Guillaume Pineton de Chambrun

Clinical implications of mucosal healing for the management of IBD

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 Crohns 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.

Natural history of eosinophilic gastroenteritis.

BACKGROUND & AIMS Eosinophilic gastroenteritis (EGE) is a rare gastrointestinal disorder; little is known about its natural history. We determined the clinical features and long-term outcomes of patients with EGE. METHODS We reviewed files from 43 patients diagnosed with EGE who were followed from January 1988 to April 2009. The diagnosis was made according to standard criteria after other eosinophilic gastrointestinal disorders were excluded. We analyzed data on initial clinical presentation and long-term outcomes. RESULTS EGE was classified as mucosal, subserosal, or muscular in 44%, 39%, and 12% of cases, respectively. Disease location was mostly duodenal (62%), ileal (72%), or colonic (88%); it was less frequently esophageal (30%) or gastric (38%). Blood eosinophilia (numbers >500/mm(3)) was observed in 74% of cases. Spontaneous remission occurred in 40% of patients; the majority of treated patients (74%) received oral corticosteroids, which were effective in most cases. After a median follow-up period of 13 years (0.8-29 years), we identified 3 different courses of disease progression: 18 patients (42%; 9 with subserosal disease) had an initial flare of the disease without relapse, 16 (37%) had multiple flares that were separated by periods of full remission (recurring disease), and 9 (21%) had chronic disease. CONCLUSIONS The clinical presentation of EGE is heterogeneous and varies in histologic pattern; about 40% of patients resolve the disease spontaneously, without relapse. Approximately 50% have a more complex disease, which is characterized by unpredictable relapses and a chronic course.

Pathogenic agents in inflammatory bowel diseases

Purpose of review Infectious agents are still thought to be involved in the origin of inflammatory bowel disease. The focus in recent years has been more on Mycobacterium avium subsp paratuberculosis, adherent-invasive Escherichia coli or yeasts. Recent findings A metaanalysis has shown a significant association of M. avium subsp paratuberculosis and Crohns disease and a large randomized placebo-controlled trial reported an absence of sustained beneficial effects of combined antibiotic therapy on remission of active Crohns disease. Adherent-invasive E. coli adhere via type 1 pili to carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), abnormally expressed by intestinal epithelial cells in Crohns disease patients. Both colonization of the ileal mucosa and stimulation of ileal epithelial cells by tumour necrosis factor-α induce overexpression of CEACAM6, leading to an amplification loop of colonization and inflammation. Anti-Saccharomyces cerevisiae mannan antibodies are the most prevalent serologic marker in Crohns disease. Major oligomannose epitopes supporting antibody formation are expressed by Candida albicans in human tissues, suggesting that a loss of tolerance to C. albicans could lead to antibody formation in a subset of Crohns disease patients who are genetically predisposed. Summary M. avium subsp paratuberculosis, adherent-invasive E. coli and Candida are good candidates for an infectious aetiology of Crohns disease on the basis of genetic susceptibility, which relates to impaired function in the defence against intracellular bacteria.

TLR3, TRIF, and Caspase 8 Determine Double-Stranded RNA-Induced Epithelial Cell Death and Survival In Vivo

TLR3 signaling is activated by dsRNA, a virus-associated molecular pattern. Injection of dsRNA into mice induced a rapid, dramatic, and reversible remodeling of the small intestinal mucosa with significant villus shortening. Villus shortening was preceded by increased caspase 3 and 8 activation and apoptosis of intestinal epithelial cells (IECs) located in the mid to upper villus with ensuing luminal fluid accumulation and diarrhea because of an increased secretory state. Mice lacking TLR3 or the adaptor molelcule TRIF mice were completely protected from dsRNA-induced IEC apoptosis, villus shortening, and diarrhea. dsRNA-induced apoptosis was independent of TNF signaling. Notably, NF-κB signaling through IκB kinase β protected crypt IECs but did not protect villus IECs from dsRNA-induced or TNF-induced apoptosis. dsRNA did not induce early caspase 3 activation with subsequent villus shortening in mice lacking caspase 8 in IECs but instead caused villus destruction with a loss of small intestinal surface epithelium and death. Consistent with direct activation of the TLR3–TRIF–caspase 8 signaling pathway by dsRNA in IECs, dsRNA-induced signaling of apoptosis was independent of non-TLR3 dsRNA signaling pathways, IL-15, TNF, IL-1, IL-6, IFN regulatory factor 3, type I IFN receptor, adaptive immunity, as well as dendritic cells, NK cells, and other hematopoietic cells. We conclude that dsRNA activation of the TLR3–TRIF–caspase 8 signaling pathway in IECs has a significant impact on the structure and function of the small intestinal mucosa and suggest signaling through this pathway has a host protective role during infection with viral pathogens.

Cholera Toxin Disrupts Barrier Function by Inhibiting Exocyst-Mediated Trafficking of Host Proteins to Intestinal Cell Junctions

Cholera toxin (CT), a virulence factor elaborated by Vibrio cholerae, is sufficient to induce the severe diarrhea characteristic of cholera. The enzymatic moiety of CT (CtxA) increases cAMP synthesis in intestinal epithelial cells, leading to chloride ion (Cl(-)) efflux through the CFTR Cl(-) channel. To preserve electroneutrality and osmotic balance, sodium ions and water also flow into the intestinal lumen via a paracellular route. We find that CtxA-driven cAMP increase also inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function. Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression. These barrier-disrupting effects of CtxA may act in parallel with Cl(-) secretion to drive the pathophysiology of cholera.

Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia.

Background:The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. Methods:Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. Results:In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. Conclusions:FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.

Postoperative Complications in Pediatric Inflammatory Bowel Disease: A Population-based Study.

Background:We describe, in a population-based cohort, the incidence of and factors associated with postoperative complications (POCs) in pediatric-onset inflammatory bowel disease. Methods:Using the pediatric population-based EPIMAD Cohort (1988–2004), among 692 incident inflammatory bowel disease cases, 128 patients with Crohns disease (CD) and 25 with ulcerative colitis (UC) (22%) had undergone at least 1 major abdominal surgery at a median age of 16 years [interquartile range, Q1–Q3 = 14–17]. Factors associated with POC were assessed using Cox models. Results:After a median postoperative follow-up of 8 years (3–12), 76 (49.7%) patients had experienced at least 1 POC with a total of 113 complications. The frequency of severe POC (grade >2) was similar in CD and UC (28% of all complications versus 27%, P = 0.95). A total of 64 early POCs (within 30 d of surgery) were observed in 47 patients (31%), with 33 being infectious and 31 noninfectious, higher in UC than in CD (25% of patients with CD versus 60% of patients with UC, P < 0.001). Forty-nine late POCs (≥30 d) were observed in 37 patients (24%). The occurrence of late POC was similar in UC and CD. The cumulative probability of POC was 31% (95% confidence interval, 24–39) at 1 month, 46% (38–54) at 1 year, and 48% (41–57) at 5 years. Multivariate analysis found that the UC type was the only factor associated with early POC (hazard ratio = 2.9; 95% confidence interval, 1.6–5.4). Conclusions:One-half of the children with inflammatory bowel disease had experienced at least 1 POC. Only UC relative to CD was significantly associated with an increased risk of early POC.

The Role of Anti(myco)bacterial Interventions in the Management of IBD: Is There Evidence at All?

Background/Aims: The etiology of IBD is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn’s disease (CD) and ulcerative colitis (UC). The aim of this review was to compel the evidence for the use of antibiotics in the treatment of IBD. Methods: We performed a systematic review of the literature regarding the use of antibiotics for inducing or maintaining remission in IBD. Results: Current data are conflicting, but a recent systematic review of randomized controlled trials has shown a statistically significant effect of antibiotics being superior to placebo for active, perianal and quiescent CD and for active UC. These data have been poorly translated in clinical practice and the place of antibiotics is restricted to certain specific situations in the international guidelines. This is first linked to the difficulties in interpreting clinical trials because of their heterogeneity in study design, endpoints, type of antibiotic and concomitant therapies. The exception to this is the use of either ciprofloxacin or metronidazole for treating CD perianal fistulas. Conclusion: The pathology of CD, the likely primary and known secondary pathogens in this disease and the successful responses in animal models all plead for new trials of antibiotics in IBD. This is a call to select patients more carefully, and to continue antibiotics for longer than is customary. Beside antibiotics, new therapeutic approaches that can balance gut dysbiosis should be tested.

Stevens–Johnson syndrome with sulfasalazine treatment: Report of two cases

We report two cases of Stevens-Johnson syndrome (SJS) associated with the use of sulfasalazine in two ulcerative colitis patients previously tolerant to mesalamine. SJS and toxic epidermal necrolysis (TEN) are very rare adverse cutaneous reactions that can be associated with the use of sulfasalazine. The most severe cases can result in death, and for the others, permanent skin, mucosal or ocular sequelae, which can impair the quality of life in our young IBD patients. Clinicians and patients need to be aware of the signs and symptoms that often precede the appearance of the mucocutaneous lesions in a SJS or TEN, such as fever, influenza-like symptoms, sore throat or burning eyes. For patients with SJS or TEN, immediate withdrawal of the offending medication should be done when blisters or erosions appear in the course of a drug eruption, as this may improve the prognosis.

Vaccination and Risk for Developing Inflammatory Bowel Disease: A Meta-Analysis of Case–Control and Cohort Studies

BACKGROUND & AIMS Environmental factors may play a key role in the pathogenesis of inflammatory bowel disease (IBD). Whether vaccination is associated causally with IBD is controversial. We performed a meta-analysis of case-control and cohort studies on the association between vaccination and the risk for IBD. METHODS Studies and abstracts investigating the relationship between vaccination and subsequent risk for developing IBD were reviewed. Childhood or adult immunizations with any vaccine type, at any dose, and with any vaccine schedule were used as inclusion criteria. RESULTS Eleven studies were included in the systematic review and meta-analysis: 8 case-control studies and 3 cohort studies. Studied vaccines were bacille Calmette-Guérin), vaccines against diphtheria, tetanus, smallpox, poliomyelitis, pertussis, H1N1, measles, rubella, mumps, and the combined measles, mumps, and rubella vaccine. Only a few details about vaccine type or route of administration were found in studies. Overall, there was no association between childhood immunization and risk for developing IBD: bacille Calmette-Guérin, relative risk (RR) of 1.04 (95% confidence interval [CI], 0.78-1.38), diphtheria, RR of 1.24 (95% CI, 0.80-1.94), tetanus, RR of 1.27 (95% CI, 0.77-2.08), smallpox, RR of 1.08 (95% CI, 0.70-1.67), poliomyelitis, RR of 1.79 (95% CI, 0.88-3.66), an measles containing vaccines, RR of 1.33 (95% CI, 0.31-5.80) in cohort studies, and RR of 0.85 (95% CI, 0.60-1.20) in case-control studies. Subgroup analysis for Crohns disease (CD) and ulcerative colitis (UC) found an association between the poliomyelitis vaccine and risk for developing CD (RR, 2.28; 95% CI, 1.12-4.63) or UC (RR, 3.48; 95% CI, 1.2-9.71). The RR of developing IBD after H1N1 vaccination was 1.13 (95% CI, 0.97-1.32). CONCLUSIONS Results of this meta-analysis show no evidence supporting an association between childhood immunization or H1N1 vaccination in adults and risk of developing IBD. The association between the poliomyelitis vaccine and the risk for CD or UC should be analyzed with caution because of study heterogeneity.