Ulcerative Colitis: Gassull MA

Obrador A, López San Román A, Muñoz P, Fortún J, Gassull MA, Anonymous00002. · Servicio de Digestivo. Hospital Son Dureta. Palma de Mallorca. España. · Gastroenterol Hepatol. · Pubmed #12525326 No free full text.

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Gassull MA. · Department of Gastroenterology and Hepatology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain. · Aliment Pharmacol Ther. · Pubmed #16961752 No free full text.

Abstract: Undigested carbohydrates reaching the colon can act as competitors for epithelial bacterial receptors, making it difficult for noncommensal bacteria to adhere to them. On the contrary, fermentation of these carbohydrates by anaerobic flora produces - among other substrates - butyrate that is involved in numerous important metabolic processes. These include the provision of energy to the colonocytes, the enhancement of sodium and water absorption and the synthesis of mucus and cell membranes. In addition, butyrate inhibits the nuclear translocation of the transcription factor NFkappaB, which exerts a potent anti-inflammatory activity. Clinical experience with probiotics in inflammatory bowel disease (IBD) is controversial. Whereas some probiotic preparations appear to be useful in ulcerative colitis (UC) and pouchitis, most attempts to use probiotics for treating or preventing recurrence in Crohn's disease have failed. It should be pointed out that - unlike in the small bowel - the colon and ileal pouches are well-established microbiological ecosystems with increasing amounts of a wide variety of bacterial strains. These bacterial strains have a high degree of metabolic interaction with luminal nutrients and a greater probability of developing dysbiosis. With this in mind, the rationale for using pre- and probiotics appears to be stronger for colonic IBD (UC or Crohn's colitis) and pouchitis than for IBD mostly involving the small bowel.

Mañosa M, Domènech E, Sánchez-Delgado J, Bernal I, Garcia-Planella E, Gassull MA. · Servicio de Aparato Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. · Gastroenterol Hepatol. · Pubmed #15871811 No free full text.

Abstract: The incidence of immunological disorders has been reported to be greater in patients with inflammatory bowel disease than among the general population. The association of ulcerative colitis (UC) and autoimmune hemolytic anemia (AIHA) was first described in the early 1950s but no more than 50 cases have been described in the international literature. Detailed description of the pathogenic mechanisms involved in this association is lacking. The clinical course of AIHA and treatment response in these patients seems to be independent of UC, sometimes requiring immunosuppressive treatment and even surgery. We present 2 cases of AIHA associated with UC with distinct response to conventional treatment. We also review the literature on the subject.

Gassull MA. · Department of Gastroenterology and Hepatology, Hospital Universitari Germans, Trias i Pujol, Catalonia, Spain. · Aliment Pharmacol Ther. · Pubmed #15352899 links to  free full text

Abstract: Nutrients may be involved in the modulation of the immune response through at least three different mechanisms. First, the intestinal ecosystem plays a pivotal role in the pathogenesis of inflammatory bowel disease, triggering the uncontrolled inflammatory response in genetically predisposed individuals. Nutrients, together with bacteria, are major components of, and can therefore influence, the intestinal environment. Second, as components of cell membranes, nutrients can mediate the expression of proteins involved in the immune response, such as cytokines, adhesion molecules and nitric oxide synthase. The composition of lipids in the cell membrane is modified by dietary changes and can influence cellular responses. Indeed, various epidemiological, experimental and clinical data suggest that the immune response may be sensitive to changes in dietary composition. Finally, suboptimal levels of micronutrients are often found in both children and adults with inflammatory bowel disease, although, with the exception of iron and folate, it is unusual to discover symptoms attributable to these deficits. However, subclinical deficits may have a pathophysiological significance, as they may favour the self-perpetuation of the disease (due to defects in the mechanisms of tissue repair), cause defective defence against damage produced by oxygen free radicals and facilitate lipid peroxidation. These events can occur even in clinically inactive or mildly active disease, as well as in the development of dysplasia in the intestinal mucosa. Some dietary manipulations have been attempted as primary treatment for rheumatoid arthritis, and specially formulated diets for enteral nutrition have proved to be an effective treatment for Crohn's disease. Most trials, although lacking sufficient patient numbers, have demonstrated a role for dietary manipulation as primary therapy for inflammatory disease. Dietary lipids are one of the most active nutritional substrates modulating the immune response. Recently, it has been demonstrated that lipids may be a key factor explaining the therapeutic effect of clinical nutrition in Crohn's disease.

Gassull MA. · Department of Gastroenterology and Hepatology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. · Dig Dis. · Pubmed #14571095 No free full text.

Abstract: Nutritional deficiencies are frequent in patients with ulcerative colitis and Crohn's disease, and negatively influence the outcome of the disease. Growth retardation, osteopenia and thromboembolic phenomena are some of the inflammatory bowel disease complications in which nutritional deficits are involved. Moreover, nutrients can play a role in the pathogenesis of the disease and, in some cases, can be a primary therapeutic tool. Enteral nutrition has proven to play a therapeutic role in Crohn's disease. The nutrient(s) responsible for this effect are not well identified but dietary fat appears to be a major factor. In ulcerative colitis, unabsorbable carbohydrates can modulate the intestinal microbial environment, thus contributing to improve colonic inflammation.

Gassull MA, Cabré E. · Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. · Curr Opin Clin Nutr Metab Care. · Pubmed #11706295 No free full text.

Abstract: Nutritional derangements are frequent in inflammatory bowel disease. In the past year significant work has been published examining the mechanisms of impaired food intake in animal models of inflammatory bowel disease, which allow a better understanding of these processes. Data from the same laboratory have shed further light on the relative role of underfeeding and inflammation on the growth retardation associated with intestinal inflammation. Other studies have provided further data on the risk factors and predictive biomarkers of bone loss in patients with inflammatory bowel disease. The potential role of enteral nutrition as primary therapy for Crohn's disease is particularly addressed in this review. Recent contributions to the field emphasized the special importance of this modality of therapy in paediatric patients. The possible mechanisms for such a therapeutic action are not well understood. Other nutrients may have a therapeutic potential in inflammatory bowel disease. In particular, recent data on the in-vivo anti-inflammatory actions of butyrate merit special mention. Finally, novel nutritional therapeutic strategies for inflammatory bowel disease, such as transforming growth factor-beta2-enriched enteral feeding, or hydrothermally processed cereals have recently been explored.

Hinojosa J, Gomollón F, García S, Bastida G, Cabriada JL, Saro C, Ceballos D, Peñate M, Gassull MA, Anonymous00211. · Hospital de Sagunto, Valencia, Spain. · Aliment Pharmacol Ther. · Pubmed #17269996 No free full text.

Abstract: BACKGROUND: The use of tumour necrosis factor antagonists has changed the therapeutic approach to Crohn's disease. AIM: To determine response and remission rates associated with the 4-week induction phase of adalimumab treatment in patients with luminal and/or fistulizing Crohn's disease, who have lost response to or become intolerant of infliximab. METHODS: In this multicentre, prospective, open-label, observational, 52-week study, 50 adults received an induction dose of adalimumab (160 mg at baseline followed by 80 mg at week 2). RESULTS: Of the 36 patients with luminal Crohn's disease, 83% achieved clinical response [> or =70-point reduction in the Crohn's Disease Activity Index (CDAI) score] and 42% achieved clinical remission (CDAI score <150) at week 4. Of the 22 patients with fistulizing disease, five (23%) experienced fistula remission (complete closure of all fistulas that were draining at baseline), and nine (41%) experienced fistula improvement (> or =50% decrease in the number of fistulas that were draining at baseline) at week 4. Of the 19 adverse events, most [13 (68%)] were mild, and no serious or infectious adverse events occurred. CONCLUSIONS: Adalimumab may be an effective alternative in patients with luminal and/or fistulizing Crohn's disease who have lost response to or become intolerant of infliximab.

Panés J, Esteve M, Cabré E, Hinojosa J, Andreu M, Sans M, Fernandez-Bañares F, Feu F, Gassull MA, Piqué JM. · Gastroenterology Department, Institut Clinic de Malalties Digestives, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona. · Gastroenterology. · Pubmed #11040177 No free full text.

Abstract: BACKGROUND & AIMS: Unfractionated heparin has been found to reduce symptoms and improve healing as adjuvant therapy in patients with ulcerative colitis. The current study evaluated the efficacy and safety of unfractionated heparin in the treatment of ulcerative colitis in comparison with methylprednisolone. METHODS: A multicenter randomized trial with blinded endpoint evaluation was conducted in patients hospitalized for moderate or severe ulcerative colitis. Patients were randomized to receive heparin as a continuous infusion or methylprednisolone (0.75-1 mg x kg(-1) x day(-1)). RESULTS: Twenty-five patients entered the study: 13 received methylprednisolone and 12 received heparin. By day 10, 69% of patients in the methylprednisolone group, but none in the heparin group, achieved significant improvement or remission. C-reactive protein levels significantly decreased in the methylprednisolone group but not in the heparin group. Three patients in the heparin group were withdrawn before day 10 because of an adverse event: rectal bleeding needing transfusion (2 cases) or surgery (1 case). The proportion of patients with persistent rectal bleeding at day 10 was 31% in the methylprednisolone group and 90% in the heparin group (P<0.05). CONCLUSIONS: Unfractionated heparin as monotherapy is not effective in the treatment of moderate or severe ulcerative colitis and is associated with significant bleeding complications.

Fernández-Bañares F, Hinojosa J, Sánchez-Lombraña JL, Navarro E, Martínez-Salmerón JF, García-Pugés A, González-Huix F, Riera J, González-Lara V, Domínguez-Abascal F, Giné JJ, Moles J, Gomollón F, Gassull MA. · No affiliation provided · Am J Gastroenterol. · Pubmed #10022641 No free full text.

Abstract: OBJECTIVE: Butyrate enemas may be effective in the treatment of active distal ulcerative colitis. Because colonic fermentation of Plantago ovata seeds (dietary fiber) yields butyrate, the aim of this study was to assess the efficacy and safety of Plantago ovata seeds as compared with mesalamine in maintaining remission in ulcerative colitis. METHODS: An open label, parallel-group, multicenter, randomized clinical trial was conducted. A total of 105 patients with ulcerative colitis who were in remission were randomized into groups to receive oral treatment with Plantago ovata seeds (10 g b.i.d.), mesalamine (500 mg t.i.d.), and Plantago ovata seeds plus mesalamine at the same doses. The primary efficacy outcome was maintenance of remission for 12 months. RESULTS: Of the 105 patients, 102 were included in the final analysis. After 12 months, treatment failure rate was 40% (14 of 35 patients) in the Plantago ovata seed group, 35% (13 of 37) in the mesalamine group, and 30% (nine of 30) in the Plantago ovata plus mesalamine group. Probability of continued remission was similar (Mantel-Cox test, p = 0.67; intent-to-treat analysis). Therapy effects remained unchanged after adjusting for potential confounding variables with a Cox's proportional hazards survival analysis. Three patients were withdrawn because of the development of adverse events consisting of constipation and/or flatulence (Plantago ovata seed group = 1 and Plantago ovata seed plus mesalamine group = 2). A significant increase in fecal butyrate levels (p = 0.018) was observed after Plantago ovata seed administration. CONCLUSIONS: Plantago ovata seeds (dietary fiber) might be as effective as mesalamine to maintain remission in ulcerative colitis.

Navarro-Llavat M, Domènech E, Bernal I, Sánchez-Delgado J, Manterola JM, Garcia-Planella E, Mañosa M, Cabré E, Gassull MA. · Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Digestion. · Pubmed #19439968 No free full text.

Abstract: BACKGROUND: Intestinal infections have been claimed to precipitate or aggravate flares of inflammatory bowel disease (IBD). The reported incidence of such infections among IBD patients varies between 9 and 13%, but only a few prospective studies have been conducted. AIMS: To evaluate the incidence of intestinal infections by enteropathogens in patients with active IBD, their impact on clinical outcome, and to identify associated risk factors. PATIENTS AND METHODS: Consecutive patients admitted because of a relapse or suspected onset of IBD were prospectively included. At admittance, stool samples for culture, examination for intestinal parasites, and cytotoxin assay for Clostridium difficile were collected. Baseline clinical characteristics, potential risk factors for gastrointestinal infections, and clinical outcome were recorded. RESULTS: Ninety-nine episodes were included. Six intestinal infections were diagnosed in 6 patients (5 ulcerative colitis, 1 ileocolonic Crohn's disease), Campylobacter jejuni being the most frequent isolated microbe (n = 5). None of the patients with intestinal infection needed surgery, but two of them required second-line therapies. CONCLUSIONS: Gastrointestinal infections among IBD patients do not exceed 10% and occur mostly in patients with extensive involvement of the colon. Infection by enteropathogenic bacteria does not appear to be associated with a poorer clinical outcome of the IBD flare.

Domènech E, Vega R, Ojanguren I, Hernández A, Garcia-Planella E, Bernal I, Rosinach M, Boix J, Cabré E, Gassull MA. · Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain. · Inflamm Bowel Dis. · Pubmed #18452205 No free full text.

Abstract: BACKGROUND: Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid-refractory disease. However, its role in steroid-refractoriness remains unknown. Our goals were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development. METHODS: Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid-refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65-antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV-pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies. RESULTS: CMV disease was found in 6 steroid-refractory, CMV-IgG-positive UC patients but not among controls, inactive UC, or steroid-responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7-10 days on cyclosporine. CONCLUSIONS: CMV disease in UC only affects seropositive, steroid-refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated.

Aceituno M, García-Planella E, Heredia C, Zabana Y, Feu F, Domènech E, Gassull MA, Panés J. · Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBER-EHD, Barcelona, Spain. · Inflamm Bowel Dis. · Pubmed #18050296 links to  free full text

Abstract: BACKGROUND: One-third of patients with steroid-refractory ulcerative colitis (UC) do not respond to cyclosporine and require colectomy. Since alternative pharmacological treatments for this condition are available, it is pertinent to identify factors that predict response. The objective of this study was to determine predictive factors of response prior to cyclosporine administration, with validation in an independent cohort. METHODS: The 2 cohorts of patients were identified from prospectively established databases. All patients had received 1 mg/kg/day prednisolone or equivalent for at least 5 days before cyclosporine. The efficacy measure was need of early surgery (within 3 months). RESULTS: From 1998 to 2005, 34 patients were treated in 1 institution (derivation cohort) and 38 patients in the second institution (validation cohort). Eleven patients in the derivation cohort and 9 patients in the validation cohort underwent early colectomy. Univariate analysis in the derivation cohort demonstrated a significant association of colectomy with C-reactive protein (P = 0.012) and the Ho index before initiation of cyclosporine (P = 0.013). Regression analysis showed that only the Ho index (P = 0.011) had an independent predictive value. The Ho index predicted need of colectomy, with an area under the characteristic receiver operating curve of 0.79 (95% confidence interval [CI], 0.59-0.99) in the derivation cohort and 0.74 (95% CI, 0.53-0.96) in the validation cohort. The cutoff point with the best sensitivity and specificity ratio was > or =5. CONCLUSIONS: The Ho-based predictive score is a good predictor of response to cyclosporine and avoidance of colectomy, and may aid in the indication of this treatment for management of steroid-resistant UC.

Zabana Y, Domènech E, Latorre N, Ojanguren I, Mañosa M, Gassull MA. · Servicio de Aparato Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. · Gastroenterol Hepatol. · Pubmed #17335713 No free full text.

Abstract: Appendectomy is associated with a reduced risk of developing ulcerative colitis (UC). In addition, there may be appendicular involvement in UC in patients with extensive or even left-sided disease. However, no data are available on the incidence, clinical presentation and outcome of acute appendicitis in patients previously diagnosed with UC. The impact of appendectomy in this subset of patients also remains to be determined. We describe 2 cases of acute appendicitis in the setting of inactive extensive ulcerative colitis and compare their histologic features with those of the surgical specimens of 2 further UC patients colectomized for refractory and extensive disease.

García-Planella E, Marín L, Domènech E, Bernal I, Mañosa M, Zabana Y, Gassull MA. · Servicio de Aparato Digestivo, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España. · Med Clin (Barc). · Pubmed #17266900 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: The use of complementary and alternative medicine (CAM) is increasing in last years. Studies performed out of Spain have reported rates of CAM use of 40-50% among IBD patients. There are no available data on drug abuse among IBD patients. The aims of our study were to evaluate the rate and associate factors of CAM use and drug abuse among Spanish IBD patients. PATIENTS AND METHOD: Anonymous, structured questionnaire, administered to consecutive patients with IBD of at least 2 years of duration, seen in a IBD outpatient clinic. RESULTS: Twenty-six per cent of the 214 included patients reported having used CAM. No associated factors were found, although patients with ulcerative colitis tended to a higher rate of CAM use. Ten per cent of patients admitted to consume drugs, mainly cannabis derivatives. Younger age and college and universitary degree were the only factors associated to cannabis consumption. CONCLUSIONS: The rate of CAM use in IBD patients from a Spanish referral centre is lower than those described in other countries. About 10% of IBD patients consume cannabis, but only one third of them inform their physician about it.

Bernal I, Domènech E, Garcia-Planella E, Marín L, Mañosa M, Navarro M, Cabré E, Gassull MA. · Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, 5a planta, edifici general, Ctra. del Canyet, s/n, 08916, Badalona, Catalonia, Spain. · Dig Dis Sci. · Pubmed #17086434 No free full text.

Abstract: Recent studies have shown a low adherence rate to maintenance treatment in patients with inflammatory bowel disease (IBD). We sought to assess the medication-taking behavior in a cohort of patients with IBD. We prospectively included IBD patients from the outpatient clinic who agreed to answer a questionnaire about prescribed treatment and adherence. Physicians registered clinical data including prescribed medications. Two hundred fourteen patients (115 Crohn's disease/99 ulcerative colitis) were included. The most prescribed medications were oral mesalazine (56.5%) and immunomodulators (41.1%). Forty-three percent of patients admitted to occasionally forgetting to take their medication but only 7.5% of them did it voluntary. Oral mesalazine and azathioprine were the drugs with the poorest compliance, with nonadherence rates of 45% and 25% of the total prescribed doses, respectively. The only factor associated with a better adherence was a more complicated course of the disease-steroid dependency, steroid refractoriness, need for infliximab treatment, hospitalization, or surgery (P=.02). Twenty percent of patients admitted to self-medicating. An important proportion of patients with IBD admit to forget some doses of the prescribed medication in the setting of a specialized unit of a referral centre.

Bernal I, Mañosa M, Domènech E, Garcia-Planella E, Navarro M, Lorenzo-Zúñiga V, Cabré E, Gassull MA. · Gastroenterology Department Hospital Universitari Germans Trias i Pujol, 5 planta, edifici general, Ctra. del Canyet, s/n, 08916, Badalona, Spain. · Dig Dis Sci. · Pubmed #16868820 No free full text.

Abstract: Although systemic steroids remain as the gold standard for the treatment of acute moderate to severe active ulcerative colitis (UC), 15-57% of patients do not achieve clinical remission. We sought to identify clinical, biological, or radiologic predictive factors of response to steroid treatment in acute UC attacks. The medical records of 39 consecutive patients admitted for an acute attack of UC and treated with systemic steroids, were reviewed. Epidemiologic, demographic, and clinical data at baseline and clinical data 3 days after starting steroid treatment were registered. Treatment failure was defined as the need of IV cyclosporine or colectomy before hospital discharge. Twenty-four patients (62%) responded to systemic steroids. Thirteen out of the 15 nonresponders, were treated with IV cyclosporine, avoiding colectomy in 7 cases (54%). More than six bowel movements per day at the third day of treatment, blood in stools in the third day of therapy, extensive UC, and the presence of malnutrition were associated with steroid treatment failure, but only blood in stools (P=.04), and more than six movements per day (P=.012) after 3 days of treatment, were found to be independent predictive factors of steroid refractoriness. In conclusion, clinical evaluation 3 days after starting systemic steroids seems to be the best tool to assess short-term prognosis.

Domènech E, Nos P, Papo M, López-San Román A, Garcia-Planella E, Gassull MA. · Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Scand J Gastroenterol. · Pubmed #15841714 No free full text.

Abstract: OBJECTIVE: Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable. MATERIAL AND METHODS: All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed. RESULTS: Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects. CONCLUSIONS: Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.

Domènech E, Hinojosa J, Esteve-Comas M, Gomollón F, Herrera JM, Bastida G, Obrador A, Ruiz R, Saro C, Gassull MA, Anonymous00177. · Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Aliment Pharmacol Ther. · Pubmed #15606397 links to  free full text

Abstract: BACKGROUND: Uncontrolled studies suggest that granulocyteaphaeresis might be useful in the management of active ulcerative colitis. AIM: To assess the efficacy of granulocyteaphaeresis treatment in active steroid-dependent inflammatory bowel disease. METHODS: We conducted a multicentre, prospective, open, pilot study in patients with steroid-dependent inflammatory bowel disease. All patients were started on 60 mg/day of prednisone; after 1 week, a five-session programme of granulocyteaphaeresis (once per week) was started. The steroid dose was tapered weekly if there was clinical improvement. Remission was defined as an inactive clinical activity index together with complete withdrawal of steroids at week 6. The patients were followed up for at least 6 months or until disease relapse. RESULTS: Twenty-six patients (14 ulcerative colitis, 12 Crohn's disease) were included. More than a half had been previously treated with immunomodulators. Remission was achieved in 62 and 70% of ulcerative colitis and Crohn's disease, respectively. During a median follow-up of 12.6 months, six of eight ulcerative colitis patients maintained their clinical remission; however, only one Crohn's disease patient remained in remission after the first 6 months of follow-up. CONCLUSIONS: Granulocyteaphaeresis is a safe treatment option in inflammatory bowel disease. A five-session programme of granulocyteaphaeresis seems to be efficient in the treatment of steroid-dependent ulcerative colitis, but not in Crohn's disease.

Torres MI, Le Discorde M, Lorite P, Ríos A, Gassull MA, Gil A, Maldonado J, Dausset J, Carosella ED. · Department of Experimental Biology, University of Jaén, Jaén, Spain. · Int Immunol. · Pubmed #15039388 links to  free full text

Abstract: In addition to being involved in nutrient uptake, the epithelial mucosa constitute the first line of defense against microbial pathogens. A direct consequence of this physiological function is a very complex network of immunological interactions that lead to a strong control of the mucosal immune balance. The dysfunction of immunological tolerance is likely to be a cause of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I molecule, which is highly expressed by human cytotrophoblast cells. These cells play a role in immune tolerance by protecting trophoblasts from being killed by uterine NK cells. Because of the deregulation of immune system activity in IBD, as well as the immunoregulatory role of HLA-G, we have analyzed the expression of HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the differential expression of HLA-G provides a potential way to distinguish between UC and CD. Although the reason for this differential expression is unclear, it might involve a different mechanism of immune regulation. In addition, we demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is strongly expressed. In conclusion, the presence of HLA-G on the surface of intestinal epithelial cell in patients with UC lends support to the notion that this molecule may serve as a regulator of mucosal immune responses to antigens of undefined origin. Thus, this different pattern of HLA-G expression may help to differentiate between the immunopathogenesis of CD and UC.

Domènech E, Garcia-Planella E, Bernal I, Rosinach M, Cabré E, Fluvià L, Boix J, Gassull MA. · Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. · Aliment Pharmacol Ther. · Pubmed #12452938 links to  free full text

Abstract: BACKGROUND: Intravenous ciclosporin is considered to be the only alternative to avoid surgery in severe, steroid-refractory ulcerative colitis. In responders, some authors recommend a switch to oral ciclosporin to act as a 'bridge' until the therapeutic action of azathioprine is achieved for maintenance treatment. AIM: To report the short- and long-term outcome of intravenous ciclosporin-responsive ulcerative colitis patients treated with oral azathioprine without oral ciclosporin. METHODS: The records of all patients treated with intravenous ciclosporin for severe, steroid-refractory ulcerative colitis were reviewed. Responders following treatment with azathioprine but without oral ciclosporin as maintenance therapy were included. Patients with colonic cytomegalovirus infection and/or follow-up of less than 1 year were excluded. RESULTS: Twenty-seven patients were included. Steroids were discontinued in 24 (89%). The median follow-up was 36 months. Eighteen (75%) patients presented mild or moderate relapses, which were easily managed with salicylates or steroids. Cumulative probabilities of relapse were 42%, 72% and 77% at 1, 3 and 5 years, respectively. Eleven (40.7%) patients underwent elective colectomy. Cumulative probabilities of colectomy were 29%, 35% and 42% at 1, 3 and 5 years, respectively. No opportunistic infections were observed. CONCLUSIONS: Oral azathioprine seems to be enough to maintain long-term remission induced by intravenous ciclosporin in patients with steroid-refractory ulcerative colitis. The 'bridging step' with oral ciclosporin may not be necessary in this subset of patients, although a randomized controlled trial is warranted to confirm this hypothesis.

García-Planella E, Domènech E, Cabré E, Bernal MI, Gassull MA. · Servicio de Aparato Digestivo. Hospital Universitari Germans Trias i Pujol. Badalona. Barcelona. España. · Med Clin (Barc). · Pubmed #12433336 No free full text.

Abstract: BACKGROUND: Intravenous cyclosporine (iv CyA) is efficient in ulcerative colitis, but data are scarce in Crohn's disease (CD). PATIENTS AND METHOD: Patients with CD refractory to standard therapy who were treated with iv CyA. RESULTS: All patients with steroid-refractory disease achieved a complete response. In perianal disease, a complete response was attained in 3 out of 16 patients, while 9 showed a partial response. Only 1 out of 8 patients with enteric fistulae showed a complete response and a further one had a partial response. CONCLUSIONS: Intravenous CyA seems to be useful in steroid-refractory CD but not in fistulizing CD.

Mallolas J, Esteve M, Rius E, Cabré E, Gassull MA. · Department of Gastroenterology, Hospital Universitari "Germans Trias i Pujol", Carretera de Canyet s/n, 08916 Badalona, Catalonia, Spain. · Gut. · Pubmed #10861267 links to  free full text

Abstract: BACKGROUND: Cell death by apoptosis seems to be an important mechanism for translocation to the cell surface of a variety of intracellular components capable of inducing autoantibody production. AIMS: To identify the cellular location of antigen (Ag)-antineutrophil cytoplasmic antibodies (ANCA) in non-apoptotic human neutrophils, and to assess if ANCA associated with ulcerative colitis reacts with neutrophil antigen(s) during neutrophil apoptosis. The cellular distribution of Ag-ANCA in apoptotic neutrophils was also investigated. METHODS: Sera from 18 ulcerative colitis patients known to be positive for perinuclear IgG-ANCA (titre > or =1/320), as assessed by indirect immunofluorescence (IIF), were analysed by immunofluorescent confocal laser scanning microscopy. ANCA were identified with fluorescein isothiocyanate (FITC) and tetramethylrhodamine isothiocyanate (TRITC) in non-apoptotic and apoptotic neutrophils, respectively. Apoptotic and non-apoptotic DNA was labelled with FITC and propidium iodide, respectively. Cycloheximide was added to polymorphonuclear leucocyte culture to induce apoptosis. RESULTS: Three patterns of scanning laser immunofluorescence microscopy in non-apoptotic neutrophils were observed with respect to cellular ulcerative colitis associated ANCA distribution: (1) diffuse nuclear localisation (16.7%); (2) nuclear localisation in the nuclear periphery (50%); and (3) mixed nuclear and cytoplasmic localisation (33.4%). In all sera ANCA fluorescence colocalised almost completely with apoptotic DNA, with persistence of a diffuse and intense fluorescence. No significant changes in ANCA titres were found in non-apoptotic neutrophils. CONCLUSIONS: The antigen(s) of ANCA associated with ulcerative colitis seems to be localised in most cases in the neutrophil nucleus. The almost identical colocalisation of ANCA and apoptotic cleaved DNA suggests that intracellular DNA redistribution during neutrophil apoptosis may play a role in antigen exposure to the immune system and ANCA production in ulcerative colitis.

Meuwissen SG, Ewe K, Gassull MA, Geboes K, Jewell D, Pallone F, Rachmilewitz D, Rask-Madsen J, Riddell BH, Sandborn BJ, Schmuck ML. · International Organization for the Study of Inflammatory Bowel Disease, Department of Gastroenterology, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #10656204 No free full text.

Abstract: OBJECTIVE: To obtain information on the clinical experience with azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the treatment of patients with inflammatory bowel disease (IBD) by gastroenterologists and internists in different countries. DESIGN: A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living in North America (n = 76) and Europe (n = 224) (12 countries), to obtain information on clinical experience. PARTICIPANTS: More than half of the respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in general (non-university) hospitals. Two-thirds (65%) had more than 10 years' experience in gastroenterology. RESULTS: The respondents had personal experience with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6-MP less frequently by the European than the North American respondents (23.8 and 53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA together with steroids to Crohn's disease patients; 62.4% of the respondents prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9% had experience with AZA (Europe > North America, P = 0.0001). AZA had been prescribed by 69 respondents to pregnant patients, without apparent toxicity. Acute pancreatitis had been observed after AZA by 56.7% respondents; 25 malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer, four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by 33.9% in Europe (not significant). Several significant differences were observed between the prescription behaviour of respondents working at university hospitals and non-university hospitals, in particular in relation to participation in clinical trials. CONCLUSIONS: Considerable experience exists in the use of immunosuppressive therapy in IBD; however, differential prescription behaviour exists in the choice of immunosuppressives between North America and Europe. These IOIBD study results may contribute to a better insight in the daily use of immunosuppressive agents in IBD by gastroenterologists and other specialists.

Vega R, Bertrán X, Menacho M, Domènech E, Moreno de Vega V, Hombrados M, Cabré E, Ojanguren I, Gassull MA. · Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain. · Am J Gastroenterol. · Pubmed #10201482 No free full text.

Abstract: OBJECTIVE: It has been suggested that, in inflammatory bowel disease, cytomegalovirus behaves in the intestine as a nonpathogenic bystander, and even its finding in intestinal mucosa has unclear clinical relevance. We report our experience with a small series of patients with refractory inflammatory bowel disease and cytomegalovirus infection and their clinical outcome. METHODS AND RESULTS: Nine patients with moderate-severe attacks of inflammatory bowel disease did not respond to i.v. prednisone (1 mg/kg/day) for a mean of 24 days. Four of these patients were further treated with i.v. cyclosporine A (4 mg/kg/day). Cytomegalovirus infection was diagnosed in two patients after resection for treatment failure. In the remaining patients, cytomegalovirus infection was diagnosed in endoscopic mucosal biopsies and i.v. ganciclovir was then administered at a dose of 10 mg/kg/day for 2-3 wk. Five of these patients went into clinical remission, allowing corticosteroid and cyclosporine A discontinuation. Follow-up biopsies were performed and in all cases cytomegalovirus could not be detected in the colonic tissue. Two patients needed to be treated with intravenous cyclosporine A after antiviral therapy because of persistence of clinical symptoms despite the elimination of cytomegalovirus infection. CONCLUSIONS: Cytomegalovirus infection may play a role in the natural history of refractory inflammatory bowel disease and in some of its complications. The clearance of cytomegalovirus in colonic mucosa may lead some of these patients to remission.

Domènech E, Gomollón F, Obrador A, Panés J, Gassull MA. · No affiliation provided · Aliment Pharmacol Ther. · Pubmed #16441478 No free full text.

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