Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: a randomised controlled study in Kenyan infants Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-03 Daniela Paganini, Mary A Uyoga, Guus A M Kortman, Colin I Cercamondi, Diego Moretti, Tanja Barth-Jaeggi, Clarissa Schwab, Jos Boekhorst, Harro M Timmerman, Christophe Lacroix, Simon Karanja, Michael B Zimmermann
Objective Iron-containing micronutrient powders (MNPs) reduce anaemia in African infants, but the current high iron dose (12.5 mg/day) may decrease gut Bifidobacteriaceae and Lactobacillaceae , and increase enteropathogens, diarrhoea and respiratory tract infections (RTIs). We evaluated the efficacy and safety of a new MNP formula with prebiotic galacto-oligosaccharides (GOS) combined with a low dose (5 mg/day) of highly bioavailable iron.Design In a 4-month, controlled, double-blind trial, we randomised Kenyan infants aged 6.5–9.5 months (n=155) to receive daily (1) a MNP without iron (control); (2) the identical MNP but with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) (Fe group); or (3) the identical MNP as the Fe group but with 7.5 g GOS (FeGOS group).Results Anaemia decreased by ≈50% in the Fe and FeGOS groups (p<0.001). Compared with the control or FeGOS group, in the Fe group there were (1) lower abundances of Bifidobacterium and Lactobacillus and higher abundances of Clostridiales (p<0.01); (2) higher abundances of virulence and toxin genes (VTGs) of pathogens (p<0.01); (3) higher plasma intestinal fatty acid-binding protein (a biomarker of enterocyte damage) (p<0.05); and (4) a higher incidence of treated RTIs (p<0.05). In contrast, there were no significant differences in these variables comparing the control and FeGOS groups, with the exception that the abundance of VTGs of all pathogens was significantly lower in the FeGOS group compared with the control and Fe groups (p<0.01).Conclusion A MNP containing a low dose of highly bioavailable iron reduces anaemia, and the addition of GOS mitigates most of the adverse effects of iron on the gut microbiome and morbidity in African infants.Trial registration number NCT02118402.
Serrated pathway: a paradigm shift in CRC prevention Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-01 Evelien Dekker, Joep Evert Godfried IJspeert
In the prevention of colorectal cancer (CRC), hyperplastic polyps have long been regarded as innocent bystanders and only adenomas were thought to be precursors for CRC. Therefore, focus during colonoscopy was on adenomas only. In the past decade, evidence has accumulated that serrated polyps might progress to cancer as well via the serrated neoplasia pathway. On the one hand, patients with multiple serrated polyps, nowadays classified as having serrated polyposis syndrome, demonstrated an increased risk of CRC development, and small cancers were detected within serrated lesions. On the other hand, a growing body of circumstantial evidence suggests that at least 15% of all CRCs arise through the serrated neoplasia pathway, and an even larger proportion of postcolonoscopy CRCs arise from serrated polyps.1This growing body of evidence has gradually led to a paradigm shift in both cancer prevention as well as treatment strategies. To reduce the number of postcolonoscopy CRCs and to optimise current clinical care for patients with serrated polyps, several issues are at stake. The new British Society of Gastroenterology (BSG) position statement on serrated polyps in the colon and rectum is therefore timely as well as important.2 It discusses current knowledge on serrated polyps and provides recommendations for daily clinical practice as well as research. We hope that this publication will increase the awareness among clinicians on this topic and will be an incentive for appropriate management of these lesions. In the light of rapidly developing evidence on this topic, we would like to comment on this excellent work of the BSG.As the terminology of serrated polyps is confusing, and does not help to bring a clear message to the general gastrointestinal practice, the BSG proposes new terminology. We support the proposal of the BSG to simplify the WHO classification slightly by renaming ‘sessile serrated adenomas/polyps’ …
Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-01 Lowiek M Hubers, Harmjan Vos, Alex R Schuurman, Robin Erken, Ronald P Oude Elferink, Boudewijn Burgering, Stan F J van de Graaf, Ulrich Beuers
Objective Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD.Design We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry.Results Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes.Conclusion Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.
Mucosal microbiome dysbiosis in gastric carcinogenesis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-01 Olabisi Oluwabukola Coker, Zhenwei Dai, Yongzhan Nie, Guijun Zhao, Lei Cao, Geicho Nakatsu, William KK Wu, Sunny Hei Wong, Zigui Chen, Joseph J Y Sung, Jun Yu
Objectives We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis.Design We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China.Results We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis , Streptococcus anginosus , Parvimonas micra , Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori -negative samples compared with H. pylori -positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81.Conclusions In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis , D. pneumosintes , S. exigua , P. micra and S. anginosus in GC progression.
High on drugs: lessons from opiates in pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-01 Vijay P Singh
The current opiate epidemic, the widespread clinical utilisation of opiates, along with the controversies that revolve around their use, mandate that we take a fresh look at the risks and benefits of this invaluable yet potentially hazardous class of drugs. Pancreatitis is a common illness in which opiates are used extensively for pain control. With the well-known overlap between the complications of acute pancreatitis and opiate use, that is, ileus and bacterial translocation, and the difficulty in identifying the underlying causality in a clinical scenario, it is appropriate that this dilemma be approached using animal models. Additionally, the recent paradigm1 that chronic pancreatitis (for which opioids may be used for long periods) evolves from recurrent acute attacks reinforces the need to weigh the risks this usage may create apart from opiate abuse. In the study entitled ‘Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis’, Balrass et al 2 present a clinically relevant argument of the multiple ways in which opiates may be worsening the outcomes of acute pancreatitis (AP). They postulate three mechanisms: (1) increased bacterial translocation, (2) a temporal delay in the reparative inflammatory response and (3) a delay in the regenerative response. Additionally, they note that morphine worsens pancreatic necrosis and acute inflammation in mechanistically distinct models. These effects of morphine are prevented in μ-opioid receptor knockout mice. The influence …
Faecal microbiota composition associates with abdominal pain in the general population Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-01 Fatemeh Hadizadeh, Ferdinando Bonfiglio, Meriem Belheouane, Marie Vallier, Sascha Sauer, Corinna Bang, Luis Bujanda, Anna Andreasson, Lars Agreus, Lars Engstrand, Nicholas J Talley, Joseph Rafter, John F Baines, Susanna Walter, Andre Franke, Mauro D'Amato
We read with great interest the recent communication by Simrén et al ,1 reporting a correlation between visceral hypersensitivity and GI symptom severity in functional GI disorders (FGID). Previously, it has been shown that visceral hypersensitivity can be modulated or even induced in animal models, by altering the composition of their gut microbiota with antibiotics or faecal transplantation from IBS donors.2 3 Hence, while a direct link between gut microbiota composition and visceral pain may need to be conclusively established, this holds great potential for translational exploitation in the treatment of IBS and other FGID. Thus far, the potential association between microbiota and abdominal pain in humans has only been investigated in one study that included 15 individuals.4 For this purpose, we studied 159 individuals (average age 59.1, 39.6% men) from the Swedish Population-based Colonoscopy (PopCol) cohort, previously described and with faecal microbiota 16S sequencing data and daily recordings of abdominal pain (number of episodes, duration and intensity) collected over the same period (7.41±7.91 days).5–7 Among these, 52 individuals (assigned to the case group) reported at least one episode …
Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-01-01 Pål Møller, Toni T Seppälä, Inge Bernstein, Elke Holinski-Feder, Paulo Sala, D Gareth Evans, Annika Lindblom, Finlay Macrae, Ignacio Blanco, Rolf H Sijmons, Jacqueline Jeffries, Hans F A Vasen, John Burn, Sigve Nakken, Eivind Hovig, Einar Andreas Rødland, Kukatharmini Tharmaratnam, Wouter H de Vos tot Nederveen Cappel, James Hill, Juul T Wijnen, Mark A Jenkins, Kate Green, Fiona Lalloo, Lone Sunde, Miriam Mints, Lucio Bertario, Marta Pineda, Matilde Navarro, Monika Morak, Laura Renkonen-Sinisalo, Mev Dominguez Valentin, Ian M Frayling, John-Paul Plazzer, Kirsi Pylvanainen, Maurizio Genuardi, Jukka-Pekka Mecklin, Gabriela Moeslein, Julian R Sampson, Gabriel Capella
Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. Objective and design This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. Results 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_ MLH1 , path_ MSH2 and path_ MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. Conclusion Carriers of different path\_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path\_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.
Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-28 Jonas Rosendahl, Holger Kirsten, Eszter Hegyi, Peter Kovacs, Frank Ulrich Weiss, Helmut Laumen, Peter Lichtner, Claudia Ruffert, Jian-Min Chen, Emmanuelle Masson, Sebastian Beer, Constantin Zimmer, Katharina Seltsam, Hana Algül, Florence Bühler, Marco J Bruno, Peter Bugert, Ralph Burkhardt, Giulia Martina Cavestro, Halina Cichoz-Lach, Antoni Farré, Josef Frank, Giovanni Gambaro, Sebastian Gimpfl, Harald Grallert, Heidi Griesmann, Robert Grützmann, Claus Hellerbrand, Péter Hegyi, Marcus Hollenbach, Sevastitia Iordache, Grazyna Jurkowska, Volker Keim, Falk Kiefer, Sebastian Krug, Olfert Landt, Milena Di Leo, Markus M Lerch, Philippe Lévy, Markus Löffler, Matthias Löhr, Maren Ludwig, Milan Macek, Nuria Malats, Ewa Malecka-Panas, Giovanni Malerba, Karl Mann, Julia Mayerle, Sonja Mohr, Rene H M te Morsche, Marie Motyka, Sebastian Mueller, Thomas Müller, Markus M Nöthen, Sergio Pedrazzoli, Stephen P Pereira, Annette Peters, Roland Pfützer, Francisco X Real, Vinciane Rebours, Monika Ridinger, Marcella Rietschel, Eva Rösmann, Adrian Saftoiu, Alexander Schneider, Hans-Ulrich Schulz, Nicole Soranzo, Michael Soyka, Peter Simon, James Skipworth, Felix Stickel, Konstantin Strauch, Michael Stumvoll, Pier Alberto Testoni, Anke Tönjes, Lena Werner, Jens Werner, Norbert Wodarz, Martin Ziegler, Atsushi Masamune, Joachim Mössner, Claude Férec, Patrick Michl, Joost P H Drenth, Heiko Witt, Markus Scholz, Miklós Sahin-Tóth
Objective Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.Results We replicated previously reported risk loci CLDN2-MORC4 , CTRC , PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956 . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.Conclusion An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.
Quantitative liver MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis: a prospective proof-of-concept study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-27 Julian A Luetkens, Sabine Klein, Frank Traeber, Frederic C Schmeel, Alois M Sprinkart, Daniel L R Kuetting, Wolfgang Block, Kanishka Hittatiya, Frank E Uschner, Robert Schierwagen, Juergen Gieseke, Hans H Schild, Jonel Trebicka, Guido M Kukuk
We read with interest the recent reviews published in Gut , emphasising that even though the understanding of the pathobiology of liver fibrosis has been improved in the last three decades,1 novel and easy to implement diagnostic and therapeutic approaches are required.2 Indeed, fibrosis is the most important histological feature of patients with chronic liver disease (CLD), such as non-alcoholic fatty liver disease, and is associated with long-term overall mortality, liver transplantation and liver-related events.3 Diagnostic and therapeutic approaches,2 therefore, require accurate measurements that ideally allow non-invasive fibrosis quantification, representing the whole liver free of bias and easily integrated in clinical routine.A liver biopsy, still the reference standard, has substantial drawbacks (complications, intraobserver and interobserver variabilities).4 Transient elastography (TE), suggested for population-wide screens (eg, patients with diabetes),5 requires additional expensive devices and trained personnel. However, contrast-enhanced MRI is …
The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-27 Dai-Min Xiang, Wen Sun, Bei-Fang Ning, Teng-Fei Zhou, Xiao-Feng Li, Wei Zhong, Zhuo Cheng, Ming-Yang Xia, Xue Wang, Xing Deng, Wei Wang, Heng-Yu Li, Xiu-Liang Cui, Shi-Chao Li, Bin Wu, Wei-Fen Xie, Hong-Yang Wang, Jin Ding
Background and aims Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.Methods The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.Results Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.Conclusions In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-24 Julien Kirchgesner, Laurent Beaugerie, Fabrice Carrat, Nynne Nyboe Andersen, Tine Jess, Michaël Schwarzinger
Objective Magnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level. Design Using the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors. Results Among 210 162 individuals with IBD (Crohn's disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively). Conclusion Patients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk.
Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-24 Robertino M Mera, Luis E Bravo, M Constanza Camargo, Juan C Bravo, Alberto G Delgado, Judith Romero-Gallo, Maria C Yepez, José L Realpe, Barbara G Schneider, Douglas R Morgan, Richard M Peek, Pelayo Correa, Keith T Wilson, M Blanca Piazuelo
Objective To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. Design 795 adults with precancerous gastric lesions were randomised to receive anti- H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1–6). The score difference between baseline and 16 years was modelled by generalised linear models. Results Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori . The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). Conclusions Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.
Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-24 Won-Tak Choi, Jia-Huei Tsai, Peter S Rabinovitch, Thomas Small, Danning Huang, Aras N Mattis, Sanjay Kakar
Objective The diagnosis of dysplasia in Barrett’s oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia. Design DNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected. Results DNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =<0.001). Conclusions This study demonstrates the promise of DNA flow cytometry using FFPE tissue in the diagnosis and risk stratification of dysplasia in BO. The presence of DNA content abnormality correlates with increasing levels of dysplasia, as 95% of HGD samples showed DNA content abnormality. DNA flow cytometry also identifies a subset of patients with LGD and IND who are at higher risk for subsequent detection of HGD or OAC.
Incidence of irritable bowel syndrome and chronic fatigue following GI infection: a population-level study using routinely collected claims data Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-24 Ewan Donnachie, Antonius Schneider, Michael Mehring, Paul Enck
Objectives To investigate the occurrence of postinfectious IBS in routine outpatient care, comparing different types of GI infection and its interaction with psychosomatic comorbidity. Design Retrospective cohort study using routinely collected claims data covering statutorily insured patients in Bavaria, Germany. Cases were defined as patients without prior record of functional intestinal disorder with a first-time diagnosis of GI infection between January 2005 and December 2013 and classed according to the type of infection. Each case was matched by age, sex and district of residence to a patient without history of GI infection. Prior psychological disorder (depression, anxiety or stress reaction disorder) was assessed in the 2 years prior to inclusion. Proportional hazards regression models were used to estimate the HRs for GI infection and psychological disorder. Chronic fatigue syndrome (CFS) was assessed as a comparator outcome. Results A total of 508 278 patients with first diagnosis of GI infection were identified, resulting in a matched cohort of 1 016 556 patients. All infection types were associated with an increased risk of IBS (HR: 2.19–4.25) and CFS (HR 1.35–1.82). Prior psychological disorder was a distinct risk factor for IBS (HR: 1.73) and CFS (HR: 2.08). Female sex was a further risk factor for both conditions. Conclusion Psychological disorder and GI infections are distinct risk factors for IBS. The high incidence of non-specific GI infection suggests that postinfectious IBS is a common clinical occurrence in primary care. Chronic fatigue is a further significant sequela of GI infection.
Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-21 Steven P O’Hara, Tom H Karlsen, Nicholas F LaRusso
In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric accumulation of connective tissue around bile ducts suggests that the cholangiocyte plays an integral role in PSC pathogenesis. However, what initiates changes in cholangiocyte phenotype and how cholangiocytes interact with cells in the peribiliary extracellular matrix like immune cells and stromal components is largely unknown. Over the last 10 years, genome-wide association studies in PSC have revealed >20 risk genes.2–5 A significant observation that can be derived from these data, which also applies to other non-Mendelian phenotypes, is that the predominant risk contribution is likely to come from one or more environmental sources, rather than the genetic aberrations. Indeed, in PSC, we estimate that <10% of the overall liability is accounted for by the genetic findings; with extrapolations into hypothetical, larger study populations, it is unlikely to exceed 30%–40%.6 7 Research dissecting the remaining environmental contribution to PSC and other complex diseases is methodologically challenging. The exposures of an organism throughout life as a whole have recently been referred to as the exposome8 and include a myriad of components of both the external (eg, xenobiotics) and internal (eg, gut microbes) milieu. There is a long tradition and effective means for detecting infectious exposures in medicine. Robert Koch in the late 19th century proposed criteria to identify a disease as infectious.9 These included (i) the organism is regularly associated with the disease, (ii) the organism can be isolated from the diseased host and grown in culture and (iii) the disease can be reproduced when the organism is introduced into a healthy susceptible host. With the development of nucleic acid sequence-based identification of microbes, as well as the …
Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-04 Johanna C Sierra, Mohammad Asim, Thomas G Verriere, M Blanca Piazuelo, Giovanni Suarez, Judith Romero-Gallo, Alberto G Delgado, Lydia E Wroblewski, Daniel P Barry, Richard M Peek, Alain P Gobert, Keith T Wilson
Objective Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. Design We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr ( Efgr Δ epi mice) were also used. Results In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected Egfr Δ epi versus Egfrfl/fl control mice. In H. pylori -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylo ri-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from Efgr Δ epi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. Conclusions These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori -infected individuals.
Can we prevent and modify cardiometabolic disorders by controlling HCV infection? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-13 Salvatore Petta, Antonio Craxi
HCV infection has an estimated global prevalence of 1.0%, corresponding to roughly 71.1 million of infected individuals in 2015, with major geographical heterogeneity.1 Due to the large burden of infected individuals in the general population, the likelihood of co-occurrence of chronic HCV infection and common comorbidities is substantial regardless of causal linkages. Population-based studies show a higher overall mortality, both for liver-related and unrelated causes in HCV infected subjects compared with those uninfected, and cross-sectional and cohort studies identify HCV as an independent risk factor for extrahepatic manifestations.2 These issues are summarised in two meta-analyses reporting that HCV-infected patients are at higher risk of mixed cryoglobulinaemia, lymphoma, lichen planus, Sjögren’s syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, depression, chronic kidney or end-stage renal disease, type 2 diabetes and cardiovascular disorders/mortality.3 4 While the link between HCV and some of these comorbidities—mixed cryoglobulinaemia, lymphoma and glomerulonephritis—is well established and driven by recognised pathophysiological mechanisms, the nature of the association between the infection and other common extrahepatic comorbidities is less clear. Clinical and experimental evidences suggest an intrinsic link between HCV infection and insulin-resistance/diabetes driven by the ability of the virus to interfere with insulin signalling, even if the strength of this association is not always confirmed. Emerging data also support a link between HCV infection and cardiovascular alterations. However, relative to this topic, contrasting data exist and the basis of this association stems on associative data, theoretical speculations and inconclusive experimental evidence.5 This mass of data and the recent availability of highly effective antiviral regimens, able …
Chromoendoscopy versus narrow band imaging in UC: a prospective randomised controlled trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-11 Raf Bisschops, Talat Bessissow, Joseph A Joseph, Filip Baert, Marc Ferrante, Vera Ballet, Hilde Willekens, Ingrid Demedts, Karel Geboes, Gert De Hertogh, Séverine Vermeire, Paul Rutgeerts, Gert Van Assche
Background Patients with long-standing UC have an increased risk for the development of colonic neoplastic lesions. Chromoendoscopy (CE) has been proven to enhance neoplasia detection while the role of virtual chromoendoscopy (VC) is still to be defined. Objective To compare the performance of CE to VC for the detection of neoplastic lesions in patients with long-standing UC. Design A multicentre prospective randomised controlled trial. 131 patients with long-standing UC were randomised between CE with methylene blue 0.1% (n=66) or VC with narrow band imaging (NBI) (n=65). Biopsies were taken from visible lesions and surrounding mucosa. No random biopsies were performed. The primary outcome was the difference in total number of neoplastic lesions detected in each group. Results There was no significant difference between NBI and CE for neoplasia detection. Mean number of neoplastic lesions per colonoscopy was 0.47 for CE and 0.32 for NBI (p=0.992). The neoplasia detection rate was not different between CE (21.2%) and NBI (21.5%) (OR 1.02 (95% CI 0.44 to 2.35, p=0.964). Biopsies from the surrounding mucosa yielded no diagnosis or dysplasia. The per lesion neoplasia detection was 17.4% for CE and 16.3% for NBI (OR 1.09 (95% CI 0.59 to 1.99, p=0.793). The total procedural time was on average 7 min shorter in the NBI group. Conclusion CE and NBI do not differ significantly for detection of colitis-associated neoplasia. Given the longer withdrawal time for CE and easier applicability, NBI may possibly replace classical CE. Trial registration number NCT01882205; Results.
Massive gastrointestinal bleeding after transjugular intrahepatic portosystemic shunt (TIPS) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-07 Juan E Corral, Omar Y Mousa, Douglas L Riegert-Johnson
A patient with end-stage liver disease secondary to haemochromatosis was transferred to our hospital for variceal bleeding. During the previous 5 months, she underwent 10 oesophagogastroduodenoscopies (EGD) with repeated endoscopic band ligations (EBL). Following the most recent EBL, she was transferred to our hospital for emergent transjugular intrahepatic portosystemic shunt (TIPS) procedure. The patient arrived on mechanical ventilator support with continuous infusion of intravenous inotropes. After multiple blood transfusions and supportive measures, she had a successful TIPS procedure (mean portal-systemic gradient decreased from 11 mm Hg to 4 mm Hg). She recovered and was transferred to the general medical ward. Six days after the TIPS, she had another episode of hematochezia, …
Targeting toll-like receptor 7/8 improves host anti-infective response in alcoholic cirrhosis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-07 Emanuele Albano, Felix Stickel
The production of reactive oxygen species (ROS) by activated macrophages and neutrophil granulocytes represents an important cause of alcohol-induced oxidative stress and significantly contributes to the pathogenesis of alcoholic liver disease (ALD).1 Furthermore, diffuse neutrophil infiltration of the liver is a key feature of acute alcoholic hepatitis actively participating to parenchymal injury.2 However, during ALD progression to cirrhosis, neutrophil functions such as ROS production, bacterial phagocytosis and granule exocytosis are impaired leading to an increased susceptibility to bacterial infections of cirrhotic patients.3 Indeed, the development of bacterial peritonitis is a common complication of cirrhosis, while sepsis is a major cause of mortality in patients with decompensated alcoholic cirrhosis being also associated with multiorgan failure and immune deficiencies.4 The key role of neutrophils in antibacterial defences mainly relies on the capacity of the enzyme NADPH oxidase 2 (NOX2) to generate superoxide anion (O2−) during a process known as oxidative burst. Superoxide anion, in fact, by conversion to hydrogen peroxide, fuels myeloperoxidase-mediated production of the powerful bactericidal agents, hypochlorite and chloramine.5 NOX2 is a multiprotein enzymatic system consisting of the transmembrane proteins gp91 phox and p22 phox forming the …
Persistent cough: A question for the gastroenterologist? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-29 Elizabeth Parsons, Bronwen E Warner, Barbara Braden
An 80-year-old female retired teacher was admitted under the medical team with right-lower-lobe pneumonia. The patient, a non-smoker with minimal alcohol intake, had a medical history of non-Hodgkin’s lymphoma treated with radiotherapy and splenectomy 30 years before, Barrett’s oesophagus (C9M9 Prague Classification) with distal oesophageal ulcer diagnosed 8 months previously, hiatus hernia and dual-chamber pacemaker for sinus-arrest. Medications were omeprazole 80 mg and ranitidine 300 mg daily. During the preceding two years, the patient had consulted Respiratory and Gastroenterology teams for a persistent cough worsened by eating and drinking and two stone weight loss (admission BMI 16). High-resolution CT demonstrated subsegmental atelectasis and ground glass changes in …
The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-29 Parag Mahale, Eric A Engels, Ruosha Li, Harrys A Torres, Lu-Yu Hwang, Eric L Brown, Jennifer R Kramer
Background and aim Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited. Methods We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models. Results Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin's lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke. Conclusions Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke.
Endothelial dysfunction: what is the role of the microbiota? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-28 Erwin G Zoetendal, Hauke Smidt
In this issue, Catry et al described a study in which inulin-type fructans (ITF) improved endothelial dysfunction in mice.1 They demonstrated that the supplementation of ITF reverses endothelial dysfunction in mesenteric and carotid arteries of apolipoprotein E ( apoE ) gene knockout mice that were fed an n-3 polyunsaturated fatty acid-depleted diet. They further showed that improvement of endothelial dysfunction was accompanied with a change in microbiota composition and key gut peptides. Endothelial dysfunction is a pathological state of the inner lining of the blood vessels which is characterised by a reduction in vasodilation in response to endothelial stimuli and considered an early key marker of cardiovascular disease.2 Impaired synthesis and release of nitric oxide (NO) by the endothelium is considered one of the important mechanisms associated with endothelial dysfunction. A wide variety of risk factors associated with cardiovascular disease have been identified. These include general lifestyle factors such as the typical ‘Western diet’ and smoking, but also disorders, such as metabolic syndrome and type 2 diabetes as well as chronic inflammation. Increasing evidence indicates that the intestinal microbiota plays a key role in the latter risk factors for cardiovascular disease. A recent study demonstrated …
Non-coding regulatory variations: the dark matter of pancreatic cancer genomics Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-28 Aldo Scarpa, Andrea Mafficini
Pancreatic ductal adenocarcinoma (PDAC) is the seventh cause of death for cancer worldwide and the third in the USA, where it is expected to become the second by year 2030. Unlike other cancers, little progress has been made when it comes to therapeutic options other than surgery, which is possible only for a small fraction (~20%) of patients presenting with localised disease.1 2 For the above reasons, large efforts have been undertaken to get a deeper understanding of the molecular alterations and their effects on cancer cells and tumour microenvironment, by exploiting both innovative disease models and high-throughput studies for genomic and transcriptomic profiling of PDAC.3 4 In the meanwhile, genome-wide association studies, and the study of familial pancreatic cancer, have been looking for and found genetic variations associated to PDAC onset and outcome.5 6 At the genomic level, mutations in the coding region of several genes have been consistently identified, together with disruptive structural alterations whose effect has been linked to the altered functionality (eg, KRAS, TP53 ) or loss (eg, CDNK2A , SMAD4, ARID1A, ROBO2, BRCA1/2 ) of the respective gene products. Frequent and rare alterations identified converge in specific pathways, such as Wnt/Notch, Hedgehog, axon guidance, transforming growth factor beta, SWI/SNF (SWItch/sucrose non-fermentable) and DNA damage repair.3 RNA expression profiles, on the other …
HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-26 Keiichiro Sakuma, Eiichi Sasaki, Kenya Kimura, Koji Komori, Yasuhiro Shimizu, Yasushi Yatabe, Masahiro Aoki
Objective Despite the recent advances in treatment of colon cancer, the prognosis is unfavourable for patients with distant metastases. The aim of this study was to identify targets for prevention and/or therapy of colon cancer metastasis. Design CMT93 cells, a murine rectal cancer cell line with poor metastasising activity, were transduced with lentiviral shRNA library and transplanted into the rectum of syngeneic C57BL/6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNA were retrieved by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNA. Results The genome-wide shRNA library screen identified Hnrnpll ( heterogeneous nuclear ribonucleoprotein L-like ) encoding a pre-mRNA splicing factor as a candidate metastasis suppressor gene. Knockdown of Hnrnpll enhanced matrigel invasion activity of colon cancer cells in vitro, as well as their metastatic ability in vivo. An RNA-immunoprecipitation analysis showed Hnrnpll-binding to Cd44 pre-mRNAs, and the level of Cd44 variable exon 6 ( Cd44v6 ) , a poor prognosis marker of colorectal cancer, was increased by knocking down Hnrnpll . A neutralising Cd44v6 antibody suppressed the matrigel invasion ability induced by Hnrnpll knockdown. HNRNPLL expression was downregulated when colon cancer cells were induced to undergo epithelial-mesenchymal transition (EMT). Immunohistochemistry of clinical samples indicated that colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression. Conclusions HNRNPLL is a novel metastasis suppressor of colorectal cancer, and modulates alternative splicing of CD44 during EMT.
IRTKS is correlated with progression and survival time of patients with gastric cancer Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-24 Li-Yu Huang, Xuefei Wang, Xiao-Fang Cui, He Li, Junjie Zhao, Chong-Chao Wu, Lingqiang Min, Zhicheng Zhou, Lixin Wan, Yu-Ping Wang, Chao Zhang, Wei-Qiang Gao, Yihong Sun, Ze-Guang Han
Background and objectives IRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear. Design We used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS -deficient and p53 -deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53. Results IRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53 +/− mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/− MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21 . Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation. Conclusion IRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.
Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-23 Judith-Mira Pohl, Sebastian Gutweiler, Stephanie Thiebes, Julia K Volke, Ludger Klein-Hitpass, Denise Zwanziger, Matthias Gunzer, Steffen Jung, William W Agace, Christian Kurts, Daniel Robert Engel
Objective Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. Design POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment. Results We found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C– macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI. Conclusions Our findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.
Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-23 Sepideh Levander, Fredrik Holmström, Lars Frelin, Gustaf Ahlén, Daniel Rupp, Gang Long, Ralf Bartenschlager, Matti Sällberg
Objective HCV is characterised by its ability to establish chronic infection in hepatocytes and to replicate in the presence of an inflammation. We mimicked this situation in vivo in immune-competent mice by syngeneic transplantation of HCV replicon-containing mouse hepatoma cells. Design A total of 5 million H-2b positive Hep56.1D cells, carrying a subgenomic genotype (gt) 2a replicon (HCV replicon cells) or stably expressing comparable levels of the HCV NS3/4A protease/helicase complex (NS3/4A hepatoma cells), were injected subcutaneously into syngeneic H-2b-restricted mice. Kinetics of tumour growth, HCV RNA replication levels and HCV-specific immune responses were monitored. For immune monitoring, new H-2b-restricted cytotoxic T cell epitopes within the gt2a NS3/4A region were mapped. Immune mice were generated by DNA-based vaccination. Results HCV replicon and NS3/4A hepatoma cells generated solid tumours in vivo. Similar to what is seen in human HCV infection did HCV RNA replicate in the presence of inflammation. NS3/4A-specific CD8+ T cells seemed to transiently reduce HCV RNA levels. Both CD4+ and CD8+ T cells were required for protection against tumour growth. Vaccine-induced NS3/4A(gt2a)-specific T cells protected against HCV replicon tumours in wild-type, but not in HCV NS3/4A(gt1a)-transgenic mice with dysfunctional HCV-specific T cells. Importantly, as in human HCV infection, HCV replicon cells neither primed nor boosted a strong NS3/4A-specific T cell response. Conclusion Syngeneic transplantation of mouse HCV replicon cells into immune-competent animals mirrors many in vivo events in humans. This system is versatile and can be applied to any genetically modified H-2b-restricted mouse strain.
Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-22 Usman Barlass, Raini Dutta, Hassam Cheema, John George, Archana Sareen, Ajay Dixit, Zuobiao Yuan, Bhuwan Giri, Jingjing Meng, Santanu Banerjee, Sulagna Banerjee, Vikas Dudeja, Rajinder K Dawra, Sabita Roy, Ashok K Saluja
Background Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis. Methods Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol–palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (µ) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of µ-opioid receptors in morphine’s effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR. Results Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine’s effect on severity of acute pancreatitis are mediated through the µ-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1. Conclusion Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies.
Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-20 Mingfeng Zhang, Soren Lykke-Andersen, Bin Zhu, Wenming Xiao, Jason W Hoskins, Xijun Zhang, Lauren M Rost, Irene Collins, Martijn van de Bunt, Jinping Jia, Hemang Parikh, Tongwu Zhang, Lei Song, Ashley Jermusyk, Charles C Chung, Bin Zhu, Weiyin Zhou, Gail L Matters, Robert C Kurtz, Meredith Yeager, Torben Heick Jensen, Kevin M Brown, Halit Ongen, William R Bamlet, Bradley A Murray, Mark I McCarthy, Stephen J Chanock, Nilanjan Chatterjee, Brian M Wolpin, Jill P Smith, Sara H Olson, Gloria M Petersen, Jianxin Shi, Laufey Amundadottir
Objective To elucidate the genetic architecture of gene expression in pancreatic tissues. Design We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. Results We identified 38 615 cis -eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis -eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis -eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis -eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10−8) and tumour-derived (p=8.3×10−5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the ‘O’ mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. Conclusions We have identified cis -eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.
Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-14 Hung-Yu Sun, Pin-Nan Cheng, Chiung-Ying Tseng, Wei-Jen Tsai, Yen-Cheng Chiu, Kung-Chia Young
Objective Lipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment. Design Twenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unit Results DAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism. Conclusion The DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.
CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-14 Giovanna Farro, Michelle Stakenborg, Pedro J Gomez-Pinilla, Evelien Labeeuw, Gera Goverse, Martina Di Giovangiulio, Nathalie Stakenborg, Elisa Meroni, Francesca D’Errico, Yvon Elkrim, Damya Laoui, Zofia M Lisowski, Kristin A Sauter, David A Hume, Jo A Van Ginderachter, Guy E Boeckxstaens, Gianluca Matteoli
Objective Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. Design IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2−/ − mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation. Results At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 − / − mice. However, GI transit recovery after IM was significantly delayed in Ccr2 − / − mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in Ccr2 − / − mice. Conclusion Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.
Janus-like monocytes regulate postoperative ileus Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-14 Allan McI Mowat
In this issue of Gut , Farro et al and Pohl et al present new findings on the role of myeloid cells in postoperative ileus (POI).1 2 POI is a frequent consequence of abdominal surgery that can lead to costly delays in patient recovery.3 The failure of peristalsis reflects paralysis of the smooth muscles of the intestine and several studies have suggested that this is dependent on macrophages in the muscularis externa (ME) layer of the gut wall that produce nitric oxide (NO).4 The intestine contains one of the largest pools of macrophages in the body, the majority of which is located in the lamina propria (LP) of the mucosa, near the epithelium. However macrophages are also present between the longitudinal and circular muscle layers of the ME, where they are in close proximity to the myenteric plexus.5 6 Recent studies indicate that LP and ME macrophages are phenotypically and functionally distinct under steady-state conditions.6 In particular, ME macrophages appear to have specialised tissue protection functions, including the production of factors such as bone morphogenic protein-2 (BMP2) that promote neuronal growth. In return, β2-adrenergic receptors on ME macrophages allow them to be sustained by sympathetic neurons and these two-way interactions are at least partly dependent on the …
The somatic mutation landscape of premalignant colorectal adenoma Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-12 Shu-Hong Lin, Gottumukkala S Raju, Chad Huff, Yuanqing Ye, Jian Gu, Jiun-Sheng Chen, Michelle A T Hildebrandt, Han Liang, David G Menter, Jeffery Morris, Ernest Hawk, John R Stroehlein, Andrew Futreal, Scott Kopetz, Lopa Mishra, Xifeng Wu
Objective There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. Design Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. Results Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. Conclusion The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.
PRSS1 copy number variants and promoter polymorphisms in pancreatitis: common pathogenetic mechanism, different genetic effects Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Emmanuelle Masson, Jian-Min Chen, David N Cooper, Claude Férec
We have read with interest three related papers that were recently published in this journal.1–3 Taken together, the findings reported in these papers (summarised in online supplementary note) suggest that loss-of-function PRSS1 promoter variants can protect against pancreatitis. The other side of the coin is however that gain-of-function PRSS1 promoter variants predispose to pancreatitis. It therefore follows that the risk-associated [rs4726576C; rs10273639C] allele shares a common pathogenetic mechanism with the previously reported trypsinogen duplication and triplication copy number variants (CNVs)4 5 as both types of variant predispose to pancreatitis by increasing PRSS1 expression; this mechanism is quite distinct from either the increased activation and/or stability of trypsin(ogen) or misfolding-induced endoplasmic reticulum stress caused by disease-associated PRSS1 missense mutations.6 However, despite both serving to increase PRSS1 expression, the promoter variant and the CNVs differ significantly in terms of the …
The role of hepatokines in NAFLD-related extrahepatic diseases: culprit or accomplice? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Ri-Yue Jiang, Ling Yang
We recently read with great interest a review by Adams et al 1 showing that non-alcoholic fatty liver disease (NAFLD) has a profound impact on the onset of extrahepatic diseases, such as cardiovascular diseases and kidney diseases. We fully agree with this conclusion, and the authors have fully elucidated the relationship between NAFLD and extrahepatic diseases. We think that hepatokines produced and secreted by liver may play a critical role in NAFLD-related extrahepatic diseases, which would deepen the understanding of this disease. Fibroblast growth factor 21 (FGF21), a hepatokine that is mainly secreted by the liver, has beneficial effects for improving metabolic …
Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Jatinder Goyal, Jodie A Barkin, Jamie S Barkin
We read with great interest the article by Masamune et al 1 regarding the role of long-term maintenance corticosteroids in patients with autoimmune pancreatitis (AIP).1 AIP is a steroid responsive disorder, which has two distinct entities with overlapping features, classified as type I and type II AIP. While type I AIP is a part of a spectrum of IgG4-related disease with extrapancreatic manifestations, type II is a pancreas-specific disease. The diagnostic criteria, treatment approach and prognosis are different between the …
Adalimumab in Crohn's disease and symptomatic small bowel strictures Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Yoram Bouhnik, Jean-Yves Mary
We thank Sonambekar et al 1 for their pertinent remarks, which raised the problem of some errors in our manuscript2 and gave us the opportunity to correct them: (1) the length of the strictures on MRI is in centimetres and not in millimetres (table 3); …
Longitudinal analysis indicates symptom severity influences immune profile in irritable bowel syndrome Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Chris Mavrangelos, Melissa A Campaniello, Jane M Andrews, Peter A Bampton, Patrick A Hughes
The recent study by Wouters et al 1 reported that psychological status inversely correlates with immune profile in the development of postinfectious IBS. While there is increasing evidence of chronic low-grade immune activation in IBS, this field is mired in controversy.2 In our opinion, this contention is related to two major methodological issues: the tendency to group all patients with IBS together rather than stratifying according to bowel habit,3 and the overwhelming predominance of cross-sectional studies. We addressed these issues by performing a longitudinal study of patients with IBS comparing immune function within patients when symptom free and when they experience symptom flare. Eleven subjects with long-standing IBS (initially characterised by ROME II criteria: 5 IBS-D, 4 IBS-A, 2 IBS-C; 10 female; 59±3 years (mean±SEM)) were enrolled sequentially from tertiary centres in Adelaide, Australia. Subjects completed a valid self-report Bowel Disease Questionnaire3 and …
NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-10 Loïc Rolas, Abdelali Boussif, Emmanuel Weiss, Philippe Lettéron, Oualid Haddad, Jamel El-Benna, Pierre-Emmanuel Rautou, Richard Moreau, Axel Périanin
Objective Cirrhosis downregulates phagocyte oxidant production via their antibacterial superoxide-generating system, NADPH oxidase (NOX2) and increases patients’ susceptibility to infection and mortality rate. To explore novel biochemical parameters that explain susceptibility to infections, we investigated the expression of NOX2 and partners in neutrophils of patients with severe alcoholic cirrhosis and have provided a novel approach to restore superoxide production capacity in patients’ neutrophils and blood. Design Neutrophils were isolated from patients with decompensated alcoholic cirrhosis. NOX2 activity was assessed after stimulation of purified neutrophils or whole blood with the bacterial-derived peptide fMet-Leu-Phe. The expression of NOX2 and partners was studied by western blot analysis, flow cytometry and reverse transcription-PCR. Results The impaired superoxide production by patients’ neutrophils was associated with a severe deficient expression of the NADPH oxidase catalytic core flavocytochrome-b558 (gp91 phox /NOX2 and p22 phox ), its cytosolic partner p47 phox but not p67 phox . NOX2 expression decreased rapidly by protein degradation involving elastase released during degranulation of healthy neutrophils stimulated with fMet-Leu-Phe, or highly present in patients’ plasma. Interestingly, the deficient superoxide production was reversed by treatment of patients’ neutrophils and whole blood with toll-like receptor 7/8 (TLR7/8) agonists. This treatment stimulated a rapid NOX2 transcription and translation through a process involving mammalian target of rapamycin (mTOR) whose expression was also deficient in patients’ neutrophils. NOX2 expression was also increased by the TLR4 agonist lipopolysaccharide but with only a modest improvement of reactive oxygen species production. Conclusion Impairment of neutrophil oxidants production in alcoholic cirrhosis is associated with NOX2 degradation and deficient mTOR-dependent translational machinery. The NOX2 depletion can be reversed via TRL7/8 activation and might be used to restore antimicrobial responses of immunocompromised patients.
High body mass index and the risk of hepatocellular carcinoma Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-07 Zheng Wang, Han Zhang, Jun Han, Meng-Chao Wu, Tian Yang
We read with great interest the recent article by Hagström et al, 1 in which they used register data from more than 1.2 million Swedish men enlisted for conscription between 1969 and 1996 in order to investigate the relationship between body mass index (BMI) in late adolescence and future liver diseases. During a follow-up of more than 34 million person-years, 251 cases of hepatocellular carcinoma (HCC) were identified from the Swedish Cancer Register (SCR). In this study, the authors used a sample survey …
Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-07 Kewin Tien Ho Siah, Xiaorong Gong, Xi Jessie Yang, William E Whitehead, Minhu Chen, Xiaohua Hou, Nitesh Pratap, Uday C Ghoshal, Ari F Syam, Murdani Abdullah, Myung-Gyu Choi, Young-Tae Bak, Ching-Liang Lu, Sutep Gonlachanvit, Chua Seng Boon, Fan Fang, Pui Kuan Cheong, Justin C Y Wu, Kok-Ann Gwee
Objective Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID. Design 1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters. Results Nine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence). Conclusion We found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.
FOXAI: a phase II trial evaluating the efficacy and safety of hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced hepatocellular carcinoma Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-07 Ning Lyu, Youen Lin, Yanan Kong, Zhenfeng Zhang, Longzhong Liu, Lie Zheng, Luwen Mu, Jianpeng Wang, Xishan Li, Tao Pan, Qiankun Xie, Yaru Liu, Aihua Lin, Peihong Wu, Ming Zhao
We read with interest the article of recent advances in clinical practice of hepatocellular carcinoma (HCC) treatment by Bruix et al in Gut. 1 In this review, the Barcelona Clinic Liver Cancer (BCLC) Group recommended sorafenib as the standard treatment for BCLC-C stage (advanced stage) HCC. However, application of sorafenib as first treatment for advanced HCC worldwide was low according to a multiregional, large-scale, longitudinal cohort study.2 This may be attributed to some limitations of sorafenib: low response rate, modest survival advantage, complex mechanism underlying acquired resistance and high-level heterogeneity of individual response.3 4 Recently, evidence from an individual patient data meta-analysis of phase III randomised controlled trial showed no improvement in overall survival attributable to sorafenib for HBV-related HCC.5 Therefore, more alternative strategies are highly required.6 Hepatic arterial infusion (HAI) chemotherapy (HAIC) attracted more attentions in recent years …
CD14+CD15-HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-07 Christine Bernsmeier, Evangelos Triantafyllou, Robert Brenig, Fanny J Lebosse, Arjuna Singanayagam, Vishal C Patel, Oltin T Pop, Wafa Khamri, Rooshi Nathwani, Robert Tidswell, Christopher J Weston, David H Adams, Mark R Thursz, Julia A Wendon, Charalambos Gustav Antoniades
Objective Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. Design Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. Results Circulating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. Conclusion Immunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.
Fungal dysbiosis in cirrhosis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-06-03 Jasmohan S Bajaj, Eric J Liu, Raffi Kheradman, Andrew Fagan, Douglas M Heuman, Melanie White, Edith A Gavis, Phillip Hylemon, Masoumeh Sikaroodi, Patrick M Gillevet
Objective Cirrhotics have a high rate of infections, which are increasingly fungal or culture-negative in nature. While infected cirrhotics have bacterial dysbiosis, the role of fungi is unclear. We aimed to evaluate gut bacterial and fungal dysbiosis in cross-sectional and longitudinal analyses of outpatient and inpatient cirrhotics and prediction of hospitalisations. Methods Cross-sectional: Age-matched controls, outpatients (with/without antibiotics) and hospitalised uninfected, culture-negative and culture-positive cirrhotics were included and followed for 90 days. Longitudinal: Three studies were conducted: (1) cirrhotics followed over 6 months, (2) outpatient cirrhotics administered antibiotics per standard of care for 5 days and (3) cirrhotics and controls administered omeprazole over 14 days. In all studies, stool bacterial/fungal profiles were analysed. Results Cross-sectional: In 143 cirrhotics and 26 controls, bacterial and fungal diversities were significantly linked. Outpatients on antibiotics and patients with culture-positive infections had the lowest diversities. Bacterial and fungal correlations were complex in uninfected, outpatient and control groups but were markedly skewed in infected patients. 21% were admitted on 90-day follow-up. A lower Bacteroidetes/Ascomycota ratio was associated with lower hospitalisations. Longitudinal: Fungal and bacterial profiles were stable on follow-up (5 days and 6 months). After antibiotics, a significantly reduced bacterial and fungal diversity, higher Candida and lower autochthonous bacterial relative abundance were seen. After omeprazole, changes in bacterial diversity and composition were seen but fungal metrics remained stable. Conclusion There is a significant fungal dysbiosis in cirrhosis, which changes differentially with antibiotics and proton pump inhibitor use, but is otherwise stable over time. A combined bacterial–fungal dysbiosis metric, Bacteroidetes/Ascomycota ratio, can independently predict 90-day hospitalisations in patients with cirrhosis. Clinical trial number NCT01458990.
Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-26 Christoph Grander, Timon E Adolph, Verena Wieser, Patrick Lowe, Laura Wrzosek, Benedek Gyongyosi, Doyle V Ward, Felix Grabherr, Romana R Gerner, Alexandra Pfister, Barbara Enrich, Dragos Ciocan, Sophie Macheiner, Lisa Mayr, Matthias Drach, Patrizia Moser, Alexander R Moschen, Gabriel Perlemuter, Gyongyi Szabo, Anne Marie Cassard, Herbert Tilg
Objective Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila , a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD. Design The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed. Results Patients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration. Conclusion Ethanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation.
A metabolomics-based biomarker signature discriminates pancreatic cancer from chronic pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-24 Eithne Costello
The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. The projection that it will surpass breast cancer to become the second-leading cause of cancer-related deaths by 2030 serves as a wake-up call to stakeholders, including healthcare systems and researchers.1 Earlier diagnosis is one factor that could alter this trajectory. Correspondingly, the research community has made substantial efforts to find biomarkers that will enable the diagnosis of pancreatic cancer at a stage where it can be successfully treated.2 There are however, significant challenges. Pancreatic cancer is a very heterogeneous disease with great interindividual variation, as well as significant heterogeneity within the tumours of individuals.3 4 This calls for large sample sizes to ensure adequate representation of subtypes. Moreover, biomarker development programmes require samples to be separated into independent training and test sets, further increasing the quantity of samples needed. However, the number of new cases of pancreatic cancer per year is low compared with other common cancers. Therefore, in order to acquire sufficient samples of patients with cancer and control individuals for biomarker studies, multicentre collaborations are essential. Such collaborations require orchestration, as the use of standardised protocols for collection and storage of both case and control samples across centres minimises …
Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-15 Tao Zuo, Sunny H Wong, Kelvin Lam, Rashid Lui, Kitty Cheung, Whitney Tang, Jessica Y L Ching, Paul K S Chan, Martin C W Chan, Justin C Y Wu, Francis K L Chan, Jun Yu, Joseph J Y Sung, Siew C Ng
Objective Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. Design Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. Results Subjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria , Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. Conclusions In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. Trial registration number [NCT02570477] : https://clinicaltrials.gov/ct2/show/NCT02570477?term=NCT02570477&rank=1
Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-03-24 Allison Cabinian, Daniel Sinsimer, May Tang, Youngsoon Jang, Bongkum Choi, Yasmina Laouar, Amale Laouar
Background Interactions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field. Aim We have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is. Methods Expression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFPtg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium . Results SLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC) TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death. Conclusions SLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.
Repair macrophages in acute liver failure Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-06 Tobias Puengel, Frank Tacke
Inflammation is increasingly recognised to critically determine the clinical course and outcome of acute liver failure (ALF). On the one hand, massive hepatocyte cell death triggers immune cell activation and recruitment to the liver, which can stimulate immune-mediated liver damage. On the other hand, systemic activation of inflammation, systemic inflammatory response syndrome, promotes multiple organ failure and defective antimicrobial responses.1 Innate immune mechanisms play a prominent role in ALF. Mouse models of acute liver injury revealed that liver-resident macrophages, Kupffer cells, sense hepatocyte-mediated release of alarmins, which results in Kupffer cell activation and cytokine release.2 Hence, neutrophils and monocytes are recruited from the bloodstream to the site of injury. During the early phase after recruitment, neutrophils and monocytes have an inflammatory phenotype and aggravate tissue damage.3 4 However, there is ample experimental evidence that monocyte-derived macrophages change their phenotype in the liver, if injury has terminated, towards repair-promoting phagocytes.5 6 Up to now, the ‘human counterpart’ of inflammatory versus restorative macrophages in ALF has been vague. In this issue of Gut , Dr. Antoniades and coworkers present compelling experimental evidence from human samples and a mouse model that restorative macrophages in ALF …
Hepatitis B virus X protein: TRIMming antiviral defences in hepatocytes Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-05 Emmanuel Thomas
Humans and viruses have coevolved over thousands of years; however, very few viruses are able to manifest as chronic infections with most being cleared after an acute course. Consequently, success of the human species has relied on a functional immune system that is capable of fighting off most viral pathogens. The heptatitis B virus (HBV) is one of the most successful viruses to establish chronic infection in man with over 300 million individuals currently infected worldwide and over 2 billion humans having been infected by this virus.1 These numbers underscore the tremendous ability of HBV to thwart the human immune system and establish chronic infection. In this issue of Gut , Lim et al 2 have provided evidence for a new mechanism through which HBV is able to establish and maintain chronic infection. They specifically examine the role of the enigmatic HBx protein3 in the regulation of TRIM22, a protein that has increasingly become associated with innate antiviral responses.4 5 Previous studies have demonstrated that HBx, a virally encoded protein that plays unusual roles in its life cycle, can block the antiviral response in addition …
Chromosomal instability in HCC: a key function for checkpoint kinase 2 Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-05 Robert Eferl, Michael Trauner
The German cytologist Theodor Boveri proposed about 100 years ago that cancer is caused by an abnormal distribution of microscopic bodies called chromosomes. At that time, researchers had no idea of the cellular component for inheritance and challenged his hypothesis. Meanwhile, genomic instability is viewed as a hallmark of cancer1 and an alternative model for cancer formation was put forward that proposed acquisition of a ‘mutator’ phenotype as the initiating event. Although supported by the vast plasticity of sequence changes and chromosomal aberrations in individual cells of single tumours, these observations did not solve the issue whether the ‘mutator’ phenotype is a precondition or a consequence of tumourigenesis. The ‘mutator’ phenotype is causative for genomic instability, an umbrella term for small DNA structure variations, microsatellite instability and chromosomal instability (CIN).2 The latter affects chromosome number and structure and is a characteristic feature of many cancer types including hepatocellular carcinoma (HCC).3 It is also associated with the formation of extranuclear bodies that contain damaged chromosome fragments or whole chromosomes. Such micronuclei were identified in regenerative and dysplastic nodules of the liver indicating that CIN can be acquired already in early stage hepatocarcinogenesis.3 Apparently, CIN is linked to certain cancer genotypes because HCC has been originally divided into two major subclasses: one displaying a stable cancer genome and activating β-catenin mutations, and the other with extensive CIN, p53 and Axin …
The microbiota: an underestimated actor in radiation-induced lesions? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-04 Harry Sokol, Timon Erik Adolph
The co-evolution of humans and microbes that colonise the GI tract is shaped by environmental factors and evolved to promote health.1 Microbial derangements (termed dysbiosis) have been observed for a variety of intestinal and extraintestinal diseases.1 Metabolic, autoimmune, liver and intestinal disorders have been linked to microbial dysbiosis which promotes susceptibility to inflammatory disease in some cases as largely assessed in animal models.2 Intestinal dysbiosis has also been implicated in colorectal cancer3 and microbes may determine treatment response for non-intestinal malignancies.4 For more than 10 years, intestinal microbial alterations have been associated with localised radiation in humans and mouse models.5–8 Importantly, mice that lack colonisation of microbes (ie, raised germ free) were resistant to lethal radiation enteritis, indicating that the microbiota controls intestinal disease processes consequent to radiation-induced damage.9 In this context, however, the …
Tumour-associated and non-tumour-associated microbiota in colorectal cancer Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-04 Hafid Omar Al-Hassi, Oliver Ng, Matthew Brookes
We read with interest the elegant study published by Flemer et al 1 and commend the authors on their work. The authors provide convincing data to illustrate that faecal microbiota does not reflect accurately the underlying mucosal microbiota in patients with colorectal cancer (CRC).1 The authors also provide supporting evidence to illustrate that microbiota from sampled mucosa both on and off the cancer site is not significantly different. As previously demonstrated, they also provide corroboratory evidence to further conclude that microbiota is different in patients with CRC. We are however concerned about the conclusions relating to the variability of mucosal microbiota based on tumour site. …
Pioglitazone for the treatment of NASH in patients with prediabetes or type 2 diabetes mellitus—authors' response Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-03 Yaron Rotman, Arun J Sanyal
We would like to thank Professor Cusi1 for pointing out the omission of the important randomised controlled trial,2 in which he and his colleagues have essentially …
CD177+ neutrophils as functionally activated neutrophils negatively regulate IBD Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-05-03 Guangxi Zhou, Lin Yu, Leilei Fang, Wenjing Yang, Tianming Yu, Yinglei Miao, Minhu Chen, Kaichun Wu, Feidi Chen, Yingzi Cong, Zhanju Liu
Background Neutrophils are accumulated in inflamed mucosa of IBD and play an important role in the pathogenesis. CD177 is expressed in neutrophils specifically and upregulated during inflammation. However, the role of CD177+ neutrophils in pathogenesis of IBD remains elusive. Materials and methods Expression of CD177 was analysed in peripheral blood and intestinal mucosa from patients with IBD using quantitative RT-PCR, flow cytometry and immunohistochemistry. CD177+ and CD177− neutrophils were isolated to determine gene differences by RNA sequencing. Colitis was established in CD177−/− and wild-type mice in response to dextran sulfate sodium (DSS) insults to determine the role of CD177+ neutrophils in IBD. Results CD177+ neutrophils were markedly increased in peripheral blood and inflamed mucosa from patients with active IBD compared with healthy controls. RNA sequencing revealed that differential gene expression between CD177+ and CD177− neutrophils from patients with IBD was associated with response to bacterial defence, hydrogen peroxide and reactive oxygen species (ROS). CD177+ neutrophils produced lower levels of proinflammatory cytokines (ie, interferon-γ, interleukin (IL)-6, IL-17A), but higher levels of IL-22 and transforming growth factor-β, and exhibited increased bactericidal activities (ie, ROS, antimicrobial peptides, neutrophil extracellular trap) compared with CD177− subset. CD177−/− mice developed more severe colitis on DSS insults compared with wild-type mice. Moreover, CD177 deficiency led to compromised intestinal barrier and impaired antibacterial immunity through decreased production of IL-22 by CD177− neutrophils. Conclusions CD177+ neutrophils represent functionally activated population and play a protective role in IBD through increased bactericidal activity and IL-22 production. Targeting CD177+ neutrophils may be beneficial for treatment of IBD.
MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-04-27 Evangelos Triantafyllou, Oltin T Pop, Lucia A Possamai, Annika Wilhelm, Evaggelia Liaskou, Arjuna Singanayagam, Christine Bernsmeier, Wafa Khamri, Gemma Petts, Rebecca Dargue, Scott P Davies, Joseph Tickle, Muhammed Yuksel, Vishal C Patel, Robin D Abeles, Zania Stamataki, Stuart M Curbishley, Yun Ma, Ian D Wilson, Muireann Coen, Kevin J Woollard, Alberto Quaglia, Julia Wendon, Mark R Thursz, David H Adams, Chris J Weston, Charalambos G Antoniades
Objective Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. Design Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
Clinical relevance of detecting anti-infliximab antibodies with a drug-tolerant assay: post hoc analysis of the TAXIT trial Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-04-27 Thomas Van Stappen, Niels Vande Casteele, Gert Van Assche, Marc Ferrante, Séverine Vermeire, Ann Gils
Objective To evaluate the clinical relevance of antidrug antibodies (ADAs) measured using a drug-tolerant assay in a post hoc analysis of the Trough Concentration (TC) Adapted Infliximab Treatment (TAXIT) randomised controlled trial. Design ADA in serum samples (n=221) of 76 patients enrolled in TAXIT, who presented with an infliximab TC <3 µg/mL at screening, were reanalysed after optimisation and at the end of the study using a drug-tolerant ADA assay. Patients underwent dose escalation to achieve therapeutic TCs between 3 µg/mL and 7 µg/mL prior to randomisation. Patients were grouped into quartiles (Q1–4) according to ADA concentration at screening. Results Using a drug-tolerant assay, the immunogenicity detection rate increased from 21% (drug-sensitive assay) to 63% at screening, from 0% to 51% after optimisation and from 3% to 42% at the end of TAXIT. Patients in ADA Q4 required a higher cumulative infliximab dose (2390 (880–2998) mg) to achieve target TCs, resulting in a higher drug cost (€10 712 (4120–13 596)) compared with ADA-negative patients (€2060 (1648–3296)) and patients in ADA Q1/Q2 (€2060 (1648–4120)/€2060 (1751–3296), p<0.001). However, all but one patient belonging to ADA Q4 were also ADA-positive using a drug-sensitive assay. Conclusions Upon dose intensification, low concentration ADAs, not detectable using a drug-sensitive assay, disappear in more than half of the patients over time and are clinically non-relevant. In contrast, high concentration ADAs which are typically also detected in a drug-sensitive assay, persist over time and necessitate a higher cumulative dose and drug cost. In the latter group, proactive drug switching may be more cost-efficient. Clinical Trials Register 2011-002061-38; Post-results.
Gastro-oesophageal reflux events: just another trigger in chronic cough? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-04-25 L A Houghton, J A Smith
GORD is considered a common cause of chronic cough, either alone or in association with nasal disease and/or asthma.1 This, along with the fact that there are currently no specific therapies approved for the treatment of chronic cough, has led to extensive use of acid suppressants, such that one US study in patients with extraoesophageal manifestations of GORD, of which 50% had cough, estimated costs to be four to five times those associated with their use in typical GORD.2 Despite this widespread use, a significant proportion of patients with chronic cough thought to be due to GORD remain refractory to acid suppression. Indeed, multiple studies and meta-analyses have failed to document a therapeutic benefit of acid suppression in chronic cough.3 A growing number of studies suggest that in 30%–48% of patients, coughing episodes seem to be temporally linked to reflux events, irrespective of their acidity or the presence of other conditions contributing to coughing.1 ,4 ,5 Notably, patients exhibiting such associations, that is, a positive symptom association probability (SAP) for cough preceded by reflux (SAPR-C), appear to have no more erosive disease or oesophageal exposure to reflux, with little reaching the proximal oesophagus, than those with a negative SAPR-C.5 SAPR-C-positive patients, however, do have a heightened cough …
Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-04-25 Xiaofang Huo, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Kerry B Dunbar, Thai H Pham, John P Lynch, David H Wang, Robert S Bresalier, Stuart J Spechler, Rhonda F Souza
Objective In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. Design We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. Results In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. Conclusions Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
- Acad. Manag. Ann.
- Acc. Chem. Res.
- ACS Appl. Mater. Interfaces
- ACS Biomater. Sci. Eng.
- ACS Catal.
- ACS Cent. Sci.
- ACS Chem. Biol.
- ACS Chem. Neurosci.
- ACS Comb. Sci.
- ACS Earth Space Chem.
- ACS Energy Lett.
- ACS Infect. Dis.
- ACS Macro Lett.
- ACS Med. Chem. Lett.
- ACS Nano
- ACS Omega
- ACS Photonics
- ACS Sens.
- ACS Sustainable Chem. Eng.
- ACS Synth. Biol.
- Acta Mater.
- Acta Neuropathol.
- Adv. Drug Deliver. Rev.
- Adv. Electron. Mater.
- Adv. Energy Mater.
- Adv. Funct. Mater.
- Adv. Healthcare Mater.
- Adv. Mater.
- Adv. Opt. Mater.
- Adv. Opt. Photon.
- Adv. Phys.
- Adv. Sci.
- Adv. Synth. Catal.
- AlChE J.
- Alzheimers Dement.
- Am. J. Hum. Genet.
- Am. J. Psychiatry
- Am. J. Respir. Crit. Care Med.
- Anal. Chem.
- Anal. Chim. Acta
- Anal. Methods
- Angew. Chem. Int. Ed.
- Ann. Intern. Med.
- Ann. Neurol.
- Ann. Oncol.
- Ann. Rheum. Dis.
- Annu. Rev. Anal. Chem.
- Annu. Rev. Astron. Astrophys.
- Annu. Rev. Biochem.
- Annu. Rev. Biomed. Eng.
- Annu. Rev. Biophys.
- Annu. Rev. Cell Dev. Biol.
- Annu. Rev. Clin. Psychol.
- Annu. Rev. Condens. Matter Phys.
- Annu. Rev. Earth Planet. Sci.
- Annu. Rev. Ecol. Evol. Syst.
- Annu. Rev. Entomol.
- Annu. Rev. Fluid Mech.
- Annu. Rev. Immunol.
- Annu. Rev. Mar. Sci.
- Annu. Rev. Mater. Res.
- Annu. Rev. Med.
- Annu. Rev. Microbiol.
- Annu. Rev. Neurosci.
- Annu. Rev. Nutr.
- Annu. Rev. Pathol. Mech. Dis.
- Annu. Rev. Pharmacol. Toxicol.
- Annu. Rev. Phys. Chem.
- Annu. Rev. Physiol.
- Annu. Rev. Phytopathol.
- Annu. Rev. Plant Biol.
- Annu. Rev. Psychol.
- Annu. Rev. Publ. Health
- Annu. Rev. Virol.
- Antivir. Res.
- Appl. Catal. A Gen.
- Appl. Catal. B Environ.
- Appl. Energy
- Appl. Phys. Lett.
- Appl. Phys. Rev.
- Arch. Pharm.
- Asian J. Org. Chem.
- CA: Cancer J. Clin.
- Cancer Cell
- Cancer Discov.
- Cancer Res.
- Carbohydr. Polym.
- Catal. Sci. Technol.
- Catal. Today
- Cell Chem. Bio.
- Cell Host Microbe
- Cell Metab.
- Cell Res.
- Cell Stem Cell
- Ceram. Int.
- Chem. Asian J.
- Chem. Bio. Drug Des.
- Chem. Commun.
- Chem. Educ. Res. Pract.
- Chem. Eng. J.
- Chem. Eur. J.
- Chem. Mater.
- Chem. Phys.
- Chem. Phys. Lett.
- Chem. Res. Toxicol.
- Chem. Rev.
- Chem. Sci.
- Chem. Soc. Rev.
- Circ. Res.
- Clin. Cancer Res.
- Clin. Microbiol. Rev.
- Compos. Part A Appl. Sci. Manuf.
- Comput. Fluids
- Coordin. Chem. Rev.
- Corros. Sci.
- Crit. Rev. Food Sci. Nutr.
- Cryst. Growth Des.
- Curr. Opin. Biotech.
- Curr. Opin. Cell Biol.
- Ecol. Lett.
- Electrochem. Commun.
- Electrochim. Acta
- Endocr. Rev.
- Energy Environ. Sci.
- Energy Fuels
- Environ. Pollut.
- Environ. Sci. Technol.
- Environ. Sci. Technol. Lett.
- Environ. Sci.: Nano
- Environ. Sci.: Processes Impacts
- Environ. Sci.: Water Res. Technol.
- Eur. Heart J.
- Eur. J. Inorg. Chem.
- Eur. J. Med. Chem.
- Eur. J. Org. Chem.
- Eur. Polym. J.
- Eur. Respir. J.
- Eur. Urol.
- Ecol. Lett.
- Electrochem. Commun.
- Electrochim. Acta
- Endocr. Rev.
- Energy Environ. Sci.
- Energy Fuels
- Environ. Pollut.
- Environ. Sci. Technol.
- Environ. Sci. Technol. Lett.
- Environ. Sci.: Nano
- Environ. Sci.: Processes Impacts
- Environ. Sci.: Water Res. Technol.
- Eur. Heart J.
- Eur. J. Inorg. Chem.
- Eur. J. Med. Chem.
- Eur. J. Org. Chem.
- Eur. Polym. J.
- Eur. Respir. J.
- Eur. Urol.
- J Nucl. Med.
- J. Agric. Food Chem.
- J. Allergy Clin. Immunol.
- J. Alloys Compd.
- J. Am. Ceram. Soc.
- J. Am. Chem. Soc.
- J. Am. Coll. Cardiol.
- J. Anal. At. Spectrom.
- J. Antibiot.
- J. Cachexia Sarcopenia Muscle
- J. Catal.
- J. Chem. Educ.
- J. Chem. Eng. Data
- J. Chem. Inf. Model.
- J. Chem. Phys.
- J. Chem. Theory Comput.
- J. Chromatogr. A
- J. Chromatogr. B
- J. Clin. Invest.
- J. Clin. Oncol.
- J. Comput. Chem.
- J. Comput. Phys.
- J. Control. Release
- J. Cryst. Growth
- J. Electrochem. Soc.
- J. Eur. Ceram. Soc.
- J. Exp. Med.
- J. Fluid Mech.
- J. Fluorine Chem.
- J. Funct. Foods
- J. Hazard. Mater.
- J. Hepatol.
- J. Mater. Chem. A
- J. Mater. Chem. B
- J. Mater. Chem. C
- J. Med. Chem.
- J. Membr. Sci.
- J. Nat. Gas Sci. Eng.
- J. Nat. Prod.
- J. Natl. Cancer Inst.
- J. Org. Chem.
- J. Photochem. Photobiol. C Photochem. Rev.
- J. Phys. Chem. A
- J. Phys. Chem. B
- J. Phys. Chem. C
- J. Phys. Chem. Lett.
- J. Pineal. Res.
- J. Power Sources
- J. Proteome Res.
- J. Virol.
- JACC Cardiovasc. Imag.
- JAMA Intern. Med.
- JAMA Neurol.
- JAMA Oncol.
- JAMA Pediatr.
- JAMA Psychiatry