Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease.

OBJECTIVES: Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD. METHODS: The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices. RESULTS: The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919  pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001). CONCLUSIONS: We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.

Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease.

Accumulating evidence implicates defective innate immunity in the pathogenesis of Crohn's disease (CD). Ineffectual NOD2 (nucleotide-binding oligomerization domain 2) is the most common susceptibility gene contributing to CD. Vitamin D (vD), a potent modulator of innate and adaptive immunity, induces NOD2 gene expression and its downstream function. We hypothesized that the hormonal form of vD (1,25D) could beneficially modulate innate immune function in CD. Using peripheral mononuclear cells and monocyte-derived dendritic cells (Mo-DCs) from CD, it was found that 1,25D decreased Toll-like receptor (TLR)-induced cytokine production and enhanced cytokine levels induced by muramyl dipeptide (MDP), the NOD2 ligand. 1,25D increased the synergistic effect provided by NOD2 and TLR co-activation on interleukin (IL)-10, IL-23, and tumor necrosis factor-alpha (TNF-α). Whereas 1,25D inhibits Mo-DC TLR-induced cytokines, co-stimulation of NOD2 results in increased IL-10 and IL-23. IL-12p70 was completely abrogated by 1,25D. 1,25D similarly modulated cytokine production by immune cells in ulcerative colitis patients and healthy controls. Mo-DCs from CD patients heterozygous for NOD2 mutations had a response similar to those from patients without NOD2 mutations. Immune cells from patients homozygous for the 1007 fs mutation were unresponsive to MDP and 1,25D. Our in vitro data support 1,25D as a potential modulator of immunity. However, these results cannot be extrapolated to CD patients without further controlled studies.

Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.

BACKGROUND: Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD). AIM: To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. METHODS: This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day. RESULTS: After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07). CONCLUSIONS: Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Susceptibility loci reported in genome-wide association studies are associated with Crohn's disease in Canadian children.

BACKGROUND: Recent genome-wide association studies based on adult and paediatric populations have implicated >30 genes/loci as susceptibility loci for Crohn's disease (CD). AIMS: To investigate whether reported genes/loci were also associated with CD in Canadian children. DESIGN AND METHODS: A case-control design was implemented at three paediatric gastroenterology clinics in Canada. Children < or =18 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in five genome-wide association studies reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. RESULTS: A total of 406 cases and 415 controls were studied. The mean (+/-s.d.) age of the cases was 12.3 (+/-3.2) years. Most cases were male (56.6%), had ileo-colonic disease (L3 +/- L4, 52.0%) and inflammatory behaviour (B1 +/- p, 86.9%) at diagnosis. Allelic association analysis (two-tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01). Associations with SNP rs4613763 in the PTGER4 locus were marginally nonsignificant (P = 0.07). The ZNF365 and STAT3 SNPs were predominantly associated with ileal disease with or without colonic involvement. CONCLUSION: The identified susceptibility genes/loci for adult-onset CD also confer risk for paediatric-onset CD.

Interleukin 10 (IL-10) gene variants and susceptibility for paediatric onset Crohn's disease.

BACKGROUND: A recent genome-wide association study in adult patients with ulcerative colitis (UC) has implicated the interleukin 10 (IL-10) gene as an important candidate gene. Moreover, a UC-associated single nucleotide polymorphism (SNP) rs3024405 was also significantly associated with adult Crohn's disease (CD). AIMS: To examine whether IL-10-CD associations extended to paediatric-onset CD. METHODS: We implemented the case-control design at three paediatric gastroenterology clinics in Canada. CD patients (

Successful videocapsule endoscopy in patients with an abdominal cardiac pacemaker.

Pacemaker location in the abdominal wall is considered a contraindication to videocapsule endoscopy (VCE). The aim of this study was to review our experience on the use of VCE in patients with a pacemaker located in the abdominal wall. VCE was carried out with monitoring of cardiac rhythm. This was a retrospective review of VCE case studies performed at two tertiary care university medical centers (pediatric and adult). The main outcome measures were adverse events and quality of VCE images. No adverse events were experienced in any of the five patients with implanted cardiac pacemakers, including the two with abdominal pacemaker. No interference with the VCE recording was observed during the studies, although the capsule was observed to be briefly inactivated by the pacemaker in one case. The present study, though small, suggests that VCE is safe in adult and pediatric patients who are fitted with cardiac pacemakers, even when implanted in the abdominal wall. The VCE exam can be carried out successfully under close supervision. Dysfunction of the capsule appears to be more likely than problems with cardiac pacing.

Mannan-binding lectin in children with Escherichia coli O157:H7 haemmorrhagic colitis and haemolytic uraemic syndrome.

Mannan-binding lectin (MBL) triggers complement activation upon binding to microbial surfaces. MBL deficiency has been associated with increased susceptibility to severe bacterial infections. We hypothesized that MBL deficiency may predispose children to Shiga toxin-producing Escherichia coli (STEC) O157:H7 infections and the associated haemolytic uraemic syndrome (HUS). We compared circulating levels of MBL among children with uncomplicated O157:H7 haemorrhagic colitis (HC), patients with O157:H7 HUS, normal and diseases control groups. Circulating MBL concentrations on admission were as follows: 3.22 +/- 2.43 micro g/ml among normal controls (n = 23); 2.90 +/- 2.44 micro g/ml in patients with rotavirus enteritis (n = 10); 2.78 +/- 1.65 micro g/ml in children with HC due to non-STEC bacterial pathogen (n = 15); 2.67 +/- 2.44 micro g/ml in patients with uncomplicated O157:H7 HC (n = 27); 2.80 +/- 2.97 micro g/ml in children with O157:H7 HUS (n = 15); 6.70 +/- 4.49 micro g/ml in patients with chronic renal failure unrelated to O157:H7 infection (n = 6). Higher MBL levels were found in patients with chronic renal failure compared to O157:H7 HC (P < 0.047). However, MBL concentrations <0.5 micro g/ml, which have been associated with MBL deficiency in relation to increased susceptibility to infections, were noted at comparable rates between the different groups (P = NS). Our data does not support that MBL deficiency may predispose to O157:H7 infections nor than the development of diarrhoea associated HUS.

Modulation of cytokine release from colonic explants by bacterial antigens in inflammatory bowel disease.

The intestinal flora play an important role in experimental colitis and inflammatory bowel disease (IBD). Using colonic explant cultures from 132 IBD and control subjects, we examined tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 and interleukin-1 receptor antagonist (IL-1RA) production in vitro in response to bacterial activators. Unstimulated TNF-alpha release was increased significantly in rectal biopsies from involved IBD tissue, correlating with inflammation severity. Whereas lipopolysaccharide (LPS) only moderately stimulated TNF-alpha production from inflamed tissue, pokeweed mitogen (PWM) induced its release in all groups, with a stronger response in involved IBD tissue. Superantigen staphylococcal enterotoxin A (SEA) had a similar, but weaker effect. SEB was observed to be the strongest inducer of TNF-alpha for all groups, again with a more marked response in inflamed tissue. Stimulated release of IL-1 was considerably less than for TNF-alpha. The superantigens' superior potency over LPS was not as marked for IL-1 as it was for TNF-alpha. In addition to IL-1, IL-1RA release was also triggered by the bacterial products. The net effect of activation on the IL-1RA/IL-1 ratio was relatively modest. Release of the proinflammatory cytokines TNF-alpha and IL-1, as well as that of the anti-inflammatory cytokine IL-1RA was increased by incubation of colonic tissue with bacterial factors. TNF-alpha production and release was increased significantly in involved colonic explants from IBD. SEB was even capable of inducing TNF-alpha release from uninvolved colonic tissue.

Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway.

BACKGROUND: During the process of tumorigenesis most colon cancer cells acquire resistance to apoptosis. The short chain fatty acid butyrate is well established as an antitumour agent which selectively induces apoptosis in colon cancer cells but not in normal intestinal epithelial cells. AIMS: To analyse the signalling pathway of butyrate induced apoptosis. METHODS: Using Caco-2 cells we focused on the bcl family of proteins, mitochondrial pathway, and caspase signalling cascade involved in butyrate induced apoptosis. Techniques employed included western blots, immunofluorescence, as well as experiments with peptide inhibitors of specific caspases. RESULTS: Butyrate induced a clear shift of the mitochondrial bcl rheostat towards a proapoptotic constellation, as demonstrated by upregulation of proapoptotic bak accompanied by reduced antiapoptotic bcl-x(L) levels. This was associated with translocation of cytochrome-c from the mitochondria to the cytosol, resulting in activation of the caspase cascade via caspase-9. Key executioner enzymes were caspases-3 and -1. No effect of butyrate on regulatory proteins of the inhibitor of apoptosis family was observed. CONCLUSIONS: Butyrate induced Caco-2 cell apoptosis via the mitochondrial pathway. Upregulation of bak and translocation of cytochrome-c were upstream of the caspase cascade. Subsequently, this cascade was activated via the formation of an apoptosome.

Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha.

BACKGROUND: Circulating levels of endotoxin (or lipopolysaccharide (LPS)) and anti-endotoxin antibodies are increased in patients with inflammatory bowel disease, supporting the hypothesis of a role for endogenous bacterial products in the pathogenesis of these disorders. AIM: The aim of this study was to analyse the direct effects of LPS on intestinal epithelial cell turnover. METHODS AND RESULTS: LPS significantly inhibited growth of the human non-transformed immature crypt cell line (HIEC), whereas IEC-6 cell proliferation was stimulated by LPS. As LPS is a physiological inducer of tumour necrosis factor alpha (TNFalpha) in various cell systems and this cytokine exerted similar anti-proliferative (HIEC) or growth stimulatory (IEC-6 cells) effects, the study thus tested the hypothesis that endogenously produced TNFalpha in response to LPS mediates this growth modulatory effect in an autoparacrine/paracrine way. Therefore, during LPS stimulation, the biological activity of TNFalpha was blocked using neutralising anti-TNFalpha antibodies, as well as inhibitory, antagonistic antibodies directed against the p55 TNF receptor, signalling the antimitotic TNFalpha effect in HIEC. Both experimental approaches completely abolished the growth modulatory effects of LPS in HIEC/IEC-6 cells. Production and secretion of TNFalpha by HIEC/IEC-6 cells in response to LPS was confirmed on mRNA and protein level by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay. LPS signalling was independent of CD14 in HIEC, as these cells lack this receptor. However, HIEC expressed TLR4 and MD2 resulting in a fully functional signalling complex as demonstrated by RT-PCR, western blot, and immunofluorescence analyses. CONCLUSION: These results support the hypothesis that LPS induced changes of intestinal epithelial cell turnover may directly contribute to the pathogenesis of inflammatory epithelial cell lesions by endogenous TNFalpha production by enterocytes.

The susceptibility to Fas-induced apoptosis in normal enterocytes is regulated on the level of cIAP1 and 2.

Various members of the tumor necrosis factor receptor superfamily are implicated in the regulation of enterocyte apoptosis. Previously, we observed that human intestinal epithelial cells are rather unsusceptible to Fas-induced apoptosis. In the present study we analyzed these protective mechanisms in the human intestinal epithelial cell line HIEC, focusing on antiapoptotic molecules of the IAP family which block apoptosis at the level of the caspase cascade. HIEC expressed all key molecules required to trigger Fas-induced apoptosis. However, no apoptosis occurred after activation of Fas, whereas an upregulation of antiapoptotic cIAP1 and 2 was observed. Suppression of this upregulation with the proteasome inhibitor MG132 or the protein synthesis inhibitor cycloheximide highly sensitized HIEC toward Fas-induced apoptosis. Western blot analyses revealed that both inhibitors potently suppressed endogenously produced cIAP1 and 2. No effect was observed on XIAP expression. These data indicate that enterocytes are particularly protected against Fas-induced apoptosis on the level of executionary caspases.

Role of endoscopy in inflammatory bowel disease.

Since its introduction into clinical use, flexible fiberoptic endoscopy progressively has become an indispensable tool to diagnose and treat gastrointestinal disorders. Few innovations have had a greater impact on the clinical practice of gastroenterology. In effect, diagnostic endoscopy has become an extension of physical diagnosis. This article reviews the expanding use of endoscopy in inflammatory bowel disease in the pediatric age group.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy.

BACKGROUND AND AIMS: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. METHODS: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. RESULTS: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Pathogenesis of Shiga toxin-associated hemolytic uremic syndrome.

The aim of this review is to examine recent advances in experimental and clinical research relevant to the pathogenesis of diarrhea-associated hemolytic uremic syndrome with special reference to histopathologic findings, virulence factors of Shiga toxin-producing Escherichia coli, the host response, and the prothrombotic state. Despite significant advances during the past decade, the exact mechanism by which Shiga toxin-producing E. coli leads to hemolytic uremic syndrome remains unclear. Factors such as Shiga toxin, lipopolysaccharide, the adhesins intimin and E. coli-secreted proteins A, B, and D, the 60-MD plasmid, and enterohemolysin likely contribute to the pathogenesis. Data on the inflammatory response of the host, including leukocytes and inflammatory mediators, are updated. The pathogenesis of the prothrombotic state leading to thrombocytopenia secondary to endothelial cell damage and platelet activation is also discussed. A hypothetical sequence of events from ingestion of the bacteria to the development of full-blown hemolytic uremic syndrome is proposed.

Immunolocalization, ontogeny, and regulation of microsomal triglyceride transfer protein in human fetal intestine.

To examine the multiple stages of lipoprotein packaging during development, we studied localization, ontogeny, and regulation of microsomal transfer protein (MTP), a crucial protein for lipid transport. With the use of immunofluorescence, MTP was identified in villus and crypt epithelial cells in different regions of human fetal intestine, including colon. Staining was detected as early as the 13th wk of gestation in all gut segments and was almost entirely confined to the columnar epithelial cells of the jejunum and colon. Unlike immunofluorescence, which provides qualitative but not quantitative information on MTP signal, enzymatic assays revealed a decreasing gradient from proximal small intestine to distal, as confirmed by immunoblot. Activity of MTP in small intestinal explants cultured for different incubation periods (0, 4, 8, and 24 h) peaked at 4 h but remained insensitive to different concentrations of oleic acid. Also, a trend toward increasing MTP activity was observed at 20-22 wk of gestation. Finally, in strong contrast to jejunal efficiency, colonic explants displayed impaired lipid production, apolipoprotein biogenesis, and lipoprotein assembly, in association with poor expression of MTP. These findings provide the first evidence that human fetal gut is able to express MTP and emphasize the distinct regional distribution, regulation by oleic acid, and ontogeny of MTP.

Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease.

OBJECTIVES: Confronted with nonspecific symptoms, accurate screening tests would be useful to clinicians to distinguish between functional childhood disorders and inflammatory bowel disease (IBD), thus avoiding invasive diagnostic testing. Traditional ulcerative colitis-specific perinuclear antineutrophil cytoplasmic antibody (pANCA) and Crohn's disease-specific anti-Saccharomyces cerevisiae antibody (ASCA) serodiagnostic assays have recently been modified, with ELISA cut-off values recalculated to maximize sensitivity. The aim of this study was to determine whether the combination of these serodiagnostic tests could maximize diagnostic accuracy and minimize invasive investigations in pediatric patients presenting with nonspecific symptoms suggestive of IBD. METHODS: With investigators blinded to clinical diagnoses, ASCA, ANCA, and pANCA profiles were obtained prospectively from 128 patients undergoing complete diagnostic evaluation for IBD. In phase I, diagnostic accuracy and predictive values of the modified and traditional assays were compared for the IBD (n = 54) and non-IBD groups (n = 74). In phase II, the overall accuracy of a novel sequential diagnostic testing strategy was determined. Additionally, the potential number of invasive investigations avoided with the hypothetical application of this strategy to the cohort was determined. RESULTS: For phase I, the modified serodiagnostic assay was more sensitive (81 vs 69%), whereas the traditional assay had a higher specificity (96 vs 72%) for IBD (p < 0.05) For phase II, false-positive diagnoses would have been reduced by 81%, yielding an overall sequential testing strategy accuracy of 84%. CONCLUSIONS: The incorporation of sequential noninvasive testing into a diagnostic strategy may avoid unnecessary and costly evaluations and facilitate clinical decision making when the diagnosis of IBD in children is initially uncertain.

Gastrointestinal manifestations of primary immunodeficiencies.

Congenital immunodeficiencies are relatively rare disorders that result in a marked predisposition to infection and to a variety of gastrointestinal problems. Increasingly recognized in both children and adults, accumulating worldwide experience with these disorders reveals that the long-term prognosis is poor in many cases, despite available treatments. This review highlights the past year's advances concerning the molecular basis of several of these disorders, new diagnostic considerations, and novel therapeutic approaches concerning their gastrointestinal complications. The availability of molecular diagnostic tools increases the options for earlier definitive treatments such as bone marrow transplantation and somatic gene therapy.

Doppler US in patients with crohn disease: vessel density in the diseased bowel reflects disease activity.

PURPOSE: To determine if neovascularization associated with Crohn disease, as detected with Doppler ultrasonography (US), reflects clinical disease activity. MATERIALS AND METHODS: A devised measurement, vessel density, was estimated with color Doppler US. Patients with Crohn disease underwent clinical and laboratory assessment in which the Crohn disease activity index was measured; patients underwent abdominal US the same week. Color Doppler US was performed by using a 7.5-10.0- or 8.0-12.0-MHz transducer, the lowest possible pulse repetition frequency without aliasing, a low wall filter, and high Doppler gain settings. The length and thickness of the affected loops were measured, and the number of color Doppler signals per square centimeter in the bowel loop was counted. Pulsed Doppler US was used to confirm that the signals originated from arteries or veins and not from movement artifacts. RESULTS: Ninety-two patients (aged 7-20 years; mean, 14.85 years; 44 female, 48 male) underwent 119 examinations; 85 were performed in patients with active disease. Affected loops were thicker (10.6 vs 4. 6 mm; P: <.001) and had a higher vessel density with disease (69 of 119 examinations) than during remission (two of 34 examinations; P: <.001). CONCLUSION: Vessel density in affected bowel loops, as estimated with Doppler US, and bowel wall thickness (>5 mm) reflect disease activity in patients with Crohn disease.