Ulcerative Colitis: Geboes K

Geboes K, Colombel JF, Greenstein A, Jewell DP, Sandborn WJ, Vatn MH, Warren B, Riddell RH, Anonymous00396. · Department of Pathology, University Hospital Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #18213696 links to  free full text

Abstract: The precise diagnosis of colitis cannot always be established with the available diagnostic tools. The subgroup of patients with an uncertain diagnosis has been classified as "indeterminate colitis" (IC). The definition of "indeterminate," however, has changed over the years. Originally, IC was proposed by pathologists for colectomy specimens, usually from patients operated on for severe colitis, showing overlapping features of ulcerative colitis (UC) and Crohn's disease (CD). Later, the same terminology was used for patients showing no clear clinical, endoscopic, histologic, and other features allowing a diagnosis of either UC or CD. Therefore, it is difficult to compare different studies. An International Organization of Inflammatory Bowel Diseases (IOIBD) working party confirmed 1) the ambiguous nature of the term, and 2) proposes an updated classification for the category of patients with an unclear diagnosis. According to this, the term IBD unclassified (IBDU) is confirmed, as suggested by the Montreal Working Party 2005 for patients with clinically chronic colitis, that clearly have IBD but when definitive features of CD or UC are absent. In resected specimens the term "colitis of uncertain type or etiology" (CUTE) is preferred. It is accepted that most of the time this may have a prefix, such as severe, chronic. The classification of IBD varies when based only on biopsies rather than on a colectomy specimen. The vast majority of these have severe colitis. For those that cannot bear to abandon the highly ambiguous term IC, if it is used at all, this is where it can be used parenthetically.

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR. · University Hospital Gasthuisberg, Leuven, Belgium. · Gastroenterology. · Pubmed #17258735 No free full text.

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Geboes K, De Hertogh G. · Department of Pathology, University Hospital KU Leuven, Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #14555917 No free full text.

Abstract: A diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) is based on a combination of clinical, histologic, endoscopic, and radiologic data. The distinction between UC and CD can be difficult because of the lack of a differentiating single gold standard. Indeterminate colitis (IC) was introduced by pathologists for the diagnosis of surgical colectomy specimens showing an overlap between the features of UC and CD. The diagnosis of IC was based on macroscopic and microscopic features. The term indeterminate colitis is in recent years more widely applied to include all cases with endoscopic, radiographic, and histologic evidence of chronic inflammatory bowel disease confined to the colon, but without fulfilment of diagnostic criteria for UC and CD. As for UC and CD, the diagnosis of IC has therefore become a clinicopathologic diagnosis. IC is generally considered to be a temporary diagnosis. The clinical characteristics of patients with IC are, however, somewhat different from the characteristics of those with UC. Furthermore, serologic markers such as perinuclear antineutrophil cytoplasmic antibody and anti-Saccharomyces cerevisiae, which are strongly linked with UC and CD, are both negative in a subset of patients with IC. Therefore, the possibility that IC could be a separate entity must be investigated.

Geboes K, Dalle I. · Department of Pathology, University of Leuven, Belgium. · Gut. · Pubmed #11953331 links to  free full text

Abstract: Microscopic analysis of endoscopically obtained tissue samples is important for the diagnosis of several gastrointestinal disorders such as gastritis and chronic inflammatory bowel disease (IBD). Histologically disease activity is based on the presence of neutrophilic polymorphonuclear leucocytes in conjunction with epithelial damage. Effective eradication treatment for Helicobacter pylori related gastritis reduces active inflammation rapidly whereas chronic inflammation decreases only slowly. Similar findings have been obtained for IBD. A literature review of clinical drug trials in IBD and the effect of various drugs on the microscopic features of Crohn's disease and immunohistochemistry for different markers was performed. Diagnostic microscopic features and the features characteristic for disease activity vary with time and treatment. The more recently developed drugs used for Crohn's disease can induce mucosal healing.

Rutgeerts P, Geboes K. · Department of Medicine, University Hospital Leuven, Belgium. · Eur J Surg Suppl. · Pubmed #11718529 No free full text.

Abstract: The treatment of patients with ulcerative colitis and Crohn's disease is a huge challenge to the clinician mainly because the etiology of IBD is still completely unknown. Pathogenetic mechanisms, in constrast, have partly been elucidated thanks to immunohistochemical investigation of the tissue in IBD and the study of experimental animal models of gut inflammation. There is extensive evidence that at least in Crohn's disease tolerance for commensal bacteria is lost which leads to uncontrolled inflammation mediated by a T-helper 1 response and to tissue destruction of the gut epithelium with inadequate repair. Genetic factors are probably responsible for increased susceptibility and may define disease phenotypes. These insights have led to a dramatic improvement of our therapeutic means with the development of the chimeric monoclonal antibody to TNF. The pathogenetic mechanisms are less clear in UC. The hypothesis is that UC is a T-helper 2 mediated disease. We have a very attractive way to study the early onset of Crohn's disease in the postoperative Crohn's situation. Newer therapeutic approaches should aim at preventing recurrence of Crohn's lesions in the normal postoperative bowel. Such model is also available for UC since there is increasing evidence that pouchitis is recurrent ulcerative colitis in the small bowel. Cooperation between clinicians and basic scientists is the best way to achieve fast progress in understanding IBD.

Geboes K. · Department of Pathology, University Hospital Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #11475135 No free full text.

Abstract: In most patients coming to the general practitioner or specialist with a history of bloody diarrhoea, bacteria or drugs are the most likely causative agents and it will be possible to make a diagnosis fairly easily. Because of differences in treatment, ulcerative colitis (UC) and Crohn's disease (CD) must however seriously be considered especially in younger patients, with severe symptoms and whenever the history is prolonged. A variety of colitides may indeed be clinically confused with UC and CD. Pathological mimics that should not be missed include infectious diseases such as Campylobacter colitis, yersiniosis, amoebiasis and others; drug-induced diseases (due to nonsteroidal antiinflammatory drugs...); diverticular disease-associated colitis; intestinal endometriosis; intestinal vasculitis and Behçet's disease and iatrogenic conditions such as graft-versus-host-disease and radiation colitis. In most situations a precise diagnosis of these conditions should be possible when all data are available. The term "indeterminate colitis" is used, when a diagnosis of chronic idiopathic inflammatory bowel disease (IBD) is suggested, but the differential diagnosis between UC and CD can not be solved. This occurs in approximately 5% of all patients with IBD. Diagnostic problems can occur in acute fulminant colitis, acute prolonged colitis, chronic relapsing disease and pouchitis. Indeterminate colitis is essentially a temporary diagnosis. Surgical and medical treatment of these patients can be difficult. When surgical treatment is indicated, the type of surgery must be seriously considered. The clinical course of patients with indeterminate colitis is usually more severe when compared with classical UC and these patients require often more severe medical treatment. Diagnostic problems can also arise in longstanding IBD, either UC and CD. Relapse of symptoms can be due to intercurrent infection (CMV is one of the candidates). Medical treatment can influence the microscopic features and induce a discontinuous inflammation in UC, reminiscent of CD. In cases of doubt, the original biopsies should be reviewed to ascertain the diagnosis, and orient treatment.

Geboes K, Desreumaux P, Jouret A, Ectors N, Rutgeerts P, Colombel JF. · Département de Pathologie et de Gastroentérologie, Hôpital Universitaire, KU Leuven, Belgique. · Gastroenterol Clin Biol. · Pubmed #10592879 No free full text.

This publication has no abstract.

D'Haens G, Lemmens L, Geboes K, Vandeputte L, Van Acker F, Mortelmans L, Peeters M, Vermeire S, Penninckx F, Nevens F, Hiele M, Rutgeerts P. · Department of Internal Medicine, University Hospital Gasthuisberg, Leuven, Belgium. · Gastroenterology. · Pubmed #11313301 No free full text.

Abstract: BACKGROUND & AIMS: Cyclosporine has been effective in patients with steroid-refractory attacks of ulcerative colitis (UC). We investigated the effects of intravenous (IV) cyclosporine as single IV therapy (without glucocorticosteroids) for severe UC and compared these with the response to glucocorticosteroids. METHODS: Patients with a severe attack of UC were randomized to treatment with IV cyclosporine, 4 mg x kg(-1) x day(-1), or with methylprednisolone, 40 mg/day, in a randomized, double-blind, controlled trial. After 8 days, patients who had a response received the same medication orally in combination with azathioprine. Patients were followed up clinically, endoscopically, and by scintigraphy. Renal function was assessed using urinary inulin clearances. Endpoints were clinical improvement, discharge from the hospital, and remission up to 12 months after intravenous therapy. RESULTS: Thirty patients were included. After 8 days, 8 of 15 patients (53%) who received methylprednisolone had a response to therapy vs. 9 of 14 (64%) receiving cyclosporine. In nonresponders, 3 of 7 methylprednisolone patients and 1 of 3 cyclosporine patients improved when both treatments were combined. No serious drug-related toxicity was observed with either treatment. At 12 months, 7 of 9 patients (78%) initially controlled with cyclosporine maintained their remission vs. 3 of 8 (37%) initially treated with methylprednisolone. No clinically significant decrease of renal function was observed. CONCLUSIONS: Cyclosporine monotherapy is an effective and safe alternative to glucocorticosteroids in patients with severe attacks of UC.

De Preter V, Bulteel V, Suenaert P, Geboes KP, De Hertogh G, Luypaerts A, Geboes K, Verbeke K, Rutgeerts P. · Department of Gastrointestinal Research and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Leuven, KU Leuven, Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #18942762 No free full text.

Abstract: BACKGROUND: Healthy colonic mucosa uses butyrate as the major energy source. In ulcerative colitis (UC) butyrate oxidation has been shown to be disturbed, but it remains unclear whether this is a primary defect. The aim of this study was to measure mucosal butyrate oxidation in UC (involved and noninvolved colon) and in pouchitis and to study the relationship with endoscopic as well as histological disease activity. METHODS: Butyrate oxidation was measured in 73 UC patients, 22 pouchitis patients, and 112 controls (95 colon, 17 ileum) by incubating biopsies with 1 mM 14C-labeled Na-butyrate and measuring the released 14CO2. RESULTS: Compared with that in normal colon, butyrate oxidation was significantly impaired in endoscopically active but not in quiescent disease or uninvolved colon segments. The severity of the metabolic defect was related to histological disease activity and decreased epithelial cell height. In active pouchitis, butyrate oxidation was significantly decreased compared with that in normal ileum and excluded pouches without inflammation. The histological pouchitis score correlated significantly with butyrate oxidation. CONCLUSIONS: Active UC and pouchitis show the same inflammation-related metabolic defect. Our data suggest that the defect is a consequence of inflammation and that pouchitis is metabolically similar to active UC.

Geboes K, Cazals-Hatem D, Couvelard A, Lavergne-Slove A, Haouet S, Jouret-Mourin A. · Département de pathologie, hôpital universitaire Saint-Rafaël, KU Leuven, 12 Minderbroedersstraat, Leuven, Belgium. · Ann Pathol. · Pubmed #18706357 No free full text.

This publication has no abstract.

Geboes K. · Department of Pathology, University Hospital, KU Leuven, Leuven, Belgium. · Gastroenterol Clin Biol. · Pubmed #18538968 No free full text.

Abstract: SUMMARY: Collagenous colitis and lymphocytic colitis are the two major conditions characterized by chronic watery diarrhoea, without endoscopic or radiological lesions, but with histological abnormalities and therefore considered as "microscopic colitis". The histology of colonic biopsies shows inflammation of the mucosa, and either thickening of the subepithelial collagen band or an increase of lymphocytes in the surface epithelium. Different variant forms have been reported under separate names. These are probably not specific entities. The incidence of microscopic colitis is slightly less than the incidence of chronic idiopathic inflammatory bowel diseases (IBD). Microscopic colitis and IBD are clearly different entities. The relation between both entities is weak but double. Biopsy samples from patients with IBD may mimic the features of lymphocytic or collagenous colitis, both in the initial onset and during follow-up. In the large majority of these cases, endoscopy shows or has shown mucosal lesions. In rare cases, however, a double diagnosis was made. Certain patients, usually of older age, presented first with a microscopic, usually collagenous colitis and developed subsequently genuine ulcerative colitis.

Villanacci V, Bassotti G, Nascimbeni R, Antonelli E, Cadei M, Fisogni S, Salerni B, Geboes K. · 2nd Department of Pathology, Spedali Civili and University of Brescia, Brescia, Italy. · Neurogastroenterol Motil. · Pubmed #18492026 No free full text.

Abstract: Various studies have described abnormalities of the enteric nervous system (ENS) in tissue samples from patients with chronic idiopathic inflammatory bowel diseases (IBD). The distribution of density of the different cell types of the ENS was however not studied in a systematic way. The aim of this study was to examine the density of neurons, enteroglial cells and interstitial cells of Cajal (ICC) in the different plexuses of the ENS in samples from patients with Crohn's disease (CD), ulcerative colitis (UC) and controls. Tissue samples from 16 patients with CD (ileum) and 16 patients with UC obtained in involved and non-involved areas were studied using immunohistochemistry with antibodies directed against neuron-specific enolase, S100, C-Kit and CD3. Sections were analysed blindly by two pathologists and the number of positive cells was counted for each type. Overall, an increase was noted for neuronal cell bodies, enteroglia and ICC in the deep muscular plexus in CD. In uninvolved areas of CD patients, the number of enteroglial cells was decreased. In UC, an increase of ICC in the muscularis propria and enteroglial cells was observed in diseased tissue. The study confirms the presence of abnormalities of the different cells of the ENS in IBD. The presence of lesions in samples from uninvolved areas, such as a reduction of enteroglia, supports a pathogenetic role of the ENS.

Ferrante M, Declerck S, De Hertogh G, Van Assche G, Geboes K, Rutgeerts P, Penninckx F, Vermeire S, D'Hoore A. · Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Inflamm Bowel Dis. · Pubmed #17973304 links to  free full text

Abstract: BACKGROUND: During the course of their disease, about 30% of patients with ulcerative colitis (UC) will undergo proctocolectomy with ileal pouch-anal anastomosis (IPAA). We evaluated the outcome of IPAA in a Belgian referral center. METHODS: Clinical charts were reviewed for pre- and postoperative disease course, functional outcome, and complications in all patients with UC (n = 182) and indeterminate colitis (n = 2) who underwent IPAA in 1990-2004. RESULTS: Follow-up data were available in 173 out of 184 patients (67 female, median age at proctocolectomy 39.0 years). Median functional Oresland score 1 year after IPAA was 3 (range 0-11). Early postoperative complications were seen in 27% of patients. After a median (interquartile range) follow-up of 6.5 (3.4-9.9) years, 35% of patients developed septic and/or obstructive complications. Forty-six percent of patients developed at least 1 episode of pouchitis. Risk factors for pouchitis were the presence of extraintestinal manifestations (odds ratio [OR] 1.92 (1.23-3.01), P = 0.004) and younger age at proctocolectomy (P = 0.004). Chronic pouchitis was present in 33 patients and associated with extraintestinal manifestations (OR 2.93 (1.13-7.62), P = 0.027), backwash ileitis (OR 9.28 (1.71-50.49), P = 0.010), and length of follow-up (P = 0.004). Pouch failure occurred in 5% of patients. CONCLUSIONS: Although proctocolectomy with IPAA surgery has a good functional outcome, postoperative complications, especially pouchitis, remain considerable in patients with UC.

Bardin N, Reumaux D, Geboes K, Colombel JF, Blot-Chabaud M, Sampol J, Duthilleul P, Dignat-George F. · INSERM U608, Physiopathologie de l'Endothelium, Université de la Méditerranée, UFR Pharmacie, Marseille, France. · Inflamm Bowel Dis. · Pubmed #16374253 No free full text.

Abstract: BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC), the 2 major forms of inflammatory bowel diseases (IBD), have been associated with disturbances in vascular physiology, including permeability and angiogenesis, that are in part regulated by the endothelial intercellular junctions. These junctions are composed of several adhesion molecules including the platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) and the more recently described CD146 (S-Endo1 Ag, MUC18). AIM: To study the expression of tissue and soluble form of CD146 in patients with CD or UC in relation to disease activity and location. This study was made in comparison with the soluble form of CD31 (sCD31). RESULTS: In active disease, a high expression of CD146 was observed on endothelial cells in intestinal biopsies from both CD and UC. In addition, we observed a decrease of sCD146 in relation to active disease and extensive location of CD and UC. Lower levels of sCD31 were also detected in active and extensive location of UC, but no difference could be observed in CD. CONCLUSION: sCD146 is a novel marker of the endothelial intercellular junction that reflects endothelial remodeling more effectively than soluble CD31. Further studies are warranted to determine whether sCD146 will provide a serological assay reflecting alterations in vascular permeability and vessel proliferation in the inflamed IBD intestine.

Sjöqvist U, Befrits R, Söderlund S, Ost A, Karlén P, Tribukait B, Rubio C, Rutgeerts P, Geboes K, Löfberg R. · Department of Medicine, Karolinska Institutet, Stockholm Söder Hospital, Sweden. · Anticancer Res. · Pubmed #16334114 No free full text.

Abstract: BACKGROUND: The risk of colorectal cancer (CRC) in colonic Crohn's disease (CCD) seems to be of the same magnitude as in extensive, longstanding ulcerative colitis (UC) and colonoscopic surveillance has been advocated. Mucosal dysplasia and DNA-aneuploidy are early warning markers of malignant transformation in UC. Data concerning the occurrence of such premalignant lesions in CCD are scarce. AIMS: The objective of this study was to investigate the DNA ploidy pattern in CCD-patients with manifest CRC, both in the tumour, as well as in the adjacent and distant colorectal mucosa. The results from DNA-flow cytometry analyses (FCM) prior to the development of a CRC in CCD were also investigated. MATERIALS AND METHODS: Biopsies obtained at colonoscopy and surgical specimens from 43 patients with colonic or ileocolonic CD developing CRC between 1988 and 1998 were reviewed. The CRC histological phenotype, and the occurrence of dysplasia were registered. CRC-tissue and tissue from areas with dysplasia adjacent to and/or distant from the tumour were obtained from paraffin-embedded blocks and were analysed by FCM after preparation. RESULTS: Twenty-four CRCs in 21 patients (14 men) were suitable for FCM-analyses. The median age at CRC-diagnosis was 53 years (21-73) and the median CCD-duration was 14.5 years (1-50). A predominance of CRC was found either in the cecum (9124) or in the rectum (7/24). DNA-aneuploidy was found in 62.5% (15/24) of the tumours, in 25% (2/8) in adjacent and/or distant mucosa, and in 50% (2/4) of the patients that had been subjected to colonoscopic surveillance prior to the CRC-diagnosis. In 7patients (29%), definite dysplasia was detected adjacent to andlor distant from the tumour. Of the 6 patients undergoing colonoscopic surveillance, 3 (50%) displayed definite dysplasia prior to the colectomy. CONCLUSION: Since DNA- aneuploidy is a' common feature in CRCs in CCD and precede the development of invasive carcinoma, inclusion of FCM-analyses of colorectal biopsies may enhance the sensitivity of identifying high-risk CCD-patients prone to develop CRC within the frame of colonoscopic surveillance programs.

Philippe D, Chakass D, Thuru X, Zerbib P, Tsicopoulos A, Geboes K, Bulois P, Breisse M, Vorng H, Gay J, Colombel JF, Desreumaux P, Chamaillard M. · INSERM, Lille, France. · Gut. · Pubmed #16299031 links to  free full text

Abstract: BACKGROUND AND AIMS: Recent studies with mu opioid receptor (MOR) deficient mice support a physiological anti-inflammatory effect of MOR at the colon interface. To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases (IBD), we (1) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation; and (2) tested the potential anti-inflammatory function of a specific opiate (DALDA) in inflamed and resting human mucosa. PATIENTS AND METHODS: Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues, isolated peripheral blood mononuclear cells and purified monocytes, and CD4+ and CD8+ T cells from healthy donors and IBD patients. The effect of cytokines and nuclear factor kappaB (NFkappaB) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed. Finally, DALDA induced anti-inflammatory effect was investigated in mucosal explants from controls and IBD patients. RESULTS: MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and CD4+ and CD8+ T cells. Overexpressed in active IBD mucosa, MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines. Furthermore, ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active IBD patients. CONCLUSIONS: Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active IBD, natural and/or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation.

Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus Jr EV, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. · Mount Sinai Hospital, Toronto, Canada. · Can J Gastroenterol. · Pubmed #16151544 No free full text.

Abstract: The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Geboes K. · Katholieke Universiteit Leuven, Minderbroedersstraat 12, B-3000 Leuven, Belgium. · IDrugs. · Pubmed #16025380 No free full text.

Abstract: Crohn's disease and ulcerative colitis, both chronic inflammatory bowel diseases, have become an important health problem in the US and in Northern Europe. Both diseases require significant medical therapy for treatment and prevention of relapses. Traditional treatment is based on aminosalicylates and steroids. Steroids are associated with major complications and many patients are either dependent upon or refractory to steroids. The development of new drugs is therefore very important. This is possible because of a better knowledge of the pathogenetic mechanisms of the diseases. Many of the new drugs belong to the family of biologic therapies. Because of the expense of production and the parenteral delivery systems needed for most of them, these therapies must prove to be significantly more effective than traditional drugs. Many biologic agents are still under investigation. Therapeutic strategies directed against tumor necrosis factor (TNF)-alpha, including monoclonal antibodies, such as infliximab and CDP-571 and the human recombinant TNF receptor fusion protein, etanercept, have already been proven to be beneficial, especially in treating Crohn's disease. Treatment with infliximab induces even endoscopic and histologic healing. The benefit of additional immunosuppressive therapy is under investigation. New treatment strategies that might change the natural course of the disease can be considered for Crohn's disease. The experience with biologic agents for ulcerative colitis is still limited. A preliminary study with antegren, a recombinant humanized antibody against integrins is promising. The initial safety experience with infliximab is favorable but, ultimately, evaluation of large populations of patients over many years is required to define the relative safety of biologic agents.

Geboes K. · Department of Pathology, University Hospital, KUL, Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #15587337 No free full text.

Abstract: Crohn's disease and ulcerative colitis are two chronic relapsing inflammatory bowel diseases of unknown etiology. Both conditions are characterized by a considerable morbidity and have an impact upon the social and economic aspects of the patients life. At present, medical treatment is mainly aiming at the control of the inflammation. Drugs used for ulcerative colitis can induce microscopic healing of the mucosa. Similar results have been obtained recently with immunomodulatory drugs in Crohn's disease. The cost of these drugs is however high and the use of these drugs can be associated with side effects. Furthermore, many of the drugs need to be given for a long period. Therefore it is appropriate to assess the efficacy of the drugs before commercial use and even when used in routine practice. For both ulcerative colitis and Crohn's disease, clinical parameters combined in indices and endoscopy are commonly used together with some laboratory tests for the assessment of disease activity. In ulcerative colitis, histology has been used along with the other instruments for the measurement of disease activity because it was shown that the mucosal lesions could improve. More recently, histology has also been used for Crohn's disease. Routinely, disease activity when assessed with microscopy, should be divided into mild, moderate and severe. For drug trials and study purposes, more objective scoring systems should be used. Preferentially, a generally accepted score is used. This allows comparisons between different studies. Different scoring systems have been designed for ulcerative colitis and Crohn's disease. For the latter, multiple biopsies should be analysed. Most scoring systems still need validation.

Wolf AM, Wolf D, Rumpold H, Moschen AR, Kaser A, Obrist P, Fuchs D, Brandacher G, Winkler C, Geboes K, Rutgeerts P, Tilg H. · Department of Medicine, Division of Gastroenterology and Hepatology, University Hospital Innsbruck, Internal Medicine, Innsbruck, Austria. · Clin Immunol. · Pubmed #15380529 No free full text.

Abstract: T-cells are causally involved in the pathogenesis of inflammatory bowel disease (IBD). The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) regulates T-cell proliferation and survival. We show in this report that IDO mRNA is markedly induced in lesional colonic biopsies of IBD patients. IDO is primarily expressed in CD123(+) mononuclear cells infiltrating the submucosal areas of the inflamed lesions. In Crohn's disease (CD), IDO is also strongly expressed in perifollicular regions of lymphoid follicles. Upregulation of IDO is of functional significance, as we detected an increase of kynurenine and of the kynurenine/tryptophan ratio in supernatants from colonic explant cultures (CECs) of CD patients. Immunohistochemistry of colonic biopsies taken from CD patients prior and after treatment with the TNF-blocking antibody Infliximab revealed reduced IDO expression in patients with good clinical response to Infliximab. In summary, high local expression of IDO may represent an anti-inflammatory mechanism tempting to counterbalance the tissue-damaging effects of activated T-cells infiltrating the colonic mucosa in IBD.

Maerten P, Geboes K, De Hertogh G, Shen C, Cadot P, Bullens DM, Van Assche G, Penninckx F, Rutgeerts P, Ceuppens JL. · Clinical Immunology, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium. · Clin Immunol. · Pubmed #15308117 No free full text.

Abstract: 4-1BB ligand (L) expressed on antigen presenting cells (APC) interacts with 4-1BB, expressed on activated T cells and this interaction costimulates T cells to secrete cytokines and to proliferate. We investigated whether 4-1BB/4-1BBL interactions might be involved in the pathogenesis of Crohn's disease (CD). In immunohistochemistry, we found 4-1BB expression on lamina propria (LP) cells in inflamed and to a lesser extend in non-inflamed gut tissue from CD patients. mRNA levels for 4-1BB were also elevated in intestinal CD tissue. In contrast, only few 4-1BB-expressing cells were found in inflamed tissue from ulcerative colitis (UC) patients and almost no positive cells were found in control intestinal tissue. 4-1BB expression was better sustained on in vitro activated lamina propria T cells from CD patients compared to controls. Finally, agonistic anti-4-1BB antibody enhanced interferon-gamma (IFN-gamma) production and proliferation of lamina propria T cells from CD patients. Taken together, our data suggest that 4-1BB/4-1BBL interactions contribute to the persistence of gut inflammation in CD.

Gijsbers K, Van Assche G, Joossens S, Struyf S, Proost P, Rutgeerts P, Geboes K, Van Damme J. · Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium. · Eur J Immunol. · Pubmed #15214047 No free full text.

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that are characterized by chronic intestinal inflammation and a constant influx of leukocytes mediated by pro-inflammatory cytokines and chemokines. The intestinal expression of the CXCR1-binding chemokines IL-8/CXCL8 and GCP-2/CXCL6 and the participation of immunocompetent cells in IBD were evaluated. IL-8 production by peripheral blood mononuclear cells (PBMC) from IBD patients, stimulated with endotoxin, plant lectin or double-stranded RNA, was significantly lowered in patients with CD, but not in UC patients or healthy subjects. The reduced chemokine production by PBMC from IBD patients was both IL-8 and CD specific, but not inducer dependent. In serum, most chemokines remained undetectable, while the levels of those that were measurable remained unaltered in IBD patients. GCP-2, but not ENA-78/CXCL5, nor IL-8, were highly expressed by endothelial cells in inflamed intestinal tissue of IBD patients. In contrast, stimulated endothelial cell cultures produced more IL-8 than GCP-2. The selective GCP-2 staining of endothelial cells at sites of ulcerations suggests that GCP-2, despite its low production capacity in vitro, plays a role in IBD that is different from that of structurally (ENA-78) and functionally (IL-8) related ELR(+) CXC chemokines. Thus, the chemokine network shows complementarity rather than redundancy.

Geboes K. · Department of Pathology, University of Leuven, Leuven, Belgium. · Colorectal Dis. · Pubmed #12791013 No free full text.

Abstract: The diagnosis of chronic idiopathic IBD and the differential diagnosis between Crohn's disease and ulcerative colitis can be made in most cases on cumulative clinical, radiological, endoscopical, biochemical and pathological evidence. Diagnostic difficulties can however, occur in fulminant colitis, in early onset disease and in long-standing disease. The microscopic evaluation of disease activity is based on the presence of active inflammation. Effective medical treatment has however, an influence upon the morphology and the evolution of the lesions and hence can affect the diagnostic features and the microscopic features used for the assessment of disease activity. A literature review was performed on clinical drug trials in IBD and the effect of the drugs upon the microscopic features. Several studies have shown that the diagnostic microscopic features and the features characteristic for disease activity vary with time and treatment. For an adequate analysis of biopsy samples of patients with IBD the pathologist should be aware of the duration of the symptoms and the type of treatment given to the patient.

Van Assche G, Dalle I, Noman M, Aerden I, Swijsen C, Asnong K, Maes B, Ceuppens J, Geboes K, Rutgeerts P. · Department of Gastroenterology, University of Leuven, Belgium. · Am J Gastroenterol. · Pubmed #12591057 No free full text.

Abstract: OBJECTIVES: Medical therapy of refractory ulcerative colitis (UC) is associated with long-term side effects of cyclosporine and steroids. Because cyclosporine acts by inhibiting interleukin-2 (IL-2) production, we studied the efficacy and safety of humanized anti-IL2 receptor (CD25) antibodies daclizumab for refractory UC in an open label pilot study. METHODS: Ten patients with chronically active UC received daclizumab, 1 mg/kg i.v. twice with a 4-wk interval. Clinical, endoscopic, and histological evaluation was scored at regular intervals. CD25 immunohistochemistry was followed in mucosal biopsies. The primary study endpoint was clinical improvement at wk 8. RESULTS: Nine of 10 patients completed the study. The median clinical activity score decreased from a median of 8 (95% CI = 7.2-9.2) at baseline to 3.5 (95% CI = 1.4-4.9) at wk 8 (p < 0.005). Endoscopic scores were significantly decreased at wk 8 (wk 0: 8, 95% CI = 6.3-8.5; wk 8: 5.0, 95% CI = 2.6-6.3; p < 0.01). Mucosal biopsies showed a significant decrease in CD25+ cells, and there was a trend toward lower histology scores at wk 8. Quality of life as assessed by the Inflammatory Bowel Disease Questionnaire increased after therapy (baseline: 131, 95% CI = 119-178; wk 8: 169; 95% CI = 124-216, p < 0.05). Nausea was most frequently reported as an adverse event, but always in patients that were concomitantly started on azathioprine. CONCLUSIONS: The anti-IL-2R antibody daclizumab was safe and well tolerated in acute UC. Patients experienced clinical benefit along with signs of endoscopic improvement, but further controlled trials are needed to determine the therapeutic benefit of this compound.

Geboes K, El-Zine MY, Dalle I, El-Haddad S, Rutgeerts P, Van Eyken P. · Department of Pathology, University Hospital, K. U. Leuven, Belgium. · Int J Surg Pathol. · Pubmed #12574843 No free full text.

Abstract: Tenascin is an extracellular matrix protein involved in morphogenesis of muscle tissue and in wound healing. In the present study we examined its distribution in tissue from patients with inflammatory bowel disease. Intestinal biopsies from 10 normal controls, 15 patients with Crohn's disease, and 6 with ulcerative colitis were studied. Samples were obtained both from uninvolved and involved areas. Mucosal tenascin is increased in ulcerative colitis and Crohn's disease, especially in areas of ulceration. In Crohn's disease, tenascin is also strongly expressed in the submucosa and in smooth muscle cells of the muscularis mucosae and propria, especially in areas of stricture. We conclude that tenascin is involved in stricture formation in Crohn's disease and that it is a marker of phenotypic change in smooth muscle cells.