Diagnostic Delay Is Associated With Complicated Disease and Growth Impairment in Paediatric Crohn's Disease.

BACKGROUND: Paediatric data on the association between diagnostic delay and inflammatory bowel disease [IBD] complications are lacking. We aimed to determine the effect of diagnostic delay on stricturing/fistulising complications, surgery, and growth impairment in a large paediatric cohort, and to identify predictors of diagnostic delay. METHODS: We conducted a national, prospective, multicentre IBD inception cohort study including 1399 children. Diagnostic delay was defined as time from symptom onset to diagnosis >75th percentile. Multivariable proportional hazards [PH] regression was used to examine the association between diagnostic delay and stricturing/fistulising complications and surgery, and multivariable linear regression to examine the association between diagnostic delay and growth. Predictors of diagnostic delay were identified using Cox PH regression. RESULTS: Overall (64% Crohn's disease [CD]; 36% ulcerative colitis/IBD unclassified [UC/IBD-U]; 57% male]), median time to diagnosis was 4.2 (interquartile range [IQR] 2.0-9.2) months. For the overall cohort, diagnostic delay was >9.2 months; in CD, >10.8 months and in UC/IBD-U, >6.6 months. In CD, diagnostic delay was associated with a 2.5-fold higher rate of strictures/internal fistulae (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.41-4.56). Every additional month of diagnostic delay was associated with a decrease in height-for-age z-score of 0.013 standard deviations [95% CI 0.005-0.021]. Associations persisted after adjusting for disease location and therapy. No independent association was observed between diagnostic delay and surgery in CD or UC/IBD-U. Diagnostic delay was more common in CD, particularly small bowel CD. Abdominal pain, including isolated abdominal pain in CD, was associated with diagnostic delay. CONCLUSIONS: Diagnostic delay represents a risk factor for stricturing/internal fistulising complications and growth impairment in paediatric CD. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

No Change in Surgical and Hospitalization Trends Despite Higher Exposure to Anti-Tumor Necrosis Factor in Inflammatory Bowel Disease in the Québec Provincial Database From 1996 to 2015.

BACKGROUND: Crohn disease (CD) and ulcerative colitis (UC) have high health care expenditures because of medications, hospitalizations, and surgeries. We evaluated disease outcomes and treatment algorithms of patients with inflammatory bowel disease (IBD) in Québec, comparing periods before and after 2010. METHODS: The province of Québec's public health administrative database was used to identify newly diagnosed patients with IBD between 1996 and 2015. The primary and secondary outcomes included time to and probability of first and second IBD-related hospitalizations, first and second major surgery, and medication exposures. Medication prescriptions were collected from the public prescription database. RESULTS: We identified 34,644 newly diagnosed patients with IBD (CD = 59.5%). The probability of the first major surgery increased after 2010 in patients with CD (5 years postdiagnosis before and after 2010: 8% [SD = 0.2%] vs 15% [SD = 0.6%]; P < 0.0001) and patients with UC (6% [SD = 0.2%] vs 10% [SD = 0.6%] ;P < 0.0001). The probability of the second major surgery was unchanged in patients with CD. Hospitalization rates remained unchanged. Patients on anti-tumor necrosis factor (anti-TNF) medications had the lowest probability of hospitalizations (overall 5-year probability in patients with IBD stratified by maximal therapeutic step: 5-aminosalicylic acids 37% [SD = 0.6%]; anti-TNFs 31% [SD = 1.8%]; P < 0.0001). Anti-TNFs were more commonly prescribed for patients with CD after 2010 (4% [SD = 0.2%] vs 16% [SD = 0.6%]; P < 0.0001) in the public health insurance plan, especially younger patients. Corticosteroid exposure was unchanged before and after 2010. Immunosuppressant use was low but increased after 2010. The use of 5-ASAs was stable in patients with UC but decreased in patients with CD. CONCLUSIONS: The probability of first and second hospitalizations remained unchanged in Québec and the probability of major surgery was low overall but did increase despite the higher and earlier use of anti-TNFs.

Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.

BACKGROUND & AIMS: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. METHODS: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. RESULTS: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10-4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029). CONCLUSIONS: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.

Analysis of Flagellin-Specific Adaptive Immunity Reveals Links to Dysbiosis in Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Bacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4+ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4+ T cells. We aimed to quantify and characterize flagellin-specific CD4+ T cells in Crohn's disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity. METHODS: Blood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4+ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing. RESULTS: Compared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen-specific CD4+ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4+ T cells. The proportion of flagellin-specific CD4+ T cells that were CXCR3negCCR4+CCR6+ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39+, PD-1+, and integrin ß7+ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin. CONCLUSIONS: Both CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4+ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4+ T cells in inflammatory bowel disease.

Analysis of Genetic Association of Intestinal Permeability in Healthy First-degree Relatives of Patients with Crohn's Disease.

Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn's disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10-7 - 1.4 × 10-5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.

A Cross-Sectional Study on Malnutrition in Inflammatory Bowel Disease: Is There a Difference Based on Pediatric or Adult Age Grouping?

BACKGROUND: Malnutrition, commonly observed in inflammatory bowel disease (IBD), is associated with increased morbidity and mortality and is attributed to multiple causes. The added energy costs of growth in the child and adolescent with IBD are an additional risk factor. METHODS: The aim of the study was to perform a cross-sectional comparison of nutritional parameters in IBD between pediatric and adult cases. RESULTS: We found that prevalence of undernutrition (low body mass index) and hypoalbuminemia was not different in pediatric, compared with adult patients. Anemia and iron deficiency were more often observed in pediatric subjects, compared with adults (59.1% vs 36.9%, respectively, P < 0.0001; and 37.9% vs 25.3%, P < 0.002). Vitamin B12 deficiency was significantly less common in the pediatric than in the adult group (5.4% vs 19.4%, P < 0.0001). Elevated C-reactive protein was more frequent in pediatric compared with adult cases (49.8% vs 38.4%, P < 0.01). CONCLUSIONS: Patients with active Crohn's disease were more likely to be undernourished in both pediatric and adult populations. In both groups, predicators of undernutrition included low albumin levels (odds ratio [OR], 2.53; P < 0.006) and active disease (OR, 1.99; P < 0.03). Our results call for close surveillance of nutritional status for IBD patients, regardless of age.

Pancreatic Enzyme Supplementation in Patients with Atopic Dermatitis and Food Allergies: An Open-Label Pilot Study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects both patients and their families. Current therapies often alleviate symptoms but do not prevent or eradicate the disease. OBJECTIVES: Our objective was to determine whether pancreatic enzyme supplementation is an effective and safe treatment in refractory pediatric AD associated with food allergies. METHODS: We conducted an open-label pilot study using a case-control design. Patients with severe AD and known food allergies refractory to conventional therapies and exclusion diets were recruited and treated for 6 weeks with oral supplementation of pancreatic enzymes. The primary endpoint was the severity of AD, using the Scoring Atopic Dermatitis (SCORAD) index. Secondary measures included markers of intestinal permeability (urinary sucrose and lactulose/mannitol excretion). RESULTS: A total of 11 patients met all eligibility criteria and completed the trial. Significant improvement in AD was observed after 6 weeks of pancreatic enzyme supplementation (SCORAD index 52.3 ± 5.5 vs. 34.6 ± 7.6; p = 0.0008). Beneficial effect was observed in 9 of 11 patients, without adverse events. Fractional urinary sucrose excretion improved to a level comparable to that of age-matched controls (p < 0.05). However, urinary lactulose:mannitol ratios remained abnormally high compared with those of controls (p = 0.01). CONCLUSIONS: Pancreatic enzyme supplementation was associated with improved AD and gastroduodenal permeability. Additional randomized placebo-controlled studies are required before this treatment can be recommended in this clinical setting.

Management of Paediatric Patients With Medically Refractory Crohn's Disease Using Ustekinumab: A Multi-Centred Cohort Study.

BACKGROUND: Ustekinumab [UST] is effective in the treatment of adults with moderate to severe Crohn's disease [CD]. There is a paucity of data on its use in children. AIM: To evaluate the response to UST in children with moderate to severe CD. METHODS: This multicentre retrospective cohort study identified children under 18 years old with CD, who received open-labelled subcutaneous UST. The primary outcome was changes in mean abbreviated Paediatric Crohn's Disease Activity Index [aPCDAI] between baseline and 3 and 12 months, and rate of clinical remission at 3 and 12 months. Secondary outcomes were clinical response at the same time points, changes in C-reactive protein [CRP] and albumin, improvement in growth parameters, and rate of adverse events. RESULTS: A total of 44 patients who failed at least one biological treatment were identified. Linear mixed model [LMM] analysis revealed a statistically significant effect of UST (χ2[1] = 42.7, p = 1.2 × 10-8) which lowered the aPCDAI scores by about 16 ± 2.7 at 3 months, and 19.6 ± 2.9 at 12 months. At 12 months, 38.6% of the patients achieved clinical remission and 47.8% achieved clinical response. There was a significant increase in mean weight z-score of 0.48 [±0.13] [p <0.001] and in mean body mass index [BMI] z score of 0.66 [±0.16] [p <0.001]. The probability of remaining on UST at 12 months was 76.9%. The rate of adverse events was 12.4 per 1000 patient-months. CONCLUSIONS: Subcutaneous UST should be considered a viable therapeutic option for paediatric patients who are refractory to other biological agents. Prospective randomised trials are needed.

Unsuspected Small-Bowel Crohn's Disease in Elderly Patients Diagnosed by Video Capsule Endoscopy.

BACKGROUND: Video capsule endoscopy (VCE) is increasingly performed among the elderly for obscure bleeding. Our aim was to report on the utility of VCE to uncover unsuspected Crohn's disease (CD) in elderly patients. METHODS: Retrospective review of VCE performed in elderly patients (≥70 y) at a tertiary hospital (2010-2015). All underwent prior negative bidirectional endoscopies. CD diagnosis was based on consistent endoscopic findings, exclusion of other causes, and a Lewis endoscopic score (LS) > 790 (moderate-to-severe inflammation). Those with lower LS (350-790) required histological confirmation. Known IBD cases were excluded. RESULTS: 197 VCE were performed (mean age 78; range 70-93). Main indications were iron deficiency anemia (IDA), occult GI bleeding (OGIB), chronic abdominal pain, or diarrhea. Eight (4.1%) were diagnosed as CD based on the aforementioned criteria. Fecal calprotectin (FCP) was elevated in 7/8 (mean 580 µg/g). Mean LS was 1824. Small-bowel CD detected by VCE led to a change in management in 4/8. One patient had capsule retention secondary to NSAID induced stricture, requiring surgical retrieval. CONCLUSIONS: VCE can be safely performed in the elderly. A proportion of cases may have unsuspected small-bowel CD despite negative endoscopies. FCP was the best screening test. Diagnosis frequently changed management.

Detection of Crohn Disease in Patients with Spondyloarthropathy: The SpACE Capsule Study.

OBJECTIVE: Inflammatory bowel disease (IBD) is generally reported to be associated with spondylarthropathies (SpA) in 5%-15% of cases. Systematic colonoscopic assessment by protocol demonstrated mucosal inflammation characteristic of Crohn disease (CD) in up to one-third of patients with SpA. Video capsule endoscopy (CE) is a superior diagnostic tool to detect small bowel mucosal disease. Our study compared the accuracy of CE to standard colonoscopy for detection of inflammatory bowel lesions in patients with SpA, and to describe predictors of small bowel inflammation (SBI) in this cohort. METHODS: Prospective cross-sectional study of adult patients followed for SpA. Patients were evaluated by CE and standard colonoscopy with biopsies. SBI was quantified using the Lewis Score. Additional screening tests included fecal calprotectin (FCP), C-reactive protein (CRP), and a diagnostic panel of serologic, inflammatory and genetic tests (SGI). RESULTS: There were 64 patients recruited (53% female, mean age 42 ± 13 yrs). Chronic gastrointestinal (GI) symptoms were present in 57%. CE revealed significant SBI in 27/64 (42.2%), compared to 7/64 (10.9%) by standard colonoscopy (p = 0.035). Elevated FCP was associated with small bowel CD (OR 4.5, 95% CI 1.01-19.9; p = 0.042). No correlation was observed with presence of GI symptoms, CRP, or SGI results. Finding CD led to a change in management in 65.2% of cases. CONCLUSION: CE uncovered SBI consistent with CD in 42.2% of patients with SpA, with a significant incremental yield over colonoscopy of 31%. FCP levels were significantly correlated with CE results, while GI symptoms and SGI results were poor predictors of SBI.

Allopurinol in combination with thiopurine induces mucosal healing and improves clinical and metabolic outcomes in IBD.

BACKGROUND: Thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP) are common maintenance medications for inflammatory bowel disease (IBD). Excessive methylation via thiopurine methyltransferase (TPMT) frequently causes therapeutic failure. Allopurinol reduces excessive 6-methyl-mercaptopurine (6-MMP) while enhancing 6-thioguanine (6-TGN) levels. The aim of this study was to evaluate clinical, metabolic and endoscopic impact of allopurinol in combination with low-dose thiopurine in IBD. METHODS: Retrospective review of consecutive cases treated with allopurinol. Metabolites and their ratios (6-MMP/6-TGN) were compared pre- and post-allopurinol. Clinical and endoscopic remission were assessed. RESULTS: Allopurinol (n = 66) reduced mean dose of AZA by 70% (p < 0.01). Baseline levels (SD) 6-TGN, 6-MMP and 6-MMP/6-TGN were 165 (64), 9388 (5234) and 59.8 (30.3), respectively. These values improved on allopurinol to 297 (102), 896 (1031) and 3.4 (4.0), respectively (p < 0.0001). Therapeutic 6-TGN level (>235) was achieved in 49/58 cases on allopurinol combination therapy, versus 9/58 monotherapy (p = 0.0001). Among the thiopurine failure group (40 patients), clinical remission or response was observed in 65% and 22% of patients, respectively. In the asymptomatic group with excessive 6-MMP, 11/14 achieved sustained remission on allopurinol. Repeat colonoscopy (n = 28) showed mostly endoscopic remission (67.9%) or improvement (17.8%). Few had unimproved lesions (14.3%). Importantly, 46% of cases had complete mucosal healing. Two patients had cancer on combination therapy (de novo pancreatic cancer and fatal recurrence of metastatic testicular cancer). Elevated transaminases were reduced on allopurinol (48.2 versus 6.9%) (p < 0.001); no change in leukopenic or infectious events occurred. CONCLUSION: Allopurinol in combination with low-dose thiopurine corrected excessive 6-MMP levels, resulting in clinical remission and mucosal healing in the majority of cases. The potential cancer risk of allopurinol and thiopurine combination therapy needs further research.

The influence of vitamin D on M1 and M2 macrophages in patients with Crohn's disease.

Defective bacterial clearance by macrophages plays an important role in Crohn's disease (CD). Phenotypes and functions of inflammatory M1 and anti-inflammatory M2 have not been studied in CD. Vitamin D supplementation reduces the severity of CD by unclear mechanisms. We studied macrophage characteristics in CD and controls and the effects of 1,25 vitamin D (1,25D). PBMC were isolated from CD patients and controls. M1 and M2 were generated by culturing of monocytes with GM-CSF and M-CSF, respectively. CD M1 and M2 showed normal phagocytosis and chemotaxis to CCL2 and fMLP. LPS-induced production of TNF-α, IL-12p40 and IL-10 was comparable between groups. Phagocytosis was unaltered with 1,25D; migration only increased marginally. M1 produced more IL-12p40 and TNF-α; IL-10 was greater in M2. 1,25D markedly decreased IL-12p40 by M1 and M2. 1,25D decreased TNF-α in CD M1; IL-10 levels were unaffected. M2 express F13A1, PTGS2, CD163, CXCL10, CD14 and MMP2, whereas TGF-ß, CCL1 and CYP27B1 expression was higher in M1. Marker expression was similar between CD and controls. M1 and M2 markers were not differentially modulated by 1,25D. CD macrophages are not functionally or phenotypically different vs. CONTROLS: 1,25D markedly decreased pro-inflammatory M1 cytokines but did not modulate polarization to anti-inflammatory M2 phenotype.

Vitamin D Reduces Colitis- and Inflammation-Associated Colorectal Cancer in Mice Independent of NOD2.

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer (CRC). Vitamin D (vD) induces NOD2 gene expression, enhancing immunity, while deficiency impairs intestinal epithelial integrity, increasing inflammation. This study investigated the effect of vD on CRC in colitis, and if preventive benefits are mediated via NOD2. Inflammation-associated CRC was induced by treating C57BL/6J and Nod2-/- mice with azoxymethane (AOM) and dextran sodium sulfate (DSS) cycles (×3). vD-deficient mice displayed more severe colitis compared to vD-supplemented mice, with greater weight loss, higher colitis activity index, increased colonic weight/length ratios, and lower survival rates. Increased histological inflammation score and increased IL-6 were observed in the mucosa of vD-deficient mice. Overall incidence of colonic tumors was not significantly different between vD-deficient and vD-supplemented mice. Higher tumor multiplicity was observed in vD-deficient vs vD-supplemented groups (both mouse strains). After AOM/DSS treatment, decreased plasma 25(OH)D3 levels and downregulation of vD target genes Cyp24 and Vdr were observed in both mice strains (vD-deficient or vD-supplemented diet), compared to saline-treated controls on the vD-deficient diet. In conclusion, vD supplementation reduced colitis severity and decreased the number of inflammation-associated colorectal tumors in both C57BL/6J and Nod2-/- mice, independent of NOD2.

Association Between Fecal Calprotectin Levels and Small-bowel Inflammation Score in Capsule Endoscopy: A Multicenter Retrospective Study.

BACKGROUND: Accurate inflammation reporting in capsule endoscopy (CE) is important for diagnosis and monitoring of treatment of inflammatory bowel disease (IBD). Fecal calprotectin (FC) is a highly specific biomarker of gut inflammation. Lewis score (LS) was developed to standardize quantification of inflammation in small-bowel (SB) CE images. GOALS: Multicenter retrospective study aiming to investigate correlation between LS and FC in a large group of patients undergoing CE for suspected or known small-bowel IBD, and to develop a model for prediction of CE results (LS) based on FC levels. STUDY: Five academic centers and a district general hospital offering CE in UK, Finland, Sweden, Canada, and Israel. In total, 333 patients were recruited. They had small-bowel CE and FC done within 3 months. RESULTS: Overall, correlation between FC and LS was weak (r s: 0.232, P < 0.001). When two clinically significant FC thresholds (100 and 250 µg/g) were examined, the r s between FC and LS was 0.247 (weak) and 0.337 (moderate), respectively (P = 0.307). For clinically significant (LS ≥ 135) or negative (LS < 135) for SB inflammation, ROC curves gave an optimum cutoff point of FC 76 µg/g with sensitivity 0.59 and specificity 0.41. LIMITATIONS: Retrospective design. CONCLUSIONS: LS appears to show low correlation with FC as well as other serology markers of inflammation. FC does not appear to be a reliable biomarker for significant small-bowel inflammation. Nevertheless, FC level ≥ 76 µg/g may be associated with appreciable visual inflammation on small-bowel CE in patients with negative prior diagnostic workup.

Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn's disease.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most frequent life-threatening gastrointestinal disease experienced by premature infants in neonatal intensive care units. The challenge for neonatologists is to detect early clinical manifestations of NEC. One strategy would be to identify specific markers that could be used as early diagnostic tools to identify preterm infants most at risk of developing NEC or in the event of a diagnostic dilemma of suspected disease. As a first step in this direction, we sought to determine the specific gene expression profile of NEC. METHODS: Deep sequencing (RNA-Seq) was used to establish the gene expression profiles in ileal samples obtained from preterm infants diagnosed with NEC and non-NEC conditions. Data were analyzed with Ingenuity Pathway Analysis and ToppCluster softwares. RESULTS: Data analysis indicated that the most significant functional pathways over-represented in NEC neonates were associated with immune functions, such as altered T and B cell signaling, B cell development, and the role of pattern recognition receptors for bacteria and viruses. Among the genes that were strongly modulated in neonates with NEC, we observed a significant degree of similarity when compared with those reported in Crohn's disease, a chronic inflammatory bowel disease. CONCLUSIONS: Gene expression profile analysis revealed a predominantly altered immune response in the intestine of NEC neonates. Moreover, comparative analysis between NEC and Crohn's disease gene expression repertoires revealed a surprisingly high degree of similarity between these two conditions suggesting a new avenue for identifying NEC biomarkers.

Use of patency capsule in patients with established Crohn's disease.

BACKGROUND AND STUDY AIMS: Video capsule endoscopy (VCE) is invaluable in the diagnosis of small-bowel pathology. Capsule retention is a major concern in patients with Crohn's disease. The patency capsule was designed to evaluate small-bowel patency before VCE. However, the actual benefit of the patency capsule test in Crohn's disease remains unclear. The aim of this study was to evaluate the clinical impact of patency capsule use on the risk of video capsule retention in patients with established Crohn's disease. PATIENTS AND METHODS: This was a retrospective, multicenter study of patients with established Crohn's disease who underwent VCE for clinical need. The utilization strategy for the patency capsule was classified as selective (only in patients with obstructive symptoms, history of intestinal obstruction or surgery, or per treating physician's request) or nonselective (all patients with Crohn's disease). The main outcome was video capsule retention in the entire cohort and within each utilization strategy. RESULTS: A total of 406 patients who were referred for VCE were included in the study. VCE was performed in 132 /406 patients (32.5 %) without a prior patency capsule test. The patency capsule test was performed in 274 /406 patients (67.5 %) and was negative in 193 patients. Overall, VCE was performed in 343 patients and was retained in the small bowel in 8 (2.3 %). In this cohort, the risk of video capsule retention in the small bowel was 1.5 % without use of a prior patency capsule and 2.1 % after a negative patency test (P = 0.9). A total of 18 patients underwent VCE after a positive patency capsule test, with a retention rate of 11.1 % (P = 0.01). Patency capsule administration strategy (selective vs. nonselective) was not associated with the risk of video capsule retention. CONCLUSIONS: Capsule retention is a rare event in patients with established Crohn's disease undergoing VCE. The risk of video capsule retention was not reduced by the nonselective use of the patency capsule. Furthermore, VCE after a positive patency capsule test in patients with Crohn's disease was associated with a high risk of video capsule retention.

Clinicians' guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease.

BACKGROUND: Objective monitoring of the severity of inflammation in patients with inflammatory bowel disease (IBD) is an essential part of disease management. However, repeat endoscopy to define extent and severity of inflammation is not practical. Fecal calprotectin (FC) is a biomarker that can be used as a surrogate test to distinguish inflammatory from noninflammatory gastrointestinal disease. METHODS: A targeted search of the literature regarding FC, focusing primarily on the past three years, was conducted to develop practical clinical guidance on the current utility of FC in the routine management of IBD patients. RESULTS: It is recommended that samples for FC testing be obtained from the first bowel excretion of the day. FC testing should be used as standard of care to accurately confirm inflammation and 'real-time' disease activity when a clinician suspects an IBD flare. Although FC is a reliable marker of inflammation, its role in routine monitoring in improving long-term outcomes has not yet been fully assessed. Based on available evidence, the authors suggest the following cut-off values and management strategies: when FC levels are <50 µg/g to 100 µg/g, quiescent disease is likely and therapy should be continued; when FC levels are >100 µg/g to 250 µg/g, inflammation is possible and further testing (eg, colonoscopy) is required to confirm inflammation; and when FC levels are >250 µg/g, active inflammation is likely and strategies to control inflammation should be initiated (eg, optimizing current therapies or switching to an alternative therapy). DISCUSSION: FC is a useful biomarker to accurately assess the degree of inflammation and should be incorporated into the management of patients with IBD.

Video Capsule Endoscopy of the Small Bowel for Monitoring of Crohn's Disease.

Video capsule endoscopy has revolutionized our ability to visualize the small bowel mucosa. This modality is a valuable tool for the diagnosis of suspected small bowel Crohn's disease, and it is increasingly used for the monitoring of disease activity in patients with established small bowel Crohn's. The purpose of the current article was to review the literature pertaining to the utilization of capsule endoscopy in established Crohn's disease, for monitoring of mucosal healing, postoperative recurrence, disease classification, and other indications.

Acetylcarnitine potentiates the anticarcinogenic effects of butyrate on SW480 colon cancer cells.

Butyrate is a potent anticarcinogenic compound against colon cancer cells in vitro. However, its rapid metabolism is hypothesized to limit its anticancer benefits in colonic epithelial cells. Carnitine, a potent antioxidant, is essential to fatty acid oxidation. The aims of this study were to identify a colon cancer cell line capable of transporting carnitine. We evaluated the effect of carnitine and acetylcarnitine (ALCAR) on the response of colon carcinoma cells to butyrate. We explored the mechanisms underlying the anticarcinogenic benefit. SW480 cells were incubated with butyrate ± carnitine or ALCAR. Carnitine uptake was assessed using [3H]-carnitine. Apoptosis and cell viability were assessed using an ELISA kit and flow cytometry, respectively. Modulation of proteins implicated in carnitine transport, cell death and proliferation were assessed by western blotting. SW480 cells were found to transport carnitine primarily via the OCTN2 transporter. Butyrate induced SW480 cell death occurred at concentrations of 2 mM and higher. Cells treated with the combination of butyrate (3 mM) with ALCAR exhibited increased mortality. The addition of carnitine or ALCAR also increased butyrate-induced apoptosis. Butyrate increased levels of cyclin D1, p21 and PARP p86, but decreased Bcl-XL and survivin levels. Butyrate also downregulated dephospho-ß-catenin and increased acetylated histone H4 levels. Butyrate and carnitine decreased survivin levels by ≥25%. ALCAR independently induced a 20% decrease in p21. These results demonstrate that butyrate and ALCAR are potentially beneficial anticarcinogenic nutrients that inhibit colon cancer cell survival in vitro. The combination of both agents may have superior anticarcinogenic properties than butyrate alone.