of 5,990 patients with a CT abdomen report mentioning PI, we identified 11 cases of PI with IBD, 4 UC, 6 CD, and 1 indeterminate colitis. PI was limited to the small bowel in 5 patients, the right colon in 5, and small bowel and colonic in 1. All 3 mortalities had CD, small intestinal PI and portal/mesenteric venous gas. The systematic literature search identified 9 articles describing 58 patients with IBD and PI. These cases were mostly included in larger cohorts of PI patients without extractable data on presentation or outcomes in the IBD subpopulation. Conclusions: Ours appears to be the first reporting of presentations and outcomes, outside of case reports, for those with PI and IBD. The high mortality for those with CD and PI of the small bowel appears to define a group requiring more than supportive medical care

Comparative safety and effectiveness of vedolizumab to tumour necrosis factor antagonist therapy for Crohn\u27s disease

© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd Background: Direct comparisons are lacking between vedolizumab and tumour necrosis factor (TNF)-antagonist therapy in Crohn\u27s disease (CD). Aim: To compare safety and effectiveness of vedolizumab and TNF-antagonist therapy in adult CD patients. Methods: Retrospective observational cohort (May 2014–December 2017) propensity score-weighted comparison of vedolizumab vs TNF-antagonist therapy (infliximab, adalimumab, certolizumab) in CD. Propensity scores were weighted for age, prior treatments, disease complications, extent and severity, steroid dependence, and concomitant immunosuppressive drug use. The primary outcome was comparative risk for infections or non-infectious serious adverse events (requiring antibiotics, antivirals, antifungals, hospitalisation, or treatment discontinuation, or resulting in death). Secondary comparative effectiveness outcomes were clinical remission (resolution of CD-related symptoms), steroid-free clinical remission and endoscopic remission (absence of ulcers/erosions). Results: We included 1266 patients (n = 659 vedolizumab). Rates of non-infectious serious adverse events (odds ratio [OR] 0.072, 95% confidence interval [CI] 0.012-0.242), but not serious infections (OR 1.183, 95% CI 0.786-1.795), were significantly lower with vedolizumab vs TNF-antagonist therapy. Safety comparisons for non-infectious serious adverse events remained significant after adjusting for differences in duration of exposure. No significant difference was observed between vedolizumab and TNF-antagonist therapy for clinical remission (hazard ratio [HR] 0.932, 95% CI 0.707-1.228), steroid-free clinical remission (HR 1.250, 95% CI 0.677-2.310) or endoscopic remission (HR 0.827, 95% CI 0.595-1.151). TNF-antagonist therapy was associated with higher treatment persistence compared with vedolizumab. Conclusions: There was a lower risk of non-infectious serious adverse events, but not serious infections, with vedolizumab vs TNF-antagonist therapy, with no significant difference for achieving disease remission

Identifying Ligand Binding Conformations of the β2-Adrenergic Receptor by Using Its Agonists as Computational Probes

Recently available G-protein coupled receptor (GPCR) structures and biophysical studies suggest that the difference between the effects of various agonists and antagonists cannot be explained by single structures alone, but rather that the conformational ensembles of the proteins need to be considered. Here we use an elastic network model-guided molecular dynamics simulation protocol to generate an ensemble of conformers of a prototypical GPCR, β2-adrenergic receptor (β2AR). The resulting conformers are clustered into groups based on the conformations of the ligand binding site, and distinct conformers from each group are assessed for their binding to known agonists of β2AR. We show that the select ligands bind preferentially to different predicted conformers of β2AR, and identify a role of β2AR extracellular region as an allosteric binding site for larger drugs such as salmeterol. Thus, drugs and ligands can be used as "computational probes" to systematically identify protein conformers with likely biological significance. © 2012 Isin et al

Changes in Vedolizumab Utilization Across US Academic Centers and Community Practice Are Associated With Improved Effectiveness and Disease Outcomes.

BACKGROUND:Vedolizumab effectiveness estimates immediately after Food and Drug Administration (FDA) approval for ulcerative colitis (UC) and Crohn\u27s disease (CD) are limited by use in refractory populations. We aimed to compare treatment patterns and outcomes of vedolizumab in 2 time frames after FDA approval. METHODS:We used 2 data sets for time trend analysis, an academic multicenter vedolizumab consortium (VICTORY) and the Truven MarketScan database, and 2 time periods, May 2014-June 2015 (Era 1) and July 2015-June 2017 (Era 2). VICTORY cumulative 12-month clinical remission, corticosteroid-free remission, and mucosal healing rates, and Truven 12-month hospitalization and surgery rates, were compared between Eras 1 and 2 using time-to-event analyses. RESULTS:A total of 3661 vedolizumab-treated patients were included (n = 1087 VICTORY, n = 2574 Truven). In both cohorts, CD and UC patients treated during Era 2 were more likely to be biologic naïve. Compared with Era 1, Era 2 CD patients in the VICTORY consortium had higher rates of clinical remission (31% vs 40%, P = 0.03) and mucosal healing (42% vs 58%, P \u3c 0.01). These trends were not observed for UC. In the Truven database, UC patients treated during Era 2 had lower rates of inflammatory bowel disease-related hospitalization (22.4% vs 9.6%, P \u3c 0.001) and surgery (17.2% vs 9.4%, P = 0.008), which was not observed for CD. CONCLUSION:Since FDA approval, remission and mucosal healing rates have increased for vedolizumab-treated CD patients, and vedolizumab-treated UC patients have had fewer hospitalizations and surgeries. This is likely due to differences between patient populations treated immediately after drug approval and those treated later

Predicting Novel Binding Modes of Agonists to β Adrenergic Receptors Using All-Atom Molecular Dynamics Simulations

Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of β1 and β2 adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity