Ulcerative Colitis: Ruemmele FM

Cucchiara S, Escher JC, Hildebrand H, Amil-Dias J, Stronati L, Ruemmele FM. · Pediatric Gastroenterology Unit, University of Rome La Sapienza, University Hospital Umberto I, Rome, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #19274777 No free full text.

Abstract: Inflammatory bowel diseases (IBDs) are lifelong inflammatory gastrointestinal diseases starting in about one third of patients during childhood. Treatment strategies aim to control this chronic inflammatory process. Owing to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNFalpha directed) as well as biological drugs are more and more often used. This therapeutic approach clearly improved the clinical condition of the majority of patients with IBD. However, with this more aggressive treatment strategy, safety concerns clearly arise. Recently, the description of a series of a particularly severe form of T cell lymphoma in pediatric and young adult patients with IBD under immunomodulator and biological combination therapy raised the question of the risks of treatment-induced side effects or complications. As reviewed in the present article, there is a slightly increased risk of not only lymphoma development in IBD patients, potentially related to the inflammatory process, but also to the use of immunosuppressive therapies. On the basis of the literature data, were analyzed current treatment strategies for children with moderate-to-severe IBD, who are candidates to receive immunomodulator and/or biological agents potentially accelerating the risk of lymphoma development. Comparative clinical studies in IBD are still missing; however, it is prudent to think about adapting immunosuppressive therapies to the inflammatory process of the underlying disorder and if possible to reduce them to monotherapy. Alternative treatment strategies for heavy immunosuppression exist (eg, enteral nutrition in Crohn disease or colectomy in patients with ulcerative colitis) and should be considered whenever appropriate. There is a major need for comparative studies before evidence-based guidelines can be established for safest and best treatment strategies of pediatric patients with IBD.

Dionne S, Ruemmele FM, Seidman EG. · Intestinal Immunology Laboratory, Centre de Recherche, Hôpital Ste-Justine, Departments of Pediatrics and Nutrition, Faculty of Medicine, Université de Montréal, Canada. · Nestle Nutr Workshop Ser Clin Perform Programme. · Pubmed #11490627 No free full text.

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Kapel N, Benahmed N, Morali A, Svahn J, Canioni D, Goulet O, Ruemmele FM. · Laboratoire de Coprologie, Groupe Hospitalier Pitié-Salpêtrière, France. · J Pediatr Gastroenterol Nutr. · Pubmed #19172136 No free full text.

Abstract: Defensins, endogenous antibiotic peptides, are part of the intestinal epithelial barrier. In this pilot study we analyzed the possibility of measuring fecal beta-defensin-2 (HBD2) in comparing inflammatory and noninflammatory conditions. In samples from healthy control individuals, low levels of HBD2 were detectable, which markedly rose under inflammatory conditions (P = 0.0002 vs normal control individuals), the highest levels being observed in patients with ulcerative colitis (median 356 ng/g, range 40-527). Despite frank inflammation, Crohn disease patients with colitis had significantly lower, albeit enhanced, HBD2 levels than did ulcerative colitis patients. These data confirm the possibility of quantifying HBD2 in feces and indicate that colitis in Crohn disease and colitis in ulcerative colitis differ from each other with respect to their ability to secrete HBD2.

Ruemmele FM, El Khoury MG, Talbotec C, Maurage C, Mougenot JF, Schmitz J, Goulet O. · Paediatric Gastroenterology Unit, Department of Paediatrics, Hôpital Necker-Enfants Malades, National Center for Rare Digestive Diseases INSERM EMI U793, University René Descartes, Paris, France. · J Pediatr Gastroenterol Nutr. · Pubmed #17130735 No free full text.

Abstract: BACKGROUND: Inflammatory bowel disease (IBD) is recognized in young children, however, only rare data on onset and evolution are available in children younger than 1 year. In the present clinical study, we aimed to analyze characteristics and clinical course of children with very early onset IBD. We were particularly interested in the relationship between bacterial infections and the use of antibiotics before the onset of IBD. PATIENTS AND METHODS: The IBD database of Necker-Enfants-Malades-Hospital was screened for patients with IBD with disease onset during the first year of life and a follow-up of at least 2.5 years. Ten patients were identified during the period 1996-2002. RESULTS: All patients presented with rectal bleeding and had colonic involvement. Four patients had definitive diagnosis of Crohn disease; ulcerative or indeterminate colitis was seen in 2 and 4 children, respectively. Five of the patients had a positive history of neonatal or early-onset bacterial infection with use of antibiotics before onset of IBD, 4 patients were still breastfed and 3 just weaned when GI symptoms started. Seven patients had a severe onset of disease requiring bowel rest, parenteral nutrition and steroid medication, followed by azathioprine or cyclosporine medication. Surgery was necessary in 3 of 10 patients. Disease relapses were frequent and observed in 8 of 10 children. DISCUSSION: Very early onset IBD may reflect a subgroup of patients characterized by a particular sensitivity to modifications of the intestinal flora. Neonatal IBD was most often severe in presentation and evolution.

Doering J, Begue B, Lentze MJ, Rieux-Laucat F, Goulet O, Schmitz J, Cerf-Bensussan N, Ruemmele FM. · Hôpital Necker-Enfants Malades, Paediatric Gastroenterology, INSERM EMI 0212, University Paris V, 149, Rue de Sèvres, F-75743 Paris, Cedex 15, France. · Gut. · Pubmed #15479684 links to  free full text

Abstract: BACKGROUND: Lamina propria T lymphocytes (LPL) of the intestinal mucosa are chronically activated in Crohn's disease (CD). Defective apoptosis of activated LPL was proposed as a key pathogenic mechanism. In fact, increased expression of antiapoptotic molecules was observed in CD LPL. In the present work, we aimed to analyse the effects and underlying molecular mechanisms of 5-amino salicylic acid (5-ASA) and derivatives on apoptosis of LPL and peripheral blood lymphocytes (PBL) in patients with CD compared with ulcerative colitis (UC) and in non-inflammatory controls. METHODS: PBL and LPL were isolated by Ficoll-Hypopaque gradient centrifugation and the EGTA-collagenase method, respectively. PBL/LPL were stimulated with FasL, 5-ASA, sulphapyridine, and sulphasalazine for 24/48 hours and apoptosis was quantified by flow cytometry (annexin V- propidium iodide method) and immunofluorescence. The molecular mechanisms of drug induced apoptosis were analysed in wild-type and FADD-/- Jurkat T cells using western blots and caspase assays. RESULTS: While PBL displayed a normal apoptosis pattern after Fas stimulation in patients with active CD, LPL from inflammatory areas were highly resistant. Comparable resistance to apoptosis was observed in LPL of UC patients. In contrast with 5-ASA, which did not induce apoptosis in lymphocytes, sulphasalazine proved to be a potent proapoptotic agent. Sulphasalazine induced T lymphocyte apoptosis was independent of the Fas pathway but associated with marked downregulation of antiapoptotic bcl-xl and bcl2, activation of the mitochondrial apoptosis signalling pathway, and subsequent activation of caspase-9 and caspase-3. CONCLUSION: The beneficial effect of sulphasalazine in treating inflammatory bowel disease is at least in part attributable to its proapoptotic effects on LPL which allows potent downregulation of lymphocyte activation.