Ulcerative Colitis: Wedel S

Bauditz J, Wedel S, Lochs H. · Charité University Hospital, 4th Department of Medicine, Berlin, Germany. · Gut. · Pubmed #11788559 links to  free full text

Abstract: BACKGROUND: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated. AIM: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD). METHODS: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide. RESULTS: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production. CONCLUSION: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.

Schottelius A, Wedel S, Weltrich R, Rohde W, Buttgereit F, Schreiber S, Lochs H. · IV and III Medical Department of Medicine and Institute for Experimental Endocrinology, Charité University Medical Center, Berlin, Germany. · Am J Gastroenterol. · Pubmed #10950048 No free full text.

Abstract: OBJECTIVE: Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD. METHODS: Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation. RESULTS: Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p < 0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group. CONCLUSIONS: Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.