Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-28 Javier Fernández, Juan Acevedo, Reiner Weist, Thierry Gustot, Alex Amoros, Carme Deulofeu, Enric Reverter, Javier Martínez, Faouzi Saliba, Rajiv Jalan, Tania Welzel, Marco Pavesi, María Hernández-Tejero, Pere Ginès, Vicente Arroyo
Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.
Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-03 Sandra van Brunschot, Robbert A Hollemans, Olaf J Bakker, Marc G Besselink, Todd H Baron, Hans G Beger, Marja A Boermeester, Thomas L Bollen, Marco J Bruno, Ross Carter, Jeremy J French, Djalma Coelho, Björn Dahl, Marcel G Dijkgraaf, Nilesh Doctor, Peter J Fagenholz, Gyula Farkas, Carlos Fernandez del Castillo, Paul Fockens, Martin L Freeman, Timothy B Gardner, Harry van Goor, Hein G Gooszen, Gerjon Hannink, Rajiv Lochan, Colin J McKay, John P Neoptolemos, Atilla Oláh, Rowan W Parks, Miroslav P Peev, Michael Raraty, Bettina Rau, Thomas Rösch, Maroeska Rovers, Hans Seifert, Ajith K Siriwardena, Karen D Horvath, Hjalmar C van Santvoort
Objective Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking.Design We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%).Results Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005).Conclusion In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.
Young woman with segmental colitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-12 Zaid Imam, Bradley W Anderson, Seth Sweetser
A 22-year-old woman was referred with a 4-week history of bloody diarrhoea, tenesmus, abdominal and rectal pain. Prior to presentation, a prednisone taper had been initiated given suspicion for Crohn’s disease. Her medical history was otherwise unremarkable. Physical exam showed normal vital signs and mild left lower abdominal tenderness without peritoneal signs. Laboratory evaluation was significant for mild leucocytosis (white blood cell count 14.3×109/L (normal range 3.5–10.5×109/L)). CT scan of the abdomen/pelvis showed hazy mesenteric fat stranding, mural thickening, oedema and hyperenhancement involving the rectosigmoid colon with widely …
Non-invasive diagnosis of hepatocellular carcinoma revisited Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-12 Cora Mueller, Nina Waldburger, Ulrike Stampfl, Hans-Ulrich Kauczor, Peter Schirmacher, Christof Matthias Sommer, Thomas Longerich
We read with interest the recent work by Ho et al demonstrating mutational hyperactivation of mammalian target of rapamycin signalling in a subgroup of hepatocellular carcinoma (HCC).1 As Berasain and Lechel concluded that the prospect of a positive therapeutic response may outweigh the risk associated with the HCC biopsy procedure2 and histology is essential for confirming a diagnosis of intrahepatic cholangiocarcinoma (ICC),3 we revisited the performance of non-invasive HCC diagnosis as recommended by current guidelines (eg, American Association for the Study of Liver Diseases (AASLD)) in clinical practice.4We retrospectively analysed all patients (n=182) in which a CT-guided liver biopsy was performed at a tertiary referral centre within a 9-year period due to the clinical differential diagnosis of HCC. After quality control, a total of 94 biopsies (figure 1A, see online supplementary table 1) could be evaluated. HCC development was associated with the presence of cirrhosis (n=51/65, p<0.001), which was also found in 27% (3/11) of ICC and 33% (1/3) of combined hepatocellular–cholangiocarcinoma (HCC–CC) patients. The number of false-positive non-invasive HCC diagnosis was higher in patients without cirrhosis (n=13/19; table …
NAD metabolism fuels human and mouse intestinal inflammation Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-06 Romana R Gerner, Victoria Klepsch, Sophie Macheiner, Kathrin Arnhard, Timon E Adolph, Christoph Grander, Verena Wieser, Alexandra Pfister, Patrizia Moser, Natascha Hermann-Kleiter, Gottfried Baier, Herbert Oberacher, Herbert Tilg, Alexander R Moschen
Objective Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway . NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.Design We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.Results FK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.Conclusion Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.
Fatty acids promote fatty liver disease via the dysregulation of 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-06 Meng Li, Chengfu Xu, Junping Shi, Jiexia Ding, Xingyong Wan, Dahua Chen, Jianguo Gao, Chunxiao Li, Jie Zhang, Yiming Lin, Zhenhua Tu, Xiaoni Kong, Youming Li, Chaohui Yu
Objective Accumulation of free fatty acids (FFAs) in hepatocytes induces lipotoxicity, leading to non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the underlying mechanisms by which FFA contributes to the pathogenesis of NAFLD via the regulation of 3-mercaptopyruvate sulfurtransferase (MPST), a key enzyme that regulates endogenous hydrogen sulfide (H2S) biosynthesis.Design Hepatic MPST expression was evaluated in mice and patients with NAFLD. A variety of molecular approaches were used to study the effects of MPST regulation on hepatic steatosis in vivo and in vitro.Results In vitro treatment of hepatocytes with FFAs upregulated MPST expression, which was partially dependent on NF-κB/p65. Hepatic MPST expression was markedly increased in high fat diet (HFD)-fed mice and patients with NAFLD. Partial knockdown of MPST via adenovirus delivery of MPST short hairpin RNA or heterozygous deletion of the Mpst gene significantly ameliorated hepatic steatosis in HFD-fed mice. Consistently, inhibition of MPST also reduced FFA-induced fat accumulation in L02 cells. Intriguingly, inhibition of MPST significantly enhanced rather than decreased H2S production, whereas MPST overexpression markedly inhibited H2S production. Co-immunoprecipitation experiments showed that MPST directly interacted with and negatively regulated cystathionine γ-lyase (CSE), a major source of H2S production in the liver. Mechanistically, MPST promoted steatosis via inhibition of CSE/H2S and subsequent upregulation of the sterol regulatory element-binding protein 1c pathway, C-Jun N-terminal kinase phosphorylation and hepatic oxidative stress.Conclusions FFAs upregulate hepatic expression of MPST and subsequently inhibit the CSE/H2S pathway, leading to NAFLD. MPST may be a potential therapeutic target for NAFLD.
Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-05 Jan Tack, Maura Corsetti, Michael Camilleri, Eamonn MM Quigley, Magnus Simren, Hidekazu Suzuki, Nicholas J Talley, Hans Tornblom, Lukas Van Oudenhove
Background and aims The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances.Methods A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs.Results Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism.Conclusion Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.
Early intervention in Crohn’s disease: towards disease modification trials Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-04 Silvio Danese, Gionata Fiorino, Laurent Peyrin-Biroulet
Crohn’s disease (CD) is a chronic progressive destructive inflammatory bowel disease. As in rheumatoid arthritis, there is increasing evidence that early treatment initiation with disease-modifying agents, such as biological drugs, may lead to complete disease control, prevention of disease progression thus protecting against irreversible damage and restoration of normal quality of life. Data from randomised clinical trials with immunosuppressants and biologics suggest that treating patients with a disease duration of <2 years and an absence of complications may significantly reduce the risk for complications and increase time in remission in patients with CD. Moreover, rapid disease control may effectively prevent disease progression and allow dose reduction or even withdrawal of treatment, reducing the risk of long-term adverse events and healthcare costs. However, prospective disease modification trials are needed to confirm these initial results. Here we review the literature regarding early intervention in adult patients with CD and propose criteria for future disease modification trials.
Oesophageal cancer incidence in 20-year follow-up in a population-based sample of 12 000 middle-age men with or without Helicobacter pylori infection in Finland Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-04 Ilkka Juhani Vohlonen, Matti Hakama, Matti Härkönen, Nea Malila, Eero Pukkala, Veli Koistinen, Pentti Sipponen
Two consensus reports on Helicobacter pylori (Hp), published recently in Gut , summarise the role of Hp gastritis in upper GI diseases, including gastric cancer (GCA).1 2 Although Hp gastritis definitely increases the risk of GCA as suggested in both reports, Hp is, on the other hand, also associated with a notable low incidence of oesophageal cancer (EC), of both adenomatous and squamous type.In our earlier 15-year follow-up of a large population-based sample of males aged 50–65 years (n=12 016) from two Finnish cities, with or without Hp, diagnosed in 1994–1996 by serological (IgG) Hp test (Biohit HealthCare, Helsinki, Finland), 57 GCA cases were recorded in the study population by the nationwide Cancer Registry during the follow-up.3 Of these cancers, 50 were in men and seven in those with and without Hp, respectively. The relative standardised incidence ratio (RR) of GCA incidence in Hp positive compared with that in Hp-negative men, calculated with the Altman’s procedure, was 6.0 (95%CI 2.3 to 19.0).In …
A novel prognostic model for transplant-free survival in primary sclerosing cholangitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-04 Elisabeth M de Vries, Junfeng Wang, Kate D Williamson, Mariska M Leeflang, Kirsten Boonstra, Rinse K Weersma, Ulrich Beuers, Roger W Chapman, Ronald B Geskus, Cyriel Y Ponsioen
Objective Most prognostic models for primary sclerosing cholangitis (PSC) are based on patients referred to tertiary care and may not be applicable for the majority of patients with PSC. The aim of this study was to construct and externally validate a novel, broadly applicable prognostic model for transplant-free survival in PSC, based on a large, predominantly population-based cohort using readily available variables.Design The derivation cohort consisted of 692 patients with PSC from the Netherlands, the validation cohort of 264 patients with PSC from the UK. Retrospectively, clinical and biochemical variables were collected. We derived the prognostic index from a multivariable Cox regression model in which predictors were selected and parameters were estimated using the least absolute shrinkage and selection operator. The composite end point of PSC-related death and liver transplantation was used. To quantify the models’ predictive value, we calculated the C-statistic as discrimination index and established its calibration accuracy by comparing predicted curves with Kaplan-Meier estimates.Results The final model included the variables: PSC subtype, age at PSC diagnosis, albumin, platelets, aspartate aminotransferase, alkaline phosphatase and bilirubin. The C-statistic was 0.68 (95% CI 0.51 to 0.85). Calibration was satisfactory. The model was robust in the sense that the C-statistic did not change when prediction was based on biochemical variables collected at follow-up.Conclusion The Amsterdam-Oxford model for PSC showed adequate performance in estimating PSC-related death and/or liver transplant in a predominantly population-based setting. The transplant-free survival probability can be recalculated when updated biochemical values are available.
Therapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: results from a large nationwide database analysis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-05 Naoyoshi Nagata, Hideo Yasunaga, Hiroki Matsui, Kiyohide Fushimi, Kazuhiro Watanabe, Junichi Akiyama, Naomi Uemura, Ryota Niikura
Objective To compare the risks of postendoscopy outcomes associated with warfarin with direct oral anticoagulants (DOACs), taking into account heparin bridging and various types of endoscopic procedures.Design Using the Japanese Diagnosis Procedure Combination database, we identified 16 977 patients who underwent 13 types of high-risk endoscopic procedures and took preoperative warfarin or DOACs from 2014 to 2015. One-to-one propensity score matching was performed to compare postendoscopy GI bleeding and thromboembolism between the warfarin and DOAC groups.Results In the propensity score-matched analysis involving 5046 pairs, the warfarin group had a significantly higher proportion of GI bleeding than the DOAC group (12.0% vs 9.9%; p=0.002). No significant difference was observed in thromboembolism (5.4% vs 4.7%) or in-hospital mortality (5.4% vs 4.7%). The risks of GI bleeding and thromboembolism were greater in patients treated with warfarin plus heparin bridging or DOACs plus bridging than in patients treated with DOACs alone. Compared with percutaneous endoscopic gastrostomy, patients who underwent endoscopic submucosal dissection, endoscopic mucosal resection and haemostatic procedures including endoscopic variceal ligation or endoscopic injection sclerotherapy were at the highest risk of GI bleeding among the 13 types of endoscopic procedures, whereas those who underwent lower polypectomy endoscopic sphincterotomy or endoscopic ultrasound-guided fine needle aspiration were at moderate risk.Conclusion The risk of postendoscopy GI bleeding was higher in warfarin than DOAC users. Heparin bridging was associated with an increased risk of bleeding and did not prevent thromboembolism. The bleeding risk varied by the type of endoscopic procedure.
Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-02 De-Chen Lin, Huy Q Dinh, Jian-Jun Xie, Anand Mayakonda, Tiago Chedraoui Silva, Yan-Yi Jiang, Ling-Wen Ding, Jian-Zhong He, Xiu-E Xu, Jia-Jie Hao, Ming-Rong Wang, Chunquan Li, Li-Yan Xu, En-Min Li, Benjamin P Berman, H Phillip Koeffler
Objectives Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance.Design Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures. The biological functions of novel SMGs were investigated using cell line and xenograft models. We further performed whole-genome bisulfite sequencing and chromatin immunoprecipitation (ChIP)-seq to characterise epigenetic alterations.Results OSCC and OAC displayed nearly mutually exclusive sets of driver genes, indicating that they follow independent developmental paths. The combined sample size allowed the statistical identification of a number of novel subtype-specific SMGs, mutational signatures and prognostic biomarkers. Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC. Two newly discovered SMGs, CUL3 and ZFP36L2 , were validated as important tumour-suppressors specific to the OSCC subtype. We further identified their additional loss-of-function mechanisms. CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs). Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor.Conclusions These data comprehensively contrast differences between OSCC and OAC at both genomic and epigenomic levels, and reveal novel molecular features for further delineating the pathophysiological mechanisms and treatment strategies for these cancers.
Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-02 Wanshui Yang, Li Liu, Yohei Masugi, Zhi Rong Qian, Reiko Nishihara, NaNa Keum, Kana Wu, Stephanie Smith-Warner, Yanan Ma, Jonathan A Nowak, Fatemeh Momen-Heravi, Libin Zhang, Michaela Bowden, Teppei Morikawa, Annacarolina da Silva, Molin Wang, Andrew T Chan, Charles S Fuchs, Jeffrey A Meyerhardt, Kimmie Ng, Edward Giovannucci, Shuji Ogino, Xuehong Zhang
Objective Although evidence suggests an inverse association between calcium intake and the risk of colorectal cancer, the mechanisms remain unclear. The calcium-sensing receptor (CASR) is expressed abundantly in normal colonic epithelium and may influence carcinogenesis. We hypothesized that calcium intake might be associated with lower risk of CASR-positive, but not CASR-negative, colorectal cancer.Design We assessed tumour CASR protein expression using immunohistochemistry in 779 incident colon and rectal cancer cases that developed among 136 249 individuals in the Nurses’ Health Study and Health Professionals Follow-Up Study. Duplication method Cox proportional hazards regression analysis was used to assess associations of calcium intake with incidence of colorectal adenocarcinoma subtypes by CASR status.Results Total calcium intake was inversely associated with the risk of developing colorectal cancer (ptrend=0.01, comparing ≥1200 vs <600 mg/day: multivariable HR=0.75, 95% CI 0.60 to 0.95). For the same comparison, higher total calcium intake was associated with a lower risk of CASR-positive tumours (ptrend=0.003, multivariable HR=0.67, 95% CI 0.51 to 0.86) but not with CASR-negative tumours (ptrend=0.67, multivariable HR=1.15, 95% CI 0.75 to 1.78; pheterogeneity=0.06 between the CASR subtypes). The stronger inverse associations of calcium intake with CASR-positive but not CASR-negative tumours generally appeared consistent regardless of sex, tumour location and source of calcium.Conclusions Our molecular pathological epidemiology data suggest a causal relationship between higher calcium intake and lower colorectal cancer risk, and a potential role of CASR in mediating antineoplastic effect of calcium.
Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-09-02 Wantae Kim, Sanjoy Kumar Khan, Yuchen Liu, Ruoshi Xu, Ogyi Park, Yong He, Boksik Cha, Bin Gao, Yingzi Yang
Objective Hippo signalling is a recently identified major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival and hepatocellular carcinoma (HCC) formation. Hippo kinase (Mst1 and Mst2) inhibits HCC proliferation by suppressing Yap/Taz transcription activities. As human HCC is mainly driven by chronic liver inflammation, it is not clear whether Hippo signalling inhibits HCC by shaping its inflammatory microenvironment.Design We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterised by molecular, cellular and FACS analysis, immunohistochemistry and genetic deletion of monocyte chemoattractant protein-1 ( Mcp1 ) or Yap . Human HCC databases and human HCC samples were analysed by immunohistochemistry.Results Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated Mcp1 expression and massive infiltration of macrophages with mixed M1 and M2 phenotypes. Macrophage ablation or deletion of Mcp1 in DKO mice markedly reduced hepatic inflammation and HCC development. Moreover, Yap removal abolished induction of Mcp1 expression and restored normal liver growth in the Mst1/Mst2 DKO mice. Finally, we showed that MCP1 is a direct transcription target of YAP in hepatocytes and identified a strong gene expression correlation between YAP targets and MCP-1 in human HCCs.Conclusions Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs.
Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-31 Salvatore Piano, Michele Bartoletti, Marta Tonon, Maurizio Baldassarre, Giada Chies, Antonietta Romano, Pierluigi Viale, Elia Vettore, Marco Domenicali, Marialuisa Stanco, Chiara Pilutti, Anna Chiara Frigo, Alessandra Brocca, Mauro Bernardi, Paolo Caraceni, Paolo Angeli
Introduction Patients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections. Methods 259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients). Results Sepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p<0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. Conclusions Sepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance.
High prevalence of hepatitis E virus in semen of infertile male and causes testis damage Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-31 Fen Huang, Feiyan Long, Wenhai Yu, Jianwen Situ, Lijie Fu, Zhanlong He, Hao Dong, Chenchen Yang, Yunlong Li, Fan Yang, Daqiao Wei
We read with interest the paper by Todt et al 1 concerning the mutagenesis of Hepatitis E virus (HEV) caused by ribavirin treatment. HEV is a major cause of acute hepatitis worldwide and lacks a specific treatment.1 2 It replicates in many extrahepatic sites (spleen, kidney, brain and muscle3–5), but whether the testis is included is unknown. Active HEV has been detected in body fluids (blood,2 urine4 and milk6), but no report exists for semen. Thus, HEV prevalence in the semen of infertile males (n=185) sexually abstinent for at least 2 days was investigated by reverse transcriptase-PCR. Ethical approval was obtained from the Institutional Ethics Committee. Unexpectedly, 28.11% (52/185) of the males were HEV RNA positive (HEV RNA+; detectable HEV ORF1 and ORF2 were considered as HEV RNA+, figure 1A) with comparable viral titers to that from urine (see figure S1 in the online supplementary file 1). The prevalence of HEV in semen was higher in infertile males than in serum of pregnant women (1.82%) or the general population (0.58%) in the same city. ### Supplementary file 1 [SP1.pdf] Figure 1 (A) Positive rate …
Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-24 Bruce R Stevens, Ruby Goel, Kim Seungbum, Elaine M Richards, Richard C Holbert, Carl J Pepine, Mohan K Raizada
We read with interest the recent work by Uhde et al ,1 which demonstrated that physically asymptomatic non-coeliac gluten/wheat sensitivity involves compromised intestinal epithelium barrier dysfunction in conjunction with systemic immune activation events. We also read with interest the recent work by Marchesi et al ,2 which comprehensively reviewed the role of microbiota in physical disorders of the gut and extra-gut organs. But common to these Gut papers was the lack of accounting for anxiety and depression, comorbidities often experienced in gastroenterology clinics. Patients who are otherwise physically asymptomatic often do not explicitly divulge these mental disorders, or the disorders are unintentionally overlooked, yet they report ‘diminished quality of life’. In response to this gap, we explored roles of dysbiosis and gut barrier integrity in individuals physically asymptomatic for gastrointestinal distress, yet nonetheless experiencing mental distress. We hypothesised that anxiety and depressive disorders are linked to human gut dysbiosis with microbiota that secrete lipopolysaccharide (LPS) endotoxin into plasma, which in conjunction with compromised gut barrier integrity has systemic manifestations including the brain. We further hypothesised that this correlates with altered intestinal epithelium paracellular integrity molecules discharged …
Can the performance of a quantitative FIT-based colorectal cancer screening programme be enhanced by lowering the threshold and increasing the interval? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-24 Jayne Digby, Callum G Fraser, Frank A Carey, Robert J C Steele
We read with interest the work by Haug et al published in Gut .1 Longitudinal data from 4523 participants in the first round of a faecal immunochemical test for haemoglobin (FIT)-based screening programme, of whom 3427 also participated in the second round, were studied. In both first and second rounds, a threshold of 10 µg Hb/g faeces was used. The cohort was followed up for 2 years. The cumulative positivity and the number of participants diagnosed with neoplasia over the two rounds of screening were determined and compared with a hypothetical strategy involving single round screening with use of lower faecal haemoglobin concentration (f-Hb) thresholds and omission of the second round. It was suggested that lowering the f-Hb threshold and extending the screening interval could possibly enhance population-based screening programmes. In our pilot evaluation of FIT-based screening in Scotland, a much higher f-Hb threshold (≥80 µg Hb/g faeces) was employed.2 …
Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-17 Irene Yushing Chong, Lauren Aronson, Hanna Bryant, Aditi Gulati, James Campbell, Richard Elliott, Stephen Pettitt, Paul Wilkerson, Maryou B Lambros, Jorge S Reis-Filho, Anisha Ramessur, Michael Davidson, Ian Chau, David Cunningham, Alan Ashworth, Christopher J Lord
Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets. Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer. Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway ([NCT02884453]). Trial registration number NCT02884453; Pre-results : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02884453&atom=%2Fgutjnl%2Fearly%2F2017%2F08%2F17%2Fgutjnl-2017-314408.atom
HLA-DQ:gluten tetramer test in blood gives better detection of coeliac patients than biopsy after 14-day gluten challenge Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-17 Vikas K Sarna, Gry I Skodje, Henrik M Reims, Louise F Risnes, Shiva Dahal-Koirala, Ludvig M Sollid, Knut E A Lundin
Objective Initiation of a gluten-free diet without proper diagnostic work-up of coeliac disease is a frequent and demanding problem. Recent diagnostic guidelines suggest a gluten challenge of at least 14 days followed by duodenal biopsy in such patients. The rate of false-negative outcome of this approach remains unclear. We studied responses to 14-day gluten challenge in subjects with treated coeliac disease. Design We challenged 20 subjects with biopsy-verified coeliac disease, all in confirmed mucosal remission, for 14 days with 5.7 grams per oral gluten daily. Duodenal biopsies were collected. Blood was analysed by multiplex assay for cytokine detection, and by flow cytometry using HLA-DQ:gluten tetramers. Results Nineteen participants completed the challenge. Villous blunting appeared at end of challenge in 5 of 19 subjects. Villous height to crypt depth ratio reduced with at least 0.4 concomitantly with an increase in intraepithelial lymphocyte count of at least 50% in 9 of 19 subjects. Interleukin-8 plasma concentration increased by more than 100% after 4 hours in 7 of 19 subjects. Frequency of blood CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells increased by more than 100% on day 6 in 12 of 15 evaluated participants. Conclusion A 14-day gluten challenge was not enough to establish significant mucosal architectural changes in majority of patients with coeliac disease (sensitivity ≈25%–50%). Increase in CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells in blood 6 days after gluten challenge is a more sensitive and less invasive biomarker that should be validated in a larger study. Trial registration number NCT02464150
Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-07-31 Khurum Khan, Mihaela Rata, David Cunningham, Dow-Mu Koh, Nina Tunariu, Jens C Hahne, George Vlachogiannis, Somaieh Hedayat, Silvia Marchetti, Andrea Lampis, Mahnaz Darvish Damavandi, Hazel Lote, Isma Rana, Anja Williams, Suzanne A Eccles, Elisa Fontana, David Collins, Zakaria Eltahir, Sheela Rao, David Watkins, Naureen Starling, Jan Thomas, Eleftheria Kalaitzaki, Nicos Fotiadis, Ruwaida Begum, Maria Bali, Massimo Rugge, Eleanor Temple, Matteo Fassan, Ian Chau, Chiara Braconi, Nicola Valeri
Objective Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. Design Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. Results Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06). Conclusions Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-16 Eunyoung Choi, Tyler L Lantz, Gregory Vlacich, Theresa M Keeley, Linda C Samuelson, Robert J Coffey, James R Goldenring, Anne E Powell
Objective Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice. Design We performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1- CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury. Results Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy. Conclusions Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.
Reassessment of gamma-glutamyl transpeptidase to platelet ratio (GPR): a large-sample, dynamic study based on liver biopsy in a Chinese population with chronic hepatitis B virus (HBV) infection Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-16 Wei Zhang, MiMi Sun, Gang Chen, Yong An, ChunLei Lv, YongQing Wang, QingHua Shang
Recently, Lemoine and colleagues1 presented a novel marker of liver fibrosis, the gamma-glutamyl transpeptidase to platelet ratio (GPR), as a more accurate non-invasive marker than either the aspartate aminotransferase to platelet ratio index (APRI) or the fibrosis index based on four factors (FIB-4) for diagnosing liver fibrosis in patients with chronic hepatitis B virus (HBV) infection in West Africa, and a simple and inexpensive alternative to transient elastography and liver biopsy. Boyd and colleagues2 demonstrated good results for GPR in the diagnosis of liver fibrosis in patients with HBV/HIV co-infection in France. However, Stockdale and colleagues3 reported that in patients with HBV / human immunodeficiency virus (HIV) co-infection in West Africa, GPR showed poor correlation with transient elastography. Lemoine and colleagues4 subsequently responded that the diagnostic accuracy of GPR differed when using liver biopsy or transient elastography as the reference. These inconsistent opinions indicated that the value of GPR for diagnosing liver fibrosis was still uncertain and needed further validation, not to mention its value for dynamic assessment of treatment response in patients with chronic HBV infection. To further evaluate the accuracy of GPR for diagnosing liver fibrosis, we undertook a retrospective study in China of 1168 patients, with …
Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-16 Keith Siau, Toshio Kuwai, Sauid Ishaq
We read with interest and commend the study by Ward and colleagues which explores the learning curve in gastroscopy.1 The authors apply a D2 intubation rate of >95% as a proxy marker of trainee competency, and conclude that 187–200 procedures are sufficient to achieve this, in line with Joint Advisory Group (JAG) certification criteria.2 We would like to debate the following points with the authors. While we agree that D2 intubation and J-maneouvre reflect procedural completion and rely on motor skill, we argue that this stand-alone measure is insufficient to define competence. Competence is defined by the American Society for Gastrointestinal Endoscopy as the 'minimal level of skill, knowledge and/or expertise derived through training and experience that is required to safely and proficiently perform …
Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-14 Gwen Murphy, Amanda J Cross, Sanford M Dawsey, Frank Z Stanczyk, Farin Kamangar, Stephanie J Weinstein, Philip R Taylor, Satu Männistö, Demetrius Albanes, Christian C Abnet, Neal D Freedman
Background Colorectal cancers are the third most common cancers in women and men in the USA. While dietary and lifestyle factors such as Western diet, physical inactivity and obesity have been linked to an increased risk of this malignancy, the mechanisms for these associations are unclear. GI hormones, including ghrelin, are involved in energy balance by mediating appetite and metabolism; however, the association between ghrelin and colorectal cancer has not been studied. Methods We conducted a case–control study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish smokers (aged 50–69 years) to examine serum ghrelin concentration and colorectal cancer risk. Data from 284 colon and 239 rectal cancers and 523 controls (matched on age, date of blood draw and serum availability) were analysed. ORs and 95% CIs were calculated using multivariable (conditional) logistic regression. Results Overall, low-serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI 1.05 to 2.34). For individuals developing tumours within 10 years of blood draw, those in the lowest quartile of serum ghrelin concentrations were statistically significantly more likely to develop colorectal cancers than those with higher serum ghrelin concentrations (OR: 10.86, 95% CI 5.01 to 23.55). However, for individuals with tumours developing more than 20 years after blood draw, low-serum ghrelin concentrations were associated with a decreased risk of colorectal cancer relative to those with the highest serum ghrelin concentrations (OR: 0.26, 95% CI 0.11 to 0.64). Conclusion Low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw. These results suggest that ghrelin concentrations may vary across the carcinogenic process.
Randomised controlled trial of transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND Study) Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-14 Renée M Barendse, Gijsbert D Musters, Eelco J R de Graaf, Frank J C van den Broek, Esther C J Consten, Pascal G Doornebosch, James C Hardwick, Ignace H J T de Hingh, Chrisiaan Hoff, Jeroen M Jansen, A W Marc van Milligen de Wit, George P van der Schelling, Erik J Schoon, Matthijs P Schwartz, Bas L A M Weusten, Marcel G Dijkgraaf, Paul Fockens, Willem A Bemelman, Evelien Dekker
Objective Non-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas. Design Patients with rectal adenomas ≥3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence-free days alive and out of hospital. Results Two hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609±209, TEM 652±188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately €3000 cheaper and therefore more cost-effective. Conclusion Under the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost-effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies.
Too hard to swallow! Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-14 Keith Siau, Akhmid Aziz, Lenny Liew, Sauid Ishaq
An 80-year-old woman presented with a 4-month history of intermittent oropharyngeal dysphagia and aspiration, particularly after eating peas. She had no significant medical history and denied additional symptomatology. Gastroscopy revealed a smooth lesion arising in the pharynx abutting the epiglottis (figure 1) but was otherwise unremarkable. Pillow sign was negative. No neck masses were palpable on examination after endoscopy. Figure 1 Endoscopic appearance of the pharynx. 1. What is the endoscopic finding and what are the …
Chronic hepatitis B: divide and conquer? Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-14 Michael Nassal
Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical development,6 including entry inhibitors such as Myrcludex-B (Myr-B)7 which block the interaction between HBV and its receptor Na+-taurocholate cotransporting polypeptide (NTCP; figure 1), directly target cccDNA. Not even recovery from acute self-limited hepatitis B appears to eradicate all cccDNA molecules although their number (corresponding to at least the ~1010 infected hepatocytes at the peak of infection) is massively reduced by the immune system within a few weeks,3 mostly with fully maintained liver function. Figure 1 Hepatitis B virus (HBV) covalently closed circular (ccc) DNA synthesis and immune-mediated loss. (A) HBV cccDNA synthesis and amplification from relaxed circular (rc) DNA. Hepatitis B virions exploit the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) as entry receptor into human hepatocytes. After the envelope is stripped off, the nucleocapsids (NC) transport the rcDNA genome to the nucleus where conversion into cccDNA takes place. cccDNA associates with host and viral factors into a minichromosome (not shown) that serves as transcription template for the viral RNA; …
Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8+ T cell number and tumour growth in pancreatic cancer Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-11 Vittoria Iorio, Alessandra Rosati, Raffaella D'Auria, Margot De Marco, Liberato Marzullo, Anna Basile, Michelina Festa, Maria Pascale, Paolo Remondelli, Mario Capunzo, Gianluca Sala, Verena Damiani, Giuseppina Amodio, Marta Di Nicola, Rossano Lattanzio, Maria Caterina Turco, Vincenzo De Laurenzi
We read with great interest the article by Zhang et al 1 showing that CD8+ cell infiltration in pancreatic tumours can be enhanced by depletion of myeloid cells (CD11b+ macrophages and myeloid-derived suppressor cells) and that the depletion of CD11b+ cells resulted in decreased PD-L1 expression on cancer cells thus impairing the triggering of the inhibitory receptor PD-1 on T cells.1 Recruitment and activation of CD8+ lymphocytes in tumours are suppressed by mechanisms only partially understood and rescuing CD8+ cell infiltrate in tumours is one of the objectives of immunotherapies.1 2 Tumour-associated macrophages (TAMs) play a crucial role in the relation between tumour cells and their environment.3 Here, we confirm the interplay between macrophages and CD8+ cells in pancreatic cancer and identify a potential way to exploit this enhancing effect of anti-PD-1 treatment. Indeed, we show that reduction of macrophage infiltrate, through treatment with an anti-Bcl-2-Associated athanoGene 3 (BAG3) antibody,4 results in increased number of CD8+ cells in pancreatic tumours in a murine model. …
Colonoscopic full-thickness resection using an over-the-scope device: a prospective multicentre study in various indications Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-10 Arthur Schmidt, Torsten Beyna, Brigitte Schumacher, Alexander Meining, Hans-Juergen Richter-Schrag, Helmut Messmann, Horst Neuhaus, David Albers, Michael Birk, Robert Thimme, Andreas Probst, Martin Faehndrich, Thomas Frieling, Martin Goetz, Bettina Riecken, Karel Caca
Objective Endoscopic full-thickness resection (EFTR) is a novel treatment of colorectal lesions not amenable to conventional endoscopic resection. The aim of this prospective multicentre study was to assess the efficacy and safety of the full-thickness resection device. Design 181 patients were recruited in 9 centres with the indication of difficult adenomas (non-lifting and/or at difficult locations), early cancers and subepithelial tumours (SET). Primary endpoint was complete en bloc and R0 resection. Results EFTR was technically successful in 89.5%, R0 resection rate was 76.9%. In 127 patients with difficult adenomas and benign histology, R0 resection rate was 77.7%. In 14 cases, lesions harboured unsuspected cancer, another 15 lesions were primarily known as cancers. Of these 29 cases, R0 resection was achieved in 72.4%; 8 further cases had deep submucosal infiltration >1000 µm. Therefore, curative resection could only be achieved in 13/29 (44.8%). In the subgroup with SET (n=23), R0 resection rate was 87.0%. In general, R0 resection rate was higher with lesions ≤2 cm vs >2 cm (81.2% vs 58.1%, p=0.0038). Adverse event rate was 9.9% with a 2.2% rate of emergency surgery. Three-month follow-up was available from 154 cases and recurrent/residual tumour was evident in 15.3%. Conclusion EFTR has a reasonable technical efficacy especially in lesions ≤2 cm with acceptable complication rates. Curative resection rate for early cancers was too low to recommend its primary use in this indication. Further comparative studies have to show the clinical value and long-term outcome of EFTR in benign colorectal lesions. Trial registration number NCT02362126; Results.
Minimal access necrosectomy: the newest advance of many in the treatment of necrotising pancreatitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-10 Michael G Sarr
This study by van Brunschott and international colleagues1 has shown that when possible in high-risk patients with severe acute necrotising pancreatitis, a minimal access approach for drainage combined with a necrosectomy, either via an operative (ie, laparoscopic like) or an endoscopic transgastric or transduodenal approach, decreases mortality of this horrible disease when compared with the classic open operation (laparotomy). These data are convincing and support the use of such minimal access approaches whenever feasible. This study reviews the data on another huge advance in our treatment and understanding of this horrific disease. In this commentary, I want to use this study as an example of the marked changes in our thinking of pancreatitis over the last 40 years. Our current approach to the treatment of necrotising pancreatitis really had its origin in the 1970s with the introduction of the new concept of an operative ‘necrosectomy’ rather than just peripancreatic drainage which at that time was designed to remove the bad humours believed to be the cause of the systemic aspects of the disease. Through the pioneering work of Beger and colleagues2 in Ulm, Germany and that of Bradley (and Stone) in Atlanta, Georgia, USA,3 a new era emerged with our thinking of this systemic inflammatory disease originating from endogenous pancreatic parenchymal necrosis and later, its superinfection. Indeed, the introduction of the importance of removing the infected necrotic tissues (necrosectomy) combined with drainage of the peripancreatic region immediately decreased the mortality of this disease …
Germline variation of circadian pathway genes and prognosis of gastric cancer patients Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-08 Senthilkumar Rajendran, Clara Benna, Halenya Monticelli, Giovanna Spiro, Chiara Menin, Simone Mocellin
As we have summarised in this journal,1 germline DNA variation has been long recognised as a key component of the risk to develop to gastric carcinoma, the discovery pace being greatly accelerated by genome-wide association studies.2 More recently, growing evidence is accumulating also on the association between genetic variation and prognosis of patients with gastric cancer.3 4 Furthermore, investigators have demonstrated that alterations of the circadian rhythm can predispose to a variety of illnesses, including different types of malignancies and gastrointestinal diseases.5 6 Putting together these observations, we studied the relationship between circadian genes germline variation and the overall survival of 460 patients with TNM stage I to IV gastric carcinoma. We considered 21 single nucleotide polymorphisms (SNPs) of 14 circadian pathway genes. Genotyping was performed with real-time quantitative PCR using patient peripheral blood samples. Expression quantitative trait locus (eQTL) analysis was employed to …
Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-08 Bruno Lamas, Marie-Laure Michel, Nadine Waldschmitt, Hang-Phuong Pham, Vassiliki Zacharioudaki, Louise Dupraz, Myriam Delacre, Jane M Natividad, Gregory Da Costa, Julien Planchais, Bruno Sovran, Chantal Bridonneau, Adrien Six, Philippe Langella, Mathias L Richard, Mathias Chamaillard, Harry Sokol
Objective In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 ( CARD9 ), a key innate immunity gene, is required to shape a normal gut microbiota. Card9 –/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli . Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms. Design C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9 –/– mice. To explore the impact of Card9 –/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT→GF) or Card9 –/– ( Card9–/– →GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis. Results CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium -induced colitis was observed in Card9–/– →GF mice. The microbiota of Card9 –/– mice failed to outcompete the monosaccharide-consuming C. rodentium , worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9 –/– mice. Conclusions CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-04 Rudi Alberts, Elisabeth M G de Vries, Elizabeth C Goode, Xiaojun Jiang, Fotis Sampaziotis, Krista Rombouts, Katrin Böttcher, Trine Folseraas, Tobias J Weismüller, Andrew L Mason, Weiwei Wang, Graeme Alexander, Domenico Alvaro, Annika Bergquist, Niklas K Björkström, Ulrich Beuers, Einar Björnsson, Kirsten Muri Boberg, Christopher L Bowlus, Maria C Bragazzi, Marco Carbone, Olivier Chazouillères, Angela Cheung, Georgios Dalekos, John Eaton, Bertus Eksteen, David Ellinghaus, Martti Färkkilä, Eleonora A M Festen, Annarosa Floreani, Irene Franceschet, Daniel Nils Gotthardt, Gideon M Hirschfield, Bart van Hoek, Kristian Holm, Simon Hohenester, Johannes Roksund Hov, Floris Imhann, Pietro Invernizzi, Brian D Juran, Henrike Lenzen, Wolfgang Lieb, Jimmy Z Liu, Hanns-Ulrich Marschall, Marco Marzioni, Espen Melum, Piotr Milkiewicz, Tobias Müller, Albert Pares, Christian Rupp, Christian Rust, Richard N Sandford, Christoph Schramm, Stefan Schreiber, Erik Schrumpf, Mark S Silverberg, Brijesh Srivastava, Martina Sterneck, Andreas Teufel, Ludovic Vallier, Joanne Verheij, Arnau Vich Vila, Boudewijn de Vries, Kalliopi Zachou, The International PSC Study Group, The UK PSC Consortium, Roger W Chapman, Michael P Manns, Massimo Pinzani, Simon M Rushbrook, Konstantinos N Lazaridis, Andre Franke, Carl A Anderson, Tom H Karlsen, Cyriel Y Ponsioen, Rinse K Weersma
Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3 , we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.
Nuclear orphan receptor NR2F6 as a safeguard against experimental murine colitis Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-04 Victoria Klepsch, Romana R Gerner, Sebastian Klepsch, William J Olson, Herbert Tilg, Alexander R Moschen, Gottfried Baier, Natascha Hermann-Kleiter
Objective Nuclear receptors are known to regulate both immune and barrier functions in the GI tract. The nuclear orphan receptor NR2F6 has been shown to suppress the expression of proinflammatory cytokines in T lymphocytes. NR2F6 gene expression is reduced in patients with IBS or UC, but its functional role and tissue dependency in healthy and inflamed gut have not yet been investigated. Design Intestinal inflammation was induced in wild-type, Nr2f6 -deficient, Rag1 -deficient or bone marrow-reconstituted mice by administration of chemical (dextran sodium sulfate (DSS)) and immunogenic (T cell transfer) triggers. Disease phenotypes were investigated by survival, body weight, colon length and analysis of immune cell infiltrates. Additionally, histology, intestinal permeability, tight junction proteins, bacterial fluorescence in situ hybridisation, apoptosis, cell proliferation and mucus production were investigated. Results Nr2f6 -deficient mice were highly susceptible to DSS-induced colitis characterised by enhanced weight loss, increased colonic tissue destruction and immune cell infiltration together with enhanced intestinal permeability and reduced Muc2 expression. T cell transfer colitis and bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the expression of Nr2f6 in the immune compartment but on the protective role of NR2F6 in the intestinal epithelium. Mechanistically, we show that NR2F6 binds to a consensus sequence at −2 kb of the Muc2 promoter and transactivates Muc2 expression. Loss of NR2F6 alters intestinal permeability and results in spontaneous late-onset colitis in Nr2f6 -deficient mice. Conclusion We have for the first time identified a fundamental and non-redundant role of NR2F6 in protecting gut barrier homeostasis.
Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-03 Na Jiao, Susan S Baker, Adrian Chapa-Rodriguez, Wensheng Liu, Colleen A Nugent, Maria Tsompana, Lucy Mastrandrea, Michael J Buck, Robert D Baker, Robert J Genco, Ruixin Zhu, Lixin Zhu
Objective Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Design Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Results Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. Conclusions The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.
Development of autoimmune pancreatitis is independent of CDKN1A/p21-mediated pancreatic inflammation Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-03 Gitta M Seleznik, Theresia Reding, Lukas Peter, Anurag Gupta, Sabrina G Steiner, Sabrina Sonda, Caroline S Verbeke, Emmanuel Dejardin, Igor Khatkov, Stephan Segerer, Mathias Heikenwalder, Rolf Graf
Objective Chronic pancreatitis (CP) and autoimmune pancreatitis (AIP) are characterised by different inflammatory processes. If pancreatic inflammation is a prerequisite for autoimmunity is still unclear. AIP is considered mostly a T cell-mediated disease; however, in induction of CP, macrophages play a pivotal role. p21—a member of cyclin-dependent kinase inhibitors—can influence inflammatory processes, in particular can regulate T cell activation and promote macrophage development. We therefore examined the role of p21-mediated inflammation in AIP. Design We intercrossed lymphotoxin (LT) overexpressing mice (Tg(Ela1-LTa,b))—a model to study AIP development—with p21-deficient mice. Furthermore, we characterised p21 expression in human AIP and non-AIP specimens. Results p21 deficiency in LT mice (LTp21−/−) prevented early pancreatic injury and reduced inflammation. In acinar cells, diminished proliferation and abrogated activation of non-canonical nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway was observed. In contrast, 12-month-old LT mice with and without p21 had similar inflammatory signatures and T–B cell infiltration. Interestingly, LT and LTp21−/− mice had comparable tertiary lymphoid organs (TLOs), autoantibodies and elevated IgG levels. However, acinar cell proliferation, acinar-to-ductal metaplasia and acinar non-canonical NF-κB pathway activation remained impaired in LTp21−/− pancreata. Conclusions Our findings indicate that p21 is crucial for pancreatic inflammation in LT-driven pancreatic injury. p21 is involved in early acinar secretion of inflammatory mediators that attract innate immune cells. However, p21 is not essential for humoral immune response, accountable for autoimmunity. Remarkably, p21 renders acinar cells less susceptible to proliferation and transdifferentiation. We therefore suggest that AIP can also develop independent of chronic inflammatory processes.
Improving iron supplements: cooking with GOS Ann. Rheum. Dis. (IF 12.811) Pub Date : 2017-08-03 Hal Drakesmith, Stephen J Allen
Iron is essential for oxygen transport, generation of energy, synthesis of DNA and multiple enzymatic systems. Iron deficiency impairs these functions and a familiar and important manifestation of advanced iron deficiency is anaemia. Around a quarter of a billion children worldwide are anaemic, and at least half of childhood anaemia is caused in part by a lack of iron; a heavy burden of anaemia is especially present in sub-Saharan Africa and South Asia.1 Iron replenishments, including iron-containing multiple micronutrient powders (MNPs) can be effective treatments to increase haemoglobin. However, despite the use of such agents for many years, the estimated prevalence of anaemia worldwide in preschool children only decreased from 47% to 43% between 1993 and 2011.2 Furthermore, iron replenishments have been associated with adverse events, including infections, intestinal inflammation and diarrhoea in some (but not all) trials. There is a need to make iron treatments both safer and more effective especially in the developing world, and the study in Kenya by Zimmermann and colleagues3 in this issue of Gut addresses these issues. Iron is needed for growth by humans, and the microbes that colonise and infect us. In particular, pathogenic bacteria in the gut require iron for their virulence, while conversely beneficial microbes …
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.1 This 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.
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