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A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.One Sentence Summary:We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.

Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural damage to the bowel, which may predict long-term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lemann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be "diagnostic modality driven": for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross-sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lemann score is expected to be able to portray a patient's disease course on a double-axis graph, with time as the x-axis, bowel damage severity as the y-axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. RI Loftus, Edward/E-8304-2011; Schreiber, Stefan/B-6748-2008

Acute severe ulcerative colitis is a potentially life-threatening condition. It is most readily identified by the criteria of Truelove and Witts,1 which have been adopted by international bodies: a patient who has a bloody stool frequency of six or more per day and tachycardia (>90 bpm, or temperature greater than 37.8°C, or anaemia (haemoglobin 30 mm/h).1–4 However, the response to intensive treatment with corticosteroids has remained unchanged for 50 years. In a systematic review of 32 trials of steroid therapy for acute severe colitis involving 1991 patients from 1974 to 2006, the overall response to intravenous hydrocortisone, methylprednisolone, or betamethasone was 67% (95% CI 65% to 69%), and 29% (95% CI 28% to 31%) came to colectomy.5 The only major difference from 1955 was that mortality was 1% (95% CI 0.7% to 1.6%) and not 7%. The colectomy rate did not change between 1974 and 2006. The UK national inflammatory bowel disease audit in 2008 identified a mortality of 2.8% among 317 patients.6 Old age dominated death (11/16 who died were aged 80–89years), but the morbidity in young people has yet to be quantified. A nationwide linkage analysis in Scotland also strongly implicates age as the critical determinant of mortality in patients hospitalised for ulcerative colitis—the 3-year mortality in 245 patients aged 65 years and over was 39%, whereas none of 212 patients aged 30 years or less died (p

Summary Background Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention. Aim To develop, validate and apply a questionnaire directed towards evaluating these disease aspects. Methods A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group. Results A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P

Introduction Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. Patients and methods A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy ( n = 7) and purine nucleotide analogues ( n = 6). Results Median follow-up was 8.7 (1–97) months. Surgery was required in 10 patients (66%) for intestinal complications ( n = 7) or elective small bowel resection ( n = 3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan–Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group ( p = 0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. Conclusion Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy.

Background: Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists. Infliximab and adalimumab are approved as second-line treatments for severe, active CD. Certolizumab pegol is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe, active CD. Data from trials of infliximab suggest that high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) may benefit from earlier use of this drug. Methods: A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of TNF antagonists. At the time of this survey, infliximab was the only TNF antagonist approved for the treatment of CD in Europe, Canada, and Australia. An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated. Results: The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals, and form a rationale for using TNF antagonists in CD patients. Control of inflammation and induction of mucosal healing were considered essential for bowel preservation. Consensus areas: 1) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 2) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 3) benefits of infliximab in relation to mucosal healing, bowel preservation, and clinical remission increase when therapy is initiated earlier. Conclusions: Treatment with TNF antagonists helps preserve the bowel in CD patients.

Thiopurines, such as azathioprine and mercaptopurine, are of pivotal importance in the treatment of inflammatory bowel disease. Although these drugs have been used for several decades, still many questions remain unanswered.To provide an overview of clinically and scientifically challenging topics concerning thiopurine therapy in inflammatory bowel disease treatment.The first meeting of the Thiopurine Task Force Interest Group was held during the 2009 United European Gastroenterology Week in London (GASTRO2009). The topics of this meeting were of particular clinical and scientific interest. Additional literature was identified by performing a Pubmed search using the search terms 'inflammatory bowel disease', 'azathioprine', '6-mercaptopurine' and 'thioguanine'.The following topics were discussed: therapeutic drug monitoring; the synergy of thiopurines with aminosalicylates and allopurinol; serious adverse events such as opportunistic infections, hepatotoxicity, carcinogenicity and pancreatitis; prolongation of thiopurines during clinical remission; indications for thiopurines in the postoperative setting; and the potential use of thioguanine. Specific interesting and clinically relevant topics for potential future research are provided.Thiopurines remain central to inflammatory bowel disease treatment, although future studies are required to substantiate a more personalised medicine approach to their use.

Aliment Pharmacol Ther 2011; 33: 870–879 Summary Background New medical therapies have improved outlook in inflammatory bowel disease but published impact on surgical rates has been modest suggesting that many patients are still not attaining remission. Aim To review remission rates with current medical treatments for inflammatory bowel disease. Methods We searched MEDLINE (source PUBMED, 1966 to January, 2011). Results Induction and maintenance of remission was observed in 20% (range, 9–29.5%) and 53% (range, 36.8–59.6%) of ulcerative colitis (UC) patients treated with oral 5-ASA derivatives. Induction of remission was noted in 52% (range, 48–58%) of Crohn’s disease (CD) patients and 54% of UC patients treated with steroids in population-based cohorts. Maintenance of remission was reported in 71% (range, 56–95%) of CD patients on azathioprine over a 6-month to 2-year period and in 60% (range, 41.7–82.4%) in UC at 1 year or longer. Induction and maintenance of remission was noted in 39% (range, 19.3–66.7%) and 70% (range, 39–90%) of CD patients on methotrexate over a 40-week period. Induction of remission was reported in 32% (range, 25–48%), 26% (range, 18–36%) and 20% (range, 19–23%) of CD patients on infliximab, adalimumab or certolizumab pegol, respectively. The corresponding figures were 45% (range, 39–59%), 43% (range, 40–47%) and 47.9% at weeks 20–30 among initial responders. Induction of remission was observed in 33% (range, 27.5–38.8%) and 18.5% of UC patients on infliximab or adalimumab, respectively. Maintenance of remission was noted in 33% (range, 25.6–36.9%) of UC patients on infliximab at week 30. Approximately one-fifth of CD and UC patients treated with biologicals require intestinal resection after 2–5 years in referral-centre studies. Conclusion In the era of biologics, the proportion of patients with inflammatory bowel disease not entering remission remains high.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Background & Aims Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. Methods We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Results Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03). Conclusions In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer.

The inflammatory bowel diseases (IBDs) are associated with a reduced quality of life. The impact of IBD on disability remains largely unknown. With the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), we can now rely on a globally agreed-upon framework and system for classifying the typical spectrum of problems in the functioning of persons with a specific disease given the environmental context in which they live. The aim of this article is to outline the methods to be utilized to develop ICF Core Sets for IBD. The project is a cooperation between the ICF Research Branch of the WHO, the IPNIC group, the International Society of Physical Rehabilitation Medicine (ISPRM), and the International Organization on Inflammatory Bowel Disease (IOIBD). Four worldwide studies will be conducted from 2009 to 2010. ICF categories relevant for IBD will be identified by systematic literature review of outcomes and measures used in IBD research, semistructured patient interviews, Internet-based expert survey, and cross-sectional study for clinical applicability. The final definition of ICF Core Sets for IBD will be determined at a Consensus Conference. Field testing will then be used to validate the ICF Core Sets. ICF Core Sets are being designed to provide useful standards for research and clinical practice. This tool will enable research that improves understanding of functioning, disability, and health in IBD, and may lead to interventions to improve and maintain functioning and minimize disability among IBD patients throughout the world.

Mucosal healing (MH) has emerged as an important treatment goal for patients with IBD. Historically, the therapeutic goals of induction and maintenance of clinical remission seemed insufficient to change the natural history of IBD. Evidence has now accumulated to show that MH can alter the course of IBD, as it is associated with sustained clinical remission, and reduced rates of hospitalization and surgical resection. In patients with ulcerative colitis, MH may represent the ultimate therapeutic goal because inflammation is limited to the mucosa. In patients with Crohn's disease, which is a transmural disease, MH could be considered as a minimum therapeutic goal. This Review focuses on the definition of MH and discusses the ability of each available IBD medication to induce and maintain MH. The importance of achieving MH is also discussed and literature that demonstrates improvement of disease course with MH is reviewed. Finally, we discuss how best to integrate the treatment end point of MH into clinical practice for the management of patients with IBD.

Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD.A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied.The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) whereas the "protective" (B) haplotype was significantly less transmitted to IBD and CD patients. No interaction between CARD15 and TNFSF15 was detected. We also failed to define a clinical subgroup of CD patients specifically associated with TNFSF15 haplotype A.This study confirms that TNFSF15 or a closely linked gene is involved in the genetic predisposition to CD.

To evaluate the efficacy and safety of purine analogs (azathioprine, 6-mercaptopurine (6-MP)) in the prevention of postoperative recurrence in Crohn's disease (CD). We searched MEDLINE, the Cochrane Library, and EMBASE. The primary end points, clinical and endoscopic recurrence at 1 and 2 years, and safety were analyzed by the methods of Peto and Der Simonian and Laird. Four controlled trials enrolled 433 patients and compared azathioprine (n=3) or (6-MP) (n=1) with control arms (placebo with or without antibiotic induction therapy or mesalamine). In the overall analysis, purine analogs were more effective than control arms in preventing clinical recurrence at 1 year (mean difference, 95% confidence interval (CI): 8, 1-15%, P=0.021, number needed to treat (NNT)=13) and 2 years (mean difference, 95% CI: 13%, 2-24%, P=0.018, NNT=8). In sensitivity analyses, the efficacy of purine analogs was superior to that of placebo for the prevention of clinical and endoscopic recurrence at 1 year (mean differences, 95% CI: 13, 1.8-25%, P=0.025, NNT=7, and 23%, 9-37%, P=0.0016, NNT=4, respectively). At 1 year, in the overall analysis, purine analogs were more effective than control arms were in preventing severe (i2-4) endoscopic recurrence (mean difference, CI 95%: 15, 1.8-29%, P=0.026, NNT=7), but they were not effective in the prevention of very severe (i3-4) recurrence. The rate of adverse events leading to drug withdrawal was higher in thiopurine-treated patients than in control arms (17.2 vs. 9.8%, respectively, P=0.021). Purine analogs are more effective than placebo in preventing both clinical and endoscopic postoperative recurrence in CD, but they are associated with a higher rate of adverse events leading to drug withdrawal

International audience; BACKGROUND AND AIMS: It is well established that Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). The data concerning SBA risk factors in CD are scanty. The aim of this study was to identify them. METHODS: In 11 French centers affiliated with the GETAID (Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif), we identified 29 patients with CD and SBA. Eighty-seven CD controls without SBA recruited in a single center were matched to the cases for sex, age, duration, and CD site. A conditional logistic regression, taking into account the matching between cases and controls, was performed. RESULTS: In univariate analysis, the cases had had significantly less small bowel resection and received prolonged treatment with salicylates (more than 2 yr), less often than the controls (odds ratio, OR [95% confidence interval, CI] 0.07 [0.01-0.32] and 0.29 [0.10-0.82], respectively). In multivariate analysis, both associations remained significant (OR 0.04 [0.01-0.28], P= 0.001; OR 0.16 [0.03-0.79], P= 0.02, respectively). CONCLUSION: This study suggests that small bowel resection and prolonged salicylates use may protect against SBA in CD patients.

Resume Le lipome colique est une tumeur benigne rarement rencontree en pratique clinique courante. Nous rapportons le cas d’une patiente de 61 ans, chez qui des accidents occlusifs ont fait decouvrir un lipome du colon ascendant. Le diagnostic a ete porte en preoperatoire par examen tomodensitometrique. Une lipectomie par colotomie a ete realisee. A partir de ce nouveau cas et apres analyse de la litterature, nous discutons les caracteristiques cliniques, diagnostiques et les possibilites therapeutiques de cette pathologie rare.

Acute pancreatitis is not infrequent after allogenic marrow transplantation. Several causes can predispose to pancreatitis, including Graft-Versus-Host Disease (GVHD), a condition which is probably underestimated. In the literature, few description of pancreatic GVHD can be found. Pancreatic GVHD diagnosis can be difficult if pancreatic involvement occurs without other typical manifestations of GVHD. We report the case of a woman, 54 years old, suffering from prolonged, painful pancreatitis two months after allogenic bone marrow transplantation for acute myeloid leucemia. Pancreatic GVHD diagnosis was performed after five weeks on duodenal biopsies despite the absence of diarrheoa. The patient dramatically improved within few days on corticosteroids.

Summary Background Lactulose and polyethylene glycol are osmotic agents used to treat idiopathic chronic constipation. Aim To compare the effects of low doses of lactulose and PEG 4000 on transit time measured by scintigraphy in normal subjects. Methods For 5 days, 10 healthy subjects received either 10 g b.d. of lactulose or PEG 4000 in a randomized, double-blind, crossover study. On the evening of day 4, they took a capsule containing Amberlite resin pellets labelled with 111In. On day 5, after a 1000 kcal test meal labelled with 99Tcm, gastric, small bowel and colonic transits were measured. Results Gastric emptying and small bowel transit time were not different. Ascending colon emptying curve was significantly accelerated with lactulose in comparison with polyethylene glycol (P = 0.001) and, respectively, 50 ± 18% vs. 35 ± 18% of the radioactivity had left the ascending colon at the end of the study (P

International audience; This study investigated the long-term outcome of patients with tuberculosis (TB) as a complication of tumour necrosis factor (TNF)-alpha blocker therapy. All TB cases (n = 21) complicating TNF-alpha blocker therapy from French university hospitals were collated between January 2000 and September 2002. Outcome was assessed via a postal questionnaire during September 2005. The mortality rate after 4 years was 4.8%, and one patient had relapsed and six (29%) patients had recommenced TNF-alpha antagonist treatment, after appropriate anti-TB therapy, without reactivation. These data support the concept that TNF-alpha antagonists can be restarted in TB patients provided that adequate anti-TB treatment has been completed.

To determine in a noninferiority study whether mesalamine foam is as effective as mesalamine liquid enema for inducing clinical remission in patients with active left-sided ulcerative colitis (UC). In a multicenter investigator-blind trial, 375 patients with mild-to-moderate UC were randomized to receive mesalamine foam 1 g/80 mL/day or mesalamine liquid enema 1 g/100 mL/day for 4 wk (W). Inclusion criteria were: disease extension at least 5 cm from anorectal junction and not above splenic flexure and Clinical Activity Index (CAI) 1-4 > or = 4. Primary end point was clinical remission at W4 defined as a CAI 1-4

The same drugs are used to treat hemorrhagic rectocolitis (HRC) and Crohn's disease (CD), although the aims are very different. Aminosalicylates are highly beneficial in HRC but virtually ineffective in CD, a disease in which immunosuppressants are more useful. Aminosalicylates exert their antiinflammatory effect directly on the lesions. Various oral and rectal preparations have been developed in order to deliver the active molecule to the intestinal target segment. These drugs are now known to act by stimulating the nuclear receptor PPAR-gamma, and this knowledge should help with the development of new agents. Chronic aminosalicylate treatment appears to diminish the risk of malignant transformation. Systemic steroids are still the mainstay of treatment for exacerbations of HRC and CD, yielding remissions in 60 to 90% of cases. In contrast, systemic steroids should not be used for maintenance therapy. Budesonide is a preparation that selectively releases steroids in the ileocolonic region, thereby reducing systemic adverse effects. Immunosuppressants such as azathioprine and 6-mercaptopurine, and also methotrexate in some cases, are used for maintenance therapy of steroid-dependent and highly recurrent forms. These drugs stabilize the disease in about half the patients who receive them. Treatment typically lasts several years and necessitates regular monitoring, especially of hematological status. Cyclosporine is used intravenously in severe HRC. Infliximab (RemicadeR), a chimeric monoclonal antibody targeting TNF is effective in acute forms and as maintenance therapy for CD. It was also recently shown to be effective in HRC. Infliximab is indicated in steroid-resistant forms and contraindicated in patients with latent systemic infections (tuberculosis, hepatitis B) and heart failure. Artificial nutrition is now only used in children with acute forms, in order to avoid the need for steroids. Probiotics might have a place in maintenance treatment of HRC. Surgical treatment of HRC consists of colectomy or, more radically, ileoprotectomy followed by ileoanal anastomosis with resection: however, the likely benefits and potential complications (especially nocturnal diarrhea) must be carefully weighed up. Surgical treatment of CD consists of resecting the worst-affected segments. As available medical and surgical treatments can only control these diseases, without curing them, patient management must be planned on a long-term basis. Control of exacerbations is judged on the basis of clinical parameters and biological markers of inflammation, rather than on lesion healing. The choice of maintenance therapy depends on the nature of the disease (HRC or CD) and its progressive nature. Surgery is reserved for patients with complicated and drug-resistant forms.

Background & Aims: Crohn's disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex–related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8 + T cells, γδ T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD. Methods: MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes. Results: MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4 + T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4 + NKG2D + T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4 + NKG2D + T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-γ and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4 + NKG2D + lamina propria lymphocytes from patients with CD highly expressed interleukin-15Rα, and interleukin-15 increased NKG2D and DAP10 expression in CD4 + NKG2D + T-cell clones. Conclusions: These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4 + T cells with inflammatory and cytotoxic properties in CD.

Resume L’infiltration graisseuse diffuse et primitive du pancreas est une cause rare d’insuffisance pancreatique exocrine chez l’adulte. Nous rapportons deux observations de malades ayant une diarrhee chronique avec steatorrhee chez lesquels les explorations morphologiques mettaient en evidence une infiltration graisseuse pancreatique diffuse. La tomodensitometrie montrait des anomalies morphologiques caracteristiques d’infiltration graisseuse diffuse pancreatique (pancreas atrophique et lobulaire ou pancreas non visible). L’IRM et l’echoendoscopie, realisees chez un malade, montraient egalement des anomalies suggerant une infiltration graisseuse pancreatique. Les extraits pancreatiques permettaient une diminution de la steatorrhee chez les deux malades.

Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings.Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data.In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed.Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.

Background: Cyclosporine A (CsA) is inconstantly effective in inducing remission in acute attacks of ulcerative colitis (UC) not responding to steroids. This study aimed to establish whether multidrug resistance gene (MDR)1 polymorphisms would be associated with CsA failure. Patients and Methods: The distribution of the different genotypes of single nucleotide polymorphisms (SNP) G2677T/A and C3435T of MDR1 exons 21 and 26, respectively, was studied in 154 patients (mean age, 44 yr) who had received CsA to treat severe attacks of steroid resistant UC in 11 centers in France and Belgium. Patients were classified as CsA failure (n = 50) when they needed colectomy within 30 days after CsA initiation. The SNPs were detected by use of a 5′ nuclease allelic discrimination assay. Results: There was a significant association between the G2677T/A polymorphism distribution (exon 21) and the risk for CsA failure (P = 0.0001). The TT genotype of exon 21 was significantly associated with the risk compared with the two other genotypes (odds ratio, 3.77; 95% confidence interval, 1.42–9.97, P = 0.007). There was no significant association between the genotype C3435T distribution (exon 26) and the risk of CsA failure (P = 0.23). Conclusion: The TT genotype of exon 21 MDR1 polymorphisms is associated with a higher risk of CsA failure in patients with steroid resistant UC. Further studies should be performed to establish whether other treatments could be more efficient to avoid surgery in this subset of patients. (Inflamm Bowel Dis 2007;13:19–23)

Background In Crohn's disease, studies have evaluated the ability of biological markers to predict relapse in the next 12 to 18 months, without differentiating early from late relapses. The aim of this study was to look for biological markers of short-term relapse. Materials and methods In a previous therapeutic trial, patients with a medically induced clinical remission had biological markers evaluated and updated every 6 weeks. A Cox model with time-dependent covariates was used for analysis. Results Among the 71 patients, 38 had a relapse. Multivariate analysis selected 2 markers predictive of relapse: C-reactive protein >20 mg/L and erythrocyte sedimentation rate >15 mm. A binary biological predictive score was derived: "negative" when both were lower than their limits, "positive" when otherwise. The relative risk of short-term relapse for patients with a positive score compared to those with a negative score was 8.0 (95% confidence interval 2.8-22.9). Sensitivity of the score was 89% and specificity was 43%. Assuming a 10% relapse rate every 6 weeks, negative and positive predictive values were 97% and 15%, respectively. Conclusions This simple biological score can predict short-term maintenance of remission in Crohn's disease and may help physicians in the follow-up of patients in clinical remission.

Background & Aims: The aim of this study was to evaluate the usefulness of short-term infliximab combined with azathioprine (AZA) or 6-mercaptopurine (6-MP) in steroid-dependent Crohn's disease patients. Methods: Patients with active disease despite prednisone given for more than 6 months were eligible and were stratified as follows: the failure stratum consisted of patients receiving AZA/6-MP at a stable dose for more than 6 months, and the naive stratum consisted of patients not treated previously with AZA/6-MP. Patients were randomized to infliximab 5 mg/kg or placebo at weeks 0, 2, and 6. All patients were treated with AZA/6-MP maintained at a stable dose throughout the 52 weeks of the study. The primary end point was remission off steroids at week 24. Results: Among the 113 enrolled patients (55 in the failure stratum), 57 were assigned to infliximab. At week 24, the success rate (intent-to-treat analysis) was higher in the infliximab group than in the placebo group (57% vs 29%; P = .003); at weeks 12 and 52, the corresponding rates were 75% vs 38% ( P P = .04), respectively. In each stratum, the success rate was significantly higher in the infliximab group at weeks 12 and 24, and a trend was found at week 52. In the failure stratum, only 27% of the patients in the infliximab group were still in remission off steroids, compared with 52% in the naive stratum. Steroid resistance was less common and the cumulative dose of prednisone was lower in the infliximab group. Conclusions: Infliximab plus AZA/6-MP is more effective than AZA/6-MP alone in steroid-dependent Crohn's disease patients.

Resume Objectifs Le but de cette etude etait d’etudier les modalites d’utilisation du traitement et le devenir des malades traites par infliximab pour maladie de Crohn MC en 2000 a l’Assistance Publique-Hopitaux de Paris (AP-HP). Malades et methodes Les dossiers des malades atteints de MC traites dans un des services d’Hepato Gastro-enterologie adulte de l’AP-HP par au moins une injection d’infliximab durant l’annee 2000 ont ete analyses de maniere retrospective. Resultats Cent trente-sept malades (36,0 ≥ 12,7 ans, 92 femmes) traites dans 12 centres ont ete inclus. L’indication du traitement etait une maladie fistulisee ou des lesions ano-perineales dans 39% des cas, une maladie active dans 45 % et une forme mixte dans 16 %. Le nombre moyen d’injection administre a ete de 3,6 p 2,4 injections par malade. Le suivi moyen etait de 15,2 ≥ 7,2 mois. Au total, 85 % des malades ont eu une reponse initiale. Aucun facteur predictif de duree d’efficacite n’a ete retrouve. Le delai moyen de rechute etait de 3,9 ≥ 3,1 mois. Trente-huit malades etaient en traitement d’entretien a la fin du suivi, avec echappement progressif au traitement chez 37 %. Un traitement immunosuppresseur a ete associe au traitement par infliximab dans 78 % des cas. L’efficacite de l’infliximab n’etait pas modifiee par l’adjonction d’un immunosuppresseurs (P = 0,36). Un effet indesirable, le plus souvent peu severe, a ete note chez 23 % des malades. Conclusion Cette etude retrospective confirme l’efficacite du traitement par infliximab dans la MC, son role d’epargne en corticoides et sa securite d’emploi.

Lactulose (10-20 g day(-1)) is used to treat constipation. At this therapeutic dose, its effects on colonic motility remain unknown. Twenty-two healthy subjects swallowed a probe with an infusion catheter, six perfused catheters and a balloon connected to a barostat. Colonic phasic and tonic motor activity was recorded in fasting state. In group 1, four volunteers ingested 15 g lactulose and motility was recorded for 5 h after entry of lactulose into the caecum; in group 2, motility was recorded during (3 h) and 2 h after intracolonic infusion of isoosmotic and isovolumetric solutions containing sodium chloride alone (n = 9) or with 15 g lactulose (n = 9). In a last group of volunteers, isotopic colonic transit after ingestion of lactulose (10 g,n = 9) was assessed and compared with a control group (n = 17). Ingestion or intracolonic infusion of 15 g lactulose significantly decreased barostat bag volume (maximal decrease: 45 +/- 12% and 35 +/- 9% of basal value respectively). Phasic contractions remained unchanged. Tonic and phasic motility was unchanged by the isotonic and isovolumetric infusion of saline. Ingestion of lactulose significantly accelerated isotopic colonic transit time compared with the control group. We conclude that in healthy humans, 10-15 g ingestion or intracaecal infusion of lactulose produces a prolonged tonic contraction that may be involved in the laxative effect of lactulose.

Generalized pustular psoriasis is a rare form of psoriasis that is sometimes associated with extracutaneous manifestations. Evidence for biliary involvement has been suggested in isolated cases. We investigated the prevalence and nature of liver abnormalities occurring in this disease. Twenty-two patients consecutively admitted for generalized pustular psoriasis who underwent liver biological tests at the time of the attack and during the following weeks were included. Twenty patients (90%) had at least one abnormal biological liver parameter. Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal value (7/22). These abnormalities returned to normal range at the time of remission of pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy. Persistent magnetic resonance cholangiopancreatography features similar to those observed in sclerosing cholangitis were found in 3 of the 4 patients studied. No causal factor other than pustular psoriasis could be identified. In conclusion, our results demonstrate the high frequency of liver abnormalities in patients with generalized pustular psoriasis. Biliary involvement related to neutrophilic cholangitis should be added to the spectrum of extracutaneous manifestations of this disease, and physicians should be aware of such a complication.

In an experimental model we demonstrated that endothelial cells of all organs are targets of the alloimmune reaction. Here, in 68 digestive biopsies, we found endothelial lesions by immunohistochemistry and ultrastructure in patients with severe acute graft-versus-host disease (GVHD). In contrast, no such endothelial cell alterations were found either in patients without GVHD or in nongrafted controls. In the biopsies with severe GVHD lesions, ultrastructure showed rupture of the capillary basal membrane and extravased red blood cells. These pericapillary hemorrhages were highly correlated with GVHD severity. In a separate cohort of 39 patients who underwent an allogeneic transplantation after a nonmyeloablative conditioning, 8 patients had intestinal biopsies. Three of these latter patients had both severe pathologic lesions of GVHD and similar endothelial lesions, thus, strengthening the concept that endothelial lesions are linked to GVHD severity and not to the intensity of the conditioning regimen. (Blood. 2004;103:4681-4684)

n observe au cours des maladies inflammatoireschroniques de l’intestin (MICI) deux types de lesionsosteo-articulaires : 1) l’osteopenie ou reduction dela masse osseuse, dont les mecanismes et les determinants sontmultiples, et qui expose a un risque accru de fracture ; 2) lesatteintes inflammatoires, osseuses et surtout articulaires, asso-ciees a ces maladies intestinales. Au cours des annees dernieres,l’accent a ete mis sur la frequence de l’osteopenie, et surl’importance de son depistage, de sa prevention, de sontraitement. Ces travaux ont eu un impact sur la prise en chargedes MICI en soulignant le role nocif de la corticotherapie et lanecessite de trouver des alternatives a ce traitement. Plusrecemment, l’efficacite de l’infliximab dans les pelvispondy-larthropathiesaetemontree,etcetaspectdoitdesormaisetreprisen compte dans la strategie therapeutique des MICI lorsque lesdeux affections sont associees.

Aim To evaluate the safety and long-term efficacy of per-endoscopic hydrostatic balloon dilatation in a retrospective series of patients with Crohn's disease. Methods Thirty-eight patients had balloon dilatation for intestinal symptomatic strictures which were located as follows: ileo-colonic (26) or colocolic (2) anastomosis, colon (4), ileum (3), proximal jejunum (1) and ileo-caecal valve (5); three patients had two strictures accessible to dilatation. The mean length of the strictures was 2.1 cm (s.d., 0.3 cm). Results Thirty-two of the 38 patients were successfully dilated and followed for a median of 22.8 months (0.2-103 months) until surgery or last news. The probabilities of obstructive symptom recurrence were 36% at 1 year and 60% at 5 years. Twelve patients had a second dilatation, and three a third. The probabilities of surgery for stricture were 26% at 1 year and 43% at 5 years. Results were not influenced by age, sex, activity of the disease, passage of the stricture by the colonoscope or concomitant medical therapies. Complications occurred in 9.4% of the 53 dilatation sessions, with only one perforation. Conclusions Hydrostatic balloon dilatation is effective for Crohn's symptomatic strictures, and can avoid or postpone surgery, with an acceptable rate of complications.

Summary Background: Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases. Aims : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP. Methods : An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy. Results : Forty-nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13–21 days after TG was started. No haematological side-effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG. Conclusions : TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

Background: The diagnostic and therapeutic value of EGD in patients with upper GI bleeding is often limited by the presence of residual blood or clots. When infused before EGD, erythromycin, a potent gastrokinetic drug, might improve the quality of EGD in patients with upper GI bleeding. The aim of this study was to assess the effect of erythromycin on the quality of the EGD in patients with acute upper GI bleeding. Methods: Forty-one patients admitted to the intensive care unit because of acute upper GI bleeding were included in a randomized, endoscopist-blinded, controlled trial, comparing erythromycin (3 mg/kg intravenously over 30 minutes) to no treatment (control patients). EGD was performed 30 to 90 minutes after the end of the infusion. The primary study outcome was quality of EGD examination, as evaluated on a scale of 0 to 3, and the need to perform a second diagnostic EGD within the next 8 days. Secondary outcomes were efficiency of the endoscopic hemostatic therapy and intensity of esophagogastroduodenal contractions, as evaluated on a scale of 0-3. Results: The characteristics of the patients and lesions found by EGD were similar in both groups. Quality of the EGD examination was significantly better in the erythromycin group (n = 19) compared with the control group (n = 22) (2.5 [0.8] vs. 1.5 [1.3]; p = 0.02). Three patients receiving erythromycin required a second EGD compared with 10 control patients (p = 0.089). Erythromycin did not interfere with the performance of EGD or the efficiency of hemostatic procedures. The intensity of gastroduodenal contractions was similar in both groups. No adverse event was observed. Conclusions: In patients with acute upper GI bleeding, infusion of erythromycin before endoscopy significantly improved the quality of EGD and tended to reduce the need for second-look endoscopy. (Gastrointest Endosc 2002;56:174-9.)

Summary Background : Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-α, is a new potent therapy for active Crohn's disease, but induces short-lived improvements. Aim : To evaluate the efficacy of thalidomide, a drug with anti-tumour necrosis factor-α activity, for the maintenance of infliximab-induced response in refractory Crohn's disease. Methods : Fifteen patients with severe, refractory disease (10 females, five males; mean age, 40 years; eight with luminal disease, two with fistulizing disease and five with both luminal and fistulizing disease) were started on thalidomide (100 mg daily), 29 ± 10 days after they had responded to infliximab (5 mg/kg infusions). Results : The median follow-up period was 238 days (range, 10–458 days) from the initiation of thalidomide and 265 days (range, 10–537 days) from the last infliximab infusion. The median Crohn's disease activity indices were 322 (range, 170–525), 119 (range, 24–503) and 35 (range, − 60–360) before infliximab, at the initiation of thalidomide and at the end of follow-up, respectively. Remission rates on thalidomide were 92%, 83% and 83% at 3, 6 and 12 months, respectively, after the last infliximab infusion (Kaplan–Meier). Four patients (two in remission) stopped thalidomide for suspected adverse effects. Side-effects (drowsiness, rash and peripheral neuropathy) were mild and mostly transient. Conclusions : Thalidomide appears to be an effective and relatively safe drug to maintain response to infliximab in chronically active and fistulizing refractory Crohn's disease.

Digestive tract damage during graft-versus-host reaction (GVHR) causes high morbidity and mortality. Diagnosis is often late because biopsies are performed when clinical signs are severe and pathologic markers of early inflammatory lesions are lacking. Eosinophils are inflammatory cells, cytotoxic in vitro to digestive epithelium; they are found in biopsy specimens taken during acute flare-ups of inflammatory bowel disease. We performed systematic duodenal biopsies immediately after digestive symptoms occurred and found a digestive GVHR incidence of 73.1% (n = 93), higher than that found when digestive biopsies were performed immediately after severe clinical signs. Eosinophils were only present when there were histologic signs of GVHR; eosinophil presence correlated with GVHR severity. Electron microscopy with immunogold staining showed pathologic signs of in situ eosinophil activation, such as cytoplasmic granule alterations, and eosinophil peroxidase release in all patients. Interleukin-5 presence in activated eosinophils suggests eosinophil recruitment in digestive GVHR is an autocrine mechanism. Eosinophil density also correlated with GVHR severity, whether in acute or chronic clinical phases. Tissue eosinophils could thus be a marker of acute inflammatory flare-ups in GVHR. Systematic duodenal biopsy performed at the onset of digestive symptoms should allow early GVHR detection, and pathologic signs of GVHR, together with eosinophil density, might help modulate immunosuppressive therapy.

OBJECTIVE: Prediction of the clinical course of Crohn’s disease (CD) is difficult in the long term. Our aim was to determine whether the presence of severe endoscopic lesions (SELs) may predict a higher risk of colectomy and penetrating complications. METHODS: All patients at our institution with active ileocolonic CD who had colonoscopies between 1990 and 1996 were included in the study. SELs were defined as extensive and deep ulcerations covering more than 10% of the mucosal area of at least one segment of the colon. RESULTS: Among the 102 patients included, 53 had SELs at index colonoscopy. During the follow-up (median = 52 months), 37 patients underwent colonic resection. Probabilities of colectomy at 1, 3, and 8 yr were 20%, 26%, and 42%. Risk of colectomy was independently affected by the presence of SELs at index colonoscopy (relative risk [RR] = 5.43, 95% CI = 2.64–11.18), a Crohn’s Disease Activity Index level greater than 288 (RR = 2.21, 95% CI = 1.09–4.47), and the absence of immunosuppressive therapy during the follow-up (RR = 2.44, 95% CI = 1.20–5.00). Probabilities of colectomy were, respectively, 31% and 6% at 1 yr, 42% and 8% at 3 yr, and 62% and 18% at 8 yr in patients with and without SELs. We performed a second analysis excluding the 14 patients operated on within the 3 months after the index colonoscopy: presence of SELs remained the only significant factor predictive of colectomy (RR = 6.72, 95% CI = 2.26–20.03). All six patients with penetrating complications during the follow-up had SELs at index colonoscopy. CONCLUSIONS: Patients with CD exhibiting deep and extensive ulcerations at colonoscopy have a more aggressive clinical course with an increased rate of penetrating complications and surgery.

Background This study aimed to analyse disease recurrence and fate of the rectum in patients who had a total colectomy for Crohn's disease. Methods One hundred and forty-four patients who had a total colectomy for Crohn's colitis were reviewed retrospectively. Ileorectal anastomosis (IRA) was performed in 118 patients, while 26 never had an IRA after colectomy because of severe anorectal lesions. Factors associated with recurrence and rectal preservation failure were studied. Results The probability of clinical recurrence after IRA was 58 and 83 per cent at 5 and 10 years respectively. The probability of rectal preservation at 5 and 10 years was 70 and 63 per cent after colectomy, and 86 and 86 per cent after IRA, respectively. Patients with extraintestinal manifestation had a higher risk of recurrence and of rectal preservation failure. Previous ileal involvement was associated with a higher rate of ileal recurrence after IRA. After IRA, prophylactic treatment with 5-aminosalicylic acid was associated with a lower rate of recurrence and of failure to preserve the rectum. Conclusion Overall, 63 per cent of patients had a functioning IRA 10 years after total colectomy. Absence of extraintestinal manifestation and prophylactic treatment with 5-aminosalicylates after IRA were the main factors associated with long-term rectal preservation.

The origin and mechanisms of symptoms in sugar intolerance were studied in 8 healthy volunteers. For two test periods, volunteers swallowed a probe with perfused catheters and an infusion catheter which migrated into the colon. A meal containing 40 g lactulose or 40 g sucrose was ingested; the sucrose meal was followed by colonic infusion of 40 g lactulose in order to bypass the small intestine. Recordings of small intestinal and colonic motility were performed. Abdominal pain, bloating, borborygmi, and flatulence were similar during both periods. Both meals increased small intestinal and colonic motility. Only 37% of the symptoms coincided in time with colonic motor events. Symptoms were not related to a specific motor event and were not correlated with breath hydrogen excretion. In conclusion, symptoms of sugar intolerance originate from the colon. They are not related to specific phasic motor events or to breath hydrogen excretion.

International audience; : OBJECTIVES:Although anti-tumor necrosis factor (TNF) therapy is the treatment of choice for perianal fistulizing Crohn's disease (CD), the efficacy and safety of anti-TNF therapy in enterocutaneous fistula (ECF) remains unclear.METHODS:Between January 2008 and December 2009, we retrospectively reviewed the outcomes of all CD patients with ECF (excluding perianal fistula) treated with anti-TNF therapy followed up in Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) centers. ECF closure and tolerance of anti-TNF therapy were studied using univariate and multivariate analyses.RESULTS:Forty-eight patients (twenty-six women; median age 34.6 (interquartile range=25.0-45.5) years) were included in this study. The median follow-up period was 3.0 (2.0-6.6) years. The fistula was located in the small bowel (n=38), duodenum (n=1), and colon (n=9). The fistula has been developed in ileocolonic anastomosis in 17 (35%) cases. Sixteen patients (33%) had complex fistulas with multiple tracts and eleven patients (23%) had a high ECF output (if wearing an ostomy bag). Complete ECF closure was achieved in 16 (33%) patients, of whom eight relapsed during the follow-up period. In multivariate analysis, complete ECF closure was associated with the absence of multiple ECF tracts and associated stenosis. An abdominal abscess developed in 15 (31%) patients. ECF resection was needed in 26 (54%) patients. One patient died after surgery owing to abdominal sepsis.CONCLUSIONS:In CD patients with ECF, anti-TNF therapy may be effective in up to one-third of patients, especially in the absence of stenosis and complex fistula. A careful selection of patients is mandatory to prevent treatment failure and improves the safety.Am J Gastroenterol advance online publication, 5 August 2014; doi:10.1038/ajg.2014.183.

OBJECTIVE: A 16-wk, placebo-controlled trial has recently shown weekly low-dose methotrexate to be an effective treatment for patients with chronically active Crohn’s disease. The long-term efficacy and safety of this antimetabolite drug, however, are not yet well established and are assessed in this study. METHODS: A total of 49 patients with Crohn’s disease who were treated with methotrexate for ≥6 months were studied. All patients had been chronically treated with steroids; but at the time of initiation, only 27 were still on steroids. Of the 49 patients, 42 had previously taken azathioprine but were no longer on this drug because of intolerance or failure. Clinical remission was defined as a Harvey-Bradshaw index of RESULTS: In all, 41 patients achieved complete clinical remission and were maintained on methotrexate for a median of 18 months (range, 7–59 months). In these patients the probabilities of relapse were 29%, 41%, and 48% at 1, 2, and 3 yr, respectively. A higher rate of relapse was observed in women and in patients with ileocolitis. Adverse reactions were recorded in 24 patients, requiring discontinuation of methotrexate in five. A liver biopsy was performed in 11 patients; a mild steatosis was found in five, a slight dilation of the sinusoids in one, a granulomatous hepatitis with a mild portal fibrosis in one, and a slight periportal fibrosis in one patient. CONCLUSIONS: This study suggests a long-term benefit of maintenance treatment with methotrexate in patients with chronically active Crohn’s disease, with side effects that are usually only moderate.

Background: Intensive intravenous treatment remains the first line therapy of severe, uncomplicated attacks of ulcerative colitis. Aim: To predict the failure of intensive intravenous treatment by combining clinical and laboratory parameters with endoscopy findings. Methods: Retrospective study conducted in a tertiary care referral centre. Failure of intensive intravenous treatment was defined as colectomy before day 30, intravenous cyclosporin, or death. Predictive factors of outcome were assessed using univariate and multivariate prognostic analysis. Results: Between January 1990 and May 1997, 85 consecutive patients were treated with intensive intravenous treatment for non-response to oral corticosteroids (n=59) and/or severe attack of ulcerative colitis (n=26). There were 41 successes and 44 failures (including 1 death, 13 cyclosporin and 30 colectomies before day 30). Multivariate prognostic analysis found that the presence of Truelove and Witts’ criteria (P=0.018), an attack that had lasted more than 6 weeks (P=0.001), and severe endoscopic lesions (P=0.007) were associated with an increased risk of failure. Patients with severe endoscopic lesions and Truelove and Witts’ criteria, or an attack of more than 6 weeks had a failure rate of 85–86%. Conclusion: Clinical, laboratory and endoscopic findings can predict the risk of failure of intensive intravenous treatment. A prospective study is required to confirm these results.

OBJECTIVE The aim of this randomized controlled study was to investigate the efficacy of ciprofloxacin compared with mesalazine in treating active Crohn's disease. METHODS Patients with a mild to moderate flare-up of Crohn's disease (mean Crohn's Disease Activity Index [CDAI]; 217; range, 160-305) were randomized to receive ciprofloxacin 1 g/day or Pentasa 4 g/day for 6 wk. Complete remission was defined at wk 6 as a CDAI 75. Partial remission was defined as a CDAI 150 with delta CDAI > 50 at wk 6. Group sequential procedure with triangular continuation regions was used to monitor the trial through the difference in complete remission rates, every 20 patients included. RESULTS Inclusion of patients was stopped at the second step, i.e., after 40 inclusions, with the conclusion of no difference in complete remission rates between ciprofloxacin- and Pentasa-treated groups. Among the 18 patients taking ciprofloxacin, two decided to stop treatment during the trial and three were considered as treatment failures because of deterioration at wk 3. Among the 22 patients taking mesalazine, one patient was lost to follow-up and eight patients were considered as treatment failures. Complete remission was observed in 10 patients (56%) treated with ciprofloxacin and 12 patients (55%) treated with mesalazine and partial remission was observed in three and one patient, respectively. CONCLUSIONS This study suggests that ciprofloxacin 1 g/day is as effective as mesalazine 4 g/day in treating mild to moderate flare-up of Crohn's disease.

The aim of this study was to assess in nine healthy subjects the effects of CCK octapeptide (CCK-8) on colonic tonic activity, measured by a barostat, and phasic activity, measured by manometry. On 2 consecutive days, recordings were performed in the unprepared proximal and distal colons during intravenous infusion of saline and CCK-8 at 5, 20, and 40 ng ⋅ kg−1⋅ h−1. In the proximal colon CCK-8 induced, at the 20 and 40 ng ⋅ kg−1⋅ h−1doses, a tonic relaxation with an increase in barostat bag volume to 156 ± 25 and 157 ± 19% of basal ( P < 0.01) and a decrease in phasic activity to 72 ± 7 and 76 ± 7% of basal ( P < 0.01). In the distal colon, CCK-8 induced, at the 20 and 40 ng ⋅ kg−1⋅ h−1doses, a tonic relaxation (increase in intrabag volume to 133 ± 12 and 149 ± 15%, respectively; P< 0.01), whereas phasic activity increased (128 ± 8 and 132 ± 6%, respectively; P < 0.01). Effects of CCK-8 on tonic and phasic activities are different according to the colonic segment. Because meals induce colonic tonic contraction, our results suggest that CCK, as a hormone, is not an important mediator of the response of the colon to feeding in humans.

Background: Little information is available about the safety of high doses of mesalazine during pregnancy. Aim: To study the fate of pregnancy and foetal outcome in women taking 1–4 g/day of mesalazine microgranules for inflammatory bowel disease. Patients and methods: Case reports were collected from the Pharmacovigilance Department of Ferring SA, France, from a survey conducted in three gastroenterology units, and from a teratology information service. The evolution of pregnancy and foetal outcome were assessed by questionnaire. Results: The study covered a total of 123 pregnancies (126 foetuses). Ninety-six women took mesalazine during the first trimester, 85 during the second and 83 during the third. The mean daily dose was 2.1 ± 0.8 g; 86 women received