Klinické a genetické prediktory lékové závislosti u idiopatických střevních zánětů

IN CZECH Léková závislost (dependence) jako specifický fenotyp idiopatických střevních zánětů (IBD), Crohnovy nemoci (CN) a ulcerózní kolitidy (UC), předurčuje prognózu onemocnění. Může být proto využit jako důležitý prognostický ukazatel při volbě optimálního terapeutického postupu. Dependence je dobře popsaná u IBD pacientů léčených kortikosteroidy a recentně byla také potvrzena u nemocných léčených infliximabem (IFX dependence). Cílem této práce bylo: 1) zhodnotit výskyt IFX dependence u dětských a dospělých pacientů s CN; dále identifikovat klinické a genetické prediktory odpovědi na IFX a zhodnotit vliv IFX dependence na frekvenci operací; 2) zhodnotit u pacientů s CN výsledky 5-ASA monoterapie s ohledem na výskyt 5-ASA dependence a identifikovat klinické prediktory odpovědi na 5- ASA. Zjistili jsme, že 66% dětských a 29% dospělých pacientů s CN se stalo IFX dependentními. Vysoká frekvence u dětí je v souladu s dříve publikovanými prácemi, zatímco naše výsledky naznačují nižší výskyt IFX dependence u dospělé populace. Perianální onemocnění a nepřítomnost střevní operace před zahájením IFX byly identifikovány jako prediktory pro vznik IFX dependence u dětí. U dospělých pacientů, 2 genetické varianty LTA c.207 A>G a CASP9 c.93 C>T byli asociovány s IFX odpovědí. Dětští i dospělí pacienti se...IN ENGLISH Drug dependency in inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is a specific disease phenotype which determines disease prognosis and hence may be used as a prognostic marker for treatment management. Drug dependency in IBD has been well described in corticosteroid treatment and recently also in infliximab (IFX) therapy. The aims of this thesis were: 1) to assess the occurrence of IFX dependency in paediatric and adult patients with CD; further to search for clinical and genetic predictors of IFX outcome and to evaluate the impact of IFX dependency on surgical rate; 2) to assess in CD patients the outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency and to define clinical predictors of 5-ASA treatment outcome. We found that 66% of children and 29% of adults with CD became IFX dependent. The high frequency in paediatrics is in agreement with previously published studies, while the finding in adult patients indicates a lower rate of IFX dependency in the only study to date. Perianal disease and no bowel surgery prior to IFX start were predicative of IFX dependency in paediatric patients. In adult cohort, 2 genetic variants LTA c.207 A>G and CASP9 c.93 C>T were associated with IFX outcome, whereas no relevant clinical...Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFNInstitute of Medical Biochemistry and Laboratory Medicine First Faculty of MedicineFirst Faculty of Medicine1. lékařská fakult

Impaired Deoxyribonuclease I Activity in Patients with Inflammatory Bowel Diseases

Background and Aims. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown and promotes susceptibility to autoimmune disorders. The aim of current study was to investigate serum DNase I activity in patients with inflammatory bowel diseases (IBD). Patients and Methods. A cohort of 110 IBD patients was evaluated, aged 35 ± 12 years, 77 with Crohn's disease (CD) and 33 with ulcerative colitis (UC). 50 SLE patients and 50 healthy blood donors were examined as control groups. Results. DNase I activity in IBD patients was significantly lower than in healthy individuals, but higher than in SLE patients (P < .0001). Patients with UC showed higher DNase I activity than CD patients, P = .21. DNase I activity in female patients with IBD was significantly lower than in males, P = .024; however, no differences in DNase I activity were found in relation to gender in healthy individuals. DNase I activity has shown a strong negative correlation with the serum concentration of anti-nucleosomal antibodies in the autoimmune (SLE + IBD) cohort, as well as in the separate IBD cohort. Conclusions. Reduced serum DNase I activity probably has pathogenetic consequences in IBD. Induction of autoantibodies towards nucleosomes could be a reflection of impaired DNase I activity

Clinical and genetic predictors of drug dependency in inflammatory bowel disease

IN ENGLISH Drug dependency in inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is a specific disease phenotype which determines disease prognosis and hence may be used as a prognostic marker for treatment management. Drug dependency in IBD has been well described in corticosteroid treatment and recently also in infliximab (IFX) therapy. The aims of this thesis were: 1) to assess the occurrence of IFX dependency in paediatric and adult patients with CD; further to search for clinical and genetic predictors of IFX outcome and to evaluate the impact of IFX dependency on surgical rate; 2) to assess in CD patients the outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency and to define clinical predictors of 5-ASA treatment outcome. We found that 66% of children and 29% of adults with CD became IFX dependent. The high frequency in paediatrics is in agreement with previously published studies, while the finding in adult patients indicates a lower rate of IFX dependency in the only study to date. Perianal disease and no bowel surgery prior to IFX start were predicative of IFX dependency in paediatric patients. In adult cohort, 2 genetic variants LTA c.207 A>G and CASP9 c.93 C>T were associated with IFX outcome, whereas no relevant clinical..

Fecal zonulin is elevated in Crohn’s disease and in cigarette smokers

Objectives: Human zonulin is a protein that increases permeability in the epithelial layer of the small intestine by reversibly modulating the intercellular tight junctions. There is not sufficient information available about zonulin's participation in inflammatory bowel diseases (IBD). The aim of this study was therefore to investigate fecal and serum zonulin in IBD patients and its relation to the disease localization, behavior and smoking status. Design and methods: Forty IBD patients and forty healthy persons were examined for fecal and serum zonulin concentrations by competitive ELISA (DRG International Inc). Values were correlated to IBD type, localization and behavior, and smoking. Results: Serum and fecal zonulin were significantly higher in patients with Crohn’s disease compared to ulcerative colitis (p = 0.038 for fecal zonulin, and p = 0.041 for serum zonulin concentrations). No association of serum or fecal zonulin was found with respect to IBD localization and behavior. The only difference was found with respect to smoking. Both the IBD cohort and healthy smokers showed significantly higher fecal zonulin levels (median 203 ng/mL) compared to non-smokers (median 35.8 ng/mL), p < 0.001. Conclusions: Fecal and serum zonulin levels are elevated in patients with active Crohn’s disease but not with ulcerative colitis. High fecal zonulin levels in smokers irrespective of IBD point to the significant and undesirable up-regulation of gut permeability in cigarette smokers. Keywords: Zonulin, Inflammatory bowel disease, Crohn's disease, Ulcerative colitis, Smokin

Fecal Microbial Transplantation versus Mesalamine Enema for Treatment of Active Left-Sided Ulcerative Colitis—Results of a Randomized Controlled Trial

Background and Aims: Ulcerative colitis (UC) is a chronic inflammatory disease. Fecal microbial transplantation (FMT) is a promising alternative treatment. Methods: This multicenter, open-label, noninferiority trial randomized patients with active left-sided UC (Mayo score 4–10) equally to FMT or 5-aminosalicylic acid (5-ASA) enemas. FMT enemas were administered five times in the first week and then once weekly for 5 weeks. 5-ASA enemas were administered daily for 2 weeks and then every other day. The primary study endpoint was clinical remission, with a total Mayo score ≤2 at week 12 with no subscore &gt;1. Results: Sixty-one patients were screened; 45 were enrolled and randomized to FMT (n = 23) or 5-ASA (n = 22). Twenty-one FMT and 22 5-ASA patients completed at least the week 4 study visit and were included in the mITT analysis. Twelve FMT (57%) and eight 5-ASA patients achieved the primary study endpoint. FMT noninferiority with 10% margin was confirmed (95% CI: −7.6%, 48.9%). Adverse events occurred in 12 FMT (57%) and 13 5-ASA (59%) patients. Increased microbial diversity persisted 3 months after FMT. Conclusion: FMT is an effective treatment for left-sided UC and increased recipient microbiome diversity. Targeted microbiome modification may improve FMT efficacy. Further investigation is needed to guide donor and patient selection