Ulcerative Colitis: Ludwiczek O

Tilg H, Vogelsang H, Ludwiczek O, Lochs H, Kaser A, Colombel JF, Ulmer H, Rutgeerts P, Krüger S, Cortot A, D'Haens G, Harrer M, Gasche C, Wrba F, Kuhn I, Reinisch W. · Department of Gastroenterology and Hepatology and Biostatistics, University Hospital Innsbruck, Austria. · Gut. · Pubmed #14633951 links to  free full text

Abstract: BACKGROUND: Pilot studies of interferon alpha (IFN-alpha) suggest a high remission rate in the treatment of active ulcerative colitis. We evaluated the safety of pegylated interferon alpha (PegIFN) and its role in induction of remission in patients with active ulcerative colitis, in a multicentre placebo controlled trial. METHODS: Sixty patients with a clinical activity score (CAI) of >6 were randomised to receive placebo (n=20), PegIFN 0.5 microg/kg (n=19), or PegIFN 1.0 microg/kg body weight (n=21) once weekly (PegIntron; Schering-Plough, USA) over 12 weeks. Patients receiving 5-aminosalicylates, steroids, and/or azathioprine in stable dosages were included. RESULTS: Serious adverse events were seen in none of the placebo patients, in 3/19 patients in the PegIFN 0.5 microg/kg group (hospitalisation due to disease flare up n=3), and in 3/21 in the PegIFN 1.0 microg/kg group (hospitalisation due to disease flare up n=1; thrombosis n=1; grand mal seizure n=1). Otherwise, we observed only minor IFN-alpha side effects. Clinical remission rates at week 12 (CAI < or =4) were 7/20 (35%) in the placebo, 9/19 (47%) in the PegIFN 0.5 microg/kg group, and 7/21 (33%) in the PegIFN 1.0 microg/kg group (NS). Early withdrawal from the study was observed in 11/20 placebo patients, in 6/19 in the PegIFN 0.5 microg/kg group, and in 10/21 in the PegIFN 1.0 microg/kg group, mainly due to lack of efficacy. The higher PegIFN dose was associated with a significant decrease in levels of C reactive protein (p=0.003, day 0 v 85). CONCLUSIONS: PegIFN is safe but not effective, at the dosages used, in patients with ulcerative colitis.

Ludwiczek O, Kaser A, Novick D, Dinarello CA, Rubinstein M, Tilg H. · University Hospital Innsbruck, Department of Medicine, Division of Gastroenterology and Hepatology, Innsbruck, Austria. · Eur Cytokine Netw. · Pubmed #15809203 No free full text.

Abstract: OBJECTIVES: Interleukin 18 (IL-18) is a proinflammatory cytokine and a member of the IL-1 family. Animal models and investigations in humans point to an important role for this cytokine in inflammatory bowel diseases (IBD). IL-18 binding protein (IL-18BP) is a naturally occurring antagonist of IL-18. Methods. In this study, we measured IL-18 and IL-18BP plasma concentrations and spontaneous release in cultures of colonic explants from healthy subjects (n = 41), patients with Crohn's disease (CD, n = 135), and patients with ulcerative colitis (UC, n = 93). RESULTS: Both CD and UC patients had higher IL-18BP plasma levels than controls. Plasma levels of free, unbound IL-18 were significantly elevated in CD patients compared to healthy controls, but not in UC patients. Colonic explant cultures from inflamed areas in IBD patients released significantly higher levels of IL-18 than non-inflamed areas and controls. IL-18BP levels from the same cultures were below the detection limit over a culture period of 24 h. CONCLUSIONS: Our results confirm the importance of IL-18 in the pathogenesis of IBD and suggest that especially in CD, IL-18BP might be produced in insufficient quantities to counteract the effects of endogenous IL-18.

Moschen AR, Kaser A, Enrich B, Ludwiczek O, Gabriel M, Obrist P, Wolf AM, Tilg H. · Department of Medicine, University Hospital Innsbruck, Anichstr 35, 6020 Innsbruck, Austria. · Gut. · Pubmed #15753532 links to  free full text

Abstract: BACKGROUND AND AIMS: A substantial proportion of patients with inflammatory bowel disease (IBD) develops osteopenia and osteoporosis in the course of disease. Recent data from a mouse model of colitis suggest that the receptor activator of nuclear factor kappa B (RANKL)/osteoprotegerin (OPG) system may be responsible for bone loss. METHODS: We investigated the activation state of the RANKL/OPG system and its association with bone loss in human IBD. Plasma levels of OPG and RANKL were correlated with bone mineral density and current IBD therapy. Colonic secretion of OPG and RANKL and cell types responsible for such secretion were determined. RESULTS: OPG plasma levels were elevated 2.4-fold in Crohn's disease (CD) and 1.9-fold in ulcerative colitis (UC) whereas soluble RANKL (sRANKL) levels were not significantly different in IBD patients compared with healthy controls. High levels of OPG were released from colonic explant cultures (CEC) derived from inflamed IBD specimens, and colonic macrophages and dendritic cells costained for OPG. sRANKL levels from CEC were low both in IBD patients and healthy controls. Interestingly, increased expression of RANKL was mainly confined to cells in the lamina muscularis. A significant negative correlation was found between OPG plasma levels and femoral neck/lumbar spine bone mineral density. CONCLUSIONS: We have demonstrated that IBD is associated with alterations in the RANKL/OPG system. Applying results from a murine model of colitis associated bone loss, the constellation of OPG and sRANKL regulation observed in our study raises the possibility that RANKL/OPG may contribute to the development of bone loss in IBD.

Ludwiczek O, Vannier E, Borggraefe I, Kaser A, Siegmund B, Dinarello CA, Tilg H. · Department of Medicine, University Hospital Innsbruck, Innsbruck, Austria. · Clin Exp Immunol. · Pubmed #15498044 links to  free full text

Abstract: Interleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL-1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1alpha, IL-1beta, IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1alpha and IL-1beta were not detected. IL-1sRII levels were marginally lower in CD (-10%) and UC (-9%), whereas IL-1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively (P < 0.01) with Crohn's disease activity index (r = 0.53), C-reactive protein (r = 0.46) and alpha1-acid glycoprotein (r = 0.42). In colonic explant cultures, IL-1alpha and IL-1Ra levels were elevated in non-lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non-lesional UC. IL-1beta was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL-1sRII levels were elevated in non-lesional CD (+65%), but remained unchanged in lesional CD, non-lesional and lesional UC. IL-1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL-1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL-1sRII may dampen colonic inflammation in CD, but not in UC.

Kaser A, Ludwiczek O, Holzmann S, Moschen AR, Weiss G, Enrich B, Graziadei I, Dunzendorfer S, Wiedermann CJ, Mürzl E, Grasl E, Jasarevic Z, Romani N, Offner FA, Tilg H. · Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Innsbruck, Austria. · J Clin Immunol. · Pubmed #14997037 No free full text.

Abstract: Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-alpha by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-alpha increased and anti-TNF-alpha decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin(+) immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

Ludwiczek O, Kaser A, Tilg H. · University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. · Int J Colorectal Dis. · Pubmed #12548417 No free full text.

Abstract: BACKGROUND AND AIMS: CD40/CD40 ligand (CD40L) interaction is important for induction of T cell dependent antibody production and cell-mediated immune responses. Overexpression of CD40/CD40L in the intestinal mucosa is likely to be involved in the pathogenesis of inflammatory bowel disease (IBD). A soluble form of CD40L (sCD40L) exists in the circulation. This study investigated whether plasma levels of sCD40L are higher in patients with IBD than in healthy controls. PATIENTS AND METHODS: Plasma levels of sCD40L were measured in 89 patients with Crohn's disease (CD), 56 patients with ulcerative colitis (UC), 17 patients with infectious diarrhea, and 42 healthy controls, using a specific enzyme-linked immunosorbent assay. RESULTS: In CD patients plasma levels of sCD40L were significantly higher than in healthy controls. Patients with UC and infectious diarrhea had higher sCD40L levels than healthy controls, but the differences were not significant. CD patients with fistulas and/or abscesses (n=38) had significantly higher levels of sCD40L than patients with uncomplicated CD (n=51). Only in patients with uncomplicated CD plasma levels of sCD40L correlated significantly with C-reactive protein and alpha(1)-glycoprotein. In UC patients there was a significant correlation of sCD40L with C-reactive protein. However, there was no significant correlation between plasma sCD40L levels and Crohn's disease activity index or Rachmilewitz score. CONCLUSION: Elevated plasma levels of sCD40L in CD patients supposedly reflect activation of functional CD40L in the intestine and might be a marker of intestinal inflammation.