Ulcerative Colitis: Zeuzem S

Preiss JC, Blumenstein I, Zeuzem S, Zeitz M. · Medizinische Klinik I, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin. · Z Gastroenterol. · Pubmed #19533543 No free full text.

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Plotz G, Raedle J, Spina A, Welsch C, Stallmach A, Zeuzem S, Schmidt C. · Medizinische Klinik I, Johann Wolfgang Goethe-Universität, Frankfurt, Germany. · Inflamm Bowel Dis. · Pubmed #18200512 links to  free full text

Abstract: BACKGROUND: Inflammatory bowel diseases (IBDs; ulcerative colitis, UC, and Crohn's disease, CD) show familial clustering suggestive of a genetic background. A linkage susceptibility region for these diseases (IBD9) lies on chromosome 3p and includes the DNA mismatch repair gene MLH1. Loss of MLH1 confers the characteristic microsatellite instability (MSI) phenotype which is also frequently found in the mucosa of IBD patients. A common germline alteration of MLH1 (655A>G) results in the amino acid exchange MLH1 I219V. Conflicting data exist on its effect on the function of the protein and it has recently been reported to cosegregate with refractory UC, suggesting that this alteration may impair mismatch repair activity and thereby contribute to certain forms of UC. METHODS: We analyzed the MLH1 I219V alteration using in silico and biochemical analyses and assessed its appearance in 67 well-classified UC patients in comparison to 40 healthy individuals. RESULTS: The analyses showed that I219 is a conserved, buried hydrophobic residue, and that I219V is unlikely to abolish MLH1 function but may modulate it. Quantitative biochemical evaluation showed identical stability and activity of the protein. Furthermore, the alteration occurred equally frequently in analyzed patients and healthy volunteers. CONCLUSIONS: The MLH1 I219V alteration does not directly contribute to the etiology of UC through an impairment of mismatch repair. A putative linkage disequilibrium of MLH1 I219V with the causative gene(s) of the IBD9 locus is rather distant.

Schmidt C, Giese T, Goebel R, Schilling M, Marth T, Ruether A, Schreiber S, Zeuzem S, Meuer SC, Stallmach A. · Department of Internal Medicine II, Saarland University, Homburg, Germany. · Int J Colorectal Dis. · Pubmed #17318554 No free full text.

Abstract: BACKGROUND AND AIMS: It has been suggested that Crohn's Disease (CD) is associated with an elevated T helper 1 response as manifested by increased production of interleukin-18 (IL-18). Local concentrations of neutralizing IL-18 binding proteins (IL-18 bp) may counteract biological functions of mature IL-18 in mucosal inflammation. Therefore, we investigated the IL-18/IL-18 bp system in a large group of patients with active inflammatory bowel disease (IBD) to identify patients that could respond theoretically to IL-18 neutralizing treatment strategies. PATIENT/METHODS: IL-18 and IL-18 bp messenger RNA (mRNA) expression in colonic mucosa from patients with active CD (n = 72), active ulcerative colitis (UC; n = 32), and non-IBD controls (infectious colitis or diverticulitis; n = 19) and normal, non-diseased controls (n = 20) were measured by reverse-transcribed real-time polymerase chain reaction. Mature IL-18 protein and IL-18 bp expression in inflamed mucosa were assessed by Western blotting. RESULTS/FINDINGS: Although IL-18 mRNA was increased in some patients with CD, the increase was not statistically significant. Densitometric evaluation of IL-18/alpha-actin ratio in patients with active CD (n = 20) and patients with UC (n = 10) demonstrated an increased ratio of IL-18 protein in CD when compared to UC (1.04 vs 0.72 [median]). On closer inspections, only 7/20 CD patients had an increased IL-18 protein expression in inflamed areas compared to noninflamed mucosa. INTERPRETATION/CONCLUSION: IL-18 expression in active CD is heterogeneous, only a minority of patients expresses elevated levels. Further treatment strategies targeting IL-18 expression in active CD should be concentrated on this subgroup of patients.

Schmidt C, Giese T, Ludwig B, Menges M, Schilling M, Meuer SC, Zeuzem S, Stallmach A. · Department of Internal Medicine II, Saarland University Hospital, Homburg/Saar, Germany. · Int J Colorectal Dis. · Pubmed #16133004 No free full text.

Abstract: BACKGROUND AND AIMS: After ileopouch anal anastomosis (IPAA), 10-40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohn's disease (CD). PATIENTS AND METHODS: Mucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction. RESULTS AND FINDINGS: Pro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2alpha and matrix metalloproteinase-1 transcripts was observed. INTERPRETATIONS AND CONCLUSIONS: Our data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

Jüngling B, Kindermann I, Moser C, Püschel W, Ecker KW, Schäfers HJ, Böhm M, Zeuzem S, Giese T, Stallmach A. · Department of Internal Medicine II, Saarland University, Germany. · Z Gastroenterol. · Pubmed #15700214 No free full text.

Abstract: BACKGROUND: Cardiac transplantation has become an accepted treatment modality for end-stage heart failure. Immunosuppressive agents, which are used after transplantation, are considered as therapeutic options for inflammatory bowel disease. CASE REPORT: We report on a 53-year-old patient who was treated for 2 years with cyclosporine A, azathioprine and prednisolone after heart transplantation. He developed a distal colitis with all features of ulcerative colitis. An infectious or ischemic etiology was carefully excluded. In spite of high-dose treatment with prednisolone the patient's abdominal symptoms worsened and he developed a progression of the inflammation in the entire colon and a colectomy with ileostomy was necessary. The histology was consistent with ulcerative colitis. After colectomy he recovered and remained in a good state of health. CONCLUSIONS: This report supports the concept that new onset inflammatory bowel disease can develop in a heart transplantation recipient in spite of immunosuppression.

Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S, Meuer SC, Stallmach A. · Department of Internal Medicine II , Saarland University, Homburg, Germany. · Inflamm Bowel Dis. · Pubmed #15674109 No free full text.

Abstract: BACKGROUND: It has been suggested that Crohn's disease (CD) is associated with an exaggerated T-helper 1 cytokine response manifested by increased production of interleukin (IL)-12. IL-12 is a heterodimeric protein comprising 2 disulfide-linked subunits designated p35 and p40. Recently, IL-12-related cytokines, IL-23 and IL-27, were described. Biologically active IL-23 is a heterodimer whose p40 subunit is identical to IL-12p40 whereas its p19 subunit is distantly related to IL-12p35. IL-27 consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. AIM: We sought to determine whether mucosal expression of IL-23p19 and IL-27p28 transcripts correlate with the inflammatory activity in inflammatory bowel disease (IBD). PATIENTS/METHODS: Messenger RNA expression in colonic mucosa from patients with Crohn's disease (CD; n = 37) and ulcerative colitis (UC; n = 19), and in non-IBD control subjects (specific colitis [SC]; n = 16) and normal, nondiseased control patients (n = 12) was measured by reverse-transcribed real-time polymerase chain reaction. RESULTS: IL-23p19 was significantly increased in inflamed mucosa in CD (P = 0.0377) and to a lesser extent also in UC patients but not in SC patients. Elevation of IL-23p19 transcript levels in CD correlated with the severity of endoscopic lesions. IL-27p28 transcripts and EBI3 transcripts were significantly elevated only in active CD. DISCUSSION: IL-23p19, IL-27p28, and EBI3 transcripts are strongly up-regulated in CD. The stimulatory effects of these cytokines on naive T cells in addition to a strongly synergistic action with IL-12 to trigger interferon-gamma production may contribute to the perpetuation of the inflammatory process in patients with CD. Notably, increased expression of IL-23 and IL-27 transcripts in CD suggests a T helper 1-dominated immunologic function in this disease.