Miquel A. Gassull

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management

This paper is the second in a series of three publications relating to the European evidence-based consensus on the diagnosis and management of Crohns disease and concerns the management of active disease, maintenance of medically induced remission and surgery. The aims and methods of the ECCO Consensus, as well as sections on diagnosis and classification are covered in the first paper [van Assche et al. JCC 2009a]. The final paper covers post-operative recurrence, fistulating disease, the management of paediatric and adolescent IBD, pregnancy, psychosomatics, extraintestinal manifestations and complementary or alternative therapy for Crohns disease [Van Assche et al JCC 2009b]. #### Principal changes with respect to the 2006 ECCO guidelines The early use of azathioprine/mercaptopurine or methotrexate in combination with steroids is an appropriate option in moderately active localised ileocaecal CD. Anti-TNF therapy should be considered as an alternative for patients with objective evidence of active disease who have previously been steroid-refractory, steroid-dependent, or steroid-intolerant (based on Statement 5B). For those patients with severely active localised ileocaecal Crohns disease and objective evidence of active disease who have relapsed, anti-TNF therapy with or without an immunomodulator is an appropriate option [EL1a, RG B for infliximab]. For some patients who have infrequently relapsing disease, restarting steroids with an immunomodulator may be appropriate (based on Statement 5C). All currently available anti-TNF therapies appear to have generally similar efficacy and adverse-event profiles for inflammatory (‘luminal’) Crohns disease, so the choice depends on availability, route of delivery, patient preference, cost and national guidelines \[EL5, RG D\] (Statement 5I). Patients receiving azathioprine or mercaptopurine who relapse should be evaluated for adherence to therapy and have their dose optimised. Changing their maintenance therapy to methotrexate [EL1b RG B] or anti-TNF therapy [EL1a RGB] should be considered. Surgery should always be considered as an option in localised disease [EL4, …

How Effective Is Enteral Nutrition in Inducing Clinical Remission in Active Crohn's Disease? A Meta-Analysis of the Randomized Clinical Trials

BACKGROUND The purpose of the study was to evaluate, using meta-analysis techniques, whether enteral nutrition is effective in inducing clinical remission in active Crohns disease. METHODS Randomized trials either comparing enteral nutrition with steroids or comparing elemental (amino acid-based) with nonelemental diets were selected using MEDLINE (1984 to 1994), reference lists from published articles, reviews, and abstracts from major gastrointestinal meetings. Sixteen studies fulfilled the inclusion criteria (four published as abstracts). Crude rates for induction of remission were collected on an intention-to-treat basis by three independent observers. Each study was given a quality score, based on predetermined criteria. RESULTS The pooled odds ratio (OR) for all type of enteral diets compared with steroid therapy was 0.35 (95% CI, 0.23 to 0.53). This result was similar for the best studies (by quality score) combined, for trials using tube feeding combined, and when noncompliant patients were withdrawn. Further subgroup analyses were conducted on the basis of the type of diet administered. Peptide-based diets were significantly inferior to steroids (pooled OR, 0.32; CI, 0.20 to 0.52). There was a trend to lower remission rate after elemental diets than after steroids (pooled OR, 0.44; CI 0.17 to 1.12). On the other hand, pooled OR for whole protein-based diets compared with elemental diets was 1.28 (CI, 0.40 to 4.02). CONCLUSIONS Data available to date show that steroids are better than enteral nutrition to induce remission in active Crohns disease. These results are more evident when peptide-based diets are administered, but they are not conclusive when either elemental or whole protein-based diets are used.

Fat composition may be a clue to explain the primary therapeutic effect of enteral nutrition in Crohn's disease: results of a double blind randomised multicentre European trial

Background: Dietary fat has been suggested to determine the therapeutic effect of enteral diets in Crohns disease. Aim: To assess the efficacy of two whole protein based diets with different fat compositions (n6 polyunsaturated fatty acids v monounsaturated fatty acids) in inducing clinical remission in active Crohns disease compared with steroids. Methods: Sixty two patients with active Crohns disease were randomised to receive, for not more than 4 weeks: (a) a polymeric enteral diet containing 35 g of lipids per 1000 kcal, high in oleate (79%) and low in linoleate (6.5%) (PEN1), (b) an identical enteral diet except for the type of fat which was high in linoleate (45%) and low in oleate (28%) (PEN2), or (c) oral prednisone (1 mg/kg/day). Diets were double blindly administered. The steroid group received a conventional ward diet. Treatment failure was considered when remission was not achieved at week 4. Clinical activity and biological and nutritional parameters were monitored. Independent predictors of remission were identified by stepwise logistic regression analysis. Results: Overall remission rates (by intention to treat) were 20% (4/20) for PEN1, 52% (12/23) for PEN2, and 79% (15/19) for steroids (overall p=0.001; p<0.0005 steroids v PEN1, and p=0.056 PEN2 v PEN1). After excluding those patients who were non-compliant during the first week (per protocol analysis), remission rates were 27%, 63%, and 79%, respectively (p=0.008, steroids and PEN2 v PEN1). After adjusting for confounding variables, PEN1 remained significantly associated with a poor response. Conclusion: The type of dietary fat may be of importance for the primary therapeutic effect of enteral nutrition in active Crohns disease.

Cytomegalovirus infection in patients with inflammatory bowel disease

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.

Translocated intenstinal bacteria cause spontaneous bacterial peritonitis in cirrhotic rats: molecular epidemiologic evidence

BACKGROUND/AIMS Intestinal bacterial translocation is common in cirrhotic rats with spontaneous bacterial peritonitis, and it is thought to play a major pathogenic role. There has so far been no evidence for clonality between bacteria isolated from intestine and ascites. This study aimed to use molecular epidemiology techniques to show that spontaneous bacterial peritonitis is due to translocated intestinal bacteria. METHODS Samples of ascitic fluid, portal blood, mesenteric lymph nodes and ileal contents from healthy (n=10) and ascitic cirrhotic rats with (n=12) or without (n=15) spontaneous bacterial peritonitis were cultured. In six infected rats, DNA macrorestriction fragments of 30 bacterial isolates [Escherichia coli (n=13), Enterococcus faecalis (n=12) and Proteus mirabilis (n=5)] from ascites (n=8), mesenteric lymph nodes (n=7), portal blood (n=6), and ileal flora (n=9) were compared. RESULTS Bacterial translocation was more frequent in animals with (58%) than in those without spontaneous bacterial peritonitis (20%, p=0.049) or controls (10%, p=0.026). The same bacterial strain was simultaneously isolated in ascites and in mesenteric lymph nodes and/or ileum in 7/8 (87%) instances. The identity rate for bacteria present in both ascites and mesenteric lymph nodes was 80% (4/5). Likewise, identity was demonstrated in 3/4 instances of bacteria found in both ascites and portal blood. CONCLUSIONS These results indicate that spontaneous bacterial peritonitis in cirrhotic rats is mainly due to intestinal bacteria translocated to mesenteric lymph nodes. Portal blood could be a less frequent route.

Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.

Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features. Experimental Design: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations. Results: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers. Conclusions: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.

Spontaneous bacterial peritonitis in patients with cirrhosis undergoing selective intestinal decontamination: A retrospective study of 229 spontaneous bacterial peritonitis episodes

BACKGROUND/AIMS Selective intestinal decontamination with norfloxacin is widely used to prevent spontaneous bacterial infections in cirrhosis. The study was performed to compare the spontaneous bacterial peritonitis occurring in patients with and without prophylactic norfloxacin. METHODS Two hundred and twenty-nine consecutive episodes of spontaneous bacterial peritonitis, (193 in patients without (Group A) and 36 in patients with norfloxacin prophylaxis (Group B)), were retrospectively analyzed. In 100 episodes (86 and 14, respectively), the responsible organism was isolated in ascitic fluid. RESULTS Clinical and laboratory data at diagnosis were comparable in both groups. There were marked differences (p < 0.001) between group A and B in the frequency of peritonitis caused by gram-negative (67.4% vs. 14.3%) and gram-positive (30.2% vs. 78.6%) bacteria. There were three polymicrobial episodes. Bacteria resistant to cefotaxime and gram-negative bacilli resistant to quinolones were isolated in ascitic fluid in nine (seven in Group A and two in Group B) and three episodes (all in Group A), respectively. No differences in the course of infection and patient survival were observed between groups. CONCLUSIONS Spontaneous bacterial peritonitis in patients with and without prophylaxis with norfloxacin are not different in clinical features, response to treatment and prognosis. Spontaneous bacterial peritonitis caused by gram-negative organisms resistant to quinolones is extremely uncommon in patients with cirrhosis receiving prophylactic norfloxacin.

Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety

BACKGROUND/AIMS The most rational treatment of moderate ascites is spironolactone alone or in combination with furosemide. However, it is unknown which of these two treatment schedules is preferable. METHODS One hundred nonazotemic cirrhotic patients with moderate ascites were randomly assigned to be treated with spironolactone and furosemide (Group 1: 50 patients) or with spironolactone alone (Group 2: 50 patients). If no response was obtained, the doses of diuretics were increased up to 400 mg/day of spironolactone and 160 mg/day of furosemide. In patients of group 2 not responding to 400 mg/day of spironolactone, furosemide was added. In cases with an excessive response, the dosage of diuretics was reduced. RESULTS The response rate (98% in Group 1 vs. 94% in Group 2), the rapidity of ascites mobilization and the incidence of complications induced by diuretic therapy was similar in both groups. The need to reduce the diuretic dosage was significantly higher in Group 1 than Group 2 (68% vs. 34%; P=0.002). CONCLUSIONS In the treatment of moderate ascites, spironolactone alone seems to be as safe and effective as spironolactone associated with furosemide. Since spironolactone alone requires less dose adjustment, it would be more suitable for treating ascites on an outpatient basis.

Medication-Taking Behavior in a Cohort of Patients with Inflammatory Bowel Disease

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 Crohns 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.

Serological Markers and HLA-DQ2 Haplotype Among First-Degree Relatives of Celiac Patients

Serologic markers, HLA-DQ2 haplotype, andclinical features suggestive of celiac disease werestudied to assess their diagnostic value in amulticentric study to detect celiac disease in 675first-degree relatives of 227 celiac probands. SerumIgA-class anti-endomysium and IgA-class anti-gliadinantibodies were positive in 5.8% and 1.9% of relatives,respectively. HLA-DQ2 haplotype was present in 64% of relatives, and the overall rate of celiacdisease diagnosed by intestinal biopsy was 5.5% . Thefrequency of HLA-DQ2 in the celiac patients and controlswas 93% and 18% , respectively. The most frequent clinical features — diarrhea, anemia,food intolerance, and growth retardation — werenot present in one third of the celiac diseaserelatives. We conclude that the assessment of IgA-classanti-endomysium antibodies alone seems a reasonable approachfor screening celiac disease in relatives and cannot bereplaced by an accurate clinical anamnesis. HLA-DQ2haplotype may identify the population with a high genetic susceptibility to celiacdisease.