Biologic therapy for inflammatory bowel disease: Real-world comparative effectiveness and impact of drug sequencing in 13,222 patients within the UK IBD BioResource.

BACKGROUND AND AIMS: To compare effectiveness of different biologic therapies and sequences in patients with Inflammatory Bowel Disease (IBD) using real-world data from a large cohort with long exposure. METHODS: Demographic, disease, treatment and outcome data were retrieved for patients in the UK IBD BioResource. Effectiveness of treatment was based on persistence free of discontinuation or failure, analysed by Kaplan-Meier survival analysis with inverse probability of treatment weighting to adjust for differences between groups. RESULTS: 13,222 evaluable patients received at least one biologic. In ulcerative colitis (UC) first line vedolizumab (VDZ) demonstrated superior effectiveness over five years compared to anti-TNF agents (p=0.006). VDZ was superior to both infliximab (IFX) and adalimumab (ADA) after ADA and IFX failure respectively (p<0.001 and p<0.001). Anti-TNF therapy showed similar effectiveness when used first-line, or after failure of VDZ. In Crohn's disease (CD) we found significant differences between first line treatments over ten years (p=0.045), with superior effectiveness of IFX compared to ADA in perianal CD. Non-anti-TNF biologics were superior to a second anti-TNF after first line anti-TNF failure in CD (p=0.035). Patients with UC or CD experiencing TNF-failure due to delayed loss of response or intolerance had superior outcomes when switching to a non-anti-TNF biologic, rather than a second anti-TNF. CONCLUSIONS: We provide real-world evidence to guide biologic selection and sequencing in a range of common scenarios. Our findings challenge current guidelines regarding drug selection after loss of response to first anti-TNF.

Bacteroides thetaiotaomicron-derived outer membrane vesicles promote regulatory dendritic cell responses in health but not in inflammatory bowel disease.

BACKGROUND: Bacteroides thetaiotaomicron (Bt) is a prominent member of the human intestinal microbiota that, like all gram-negative bacteria, naturally generates nanosized outer membrane vesicles (OMVs) which bud off from the cell surface. Importantly, OMVs can cross the intestinal epithelial barrier to mediate microbe-host cell crosstalk involving both epithelial and immune cells to help maintain intestinal homeostasis. Here, we have examined the interaction between Bt OMVs and blood or colonic mucosa-derived dendritic cells (DC) from healthy individuals and patients with Crohn's disease (CD) or ulcerative colitis (UC). RESULTS: In healthy individuals, Bt OMVs stimulated significant (p < 0.05) IL-10 expression by colonic DC, whereas in peripheral blood-derived DC they also stimulated significant (p < 0.001 and p < 0.01, respectively) expression of IL-6 and the activation marker CD80. Conversely, in UC Bt OMVs were unable to elicit IL-10 expression by colonic DC. There were also reduced numbers of CD103+ DC in the colon of both UC and CD patients compared to controls, supporting a loss of regulatory DC in both diseases. Furthermore, in CD and UC, Bt OMVs elicited a significantly lower proportion of DC which expressed IL-10 (p < 0.01 and p < 0.001, respectively) in blood compared to controls. These alterations in DC responses to Bt OMVs were seen in patients with inactive disease, and thus are indicative of intrinsic defects in immune responses to this commensal in inflammatory bowel disease (IBD). CONCLUSIONS: Overall, our findings suggest a key role for OMVs generated by the commensal gut bacterium Bt in directing a balanced immune response to constituents of the microbiota locally and systemically during health which is altered in IBD patients. Video Abstract.

Infliximab induction regimens in steroid-refractory acute severe colitis: a multicentre retrospective cohort study with propensity score analysis.

BACKGROUND: Accelerated induction regimens of infliximab have been proposed to improve response rates in patients with steroid-refractory acute severe colitis. AIM: To determine the differences in outcome for acute severe ulcerative colitis between accelerated and standard-dose infliximab METHODS: We collected data on hospitalised patients receiving differing regimens of rescue therapy for steroid-refractory acute severe ulcerative colitis. Our primary outcome was 30-day colectomy rate. Secondary outcomes were colectomy within index admission, and at 90 days and 12 months. We used propensity score analysis with optimal calliper matching using high risk covariates defined a priori to reduce potential provider selection bias. RESULTS: We included 131 patients receiving infliximab rescue therapy; 102 received standard induction and 29 received accelerated induction. In the unmatched cohort, there was no difference by type of induction in the 30-day colectomy rates (18% vs 20%, P = .45), colectomy during index admission (13% vs 20%, P = .26) or overall colectomy (20% vs 24%, P = .38). In the propensity score-matched cohort of 52 patients, 30-day colectomy (57% vs 27%, P = .048) and index admission colectomy (53% vs 23%, P = .045) rates were higher in those receiving standard induction compared to accelerated induction but there was no difference in overall colectomy rates (57% vs 31%, P = .09). There was no significant difference in length of stay or in complication and infection rates. CONCLUSION: In a propensity score-matched cohort, steroid-refractory acute severe ulcerative colitis patients, short-term, but not long-term, colectomy rates appear to be lower in those receiving an accelerated induction regimen.

Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies.

Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein-protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type. We found that first neighbours have at least as high degree, betweenness centrality and clustering coefficient as cancer-related proteins themselves, indicating a previously unknown central network position. We identified a complementary strategy for mutated and differentially expressed proteins, where the affect of differentially expressed proteins having smaller network centrality is compensated with high centrality first neighbours. These first neighbours can be considered as key, so far hidden, components in cancer rewiring, with similar importance as mutated proteins. These observations strikingly suggest targeting first neighbours as a novel strategy for disrupting cancer-specific networks. Remarkably, our survey revealed 223 marketed drugs already targeting first neighbour proteins but applied mostly outside oncology, providing a potential list for drug repurposing against solid cancers. For the very central first neighbours, whose direct targeting would cause several side effects, we suggest a cancer-mimicking strategy by targeting their interactors (second neighbours of cancer-related proteins, having a central protein affecting position, similarly to the cancer-related proteins). Hence, we propose to include first neighbours to network medicine based approaches for (but not limited to) anticancer therapies.

Omics Approaches to Identify Potential Biomarkers of Inflammatory Diseases in the Focal Adhesion Complex.

Inflammatory diseases such as inflammatory bowel disease (IBD) require recurrent invasive tests, including blood tests, radiology, and endoscopic evaluation both to diagnose and assess disease activity, and to determine optimal therapeutic strategies. Simple 'bedside' biomarkers could be used in all phases of patient management to avoid unnecessary investigation and guide further management. The focal adhesion complex (FAC) has been implicated in the pathogenesis of multiple inflammatory diseases, including IBD, rheumatoid arthritis, and multiple sclerosis. Utilizing omics technologies has proven to be an efficient approach to identify biomarkers from within the FAC in the field of cancer medicine. Predictive biomarkers are paving the way for the success of precision medicine for cancer patients, but inflammatory diseases have lagged behind in this respect. This review explores the current status of biomarker prediction for inflammatory diseases from within the FAC using omics technologies and highlights the benefits of future potential biomarker identification approaches.

Identification of critical paralog groups with indispensable roles in the regulation of signaling flow.

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and 'bowtieness' when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis.

Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance.

Acute upper gastrointestinal (GI) bleeding is a common medical emergency and associated with significant morbidly and mortality. The risk of bleeding from peptic ulceration and oesophagogastric varices can be reduced by appropriate primary and secondary preventative strategies. Helicobacter pylori eradication and risk stratification with appropriate gastroprotection strategies when used with antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in preventing peptic ulcer bleeding, whilst endoscopic screening and either nonselective beta blockade or endoscopic variceal ligation are effective at reducing the risk of variceal haemorrhage. For secondary prevention of variceal haemorrhage, the combination of beta blockade and endoscopic variceal ligation is more effective. Recent data on the possible interactions of aspirin and NSAIDs, clopidogrel and proton pump inhibitors (PPIs), and the increased risk of cardiovascular adverse events associated with all nonaspirin cyclo-oxygenase (COX) inhibitors have increased the complexity of choices for preventing peptic ulcer bleeding. Such choices should consider both the GI and cardiovascular risk profiles. In patients with a moderately increased risk of GI bleeding, a NSAID plus a PPI or a COX-2 selective agent alone appear equivalent but for those at highest risk of bleeding (especially those with previous ulcer or haemorrhage) the COX-2 inhibitor plus PPI combination is superior. However naproxen seems the safest NSAID for those at increased cardiovascular risk. Clopidogrel is associated with a significant risk of GI haemorrhage and the most recent data concerning the potential clinical interaction of clopidogrel and PPIs are reassuring. In clopidogrel-treated patients at highest risk of GI bleeding, some form of GI prevention is indicated.

Therapeutic advances in the management of chronic hepatitis B infection.

Hepatitis B virus (HBV) is a small nonenveloped DNA virus that is a member of the Hepadnaviridae family. Chronic HBV infection is estimated to effect more than 350 million people worldwide with over 2 billion people being exposed to the virus. Risk factors for chronic infection include age of exposure to the virus, concurrent immunosuppression and HIV infection. Individuals chronically infected are 200 times more likely to develop hepatocellular carcinoma (HCC) than uninfected individuals and are at risk of developing cirrhosis and the risks of decompensated liver disease. This article focuses on the recent therapeutic advances that reduce the risk of developing these complications, those that prevent the spread of HBV and strategies for the prevention of post-liver-transplantation recurrence of HBV.