Ulcerative Colitis: Dignass A

Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ, Dignass A, Fischer I, Fleig W, Fölsch UR, Herrlinger K, Höhne W, Jantschek G, Kaltz B, Keller KM, Knebel U, Kroesen AJ, Kruis W, Matthes H, Moser G, Mundt S, Pox C, Reinshagen M, Reissmann A, Riemann J, Rogler G, Schmiegel W, Schölmerich J, Schreiber S, Schwandner O, Selbmann HK, Stange EF, Utzig M, Wittekind C. · Medizinische Klinik I mit Schwerpunkt Gastroenterologie/Infektiologie/Rheumatologie, Charité, Universitätsmedizin Berlin. · Z Gastroenterol. · Pubmed #15455267 No free full text.

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Oxelmark L, Hillerås P, Dignass A, Mössner J, Schreiber S, Kruis W, Löfberg R. · Department of Medicine, Karolinska University Hospital, Solna, Sweden. · Scand J Gastroenterol. · Pubmed #17354122 No free full text.

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Kruis W, Dignass A, Steinhagen-Thiessen E, Morgenstern J, Mössner J, Schreiber S, Vecchi M, Malesci A, Reinshagen M, Löfberg R. · Evangelisches Krankenhaus Kalk, Innere Abteilung, Universität zu Köln, Germany. · World J Gastroenterol. · Pubmed #16437606 links to  free full text

Abstract: AIM: To study the efficacy, safety, and feasibility of a granulocyte adsorptive type apheresis system for the treatment of patients with chronically active ulcerative colitis despite standard therapy. METHODS: An open label multicenter study was carried out in 39 patients with active ulcerative colitis (CAI 6-8) despite continuous use of steroids (a minimum total dose of 400 mg prednisone within the last 4 wk). Patients received a total of five aphereses using a granulocyte adsorptive technique (Adacolumn (reg), Otsuka Pharmaceutical Europe, UK). Assessments at wk 6 and during follow-up until 4 mo comprised clinical (CAI) and endoscopic (EI) activity index, histology, quality of life (IBDQ), and laboratory tests. RESULTS: Thirty-five out of thirty-nine patients were qualified for intent-to-treat analysis. After the apheresis treatment at wk 6, 13/35 (37.1%) patients achieved clinical remission and 10/35 (28.6%) patients had endoscopic remission (CAI<4, EI<4). Quality of life (IBDQ) increased significantly (24 points, P<0.01) at wk 6. Apheresis could be performed in all but one patient. Aphereses were well tolerated, only one patient experienced anemia. CONCLUSION: In patients with steroid refractory ulcerative colitis, five aphereses with a granulocyte/monocyte depleting filter show potential short-term efficacy. Tolerability and technical feasibility of the procedure are excellent.

Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, Befrits R, Midhagen G, Rademaker J, Foldager M. · Gastroenterology, Hopital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France. · Gut. · Pubmed #15951542 links to  free full text

Abstract: BACKGROUND AND AIMS: Oral aminosalicylates are well established in the treatment of active mild/moderate ulcerative colitis (UC) when the disease is extensive (that is, beyond the splenic flexure). The majority of clinical symptoms relate to disease activity in the distal part of the colon and therefore this study was designed to investigate if adding a mesalazine enema to oral mesalazine has additional benefit for patients with extensive mild/moderate active UC. METHODS: A randomised double blind study was performed in 127 ambulatory patients. All received 4 g/day (twice daily dosing) oral mesalazine for eight weeks. During the initial four weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index, with clinical and endoscopic signs at four and eight weeks. RESULTS: Remission was obtained in 44% (95% confidence interval (CI) 31%, 58%) of the mesalazine enema group (Me) and in 34% (95% CI 21%, 49%) of the placebo enema group (Pl) at four weeks (p = 0.31) and in 64% (95% CI 50%, 76%) of the Me group versus 43% (95% CI 28%, 58%) of the Pl group at eight weeks (p = 0.03). Improvement was obtained in 89% (95% CI 78%, 96%) of the Me group versus 62% (95% CI 46%, 75%) of the Pl group at four weeks (p = 0.0008) and in 86% (95% CI 75%, 94%) of the Me group versus 68% (95% CI 53%, 81%) of the Pl group at eight weeks (p = 0.026). CONCLUSION: In patients with extensive mild/moderate active UC, the combination therapy is superior to oral therapy. It is safe, well accepted, and may be regarded as firstline treatment.

Baumgart DC, Buning C, Geerdts L, Schmidt HH, Genschel J, Fiedler T, Gentz E, Molnar T, Nagy F, Lonovics J, Lochs H, Wiedenmann B, Nickel R, Witt H, Dignass A. · Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt University of Berlin, Berlin, Germany. · Digestion. · Pubmed #18174680 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) results from an aberrant immune response to the indigenous intestinal flora in genetically susceptible hosts. Therefore, the study of candidate genes involved in host pathogen interactions is of key interest. METHODS: In this two-center, retrospective German and Hungarian cohort study, patients with Crohn's disease (CD) (n = 379; German n = 235, Hungarian n = 144) and ulcerative colitis (UC) (n = 263; German n = 145, Hungarian n = 118) and healthy controls (n = 605; German n = 403, Hungarian n = 202) were genotyped for the presence of the CD14 c.1-260C>T promoter variant and the TLR4 c.896A>G (p.D299G) variant by melting curve analysis using fluorescence resonance energy transfer probes. Data were stratified according to the presence of NOD2 (CARD15) mutations and a detailed genotype-phenotype analysis was performed. RESULTS: In the German cohort the CD14 single-nucleotide polymorphism was associated with UC, but not CD (UC p = 0.016 vs. CD p = 0.190), while the opposite was found in the Hungarian cohort (UC p = 0.083 vs. CD p = 0.019). No association of IBD with the TLR4 single-nucleotide polymorphism was found in either cohort (UC p = 0.430, CD p = 0.783 vs. UC p = 0.745, CD p = 0.383). CONCLUSION: IBD appears to be associated with the CD14 c.1-260C>T promoter variant in Germans and Hungarians, but not with the TLR4 c.896A>G (p.D299G) variant.

Büning C, Geerdts L, Fiedler T, Gentz E, Pitre G, Reuter W, Luck W, Buhner S, Molnar T, Nagy F, Lonovics J, Dignass A, Landt O, Nickel R, Genschel J, Lochs H, Schmidt HH, Witt H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany. · Am J Gastroenterol. · Pubmed #16494592 No free full text.

Abstract: OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, p.P1371Q, p.G1066G, rs2289308, DLG_e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Büning C, Halangk J, Dignass A, Ockenga J, Deindl P, Nickel R, Genschel J, Landt O, Lochs H, Schmidt H, Witt H. · Department of Gastroenterology, Hepatology and Endocrinology, Universitätsmedizin Berlin, Charité, Campus Mitte, Schumannstrasse 20/21, D-10117 Berlin, Germany. · Dig Liver Dis. · Pubmed #15248378 No free full text.

Abstract: BACKGROUND: Keratin 8 is a major component of intermediate filaments in single-layered epithelia of the gastrointestinal tract. Keratin 8 deficient mice display signs of colitis and diarrhoea characteristic for inflammatory bowel disease. Very recently, two keratin 8 mutations, Y54H and G62C, were identified. AIMS: We investigated if these keratin 8 missense mutations were associated with inflammatory bowel disease. PATIENTS: In total, 217 German patients with Crohn' s disease, 131 German patients with ulcerative colitis, and 560 German control subjects were enrolled in this study. METHODS: Samples were analysed by PCR amplification and subsequent melting curve analysis using fluorescence resonance energy transfer probes. RESULTS: The G62C mutation was detected in five (2.3%) patients presenting with Crohn's disease and in three (2.3%) with ulcerative colitis. In comparison, 9 (1.6%) out of 560 controls were heterozygous for this mutation. No patient or control was homozygous for this mutation. Patients carrying one mutant allele did not show any noticeable characteristics in their corresponding phenotype. In contrast, the Y54H mutation was observed in neither any of the 348 patients with inflammatory bowel disease nor in any control subject. CONCLUSIONS: Our data indicate that both keratin 8 mutations, G62C and Y54H, do not play a relevant pathogenic role in inflammatory bowel disease.

Büning C, Genschel J, Bühner S, Krüger S, Kling K, Dignass A, Baier P, Bochow B, Ockenga J, Schmidt HH, Lochs H. · Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Humboldt University, Schumannstrasse 20/21, 10117 Berlin, Germany. · Aliment Pharmacol Ther. · Pubmed #15142196 links to  free full text

Abstract: BACKGROUND: Mutations within the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease. AIMS: To investigate the clinical impact of the three common NOD2/CARD15 mutations in patients with Crohn's disease. METHODS: We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 3020insC) in 180 patients with Crohn's disease, 70 patients with ulcerative colitis and 97 controls. In patients with Crohn's disease, prevalence of NOD2/CARD15 mutations were correlated to clinical and demographical parameters. RESULTS: In Crohn's disease patients, 35.6% carried at least one mutant allele of NOD2/CARD15 mutations compared with 14.3% of patients with ulcerative colitis (P = 0.006) and to 15.5% of controls (P = 0.0001). Genotype phenotype analyses revealed that NOD2/CARD15 mutations determined younger age at disease diagnosis (P = 0.03), ileal disease location (P = 0.01) and ileocecal resections (P = 0.0002). Interestingly, reoperation with resection of the anastomosis was significantly more frequent in patients with NOD2/CARD15 mutations (P = 0.01). CONCLUSIONS: Our investigations support the current hypothesis that NOD2/CARD15 mutations are associated with a phenotype of Crohn's disease with younger age at diagnosis, ileal involvement, ileocecal resections and a high risk of postoperative relapse and reoperation. NOD2/CARD15 mutations might therefore be used to identify high risk patients for relapse prevention strategies.

Büning C, Ockenga J, Krüger S, Jurga J, Baier P, Dignass A, Vogel A, Strassburg C, Weltrich R, Genschel J, Lochs H, Schmidt H. · Dept. of Gastroenterology, Hepatology and Endocrinology, Charité, Humboldt University, Berlin, Germany. · Scand J Gastroenterol. · Pubmed #12795467 No free full text.

Abstract: BACKGROUND: Lactose intolerance with adult-onset is due to the inadequate enzymatic activity of lactasephlorizin hydrolase (LPH). It is frequently seen in patients with Crohn disease, but the mechanism remains to be elucidated. Two DNA genotypes, C/C(-13910) and G/G(-22018), located upstream from the LCT locus, the gene encoding for LPH, were recently identified as representing genetic markers for lactose intolerance. We utilized these two DNA genotypes to study their role in inflammatory bowel disease. METHODS: We investigated the prevalence of these two DNA variants using specific restriction enzyme digest assays in 166 patients with Crohn disease, in 120 healthy first-degree relatives of Crohn disease patients, in 63 patients with ulcerative colitis and in 187 healthy individuals. RESULTS: The analysis revealed a frequency of 21.4% of the 2 genotypes for adult-type hypolactasia in our studied German cohort of healthy individuals, which is higher than previously reported (15%) based on the hydrogen (H2) breath test. This might indicate a higher sensitivity of genotyping, but it has to be confirmed in larger cohorts. No significant difference was detectable in the frequency of the C/C(-13910) and G/G(-22018) genotypes in patients with Crohn disease (C/C(-13910): 21.7%; G/G(-22018): 22.3%) compared to first-degree relatives (C/C(-13910): 21.7%; G/G(-22018): 20.8%), patients with ulcerative colitis (C/C(-13910): 20.3%; G/G(-22018): 20.3%) and healthy individuals (C/C(-13910): 21.4%; G/G(-22018): 21.4%). CONCLUSION: The C/C(-13910) and G/G(-22018) genotype of adult-type hypolactasia is not associated with susceptibility to the pathogenesis of Crohn disease and ulcerative colitis.

Rose M, Fliege H, Hildebrandt M, Körber J, Arck P, Dignass A, Klapp B. · Medizinische Klinik und Poliklinik mit Schwerpunkt Psychosomatik, Virchow-Klinikum Humboldt Universität zu Berlin. · Z Gastroenterol. · Pubmed #10820859 No free full text.

Abstract: In the face of a hardly predictable course of illness--potentially effecting a severe diminution of daily activities--the quality of life (QOL) represents a chief outcome measure in the treatment of inflammatory bowel diseases (IBD). For the German-speaking area an economical disease-specific instrument measuring QOL has been missing, so far. Therefore, we translated and adapted the recently validated "Short Inflammatory Bowel Disease Questionnaire" SIBDQ (11). Bowel symptoms, systemic symptoms, moods, and social activities are represented by a total of 10 items. Along with this questionnaire 7 accepted instruments assessing QOL-components were administered to 125 outpatients (54 ulcerative colitis, 71 Crohn's disease) and 51 healthy controls. The psychometric properties are good. Consistency is alpha = .84, thereby slightly surpassing the Anglo-American SIBDQ (alpha = .78). Retest-reliability after 26 weeks is r = .60. Systematic covariations with accepted QOL-instruments give evidence for its convergent and discriminatory validity. Differences between groups (high vs. low inflammatory activity vs. healthy controls) substantiate its sensitivity. Thus, the German adaptation of the accepted SIBDQ supplies an economic, reliable, and valid instrument that proved able to assess clinically relevant differences in QOL in patients with IBD. We suggest that it should be used by its overall score rather than its subscales. The instrument is appropriate to be used in therapy outcome and evaluation studies. It allows international comparison.