Pediatric Ulcerative Colitis Activity Index Score Research Articles

Combination Antibiotics Improves Disease Activity and Alters Microbial Communities in Children With Ulcerative Colitis.

Combinations of antibiotics have shown promise in off-label treatment of Inflammatory Bowel Disease (IBD) flares in adult and pediatric patients1–6. In a small pediatric cohort of moderate-severe medically refractory Ulcerative Colitis (UC), half achieved remission with a regimen of 3–4 antibiotics6. The rationale is to decrease mucosal inflammation by altering intestinal microbiota, however, to date no study has documented these changes. We report our experience with combination oral antibiotics in symptomatic pediatric patients with steroid-dependent or -resistant UC, and demonstrate significant alterations in gut microbiota during and after antibiotic therapy with reductions in inflammatory markers.

Long-term Extent Change of Pediatric-Onset Ulcerative Colitis.

Data describing extent change (progression or regression) in pediatric-onset ulcerative colitis (UC) are scarce. We aimed to describe extent change in pediatric-onset UC during long-term follow-up and to assess predictors of extent change. Medical charts of pediatric-onset UC patients with at least 5-year follow-up were analyzed retrospectively. Disease extent was determined using the Paris classification. It was examined at diagnosis and during follow-up at different time points. The impact of possible predictors on extent change including age at diagnosis, gender, clinical manifestations, disease, severity indices, and different therapeutic regimens during disease course was assessed. Patients (n=134, 55% males) were followed for a median duration of 13.1 (range, 5 to 28) years. Median age at diagnosis was 13.1 (range, 2 to 17.8) years. Of 134 patients, 40.5% had extensive or pancolitis, 33.5% left-sided colitis, and 26% had proctitis at diagnosis. On follow-up (n=117), 45% had unchanged disease extent, 35% experienced extent progression, whereas 20% experienced regression of disease extent. The multivariate Cox models demonstrated that among children with left-sided disease at diagnosis, presence of extraintestinal manifestations (hazard ratio, 5.19; P=0.022), and higher pediatric UC activity index (hazard ratio, 8.77; P=0.008) were associated with extent progression to extensive disease. Predictors of extent regression have not been identified. Disease extent changes significantly over time in pediatric-onset UC. In our cohort, presence of extraintestinal manifestation and higher pediatric UC activity index score at diagnosis were associated with progression from limited to extensive disease during follow-up.

Symptoms Do Not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC-IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC-IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC-IBD and 50 children with only IBD (controls; UC or IBD-unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecalcalprotectin to identify mucosal healing in patients with PSC-IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. Patients with PSC-IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6-21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r= 0.82) than in patients with PSC-IBD (r= 0.51; P= .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC-IBD (r= 0.84) and controls (r= 0.82; P= .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC-IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut-point, 93 μg/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC-IBD than controls. Children with PSC-IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC-IBD; levels below 93 μg/g are associated with mucosal healing.

Endoscopic and Histologic Healing in Children With Inflammatory Bowel Diseases Treated With Thalidomide

Mucosal healing, determined by endoscopic evaluation, is one of the most important prognostic markers for patients with inflammatory bowel diseases. Findings from histologic evaluation, however, could complement findings from endoscopy in assessing mucosal responses to treatment. We analyzed long-term results of children treated with thalidomide to determine the association between clinical response and histology and endoscopy findings. We collected data from 2 multicenter trials of 70 children with refractory Crohn's disease (CD) or ulcerative colitis (UC) (2-18 years old; ileocolonic or colonic disease) given thalidomide or placebo (NCT00720538). Clinical remission and clinical response at 8 weeks were defined as a pediatric CD activity index scores 10 points or lower and a decrease of at least 50% from baseline, respectively,for patients with CD; and as a pediatric UC activity index score below 10 and a decrease of at least20 points from baseline, respectively, for patients with UC. Patients with a clinical response to 8weeks' treatment with thalidomide underwent endoscopic examination with biopsy collection atstudy weeks 12 and 52. Severity of inflammation in patients with UC was assessed by Mayo scoreand in patients with CD by 4-grade system. Biopsies were assessed for signs of active inflammation,erosion or ulceration, and crypt abscesses and assigned a histologic score. Clinical remission was observed in 42 patients (60.0%) and clinical response in 45 patients (64.2%) at Week 8. At Week 52, a total of 38 patients (54.3%) were still in clinical remission or still had a clinical response; 29 patients (41.4%) had mucosal healing, defined as complete healing of erosions or ulcerations, and 20 patients (27.7%) had histologic healing, defined as complete absence of markers of inflammation. Of patients with clinical remission or clinical response, 75.3% also had mucosal healing and 52.6% also had histologic healing. The probability of achieving mucosal healing decreased significantly with increasing values of erythrocyte sedimentation rate (adjusted odds ratio, 0.96; 95% CI, 0.93-0.98; P= .006). In a long-term analysis of data from 2 clinical trials of pediatric patients with CD or UC, 52 weeks' treatment with thalidomide led to clinical remission in 54.3% of patients with ileocolonic or colonic disease; of these patients, 75.3% had mucosal healing and 52.6% also had histologic healing. Further studies are needed to determine how thalidomide therapy affects long-term progression of inflammatory bowel diseases. (ClinicalTrials.gov number NCT00720538).

Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis.

AIMTo investigate of pediatric ulcerative colitis activity index (PUCAI) in ulcerative colitis correlate with mucosal inflammation and endoscopic assessment of disease activity (Mayo endoscopic score).METHODSWe reviewed charts from ulcerative colitis patients who had undergone both colonoscopy over 3 years. Clinical assessment of disease severity within 35 d (either before or after) the colonoscopy were included. Patients were excluded if they had significant therapeutic interventions (such as the start of corticosteroids or immunosuppressive agents) between the colonoscopy and the clinical assessment. Mayo endoscopic score of the rectum and sigmoid were done by two gastroenterologists. Inter-observer variability in Mayo score was assessed.RESULTSWe identified 99 patients (53% female, 74% pancolitis) that met inclusion criteria. The indications for colonoscopy included ongoing disease activity (62%), consideration of medication change (10%), assessment of medication efficacy (14%), and cancer screening (14%). Based on PUCAI scores, 33% of patients were in remission, 39% had mild disease, 23% had moderate disease, and 4% had severe disease. There was “moderate-substantial” agreement between the two reviewers in assessing rectal Mayo scores (kappa = 0.54, 95%CI: 0.41-0.68).CONCLUSIONEndoscopic disease severity (Mayo score) assessed by reviewing photographs of pediatric colonoscopy has moderate inter-rater reliability, and agreement was less robust in assessing patients with mild disease activity. Endoscopic disease severity generally correlates with clinical disease severity as measured by PUCAI score. However, children with inflamed colons can have significant variation in their reported clinical symptoms. Thus, assessment of both clinical symptoms and endoscopic disease severity may be required in future clinical studies.

A Two-Week Fecal Microbiota Transplantation Course in Pediatric Patients with Inflammatory Bowel Disease.

Dysbiosis plays a major role in the etiology of inflammatory bowel disease (IBD). Fecal microbiota transplantation (FMT) is a new promising option for IBD treatment. We aimed to assess the effectiveness of a two-week FMT course in children with IBD. Ten patients, 10-17years of age with moderate to severe IBD received a course of eight doses of freshly prepared FMT via a naso-duodenal tube or gastroscopy. All of the patients had pancolitis. There were eight cases of ulcerative colitis (UC) and two of Crohn's disease (CD). Disease activity was evaluated using the Pediatric UC Activity Index (PUCAI) and Pediatric CD Activity Index (PCDAI) for UC and CD, respectively, CRP, and fecal calprotectin on the day before the first infusion and then on the day before the next course of FMT. Clinical response, defined as a decrease of 15 points in either index, was observed in 9/10 patients (seven UC and two CD). Clinical remission, defined as a PCDAI score≤10 and PUCAI score<10 measured at the same time point, was observed in 3/8 UC patients and 2/2 CD patients. Side effects observed were self-limiting and benign. We conclude that a short, intensive course of FMT has a beneficial effect on UC and CD colitis. FMT was well-tolerated and safe. Nonetheless, an optimal protocol of FMT administration is crucial for treatment efficacy.

Relationship of clinical symptoms with biomarkers of inflammation in pediatric inflammatory bowel disease.

In adult inflammatory bowel disease (IBD) patients, there is a strong discrepancy between symptoms and biomarkers of inflammation. Data on pediatric IBD patients are conflicting. Therefore, we aimed to investigate the relationship between clinical symptoms and biomarkers of inflammation in pediatric IBD. Patients aged <18 years with previously diagnosed Crohn’s disease (CD) or ulcerative colitis (UC) were included. Clinical disease activity was determined using the abbreviated Pediatric CD Activity Index (aPCDAI) or Pediatric UC Activity Index (PUCAI). Biochemical disease activity was assessed using fecal calprotectin (FC) and C-reactive protein (CRP). In total, 127 patients (62 male; median age 14.9 years) were included (82 CD, 45 UC). FC correlated weakly with total aPCDAI score (rs = 0.32; 95 % CI 0.12–0.51; p = 0.003) and total PUCAI score (rs = 0.36; 95 % CI 0.07–0.62; p = 0.015). Only aPCDAI components abdominal examination and perirectal disease and PUCAI component activity level had a significant correlation with levels of FC. CRP correlated weakly with total aPCDAI score (rs = 0.28; 95 % CI 0.05–0.46; p = 0.012) and aPCDAI components abdominal examination and activity level. No significant correlation was observed between CRP and total PUCAI score (rs = 0.01; 95 % CI −0.34–0.29; p = 0.961) or individual PUCAI components.Conclusion: There is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD. What is Known: • A substantial proportion of asymptomatic pediatric inflammatory bowel disease (IBD) patients have elevated biomarkers of inflammation.• There is a strong discrepancy between symptoms and biomarkers of inflammation in adults with IBD. What is New: • Clinical symptoms are only weakly associated with levels of fecal calprotectin and serum C-reactive protein in children and adolescents with previously diagnosed IBD.• Similarly to adult IBD patients, there is a strong discrepancy between clinical symptoms and biomarkers of inflammation in children with IBD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00431-016-2762-2) contains supplementary material, which is available to authorized users.

Efficacy and safety of granulocyte, monocyte/macrophage adsorptive in pediatric ulcerative colitis.

To investigate efficacy and safety for granulocyte, monocyte apheresis in a population of pediatric patients with ulcerative colitis. The ADAPT study was a prospective, open-label, multicenter study in pediatric patients with moderate, active ulcerative colitis with pediatric ulcerative colitis activity index (PUCAI) of 35-64. Patients received one weekly apheresis with Adacolumn(®) granulocyte, monocyte/macrophage adsorptive (GMA) apheresis over 5 consecutive weeks, optionally followed by up to 3 additional apheresis treatments over 3 consecutive weeks. The primary endpoint was the change in mean PUCAI between baseline and week 12; the secondary endpoint was improvement in PUCAI categorized as (Significant Improvement, PUCAI decrease of ≥ 35), Moderate Improvement (PUCAI decrease of 20 < 35), Small Improvement (PUCAI decrease of 10 < 20) or No change (PUCAI decrease of < 10). Twenty-five patients (mean age 13.5 years; mean weight 47.7 kg) were enrolled. In the intention-to-treat set (ITT), the mean value for PUCAI improvement was 22.3 [95%CI: 12.9-31.6; n = 21]. In the per-protocol (PP) set, the mean improvement was 36.3 [95%CI: 31.4-41.1; n = 8]. Significant Improvement was recorded for 9 out of 20 patients (45%); 5 out of 20 patients (25%) had Moderate Improvement and one patient (5%) had No Change in PUCAI score at week 12. In the PP set, six out of eight patients (75%) showed Significant Improvement; and in two out of eight patients (25%) Moderate Improvement was recorded. The endoscopic activity index (EAI) decreased by 3 points on average. Seven (7) out of 21 (33%) patients in ITT and 4 out of 8 (50%) patients in PP have used steroids during the clinical investigation. The mean steroid dosage for these patients in the ITT set decreased from a mean 12.4 mg to 10 mg daily on average from Baseline to week 12. Adacolumn(®) GMA apheresis treatment was effective in pediatric patients with moderate active Ulcerative Colitis. No new safety signals were reported. The present data contribute to considering GMA apheresis as a therapeutic option in pediatric patients having failed first line therapy.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease

Objective. Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. Material and methods. Children aged <18 years receiving IFX maintenance treatment for Crohn’s disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3–7 µg/ml. Results. Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2–7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = −0.51; p < 0.01] and FC [rs = −0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2–5] and 2.3 µg/ml [IQR 0.3–4.6]; p = 0.2). Conclusions. IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

Feasibility and validity of the pediatric ulcerative colitis activity index in routine clinical practice.

The Pediatric Ulcerative Colitis Activity Index (PUCAI) is a noninvasive disease activity index developed as a clinical trial endpoint. More recently, practice guidelines have recommended the use of PUCAI in routine clinical care. We therefore sought to evaluate the feasibility, validity, and responsiveness of PUCAI in a large, diverse collection of pediatric gastroenterology practices. We extracted data from the 2 most recent encounters for patients with ulcerative colitis in the ImproveCareNow registry. Feasibility was determined by the percentage of patients for whom all PUCAI components were recorded, validity by correlation of PUCAI scores across physician global assessment (PGA) categories, and responsiveness to change by the correlation between the change in PUCAI and PGA scores between visits. A total of 2503 patients were included (49.5% boys, age 15.2 ± 4.1 years, disease duration 3.7 ± 3.2 years). All items in the PUCAI were completed for 96% of visits. PUCAI demonstrated excellent discriminatory ability between remission, mild, and moderate disease; discrimination between moderate and severe disease was less robust. There was good correlation with PGA (r = 0.76 [P < 0.001] and weighted kappa κ = 0.73 [P < 0.001]). The PUCAI change scores correlated well with PGA change scores (P < 0.001). Test-retest reliability of the PUCAI was good (intraclass correlation coefficient 0.72 [95% confidence interval 0.70-0.75], P < 0.001). Guyatt responsiveness statistic was 1.18, and the correlation of ΔPUCAI with ΔPGA was 0.69 (P < 0.001). The PUCAI is feasible to use in routine clinical settings. Evidence of its validity and responsiveness supports its use as a clinical tool for monitoring disease activity for patients with ulcerative colitis.

High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately active ulcerative colitis.

ABSTRACTObjective:The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis.Methods:Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ≥10 to ≤55 and a truncated Mayo Score of ≥1 for both rectal bleeding and stool frequency, were enrolled. They received body weight–dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27–71 mg · g−1 · day−1) or high-dose group (53–118 mg · g−1 · day−1). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score ≥10 with a decrease from baseline by ≥20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity.Results:The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low- and high-dose groups, respectively (P = 0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups.Conclusions:Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose.

P-107: Effect of exclusive enteral nutrition on the course of CD and intestinal microbiota

P-107: Effect of exclusive enteral nutrition on the course of CD and intestinal microbiota

P-106: The clinical relevance of tacrolimus for ulcerative colitis in children: a national survey of the treatments for pediatric inflammatory bowel disease in Japan

P-106: The clinical relevance of tacrolimus for ulcerative colitis in children: a national survey of the treatments for pediatric inflammatory bowel disease in Japan

Clinical course of infliximab treatment in korean pediatric ulcerative colitis patients: a single center experience.

PurposeInfliximab (IFX) is considered safe and effective for the treatment of ulcerative colitis (UC) in both adults and children. The aim of this study was to evaluate the short- and long-term clinical course of IFX in Korean children with UC.MethodsPediatric patients with UC who had received IFX infusions between November 2007 and May 2013 at Samsung Medical Center were retrospectively investigated. The clinical efficacy of IFX treatment was evaluated at 8 weeks (short term) and 54 weeks (long term) after the initiation of IFX treatment using the Pediatric Ulcerative Colitis Activity Index (PUCAI). The degree of response to IFX treatment was defined as complete response (PUCAI score=0), partial response (decrement of PUCAI score≥20 points), and non-response (decrement of PUCAI score <20 points). Adverse events associated with IFX treatment were also investigated.ResultsEleven pediatric patients with moderate to severe UC had received IFX. The remission rate after IFX treatment was 46% (5/11) and 82% (9/11) at 8 weeks and 54 weeks after IFX treatment, respectively. All patients who were steroid-dependent before treatment with IFX achieved remission at 54 weeks and were able to stop treatment with corticosteroids, while all steroid-refractory patients failed to achieve remission at 54 weeks after treatment with IFX.ConclusionResponse to IFX treatment after 8 weeks may predict a favorable long-term response to IFX treatment in Korean pediatric UC patients.

Fecal Microbial Transplantation Shows Efficacy in Children With Refractory Ulcerative Colitis - Early Results of Phase I Clinical Trial

Fecal microbial transplantation (FMT) is being investigated as a promising alternative treatment option for ulcerative colitis (UC). The interest and enthusiasm is very high among patients with IBD despite lack of prospective data. Interest in FMT has largely been driven by new research into the gut microbiota, which is being appreciated as a microbial human organ with important roles in immunity and energy metabolism. We hypothesize that FMT may restore ‘abnormal’ microbiota to ‘normal’ in UC thus induce remission in refractory UC. We have initiated the first phase I clinical trial for use of FMT in UC with goals of assessing 1) the safety and tolerability, and 2) evaluate clinical response to FMT. Study was approved by Spectrum Health institutional review board. We obtained investigational new drug (IND) approval from the U.S. FDA for use of human stool as a biologic. We plan to enroll ten children (age 7-21 yrs) with mild to moderate, treatment resistant UC. After extensive donor screening guided by FDA and American Blood Bank Association, every subject received freshly prepared 8 oz fecal enemas for 5 days over 1 week period. Pediatric ulcerative colitis activity index (PUCAI) was collected at baseline and weekly for a month after FMT. Safety data was collected using ‘common terminology criteria for adverse events v3.0’ and using FDA guidance for industry from ‘toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials, 2007’. Clinical response was defined as a decrease in PUCAI by 15 points at one month after FMT. We plan to enroll 10 subjects. Eight subjects have been enrolled to date and complete data is available on 3 subjects who have completed the study. Their baseline PUCAI scores were 30, 35 and 50, which improved to 15, 0 and 40 respectively, at one month after FMT. All the subjects tolerated fecal enemas without leakage. One subject received only 6 oz enemas due to feeling of fullness. No serious adverse events were noted. Symptoms associated with FMT were mild (cramping, fullness, flatulence, bloating, diarrhea and nausea, which did not need treatment) to moderate (fever in one, which responded to antipyretic and anti-histaminic medications). These symptoms were self-limiting and lasted only for the duration of FMT treatment days. Fecal microbial transplantation as an enema is feasible, well tolerated and can be performed easily in children with UC with minimal training and support. Two of three subjects achieved clinical response by reduction in PUCAI of 15 points or more. One of them had complete resolution of disease activity. More data is anticipated for the Advances in IBD meeting in December. Larger prospective and controlled studies are needed to study clinical efficacy, endoscopic healing and the mechanism of action of FMT.

Induction and Maintenance Therapy With Infliximab for Children With Moderate to Severe Ulcerative Colitis

We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC). Patients (6-17 years old) who had active UC (Mayo scores of 6-12; endoscopic subscores ≥ 2) and had not responded to or tolerated conventional treatment were given 5 mg/kg infliximab at weeks 0, 2, and 6. The primary end point was response at week 8 (decreases in Mayo scores ≥ 30% and ≥ 3 points and decreases in rectal bleeding subscores of ≥ 1 or an absolute subscore of ≤ 1). At week 8, only responders were randomly assigned to groups given infliximab every 8 or 12 weeks (q8w or q12w) and followed through week 54. Maintenance end points included pediatric UC activity index scores <10 points, defined as remission. At week 8, infliximab induced a response in 73.3% of patients (44 of 60) (95% confidence interval, 62.1%-84.5%; a positive result was defined by 95% confidence interval lower limit >40%). Among responders, twice as many were in remission at week 54 after q8w (8 of 21, 38.1%) than q12w (4 of 22, 18.2%; P = .146) therapy. Assuming the q8w remission rate for responders, the overall remission rate at week 54 would be 28.6%. Serious adverse events and infusion reactions occurred in similar proportions in the q8w and q12w groups. No deaths, malignancies, opportunistic infections, tuberculosis, or delayed hypersensitivity reactions were reported. Infliximab was safe and effective, inducing a response at week 8 in 73.3% of pediatric patients with moderate to severely active UC who did not respond to conventional therapy. The overall remission rate at week 54 for all enrolled patients was 28.6%, assuming the more effective q8w remission rate.

Profiling Hypoxia Markers in Pediatric Inflammatory Bowel Disease

Background: Inflammation-associated hypoxia has been studied extensively in murinemodels of inflammatory bowel diseases (IBD), and to a lesser extent in human IBD. Results from studies strongly implicate the potential that circulating or tissue markers of hypoxia could serve as important biomarkers of disease. A systematic analysis of hypoxia markers associated with IBD has not been pursued. Aims: To characterize markers of hypoxia in serum and colon biopsies from patients with IBD colitis and controls without colitis, and to correlate hypoxia markers with severity of disease assessed by histology, pro-inflammatory cytokines, questionnaires, and other laboratory data. Methods: Samples of blood and colon biopsies were obtained from 10 pediatric patients (mean age 13.9±2.7) with active IBD colitis and 8 controls (mean age 14.6±2.1), one of which had quiescent IBD. Protein levels of three hypoxia markers were measured in serum: erythropoietin (EPO), vascular endothelial growth factor (VEGF), and insulin-like growth factor binding protein-1 (IGFBP-1); and four proinflammatory cytokines were measured in tissue: IL-1 beta, IL-6, IL-8, and TNF alpha via an electrochemiluminescence-based ELISA platform. Pediatric Ulcerative Colitis Activity Index (PUCAI) and puberty scores were also collected. A single pathologist, blinded to diagnosis, graded biopsy histology based on a standardized scoring system. Differences by study group or PUCAI category were tested with two-sample t-tests or exact chi-square tests, and differences across histology grade by ANOVA. The monotonic relationship between hypoxia markers and pro-inflammatory cytokines and puberty score was tested with Spearman's correlation coefficient. Results: Patient demographics did not significantly differ by gender (p=0.06), race (p=0.7) or age (p=0.6). Children with active colitis had higher levels of EPO than controls (9.4 vs. 3.4, p=0.03). Notably, serum EPO levels did not correlate with hemoglobin. No significant differences were noted in total circulating VEGF (562 vs. 256, p=0.12) or IGFBP-1 (6716 vs. 3812, p=0.45), however all three serum hypoxia markers differed across histology grade (VEGF p=0.002, EPO p<0.0001, IGFBP-1=0.018). Serum VEGF was significantly correlated with tissue IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.57, p=0.014; 0.60, p=0.008), as was EPO with IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.63, p=0.005; 0.72, p=0.0008). VEGF and IGFBP-1 did not significantly differ by puberty score or across PUCAI score. Conclusions: These studies identify at least three hypoxia targets which could be pursued as potential biomarkers for disease activity. We conclude that markers of hypoxia strongly correlate with severity of colitis and that peripheral blood hypoxia markers may be useful surrogates to assess tissue inflammation.

The Course of Life and Health-Related Quality of Life of Adolescents With Inflammatory Bowel Disease

Background: Inflammation-associated hypoxia has been studied extensively in murinemodels of inflammatory bowel diseases (IBD), and to a lesser extent in human IBD. Results from studies strongly implicate the potential that circulating or tissue markers of hypoxia could serve as important biomarkers of disease. A systematic analysis of hypoxia markers associated with IBD has not been pursued. Aims: To characterize markers of hypoxia in serum and colon biopsies from patients with IBD colitis and controls without colitis, and to correlate hypoxia markers with severity of disease assessed by histology, pro-inflammatory cytokines, questionnaires, and other laboratory data. Methods: Samples of blood and colon biopsies were obtained from 10 pediatric patients (mean age 13.9±2.7) with active IBD colitis and 8 controls (mean age 14.6±2.1), one of which had quiescent IBD. Protein levels of three hypoxia markers were measured in serum: erythropoietin (EPO), vascular endothelial growth factor (VEGF), and insulin-like growth factor binding protein-1 (IGFBP-1); and four proinflammatory cytokines were measured in tissue: IL-1 beta, IL-6, IL-8, and TNF alpha via an electrochemiluminescence-based ELISA platform. Pediatric Ulcerative Colitis Activity Index (PUCAI) and puberty scores were also collected. A single pathologist, blinded to diagnosis, graded biopsy histology based on a standardized scoring system. Differences by study group or PUCAI category were tested with two-sample t-tests or exact chi-square tests, and differences across histology grade by ANOVA. The monotonic relationship between hypoxia markers and pro-inflammatory cytokines and puberty score was tested with Spearman's correlation coefficient. Results: Patient demographics did not significantly differ by gender (p=0.06), race (p=0.7) or age (p=0.6). Children with active colitis had higher levels of EPO than controls (9.4 vs. 3.4, p=0.03). Notably, serum EPO levels did not correlate with hemoglobin. No significant differences were noted in total circulating VEGF (562 vs. 256, p=0.12) or IGFBP-1 (6716 vs. 3812, p=0.45), however all three serum hypoxia markers differed across histology grade (VEGF p=0.002, EPO p<0.0001, IGFBP-1=0.018). Serum VEGF was significantly correlated with tissue IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.57, p=0.014; 0.60, p=0.008), as was EPO with IL-6, IL-8, and TNF alpha (0.62, p=0.006; 0.63, p=0.005; 0.72, p=0.0008). VEGF and IGFBP-1 did not significantly differ by puberty score or across PUCAI score. Conclusions: These studies identify at least three hypoxia targets which could be pursued as potential biomarkers for disease activity. We conclude that markers of hypoxia strongly correlate with severity of colitis and that peripheral blood hypoxia markers may be useful surrogates to assess tissue inflammation.

Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response

ObjectiveTo compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed.MethodsThis was a prospective...

Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis

Children with severe corticosteroid-resistant ulcerative colitis either need to undergo surgery or be treated with more intensive immunosuppression. Our aim was to characterize the short- and long-term outcomes and adverse events associated with the use of tacrolimus in a steroid-refractory pediatric population. We retrospectively reviewed the medical records of 46 children with steroid-refractory colitis treated with tacrolimus at Children's Hospital Boston between 1994 and 2008. Oral tacrolimus was initiated at a dose of 0.1 mg/kg twice a day and titrated to yield trough levels of 10-15 ng/mL for induction, and 5-10 ng/mL once in remission. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Ninety-three percent of patients were discharged without undergoing surgery. The median length of stay after starting tacrolimus was 10 days (range 4-37 days). The mean PUCAI score was 68 ± 13 prior to initiating tacrolimus, and 27 ± 18 at the time of hospital discharge. The probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. The most common adverse events included hypertension (52%) and tremor (44%). There was one seizure and no deaths. Tacrolimus is useful as induction therapy in pediatric patients with corticosteroid-refractory colitis and side effects are generally mild and reversible. Despite these findings, many patients develop exacerbations of colitis upon transition to maintenance therapies. The long-term colectomy rate in this challenging population remains ≈60% over time.