Ulcerative Colitis: De Vos M

Baert F, De Vos M, Louis E, Vermeire S, Anonymous00134. · Department of Gastroenterology, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #17715629 No free full text.

Abstract: BACKGROUND: The introduction of infliximab has greatly advanced the therapeutic armamentarium of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Although the benefit/risk ratio for infliximab is positive, of particular concern has been the problem of immunogenicity ascribed to the chimeric properties of the drug. Antibody formation is associated with allergic reactions and loss of response. AIMS AND METHODS: A literature search was undertaken on the magnitude of the problem of immunogenicity and on the clinical consequences. A survey was conducted about the clinical practice and management of acute and delayed allergic reactions to infliximab in different centres in Belgium. For this, a questionnaire was sent to all members of the Belgian IBD research group (n = 38 belonging to 29 centers). RESULTS AND CONCLUSION: Infusion reactions are important immunologic events induced by the presence of a substantial concentration of antibodies against infliximab (ATI) in the serum. Concomitant immunosuppressive treatment may optimize response to infliximab by preventing the formation of antibodies. Steroid administration prior to an infliximab infusion can further reduce the immunogenicity. Probably the most effective strategy to optimize treatment and avoid immunogenicity is maintenance therapy. If infliximab therapy can be discontinued is yet unclear but when treatment goals have been reached, we feel this should be attempted. In the case of relapse, infliximab should be restarted as maintenance long term. Practical guidelines on how to handle the problem of immunogenicity to infliximab are important for clinicians treating patients with IBD.

De Vos M. · Department of Gastroenterology, Ghent University Hospital, Belgium. · Clin Pharmacokinet. · Pubmed #10976656 No free full text.

Abstract: Slow release oral mesalazine (Pentasa) contains microgranules covered by a semipermeable ethylcellulose membrane. The microgranules continuously release their content from duodenum to ileum in a pH- and time-dependent way. About 75% of the microgranules pass into the colon, where further release is slower. This release pattern does not appear to be affected by food, diarrhoea or the simultaneous use of H2 antagonists. Rectal forms of mesalazine deliver active drug directly to the rectum and left colon. Plasma concentrations of mesalazine and its metabolite acetyl-5-aminosalicylic acid after oral or local administration are the result of systemic absorption and hepatic metabolism by N-acetyltransferase. Most studies report maximal plasma concentrations of less than 1 mg/L after oral administration of slow release mesalazine, much lower than those observed after uncoated mesalazine but generally higher than after azo-bound drugs such as sulfasalazine. Urinary recovery is an indicator of absorption and metabolism, and is lower after rectal administration (10 to 30%) than after oral administration (30 to 40%). Faecal recovery after oral administration of slow or delayed release mesalazine is lower than with azo-bound drugs. Mesalazine acts locally after absorption by colonic and ileal mucosa. Mean steady-state concentrations of 25.7+/-2.2 microg/kg wet weight are found in ileocolonic biopsy specimens from patients with irritable bowel syndrome treated for 1 week with slow release mesalazine 1.5 g/day. Intramucosal concentrations after slow release mesalazine differ little between healthy individuals and patients with inflammatory bowel disease. Although significant differences are found between the various aminosalicylates in release patterns and the resulting pharmacokinetic parameters, no differences in therapeutic effects have been found in comparative studies. High doses of oral mesalazine (2 to 4 g/day) are more effective than lower doses in the treatment of patients with mild to moderate active ulcerative colitis. High doses (4 g/day) are also effective in the treatment of Crohn's disease, predominantly in patients with ileitis. In contrast, no dose ranging effects were demonstrated with local treatment forms: mesalazine 1g enema seems sufficient for patients with distal colitis. Higher serum concentrations and urinary recoveries after the administration of slow or delayed release mesalazine compared with azo-bound drugs suggest a higher risk for renal adverse effects, although the reported occurrence is extremely low. Although preliminary data support an association between mucosal concentrations of mesalazine and its clinical activity, further studies are needed to correlate the effects of this drug with its pharmacokinetic parameters.

Ferdinande L, Demetter P, Perez-Novo C, Waeytens A, Taildeman J, Rottiers I, Rottiers P, De Vos M, Cuvelier CA. · Department of Pathology, Ghent University Hospital, Ghent University, De Pintelaan 185, Ghent, Belgium. · Int J Immunopathol Pharmacol. · Pubmed #18547472 No free full text.

Abstract: Indoleamine 2,3-dioxygenase (IDO) catalyzes the first step in the degradation of tryptophan, an essential amino acid. During inflammation IDO can be induced in different cell types resulting in local tryptophan depletion. This inhibits T cell proliferation and may induce apoptosis. High expression of IDO was previously found in inflammatory bowel disease and is thought to represent a mechanism for downregulation of the local immune response. Our aim is to investigate the expression pattern of IDO in normal and inflamed murine and human intestinal mucosa. Immunohistochemical staining for IDO was performed on paraffin sections of colon of two mouse models for colitis and their controls and on paraffin sections of human ileum and colon in normal and two different inflammatory conditions, namely inflammatory bowel disease and diverticulitis. IDO immunohistochemistry showed similar results in murine and human tissue. In normal, as well as in inflamed mucosa, some mononuclear cells, fibroblasts and endothelial cells were positive for IDO. In inflamed mucosa a specific expression pattern of epithelial IDO was found where epithelial cells flanking ulcers or bordering crypt abscesses showed high IDO expression. Moreover, in human intestinal inflammation, IDO was expressed in ulcer associated cell lineage. Since bacterial invasion is more pronounced in erosions and in crypt abscesses and since IDO activity and the resulting local tryptophan depletion can cause growth arrest of several tryptophan-dependent microorganisms, IDO expression in the vicinity of interruptions of the epithelial barrier may point to a role for IDO as a local anti-infectious agent. Furthermore, expression of IDO at the margin of ulcerations and in the reparative ulcer-associated cell lineage suggests involvement of IDO in repair processes.

Daniel F, Loriot MA, Seksik P, Cosnes J, Gornet JM, Lémann M, Fein F, Vernier-Massouille G, De Vos M, Boureille A, Treton X, Flourié B, Roblin X, Louis E, Zerbib F, Beaune P, Marteau P. · Department of Gastroenterology, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. · Inflamm Bowel Dis. · Pubmed #17206635 links to  free full text

Abstract: BACKGROUND: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. PATIENTS AND METHODS: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5' nuclease allelic discrimination assay. RESULTS: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42-9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). CONCLUSION: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients.

Demetter P, De Vos M, Van Huysse JA, Baeten D, Ferdinande L, Peeters H, Mielants H, Veys EM, De Keyser F, Cuvelier CA. · Department of Pathology, University Hospital, Ghent University, 5 Blok A, De Pintelaan 185, B-9000 Gent, Belgium. · Ann Rheum Dis. · Pubmed #15166002 links to  free full text

Abstract: BACKGROUND: Crohn's disease is associated with an increased number of macrophages in ileal and colonic mucosa. Data on macrophages in gut mucosa of patients with spondyloarthritis (SpA) are scarce. OBJECTIVE: To investigate macrophages and other antigen presenting cells in gut mucosa from patients with SpA and Crohn's disease, given the relationship between both entities. METHODS: Biopsy specimens from patients with SpA, Crohn's disease, ulcerative colitis, and from controls were immunohistochemically stained with different markers for macrophages and dendritic cells. Slides were scored semiquantitatively on a four point scale. RESULTS: SpA and Crohn's disease were associated with large numbers of CD68+ macrophages. Colon mucosa of both patients with SpA and Crohn's disease, but not ulcerative colitis, showed increased numbers of macrophages expressing the scavenger receptor CD163. CONCLUSIONS: Macrophages expressing the scavenger receptor CD163 are increased in colonic mucosa in SpA and in Crohn's disease, highlighting the relationship between these entities. The increased number of CD163+ macrophages in colon mucosa of patients with SpA suggests this is another argument for a role of macrophage scavenger receptors in this group of diseases.

Van Assche G, Baert F, De Reuck M, De Vos M, De Wit O, Hoang P, Louis E, Mana F, Pelckmans P, Rutgeerts P, Van Gossum A, D'Haens G. · Department of Internal Medicine-Gastroenterology, UZ Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #12619425 No free full text.

Abstract: Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the treatment of ulcerative colitis (UC). For acute treatment of mild to moderate flares and in maintenance treatment, their efficacy has been established. Since ulcerative colitis is limited to the distal colon in two thirds of the patients, topical therapy also plays an important role. In mild/moderate active disease 5-ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to 4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally well tolerated. The risk of colorectal tumours is increased in patients with longstanding ulcerative colitis and epidemiological evidence indicates that chronic 5-ASA treatment reduces this risk. However, at present there is insufficient evidence to maintain patients on life-long 5-ASA maintenance treatment for this indication.

Van Damme N, De Keyser F, Demetter P, Baeten D, Mielants H, Verbruggen G, Cuvelier C, Veys EM, De Vos M. · Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium. · Clin Exp Immunol. · Pubmed #11531945 links to  free full text

Abstract: T lymphocytes and their cytokines have an important role in the regulation of immune responses in the gut and in the pathogenesis of intestinal inflammation such as in Crohn's disease. The aim of this study was to analyse the Th1/Th2 cytokine profile (IFN-gamma, IL-2, IL-4 and IL-10) in intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) in Crohn's disease (CD) and ulcerative colitis (UC) in relation to healthy controls (C). Colonic and ileal biopsy specimens were obtained from controls (n = 13) and patients with CD (n = 32). Colonic biopsies were obtained from patients with UC (n = 11). Intracytoplasmic IFN-gamma, IL-2, IL-4 and IL-10 were determined by flow cytometry after PMA-ionomycin stimulation in IEL and LPL. In colonic LPL, a significant proportional decrease of IFN-gamma and IL-2 producing CD3+ cells was observed in patients with CD and UC compared to controls. In ileal LPL, a similar tendency was found although differences were not significant. In IEL no differences in cytokine profiles could be observed. Flow cytometric analysis of intracytoplasmic cytokines at single cell level showed a proportional decrease of IFN-gamma and IL-2 producing T cells in colonic lamina propria in patients with inflammatory bowel disease.

de Vlam K, Mielants H, Cuvelier C, De Keyser F, Veys EM, De Vos M. · Department of Rheumatology, University Hospital Gent, Belgium. · J Rheumatol. · Pubmed #11128677 No free full text.

Abstract: OBJECTIVE: To determine the overall prevalence of spondyloarthropathy (SpA) among patients with inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)]. METHODS: One hundred three consecutive patients with IBD from a gastroenterology unit were questioned and examined for SpA symptoms. Patients previously diagnosed with SpA were excluded. All patients were questioned and examined for SpA symptoms such as inflammatory back pain, joint swelling, enthesitis, and psoriasis or a specific family history. Radiographs were taken of all sacroiliac joints. HLA loci A, B, C, and DR were determined in all patients. RESULTS: Thirty-nine percent of the patients with IBD had clinical articular manifestations: 30% had inflammatory back pain, 10% had synovitis, and 7% had a peripheral enthesopathy. The majority (90%) of patients with rheumatic complaints fulfilled the classification criteria for SpA and 10% fulfilled the criteria for ankylosing spondylitis. Asymptomatic sacroiliitis was found in an additional 18% of the patients. Moreover, sacroiliitis, symptomatic or asymptomatic, was related to the disease duration. HLA-B27 conferred an additional risk for inflammatory low back pain in patients with IBD. CONCLUSION: Articular involvement in IBD can be classified as SpA. The appearance of SpA occurs irrespective of the extent of the bowel disease. Moreover, asymptomatic sacroiliac involvement is a common manifestation in IBD and it is related to disease duration, suggesting evidence for a related pathogenic mechanism.

Demetter P, De Vos M, Van Damme N, Baeten D, Elewaut D, Vermeulen S, Mareel M, Bullock G, Mielants H, Verbruggen G, De Keyser F, Veys EM, Cuvelier CA. · Department of Pathology, Ghent University Hospital, Belgium. · Am J Clin Pathol. · Pubmed #10989636 links to  free full text

Abstract: The E-cadherin-catenin complex is important for the maintenance of epithelial architecture. We studied its expression in Crohn disease, ulcerative colitis, acute ileitis, and controls. Immunohistochemical stainings for E-cadherin, alpha-catenin, beta-catenin and gamma-catenin were performed. E-cadherin messenger RNA (mRNA) was detected using riboprobes. In active inflammation, there was up-regulation of the complex. In particular, epithelium adjacent to ulcers showed increased expression of protein and mRNA, but in ulcer-associated cell lineage, the intensity of staining was weak to negative. In focal inflammation, up-regulation was found in affected areas. Reparative epithelium growing over denuded areas showed weaker expression. Since structural or functional perturbation in any of the molecules of the E-cadherin-catenin complex results in loss of intercellular adhesion, the preexistent epithelium may benefit from up-regulation to try to maintain its normal architecture under inflammatory conditions. Reduced expression in reparative epithelium and ulcer-associated cell lineage could facilitate the motility of these cells.