Peter Legnani

The Risk of Retention of the Capsule Endoscope in Patients with Known or Suspected Crohn's Disease

OBJECTIVES:Capsule endoscopy (CE) allows visualization of the mucosa of the entire small bowel and is therefore a potentially important tool in the evaluation of patients with known or suspected Crohns disease (CD). However, small bowel strictures, which are not uncommon in Crohns, are considered to be a contraindication to CE for fear of capsule retention. Our goal was to determine the risk of capsule retention in patients with suspected or known CD.METHODS:We retrospectively reviewed the records of 983 CE cases performed at three private gastroenterology practices between December 2000 and December 2003, and selected those with suspected or proven Crohns.RESULTS:A total of 102 cases were identified in which CE was used in patients with suspected (N = 64) or known (N = 38) CD. Only one of 64 patients (1.6%) with suspected CD had a retained capsule. However, in five of 38 (13%) patients with known Crohns, the capsule was retained proximal to a stricture. Of the five cases of retained capsules, three strictures were previously unknown. In four cases, the obstructing lesions were resected without complications, leading to complete resolution of the patients underlying symptoms. One patient chose not to undergo surgery and has remained without an episode of small bowel obstruction for over 38 months.CONCLUSIONS:Capsule retention occurred in 13% (95% CI 5.6%–28%) of patients with known CD, but only in 1.6% (95% CI 0.2%–10%) with suspected Crohns. A retained capsule may indicate unsuspected strictures in Crohns that may require an unexpected, but therapeutic, surgical intervention. Patients and physicians should be aware of these potential risks when using CE in CD.

Video capsule endoscopy in inflammatory bowel disease: Past, present, and future redux

Over the last 8 years, capsule endoscopy (CE) has revolutionized the visualization of the small bowel. In 2004 this journal published Capsule endoscopy in IBD: past, present and future Kornbluth et al [2004] Inflamm Bowel Dis 10:278-285). In this article we review advances since that time and discuss whether CE has achieved its potential and what remaining goals it can and should hope to achieve. In the 2004 article we listed a series of clinical questions to be answered with regard to the use of capsule endoscopy We review those questions that have been addressed in the intervening 5 years, and also update those topics for which information was available at the time of the initial article.

The Utility of Capsule Endoscopy in Patients With Suspected Crohn's Disease

OBJECTIVES:In patients with suspected Crohns disease (CD), little is known about the test characteristics of capsule endoscopy (CE) in the diagnosis of this condition. We sought to determine the utility of CE for the subsequent diagnosis of CD in patients suspected to have this condition.METHODS:All patients who underwent CE at a single tertiary-care center for investigation of suspected small bowel CD, and who had a 12-month follow-up, were included in the study. All patients had undergone other investigations that were normal or equivocal. The test characteristics of CE were determined on the basis of capsule findings of small bowel ulcers and a subsequent new diagnosis of CD within 12 months of CE.RESULTS:The study included 102 patients with 12-month follow-up data. The majority (75%) met the established criteria to define “suspected Crohns disease” as an indication for CE. Most had undergone computed tomography scan or small bowel follow-through (92%) and colonoscopy (99%) before CE. There were abnormal CE findings suggestive of CD in 39 patients. The prevalence rate of a new diagnosis of CD by 12 months in the study population was 13%. Using the presence of more than 3 ulcers as the criterion for an abnormal CE study, the sensitivity of CE for the diagnosis of CD was 77%, the specificity was 89%, the positive predictive value (PPV) was 50%, and the negative predictive value (NPV) was 96%.CONCLUSIONS:In patients with suspected CD, CE has a high sensitivity and a NPV for this condition. The PPV varies depending on the patient population and the criteria for a CE diagnosis of CD.

Innate immune receptor genetic polymorphisms in pouchitis: Is CARD15 a susceptibility factor?

Background: Pouchitis is a frequent complication after ileal pouch‐anal anastamosis (IPAA) for ulcerative colitis (UC). The aim of this study was to determine whether genetic polymorphisms in the innate immune receptors toll‐like receptor (TLR)4 and caspase activation and recruitment domain family member 15 (CARD15) genes are associated with pouchitis. Methods: From a retrospectively ascertained cohort of patients with UC 5 to 12 years after IPAA (n = 101), subjects were classified into 3 groups: no pouchitis (n = 52); 1 to 2 episodes per year (n = 11), and more than 2 episodes per year (n = 38). Single nucleotide polymorphisms in the tlr4 gene (D299G, T399I) were determined by a real‐time polymerase chain reaction‐based fluorogenic probe technique; and card15 polymorphisms (L1007fsinsC, R702W, G908R) were determined by pyrosequencing. Results: Pouchitis affected 49% (49/101) of the study population. No correlation between pouchitis and the presence of TLR4 polymorphisms was found. The percentage of patients who harbored CARD15 mutations was significantly higher in patients with pouchitis than in patients without pouchitis (18% versus 8%; P < 0.05); 24% of pouchitis patients with more than 2 episodes per year harbored CARD15 mutations (P < 0.01 compared with the no pouchitis group). The CARD15 insertion mutation L1007fsinsC was present in 14% of patients with pouchitis and in 0% without pouchitis (P < 0.05). All patients who carried L1007fsinsC developed more than 2 episodes per year. Conclusions: CARD15 polymorphisms are seen in greater frequency in patients with pouchitis after IPAA for UC. These findings, if borne out in prospective analyses, suggest that CARD15 mutations, particularly L1007fsinsC, may predispose to the development of pouchitis after IPAA for UC.

Role of capsule endoscopy in inflammatory bowel disease: where we are and where we are going.

Abstract Capsule endoscopy (CE) is an innovative technological breakthrough that for the first time provides a noninvasive method to obtain high‐resolution imaging of the entire small bowel. Since its recent inception, the diagnostic utility of CE has become well established for the evaluation of diverse ulcerative and inflammatory disorders of the jejunum and ileum. The incredible resolution of its lens (0.1 mm) detects focal villous edema or atrophy, denuded, as well as ulcerated mucosal lesions missed by other imaging techniques. CE has been shown by meta‐analysis to be a more sensitive method to investigate patients for small bowel Crohns disease, with an incremental yield above 30% versus other imaging modalities. In patients with indeterminate colitis, CE is useful in distinguishing between ulcerative and Crohns colitis. Among patients with established Crohns disease, CE may be employed to determine: (1) the extent and severity of small bowel involvement, (2) postoperative recurrence, (3) post‐therapy mucosal healing, and (4) whether active small bowel inflammatory lesions exist in the clinical setting of functional bowel disorder. Complications are rare and include capsule retention at stricture sites. The new patency capsule can diminish the risk of the latter problem in at‐risk patients. CE can also serve as a guide to sites that require biopsies or dilatation by push or double‐balloon enteroscopy. However, other causes of small bowel lesions may mimic Crohns disease. A standard terminology system has thus been developed, and a CE Crohns disease severity scoring index is currently undergoing validation studies. (Inflamm Bowel Dis 2007)

Capsule Endoscopy Is Superior to Small-bowel Follow-through and Equivalent to Ileocolonoscopy in Suspected Crohn's Disease

BACKGROUND & AIMSnEvaluation of the small intestine for inflammation has traditionally relied on small-bowel follow-through (SBFT), but multiple studies have demonstrated its low diagnostic accuracy. Capsule endoscopy (CE) transmits high-quality images of the small intestinal mucosa; it can be used to visualize the entire length of the small bowel and much of the mucosa. We compared the diagnostic yields of CE vs SBFT in a prospective study of patients with suspected small-bowel Crohns disease.nnnMETHODSnEighty patients with signs and/or symptoms of small-bowel Crohns disease (age, 10-65 years) underwent CE, followed by SBFT and ileocolonoscopy. Readers were blinded to other test results. The primary outcome was the diagnostic yield for inflammatory lesions found with CE before ileocolonoscopy compared with SBFT and ileocolonoscopy. A secondary outcome was the incremental diagnostic yield of CE compared with ileocolonoscopy and CE compared with SBFT.nnnRESULTSnThe combination of CE and ileocolonoscopy detected 107 of 110 inflammatory lesions (97.3%), whereas the combination of SBFT and ileocolonoscopy detected only 63 lesions (57.3%) (P < .001). The diagnostic yield of CE compared with ileocolonoscopy was not different (P = .09). The diagnostic yield was higher for CE than for SBFT (P < .001). Of the 80 patients with suspected Crohns disease, 25 (31.3%) had the diagnosis confirmed. Eleven were diagnosed by CE findings alone and 5 by ileocolonoscopy findings alone. In the remaining 9 patients, diagnostic findings were identified by at least 2 of the 3 modalities. No diagnoses were made on the basis of SBFT findings alone.nnnCONCLUSIONSnCE was better than SBFT and equivalent to ileocolonoscopy in detecting small-bowel inflammation. Although ileocolonoscopy remains the initial diagnostic test of choice, CE is safe and can establish the diagnosis of Crohns disease in patients when ileocolonoscopy results are negative or the terminal ileum cannot be evaluated. ClinicalTrials.gov Number: NCT00487396.

Therapeutic options in the management of strictures in Crohn's disease

Intestinal strictures are a commonly encountered problem in patients with Crohns disease. Endoscopic management with hydrostatic balloon dilation is an effective alternative to surgery in patients with endoscopically accessible lesions that are shorter than 7-8 cm. Endoscopic balloon dilation is the preferred initial modality in anastomotic strictures. The presence of inflammation near the stricture should not be considered a contraindication to dilation, and intralesional steroid injection should be considered in these patients with inflammation present in the area of the stricture. Further technological developments in endoscopes and balloon dilators may allow for broader application of these techniques.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF

BACKGROUND & AIMSnCrohns disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.nnnMETHODSnWe performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2-receptor β common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony-stimulating factor-responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared.nnnRESULTSnIn the discovery cohort, wexa0associated CD with a frameshift mutation in CSF2RB (Pxa0=xa08.52xa0× 10(-4)); the finding was validated in the replication cohort (combined Pxa0= 3.42xa0× 10(-6)). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony-stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal-regulated kinase and AK straining transforming (AKT). Cells co-transfected withxa0full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony-stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) hadxa0reduced responses to granulocyte-macrophage colony-stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance.nnnCONCLUSIONSnIn a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony-stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.

Mercaptopurine-induced hepatoportal sclerosis in a patient with Crohn's disease

Thiopurines play a pivotal role in the management of inflammatory bowel disease. Azathioprine and mercaptopurine have been associated with a number of liver abnormalities, including hepatitis, veno-occlusive disease, nodular regenerative hyperplasia, and peliosis hepatitis. Patients treated with azathioprine and mercaptopurine have their liver chemistry tests routinely checked due to this potential for hepatotoxicity. Hepatoportal sclerosis is a cause of non-cirrhotic portal hypertension that is increasingly being recognized; its etiopathogenesis is not well defined. We present the first case report of mercaptopurine-induced hepatoportal sclerosis leading to non-cirrhotic portal hypertension in a patient with Crohns disease. He had been treated with mercaptopurine for five years, and his liver chemistry tests were always within normal limits. This case underscores the potential serious liver adverse events that may arise silently and go undetected during treatment with mercaptopurine, and should alert clinicians as to the potential need to discontinue mercaptopurine in this setting.

Infants Born to Mothers with Inflammatory Bowel Disease Exhibit Distinct Microbiome Features that Persist Up to 3 Months of Life

analysis. Pregnant women with IBD present an enrichment in bacteria from the Gammaproteobacteria class, and a decrease in bacteria from the Bacteroidetes phylum, as compared to women without IBD. (B) Beta-diversity of placenta samples (p=0.001, Permanova, unweighted Unifrac distances). Women with and without IBD exhibit distinct placental microbiota composition. · Studies have demonstrated dynamic changes in the microbiome during pregnancy coinciding with changes in immune status, and maternal health status has been shown to influence the newborn’s microbiome development. Women with Inflammatory Bowel Disease (IBD) exhibit immunological and gut microbiota alterations. · No data exist on the effect of IBD on the microbiome during pregnancy, and its role on the infant gut microbiota composition. · The “Exploring MEChanisms Of disease traNsmission In Utero through the Microbiome” (MECONIUM) Study is a prospective study that recruits pregnant women with and without IBD and their offspring. The overall goal of the MECONIUM study is to explore the role that IBD plays in the composition of the maternal and infant microbiome. Infants Born to Mothers with Inflammatory Bowel Disease Exhibit Distinct Microbiome Features That Persist up to 3 Months of Life Caroline Eisele1, Jianzhong Hu1, Joana Torres1,2, Nilendra Nair1, Hinaben Panchal1, Xiuliang Bao1, Xiaohong Niu1, Justin Côté-Daigneault2, Bindia Jharap2, Elana Maser2, Asher Kornbluth2, Peter Legnani2, James George2, Marla Dubinsky3, Joanne Stone4, Ching-Lynn Chen4, José Clemente1, Jean-Frédéric Colombel2, Inga Peter1 1Department of Genetics and Genomic Sciences; 2-Division of Gastroenterology, Department of Medicine; 3-Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics; 4-Department of Obstetrics, Gynecology and Reproductive Sciences