Search

Background Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC). Methods This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used. Results Four hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]). Conclusions A small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

Objectives Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn’s disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn’s disease (SEMA-CD). Methods We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn’s disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn’s disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. Results Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. Conclusion The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.

Background Viral infections have been suggested as possible triggers for the onset of ulcerative colitis (UC). Methods We employed VirCapSeq-Vert, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe UC. We surveyed fecal samples collected at presentation, after symptom remission, and from a control group diagnosed with irritable bowel syndrome. Results Seventy subjects with UC (mean age 13 years, 45 had moderate symptoms, 25 had severe, 69 of 70 had a Mayo endoscopy subscore 2/3) were studied. We detected a wide range of animal viruses that were taxonomically classified into 12 viral families. A virus was present in 50% of fecal samples collected at presentation, 41% of samples collected after remission, and 40% of samples in our control group. The most frequently identified viruses were diet-based gyroviruses. The UC cohort had a significantly higher prevalence of anelloviruses compared with the control cohort. However, we did not identify a single virus that can be implicated in the onset of UC and did not find an association between UC disease severity and viral presence. Conclusion Presence of virus in stool was not associated with the onset of pediatric UC., We used VirCapSeq-VERT, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe ulcerative colitis. We did not identify a link between a viral infection and the onset of ulcerative colitis.

Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9–5.2). Most (94%) Crohn’s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%–15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.

Background Inflammatory bowel disease (IBD) mainly consists of Crohn's disease (CD) and ulcerative colitis (UC). About 10%-15% of patients with IBD cannot be firmly diagnosed with CD or UC; hence, they are initially diagnosed as inflammatory bowel disease unclassified (IBD-U). Having a firm diagnosis is clearly preferred to guide treatment choices, and better understanding of the nature of IBD-U is required. Methods We performed an analysis of a subset of pediatric subjects from an inception IBD cohort of patients initially enrolled in a prospective multicenter study (the RISK study). Initial diagnosis and 2-year follow-up data from the subjects diagnosed with IBD-U were analyzed. An expert panel verified final diagnosis using predefined criteria as a guide. Serological and disease-relevant ileal and rectal tissue gene expression profiles were investigated. The use and the time to initiate anti-TNFα treatment was analyzed among the outcome groups. Results A total of 1411 subjects were enrolled with initial diagnosis of IBD, and among them, 136 subjects were initially diagnosed as IBD-U at enrollment. And 26% were reclassified as UC and 14% as CD within 2 years of diagnosis, while 60% remained as IBD-U. Of those who were reclassified, there was a 2:1 ratio, UC (n = 35) to CD (n = 19). The molecular and serological features of IBD-U at the end of follow-up were very similar to UC and very different from CD. There was less likelihood of receiving anti-TNFα agents if the diagnosis was IBD-U compared with CD (P < 0.0001). Conclusions In our cohort, 60% of the IBD-U subjects remained as unclassified at 2 years; of those subsequently classified, a higher percentage followed a course more similar to UC. Most of the IBD-U subjects at diagnosis had serological and molecular signatures that are very similar to UC. Although the atypical presentations made the clinician to make an interim diagnosis of IBD-U, results of the molecular and serological factors performed at the time of diagnosis suggests that they were very similar to UC. However, long-term studies are needed to better understand the natural history and molecular characterization of pediatric onset IBD-U. 10.1093/ibd/izy136_video1Video 1.Video 1. Watch now at https://academic.oup.com/ibd/article-lookup/doi/10.1093/ibd/izy136izy136.video15791389938001.

BACKGROUND: Current treatments for pediatric ulcerative colitis (UC) are limited. We evaluated the pharmacokinetics and clinical benefits of subcutaneous golimumab, an anti-tumor necrosis factor agent, in moderately-to-severely active pediatric patients with UC refractory to conventional therapy. METHODS: We report a multicenter, open-label study of golimumab with a pharmacokinetics phase (week 0-14). Patients had moderately-to-severely active UC and were naive to anti-tumor necrosis factor treatment. At weeks 0 and 2, patients received golimumab induction dosed by weight (

Background Predicting Crohn’s disease (CD) phenotype development has proven challenging due to difficulties in biopsy image interpretation of histologically similar yet biologically distinct phenotypes. At initial diagnosis, mostly CD patients are classified as B1 (inflammatory behavior), they typically either retain B1 phenotype or develop more complicated B2 (stricturing), B3 (internal penetrating), or B2/B3 phenotypes (defined by Montreal Classification). Prediction of phenotype development based on baseline biopsies can radically improve our clinical care by altering disease management. Biopsy-based image analysis via Convolutional Neural Networks (CNNs) has been successful in cancer detection, but investigation into its utility for CD phenotypes is lacking. We applied a machine learning CNN model to classify CD phenotypes and histologically normal ileal controls. Methods Baseline hematoxylin & eosin (H&E) stained ileal biopsy slides were obtained from the Cincinnati Children’s Hospital Medical Center’s RISK validation sub cohort. At University of Virginia, biopsy slides were digitized, and a ResNet101 CNN model was trained. High resolution images were patched into 1000x1000 pixels with a 50% overlap and then resized to 256x256 pixels for training (80-20 split was kept between training and testing sets to ensure same patient patches were not mixed). Gradient Weighted Activating Mappings (GradCAMs) were used to visualize the model’s decision making process. Results We initially trained the model for CD vs. controls where it achieved 97% accuracy in detecting controls. We further trained it for classifying CD phenotypes (n=16 B1, n=16 B2, n=4 B3, n=13 B2/B3; phenotype decision at 5 year). It displayed a higher accuracy in detecting B2 (85%) while there were overlaps in the detection of other phenotypes (Figure 1). For B2, Grad-CAM heatmaps highlighted central pink areas within the lamina propria as the model’s regions of interests which were present when other phenotypes were misclassified as B2 (Figure 2). Conclusions: Here we highlight the potential utility of a machine learning image analysis model for describing CD phenotypes using H&E stained biopsies. Previous studies have shown B2 to be associated with increased activation for extracellular matrix genes (connective tissue component). Our GradCAM results support this finding as the pink central areas utilized by the model for classifying B2 could be connective tissue. Further confirmation via molecular phenotyping including Sirius Red immunohistochemistry is underway. Our work supports prediction of CD phenotypes using baseline biopsies at diagnosis and has potential to influence individualized care for children with CD.

Article first published online 26 January 2017. Supplemental Digital Content is Available in the Text, Background: IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohn's disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. Methods: Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohn's Disease Activity Index remission (Pediatric Crohn's Disease Activity Index ≤ 10) and response (Pediatric Crohn's Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. Results: Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. Conclusions: Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohn's disease were consistent with IMAgINE 1 and adult Crohn's disease adalimumab trials.

Background Despite anecdotal information about unaffordable care for patients with inflammatory bowel disease (IBD), there are no data regarding access to health care resources and expert care for patients with IBD. Our study was designed to assess IBD patients' ability to access and use care, as well as the timeliness, affordability, and financial stressors related to care. Methods We modified the Centers for Disease Control National Health Interview Survey for IBD. The resultant 59-question survey was electronically mailed to the entire Crohn's and Colitis Foundation of America (CCFA) mailing list. Three thousand six hundred eight adult U.S. respondents completed the survey. Statistical analysis was performed. Results Respondents who had insurance coverage were 96.1%, but 66.3% reported health care-related financial worry. Of the 452 patients who tried to obtain new insurance coverage in the year prior, 60.1% (n = 270) reported difficulty finding sufficient coverage. We found that 25.4% (n = 897) of patients reported delays in medical care, and 48.0% (n = 431) of those respondents reported that the delay was due to cost concerns. Respondents who were denied coverage by an insurance company were 55.3%. Risk factors for emergency department utilization included Crohn's disease, younger age, female sex, lower income, non-White race, and steroid therapy. Conclusions Our assessment of patient health care access suggests that many patients have health care-related financial worry and have forgone a variety of medical services because of cost, lack of prompt access to care, denial by insurance carriers, and worry over medical coverage. We also identify risk factors for emergency department utilization. These data inform additional studies and interventions to improve access for patients with IBD.

BACKGROUND Pediatric inflammatory bowel disease (IBD) care is complex and rapidly evolving. The Crohn's and Colitis Foundation of America and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition cosponsored a needs assessment survey of pediatric gastroenterology trainees and program directors (PDs) to inform on educational programming. METHODS A Web-based, self-completed survey was provided to North American trainees and PDs during the 2013-2014 academic year. Standard descriptive statistics summarized demographics and responses. RESULTS One hundred sixty-six of 326 (51%) trainees (62% female) and 37 of 74 (50%) PDs responded. Median trainees per program = 5 and median total faculty = 10 (3 IBD experts); 15% of programs did not have a self-identified "IBD expert" faculty member. Sixty-nine percent of trainees were confident/somewhat confident in their IBD inpatient training, whereas 54% were confident/somewhat confident in their outpatient training. Trainees identified activities that would most improve their education, including didactics (55%), interaction with national experts (50%), trainee-centered IBD Web resources (42%), and increased patient exposure (42%). Trainees were most confident in managing inpatient active Crohn's disease/ulcerative colitis, phenotype classification, managing biological therapies, and using clinical disease activity indices. They were least confident in managing J-pouch complications, performing pouchoscopy, managing extraintestinal manifestations, and ostomy-related complications. Eighty-five percent would like an IBD-focused training elective. Most directors (86%) would allow trainees to do electives at other institutions. CONCLUSIONS This IBD needs assessment survey of pediatric gastroenterology trainees and PDs demonstrated a strong resource commitment to IBD training and clinical care. Areas for educational enrichment emerged, including pouch and ostomy complications.

Supplemental Digital Content is Available in the Text. Article first published online 7 March 2016., Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW

The Crohn’s & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure.10.1093/ibd/izy205_video1 izy205.video1 5799266615001

BACKGROUND: The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84–1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). METHOD: To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. RESULTS: HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10(-8) to 5 x 10(-10)). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10(–13)) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10(–9)) and another SNP rs17188113 (OR = 0.48, p = 7.56*10(–9)). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10(-10)) and female gender (OR = 8.85, p = 4.82x10(-13)). CONCLUSION: In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Crohn’s disease is a chronic inflammatory bowel disease (IBD) with a high rate of complications that frequently lead to a decreased quality of life. Despite our better understanding of disease pathophysiology and treatment over the past three decades, the risk of intestinal complications and need for resultant surgery have not changed significantly.1 Fortunately, newer treatments and more aggressive treatment algorithms are showing promise with higher rates of clinical remission. Specifically, the earlier use of anti-tumor necrosis factor (TNF) and immunomodulator (IM) therapy may be able to alter the natural history of Crohn’s disease and prevent complications before they develop.2–4 Enthusiasm over the use of these agents earlier in the disease course is tempered by the concern of side-effects associated with immune suppression. Patients and parents appear willing to accept risks of adverse events including life-threatening infections and lymphoma, but this is dependent upon the expectation that the disease is severe (i.e., they “deserve the treatment”), and that treatment will be effective.5, 6 If we were able to identify the patients who are at the most risk from their disease, then it would allow us to more easily justify using our most effective therapies sooner. Conversely, patients at low risk can be spared exposure to potentially toxic medications. Clinical and serologic factors have been identified that appear to serve as predictors of disease severity.7, 8 Although useful in helping to risk stratify patients, the results of these studies are presented as relative statistical comparisons (e.g., odds ratios, hazard ratios, p-values), which are difficult to translate clearly for patients so that they understand the implications of their disease. A tool to present more clearly individual absolute disease risk and predicted response to therapy in real-time would enhance a provider’s ability to communicate with patients and their families. System dynamics analysis (SDA) is a methodology that addresses the inherent dynamic complexity of interactions between variables. Used more commonly in the fields of economics and engineering, SDA has had limited use in medicine.9, 10 Advantages of SDA over traditional statistical methods are that it can provide real-time individualized predictions of outcomes, it uses a straightforward control panel to input variables, and it can create simple graphs to convey predicted outcomes over time. Applied to medicine, SDA may have the ability to translate complex clinical data into patient friendly results. Using a cohort of pediatric Crohn’s disease patients with detailed clinical and serologic profiles we developed a model to predict the individualized risk of complicated Crohn’s disease and how this risk is modified by treatment. SDA provides a graphic display of these results for a real-time visual explanation predicting disease outcome with or without medical therapy.

Background: Improving granulocyte function may represent an effective therapy for Crohn's disease (CD). We performed a Phase I-2 trial of sargramostim (SRG) in children with CD. Methods: This was multicenter, open-label study in 6–16-year-old patients with moderate to severely active CD. Patients received either 4 or 6 μg/kg SRG subcutaneously daily for 8 weeks, with and without concomitant corticosteroids (CS). The primary endpoint was identification of a safe and tolerable dose in children. The secondary endpoint was establishment of the pharmacokinetics (PK). Efficacy, a tertiary endpoint, was measured by the Pediatric CD Activity Index (PCDAI). Response was defined as a decrease from baseline of ≥12.5 points and remission as absolute PCDAI of ≤10. Results: In all, 22 patients were enrolled: 12 and 10 received 4 and 6 mg/kg, respectively; 19 completed the course. Both doses were found to be safe and well tolerated. Mild injection-site reactions occurred in 90% of patients. Three patients required dose reductions due to elevated absolute neutrophil counts. Following 4 μg/kg the mean area under the curve (AUC) was 2.64 and 2.80 ngh/mL for the 6–11- and 12–16-year-old groups, respectively. The mean half-life (t1/2) was 1.22 and 1.59 hours, respectively. Following 6 μg/kg, the mean AUC was 5.01 ngh/mL for the 12–16-year-old group, a 1.8-fold increase. A total of 16/18 patients (88%) achieved remission or response. Conclusions: Sargramostim at both 4 and 6 mg/kg was well tolerated. PK analysis suggested dose proportionality unaffected by CS exposure. Remission and response data are encouraging, but further trials are needed to assess efficacy. (Inflamm Bowel Dis 2010)

Background: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. Methods: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 ± 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 ± 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. Results: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6–73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30–60]) versus those who did not, (0 points [IQR 0–10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90–0.97). Test–retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84–0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92–0.99]; standardized response mean 2.66). Conclusion: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC. (Inflamm Bowel Dis 2009)

Crohn's disease (CD) is often associated with antibodies to microbial antigens. Differences in immune response may offer clues to the pathogenesis of the disease. The aim was to examine the influence of age at diagnosis on the serologic response in children with CD.Data were drawn from 3 North American multicenter pediatric inflammatory bowel disease (IBD) research consortia. At or shortly after diagnosis, pANCA, ASCA IgA, ASCA IgG, anti-ompC, and anti-CBir1 were assayed. The results were compared as a function of age at CD diagnosis (0-7 years versus 8-15 years).In all, 705 children (798 years of age at diagnosis, 626or=8 years) were studied. Small bowel CD was less frequent in the younger group (48.7% versus 72.6%; P0.0001), while colonic involvement was comparable (91.0% versus 86.5%). ASCA IgA and IgG were seen in20% of those 0-7 years old compared to nearly 40% of those 8-15 years old (P0.001), while anti-CBir1 was more frequent in the younger children (66% versus 54%, P0.05). Anti-CBir1 detected a significant number of children in both age groups who otherwise were serologically negative. Both age at diagnosis and site of CD involvement were independently associated with expression of ASCA and anti-CBir1.Compared to children 8-15 years of age at diagnosis, those 0-7 years are more likely to express anti-CBir1 but only half as likely to express ASCA. These age-associated differences in antimicrobial seropositivity suggest that there may be different, and as yet unrecognized, genetic, immunologic, and/or microbial factors leading to CD in the youngest children.

Background: The immunomodulators (IMs) 6-mercaptopurine and azathioprine decrease corticosteroid dependence and maintain remission in Crohn's disease (CD). We describe IM use in newly diagnosed pediatric CD, comparing outcomes of “early” versus “late” initiation of therapy. Methods: Data were obtained from pediatric CD patients enrolled in a prospective, multicenter observational study. Moderate/severe disease patients treated with IM were compared for outcomes of remission, corticosteroid use, infliximab therapy, hospitalizations, and CD-related surgery based on timing of initiation of IM therapy. Results: In all, 247 children met the criteria (60% male, mean age 11.9 years); 199 were treated with IM within 1 year of diagnosis; 150 between 0–3 months (early), 49 between 3–12 months (late). Both groups showed a decrease in corticosteroid use by 12 months, at which time proportionately fewer early group patients had received corticosteroids in the preceding quarter (22%) than late groups patients (41%)(P = 0.013). The number of hospitalizations per patient was also noted to be significantly lower in the early group over the 2-year follow-up (P = 0.03). No difference was noted in the rates of remission, infliximab use over time, or surgery. Conclusions: 80% of children with newly diagnosed moderate to severe CD are treated with IM within 1 year. Early IM use is associated with reduced corticosteroid exposure and possibly fewer hospitalizations per patient. (Inflamm Bowel Dis 2008)

Background: Variation in care is a ubiquitous feature of medical practice and may lead to significant differences in health care costs, quality, and outcomes. We undertook this study to determine the extent of intercenter variation in the initial management of children newly diagnosed with Crohn’s disease. Methods: We analyzed the utilization of 5 classes of medication (immunomodulators, prednisone, antibiotics, 5-aminosalicylates, and infliximab) among 311 children with newly diagnosed Crohn’s disease followed at 10 North American pediatric gastroenterology centers. Multivariate logistic regression was used to compare the utilization rate of each class of medication at each of the 10 centers, adjusting for potential confounders including patient age, sex, race, disease severity, and anatomic location of disease. Results: Median utilization of each class of medication was: immunomodulators, 56% (range 29%–97%); prednisone, 78% (range 32%– 88%); antibiotics, 29% (range 11%– 68%); 5-aminosalicylates, 63.5% (range 18%–92%); and infliximab, 7.5% (range 3%–21%). Each of these treatments showed statistically significant intercenter variation in utilization (P 0.001 for immunomodulators, prednisone, antibiotics, and 5-ASA; P 0.02 for infliximab). After adjusting for the demographic and clinical factors listed above, intercenter variation remained significant; however, the low utilization of infliximab precluded multivariate analysis. Conclusions: Widespread intercenter variation in the medical management of newly diagnosed children with Crohn’s disease was observed, even after adjusting for possible differences in case mix between institutions. This variation may lead to unintended differences in health care costs and outcomes. (Inflamm Bowel Dis 2007;13:890 – 895)

BACKGROUND Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. METHODS Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. RESULTS Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell

The development of inflammatory bowel disease during childhood and adolescence is not uncommon. As advances in medical therapies continue to emerge, so does the recognition that treatment goals must include achieving and maintaining childhood wellness. Preservation of normal linear growth, development and psychosocial wellbeing along with appropriate vaccination and preventative care strategies are elements critical to assuring the complete health of the pediatric patient who is affected by inflammatory bowel disease.

Background: Infliximab therapy has short-term benefits in children with moderate-to-severe Crohn's disease (CD). We assessed the long-term outcome of infliximab maintenance therapy in children with CD. Methods: We performed a multicenter cohort study of 729 pediatric patients with CD enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children younger than 16 years and newly diagnosed with CD were eligible for this study. Disease and medication information were collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol. Results: In all, 202 of 729 patients received infliximab: 62%, 23%, and 15% within 1, 1–2, and >2 years of diagnosis, respectively. The mean age at infliximab initiation was 12.7 years. A total of 158 infliximab-treated patients received maintenance therapy, 29 episodic (8 converted to maintenance), and 15 had incomplete follow-up. Among 128 patients administered maintenance infliximab and followed for ≥1 year, concomitant medications at infliximab initiation included corticosteroids (52%) and immunomodulators (90%). By 1, 2, and 3 years

Background: We sought to characterize perianal disease and its treatment in pediatric patients newly diagnosed with Crohn's disease. Methods: Data were obtained from the Pediatric Inflammatory Bowel Disease (IBD) Collaborative Group Registry, a prospective, multicenter observational registry recording clinical and laboratory outcomes in children under 16 years of age newly diagnosed with IBD. Patients with Crohn's disease were selected who had data on perianal disease and at least 24 months of follow-up. The records of patients with a Pediatric Crohn's Disease Activity Index perianal subscore greater than 0 were reviewed, and patients with abscesses or fistulas were selected. The therapies used and the course of their perianal disease were then assessed. Results: Of the 276 patients identified, 41 had perianal lesions within 30 days of diagnosis. Thirteen of these had skin tags and fissures only, whereas 28 had fistulas and/or abscesses. The latter lesions resolved by 1 year in 20 patients, and 8 had chronic/recurrent perianal disease persisting for more than 1 year following diagnosis. Patients with fistulizing disease were much more likely to be treated and were treated earlier with antibiotics, infliximab, and immunomodulators than were nonfistulizing patients. Patients who developed chronic perianal disease were more likely to have low body mass indices and required more perianal surgery than did patients whose perianal disease resolved. Conclusions: Approximately 10% of newly diagnosed pediatric patients with Crohn's disease will have perianal fistulas and/or abscesses at the time of diagnosis. Most of these will resolve within a year with medical therapy alone. (Inflamm Bowel Dis 2008)

Therapy for the inflammatory bowel diseases increasingly includes the use of immune-modifying and biologic therapies. Recently, in young patients with IBD, an association has been noted between the use of infliximab along with concomitant purine analogues and the development of hepatosplenic T-cell lymphoma (HSTCL)-a rare and all but incurable form of non-Hodgkin's lymphoma. This report briefly reviews the issue of lymphoma and IBD therapy. Additionally, a description of HSTCL and a summary of the known cases of this apparent therapeutic complication are presented. Clinical options in light of this new information are explored.

Background and Aims: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. Materials and Methods: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. Results: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 ± 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. Conclusions: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.