The clinical implication of drug dependency in children and adults with inflammatory bowel disease: A review

AbstractDrug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug cessation or dose decrease. However, a quick restoration of remission and sustained response is achieved when the therapy is re-introduced or dose increased.Population-based studies have demonstrated that 22–36% of adults and 14–50% of children become corticosteroid dependent. Approximately 1/4–1/3 of treated patients undergo surgery ≤1 year after treatment start, although newer paediatric studies reported lower risk of surgery (5–11%), including dependent patients. The frequent use of immunosuppressants (68–80% of children) might explain this favourable outcome and thus reduce importance of the term corticosteroid dependency.Infliximab dependency was described in 42–66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients was suggested to postpone if not avoid the need of surgery.Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%).Identification of drug dependency is useful for prediction of a certain disease course and surgery. An adjustment of medical therapy may alter the prognosis and disease course

The CTLA4 variants may interact with the IL23R- and NOD2-conferred risk in development of Crohn's disease

<p>Abstract</p> <p>Background</p> <p>The <it>CTLA4 </it>(cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of <it>CTLA4 </it>with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases.</p> <p>Methods</p> <p>Six polymorphisms within the <it>CTLA4 </it>region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the <it>CTLA4 </it>variants and other genetic factors known to confer the disease susceptibility.</p> <p>Results</p> <p>No crude associations with Crohn's disease were found for the tested <it>CTLA4 </it>variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the <it>NOD2 </it>(the p.Leu1007fsX1008, rs5743293) or the <it>IL23R </it>(p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of <it>CTLA4 </it>CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with <it>CTLA4 </it>was apparent only in the strata defined by presence minor alleles at the <it>NOD2 </it>rs5743293 (here the <it>CTLA4 </it>CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or <it>IL23R </it>rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked <it>CTLA4 </it>markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014).</p> <p>Conclusions</p> <p>A protective effect of a <it>CTLA4 </it>haplotype was unmasked after stratification for the risk variants in the <it>NOD2 </it>and <it>IL23R </it>genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.</p

Prolonged fibroblast growth factor 19 response in patients with primary sclerosing cholangitis after an oral chenodeoxycholic acid challenge

Bile salts likely contribute to liver injury in patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Fibroblast growth factor 19 (FGF19) is a bile salt-induced enterokine with hepatoprotective potential as it suppresses de novo bile salt synthesis. Here, we evaluated the bile salt receptor FXR/FGF19 gut-liver axis in PSC and PBC patients. Fasted patients with PSC (n = 12) and PBC (n = 10), and healthy controls (HC; n = 10) were orally challenged with the natural FXR agonist chenodeoxycholic acid (CDCA 15 mg/kg). Blood was sampled hourly until 8 h afterwards. Serum FGF19 and bile salt excursions were determined. Serum levels of 7 alpha-hydroxy-4-cholesten-3-one (C4), reflecting bile salt synthesis, were measured as a biomarker of FGF19 response. Baseline serum FGF19 levels were comparable between groups, while fasted bile salt levels in PSC patients were elevated. Upon CDCA challenge, HC and PBC patients showed a serum FGF19 peak after 4 h followed by a decline. PSC patients showed a prolonged and elevated serum FGF19 response up to 8 h, combined with a sustained serum elevation of CDCA and other bile salts. In general, C4 levels declined following FGF19 elevation. In PSC patients with less favorable prognosis, baseline C4 levels were drastically suppressed and did not further decline. Following an oral CDCA challenge, PSC patients showed an impaired clearance of CDCA and a prolonged serum FGF19 response. FXR agonist therapy in PSC could cause prolonged exposure to elevated levels of FGF19, and we propose careful monitoring for detrimental side effects in patient studies

Determination of Beta-Defensin Genomic Copy Number in Different Populations: A Comparison of Three Methods

There have been conflicting reports in the literature on association of gene copy number with disease, including CCL3L1 and HIV susceptibility, and β-defensins and Crohn's disease. Quantification of precise gene copy numbers is important in order to define any association of gene copy number with disease. At present, real-time quantitative PCR (QPCR) is the most commonly used method to determine gene copy number, however the Paralogue Ratio Test (PRT) is being used in more and more laboratories.In this study we compare a Pyrosequencing-based Paralogue Ratio Test (PPRT) for determining beta-defensin gene copy number with two currently used methods for gene copy number determination, QPCR and triplex PRT by typing five different cohorts (UK, Danish, Portuguese, Ghanaian and Czech) of DNA from a total of 576 healthy individuals. We found a systematic measurement bias between DNA cohorts revealed by QPCR, but not by the PRT-based methods. Using PRT, copy number ranged from 2 to 9 copies, with a modal copy number of 4 in all populations.QPCR is very sensitive to quality of the template DNA, generating systematic biases that could produce false-positive or negative disease associations. Both triplex PRT and PPRT do not show this systematic bias, and type copy number within the correct range, although triplex PRT appears to be a more precise and accurate method to type beta-defensin copy number

High Dose Fish Oil Added to Various Lipid Emulsions Normalizes Superoxide Dismutase 1 Activity in Home Parenteral Nutrition Patients

(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven