关键词： enterocolitis   Hirschsprung-associated enterocolitis   Hirschsprung disease   inflammatory bowel disease   serology  

摘要： Objective: Hirschsprung-associated enterocolitis (HAEC) is the most frequent complication in Hirschsprung disease (HSCR) patients. Currently HAEC is diagnosed clinically, leaving uncertainty in the diagnosis thereby potentially leading to over- or undertreatment of patients. The aim of this study was to identify immune biomarkers to aid in the diagnosis of HAEC. Methods: From 2012 to 2017, 43 children with HSCR enrolled in a multicenter study, underwent retrospective evaluation of their medical records, and questionnaire-directed parent interviews. HAEC status was determined using HAEC score with cutoff >= 4. Plasma was collected and analyzed by ELISA for the inflammatory bowel disease-associated antibodies: anti-Saccharomyces cerevisiae mannan antibodies (ASCA), outer membrane porin C (OmpC), CBir1, antineutrophil cytoplasmic antibodies. Data were analyzed using t test, univariate, multivariable, and binomial regression models. Results: Eighteen patients had at least 1 episode of HAEC, 25 had no history of HAEC. The HAEC and NO HAEC groups had similar median ages (3 years) and family histories of HSCR. The HAEC group showed markedly elevated ASCA IgA and OmpC antibody levels compared with the NO HAEC group, whereas CBir1 and antineutrophil cytoplasmic antibodies were similar between the groups. Both univariate and multivariable analysis revealed higher OmpC antibody levels associated with HAEC (odds ratio 1.39, confidence interval 1-1.92, P = 0.048), whereas univariate analysis identified a trend toward elevated IgA and immunoglobulin G ASCA levels with HAEC. Conclusions: We identified elevated OmpC and ASCA serum antibody levels in HAEC patients, and that increased OmpC antibody levels correlated with HAEC occurrence, suggesting HAEC and Crohn disease share gut microbial-host immune responses. These antibodies may serve as potential biomarkers for HAEC, although prospective study with larger sample size is needed.

关键词： sclerosing cholangitis   ulcerative colitis   progressive  

摘要： Background: Current knowledge on the clinical features and natural history of childhood primary sclerosing cholangitis - inflammatory bowel disease in Asia is limited. We described the presenting features and natural history of primary sclerosing cholangitis-inflammatory bowel disease seen in a cohort of Southeast Asian children. Methods: We conducted a retrospective review of childhood primary sclerosing cholangitis-inflammatory bowel disease from three tertiary centers in Singapore and Malaysia. Results: Of 24 patients (boys, 58%;median age at diagnosis: 6.3 years) with primary sclerosing cholangitis-inflammatory bowel disease (ulcerative colitis, n = 21;Crohn's disease, n = 1;undifferentiated, n = 2), 63% (n = 15) were diagnosed during follow-up for colitis, and 21% (n = 5) presented with acute or chronic hepatitis, 17% (n = 4) presented simultaneously. Disease phenotype of liver involvement showed 79% had sclerosing cholangitis-autoimmune hepatitis overlap, 54% large duct disease, and 46% small duct disease. All patients received immunosuppression therapy. At final review after a median [+/- S.D.] duration follow-up of 4.7 [+/- 3.8] years, 12.5% patients had normal liver enzymes, 75% persistent disease, and 12.5% liver failure. The proportion of patients with liver cirrhosis increased from 13% at diagnosis to 29%;21% had portal hypertension, and 17% had liver dysfunction. One patient required liver transplant. Transplant-free survival was 95%. For colitis, 95% had pancolitis, 27% rectal sparing, and 11% backwash ileitis at initial presentation. At final review, 67% patients had quiescent bowel disease with immunosuppression. One patient who had UC with pancolitis which was diagnosed at 3 years old developed colorectal cancer at 22 years of age. All patients survived. Conclusions: Liver disease in primary sclerosing cholangitis-inflammatory bowel disease in Asian children has variable severity. With immunosuppression, two-thirds of patients have quiescent bowel d

关键词： Mesenchymal stem cells   Dog   Inflammatory bowel disease   Macrophage   Immunomodulation   Cell therapy  

摘要： Canine inflammatory bowel disease (IBD) is an intractable autoimmune disorder that results in various gastrointestinal and systemic symptoms. Mesenchymal stem cells (MSCs), which release immunomodulatory factors such as tumor necrosis factor-alpha (TNF-alpha)-induced gene/protein 6 (TSG-6) and prostaglandin E2 (PGE2), have been suggested as an alternative therapeutic option for IBD treatment in veterinary medicine. Furthermore, although it is known that MSCs pre-treated with pro-inflammatory cytokines show enhanced anti-inflammatory properties via the secretion of soluble factors, the underlying mechanisms of IBD remain unclear. The aim of this study was to demonstrate the therapeutic effects and corresponding mechanisms of canine adipose tissue-derived (cAT)-MSCs stimulated with TNF-alpha in mouse models of IBD. Mice with dextran sulfate sodium (DSS)- or dinitrobenzene sulfonic acid (DNBS)-induced colitis were injected intraperitoneally with cAT-MSCs pre-treated with TNF-alpha. Colitis severity was assessed and colon tissues were collected for histopathological, enzyme-linked immunosorbent assay, and flow cytometry analysis. cAT-MSCs stimulated with TNF-alpha secreted higher concentrations of immunomodulatory factors such as TSG-6 and PGE2, which play a key role in inducing phenotypic alterations in macrophages. Consequently, TNF-alpha-pre-treated cAT-MSCs further regulated colonic inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, and IL-10, and ameliorated DSS- or DNBS-induced colitis in mice. Additionally, we demonstrated that M1 macrophages (F4/80(+)/ANDS(+) cells) were decreased in colon tissues from mice treated with TNF-alpha-pre-treated cAT-MSCs, whereas M2 macrophages (F4/80(+)/CD206(+) cells) were increased. These results may suggest a new cell-based therapeutic option for treating IBD.

关键词： absorptive cells   crypt goblet cells   endoplasmic reticulum stress   Golgi apparatus   mucin secretion  

摘要： Inflammatory bowel disease (IBD) is a global, chronic intractable disease. The functions of drugs and food components have been evaluated in models of IBD induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Here, we used transmission (TEM) and osmium-maceration scanning (SEM) electron microscopy to evaluate the ultrastructure of colonic epithelial cells in rat models of IBD induced by TNBS. Histological evaluation revealed that the intestinal crypts in the most regions of the IBD-model colons were deformed and we classified them as having high cell migration rates (HMIG). The remaining regions in the intestinal crypts retained a relatively normal structure and we classified them as having low cell migration rates (LMIG). Osmium-maceration SEM revealed the mucosal fluid flowing in spaces without secretory granules in crypt goblet cells of both HMIG and LMIG regions, indicating the depletion of goblet cell mucin that is found in patients with IBD. The Golgi apparatus in absorptive cells was stacked and curled in both regions. Osmium-maceration SEM showed membrane network structures resembling endoplasmic reticulum that were large and expanded in absorptive cells with HMIG rather than with LMIG regions in IBD-model colons. These findings indicated that endoplasmic reticulum stress is associated with susceptibility to IBD and that the effects of various agents can be evaluated according to endoplasmic reticulum stress revealed by using electron microscopy in models of IBD induced by TNBS.

关键词： adult   biological products   Crohn disease   inflammatory bowel diseases   medication adherence   patient compliance   ulcerative colitis  

摘要： What is known and objective The application of biologics to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is well established. Our aim was to characterize the most recent five years of data on rates of adherence, persistence, switching and dose escalations with biologics used to treat IBD in the United States. Methods We systematically reviewed electronic databases MEDLINE, MEDLINE In-Process, EMBASE and Cochrane Library for 2012-2017 as well as conference proceedings for 2016-2017 published in English. Results and discussion Of 449 records identified, 41 met all screening criteria. Published studies varied greatly in methodology, data sources, population studied, follow-up time and endpoint definitions, preventing meaningful comparisons across studies. Based on studies using a medication possession rate threshold of <80% or <86%, 38%-77% of patients were found non-adherent to biologics. Discontinuation within the first 3 months occurred in 0%-25% of patients in six studies;7%-65% discontinued by 12 months in 13 studies. Among all patients who initiated an index biologic, the switch rate to another biologic ranged from 4.5% to 20% in 6 studies. Dose escalations were reported in only four studies;8%-35% of patients had their dose escalated within the first year of therapy. What is new and conclusion This study demonstrates variability in study design and methodology to assess adherence, persistence, switching and dose escalation with biologics among adults with IBD in the United States. Our findings suggest that real-world biologic use may be suboptimal and indicate new therapies and/or additional patient support may be needed.

关键词： Inflammatory Bowel Diseases   Incidence   Iron   ferric carboxymaltose   Hypophosphatemia   deficiency anemia  

摘要： Background Iron deficiency and iron deficiency anaemia are common complications in inflammatory bowel disease (IBD). In patients with moderate-to-severe anaemia, oral iron intolerance or ineffectiveness of oral iron, ferric carboxymaltose and iron isomaltoside are widely used. Hypophosphatemia is a side effect of both preparations. Aims To investigate the occurrence of hypophosphatemia in IBD patients with iron deficiency/iron deficiency anaemia treated with high-dose intravenous iron. Methods A prospective observational study of adult IBD patients with iron deficiency/iron deficiency anaemia was conducted at two study sites where patients received 1000 mg of ferric carboxymaltose or iron isomaltoside. At baseline, weeks 2 and 6, blood and faecal samples were collected. The primary endpoint was to determine the incidence of moderate-to-severe hypophosphatemia. Secondary endpoints included the total incidence of hypophosphatemia, possible risk factors for hypophosphatemia, and response to single-dose intravenous iron. Results One hundred and thirty patients were included. In the per-protocol set, 52 patients received ferric carboxymaltose and 54 patients received iron isomaltoside. Ferric carboxymaltose treatment had a significantly higher incidence of moderate-to-severe hypophosphatemia compared with iron isomaltoside at week 2 (56.9% vs 5.7%, P < 0.001) and a higher incidence at week 6 (13.7% vs 1.9%, P = 0.054).The overall incidence of hypophosphatemia was significantly higher with ferric carboxymaltose compared with iron isomaltoside treatment at weeks 2 (72.5% vs 11.3%, P < 0.001) and 6 (21.6% vs 3.7%, P = 0.013). Conclusions In IBD patients with iron deficiency/iron deficiency anaemia, ferric carboxymaltose was associated with higher incidence, severity and persistence of hypophosphatemia compared with iron isomaltoside. The presence of moderate-to-severe hypophosphatemia beyond 6 weeks is a clinical concern that requires further investigation.

关键词： Anemia   Iron therapy   Iron deficiency   Inflammatory bowel disease   Anemia care pathway  

摘要： BackgroundAnemia is a common complication of inflammatory bowel disease (IBD). Despite existing guidelines for anemia in IBD, it is frequently under-treated and the prevalence of anemia has remained high. To address this gap, the Crohn's and Colitis Foundation developed the Anemia Care Pathway (ACP).AimsTo implement the ACP in a managed care setting and identify where it improves practice habits and where barriers *** ACP was implemented from July 2016 through June 2017 and retrospectively studied. Run charts were used to identify shifts in iron deficiency screening and treatment as well as anemia prevalence. Results were compared to those of other providers in the same center not using the ***640 IBD encounters were studied. In the ACP clinic (n=213), anemics received iron therapy in only 30% of encounters at baseline but improved to 80%. Concurrently, anemia prevalence decreased from 48 to 25%. Screening for iron deficiency, however, did not improve. No shifts were seen in the non-ACP clinics (n=427) across the same period despite awareness of the ACP and other *** 1year, we observed gaps in the screening and treatment of anemia in IBD. Although screening rates did not improve, the ACP appeared to reduce missed opportunities for iron therapy by about half. Most importantly, this was associated with an overall decrease in anemia prevalence. Future refinements to the ACP should be focused on enhanced screening and follow-up.

关键词： Consensus Statement   Crohn's Disease   Ulcerative Colitis   Immunogenicity   Anti-TNF   Vedolizumab   Ustekinumab  

摘要： BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score >= 7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

关键词： SIRs   PSC   Genetics   Colon Cancer   Colitis-Associated Cancer  

摘要： BACKGROUND & AIMS: Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing colorectal cancer (CRC). Although family history of CRC is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of CRC in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). METHODS: We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. CRCs were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. CRC incidence was compared with that of the state population by standardized incidence ratios (SIRs). RESULTS: A cohort of 9505 individuals with IBD was identified and 101 developed CRC during the study period. The SIR for CRC in patients with Crohn's disease was 3.4 (95% CI, 2.3-4.4), and in patients with ulcerative colitis was 5.2 (95% CI, 3.9-6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of CRC (SIR, 14.8;95% CI, 8.3-21.2). A history of CRC in a FDR was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9;95% CI, 1.6-14.3), compared with the state population. CONCLUSIONS: Patients with IBD have a 3-to 5-fold increase in risk of CRC, and those with CRC in a FDR have an almost 8-fold increase in risk. Family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population.