Ulcerative Colitis: Baldassano RN

Grossman AB, Baldassano RN. · Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, PA, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072374 No free full text.

Abstract: Inflammatory bowel disease is one of the most prevalent chronic inflammatory disorders and commonly presents during childhood or adolescence. Occurring during a critical period of growth and development, pediatric Crohn's disease and ulcerative colitis require special consideration. Children often experience growth failure, malnutrition, pubertal delay and bone demineralization. Medical treatment must be optimized to promote clinical improvement and reverse growth failure with minimal toxicity. In addition to pharmacologic and surgical interventions, nutritional therapies play a vital role in the management of pediatric inflammatory bowel disease. This review will outline the epidemiology and clinical complications that are unique to pediatric inflammatory bowel disease, current trends, and recent advances in nutritional and pharmacologic treatment, and projected future therapeutic direction.

Grant SF, Baldassano RN, Hakonarson H. · The Center for Applied Genomics and Division of Human Genetics, The Abramson Research Center of the Joseph Stokes Jr Research Institute, Department of Pediatrics, The Children's Hospital of Philadelphia, PA 19104-4318, USA. · Expert Rev Mol Diagn. · Pubmed #18366306 No free full text.

Abstract: Inflammatory bowel disease constitutes two related clinical entities, Crohn's disease (CD) and ulcerative colitis (UC), both of which have increased in prevalence over the last decade. Family and twin studies have strongly indicated that genetic factors play a large role in an individual's risk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolate disease genes that confer susceptibility to this disease using classical candidate gene and linkage approaches, with the notable exception of the isolation of the caspase recruitment domain family, member 15 (CARD15) gene. However, over the last 2 years, genome-wide association (GWA) studies have become feasible, where modern high-throughput single nucleotide polymorphism (SNP) genotyping technologies can be applied to large and comprehensively phenotyped patient cohorts. Such approaches have enabled scientists to robustly associate specific variants with many complex diseases, including age-related macular degeneration, Type 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positive associations with CD and UC coming from GWA studies have been reported for an ever increasing number of genes. The most consistently and strongly associated variants have been in the CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiple association studies to confer strong risk for CD, although its association with UC remains more debatable. This SNP is in fact a common coding variant, specifically a threonine-to-alanine substitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears to account for all of the disease risk conferred by this locus. This review addresses recent advances in GWA studies of inflammatory bowel disease, with specific focus on the growing evidence of the ATG16L1 gene's role in CD and how its protein product operating within the autophagic pathway makes autophagy an attractive therapeutic target for this debilitating disorder.

Veres G, Baldassano RN, Mamula P. · First Department of Pediatrics, Semmelweis University, Budapest, Hungary. · Drugs. · Pubmed #17683171 No free full text.

Abstract: This review summarises the present knowledge of infliximab therapy in children with inflammatory bowel disease (IBD) based on the available published literature. Infliximab, the chimeric monoclonal IgG(1) antibody to tumour necrosis factor-alpha, is indicated for medically refractory luminal and fistulising paediatric Crohn's disease. Recently, ulcerative colitis case series in children and adolescents suggested that infliximab might also be effective for treatment of ulcerative colitis resistant to standard medical therapy. Induction therapy with infliximab 5 mg/kg at weeks 0, 2 and 6 is routinely used. Since the majority of patients will relapse if not re-treated, a long-term approach with systematic re-treatment with 5 mg/kg every 8-12 weeks is recommended. Maintenance therapy every 8 weeks was superior to 12 weeks' administration in maintaining response and remission in the largest-to-date paediatric randomised trial. Concomitant immunosuppressive therapy reduces the risk of infliximab antibody formation and infusion reactions, and prolongs the duration of treatment success. Severe reactions may not be an absolute contraindication to future infliximab therapy. Premedication does not prevent the development of infusion reactions; however, it is indicated for prevention of subsequent infusion reactions. Adverse events and safety findings in children are comparable to those observed in adults. Latent tuberculosis needs to be screened for. Malignancy rates in paediatric patients treated with infliximab do not seem to be increased. However, newly reported cases of hepatosplenic T-cell lymphoma in young patients with IBD treated with infliximab and mercaptopurine therapy raise concern, and long-term follow-up studies are necessary to determine the true malignancy risk.

Baldassano RN, Piccoli DA. · Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Pennsylvania, USA. · Gastroenterol Clin North Am. · Pubmed #10372276 No free full text.

Abstract: IBD is a chronic pediatric disease that needs to be treated by a team of experts consisting of pediatricians, pediatric gastroenterologists, psychologists, nutritionists, social workers, and nurses. A critical factor in successful management of this disease is the willingness of the patient to participate and cooperate with the team. Parents and patients must be educated and supported to treat these disorders effectively. Much further research is necessary to understand the specific causative and therapeutic issues unique to young patients with IBD.

Han PD, Burke A, Baldassano RN, Rombeau JL, Lichtenstein GR. · University of Pennsylvania School of Medicine, Philadelphia, USA. · Gastroenterol Clin North Am. · Pubmed #10372275 No free full text.

Abstract: This article reviews the nutritional aspects of inflammatory bowel disease (IBD) including the mechanisms and manifestations of malnutrition and the efficacy of nutritional therapies. Nutrient deficiencies in patients with IBD occur via several mechanisms and may complicate the course of the disease. Nutritional status is assessed by clinical examination and the use of nutritional indices such as the Subjective Global Assessment of nutritional status. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need parenteral nutrition.

Miele E, Pascarella F, Giannetti E, Quaglietta L, Baldassano RN, Staiano A. · Department of Pediatrics, University of Naples "Federico II", Naples, Italy. · Am J Gastroenterol. · Pubmed #19174792 No free full text.

Abstract: OBJECTIVES: Several probiotic compounds have shown promise in the therapy of ulcerative colitis (UC). However, a strong sustained benefit remains to be seen. Uncontrolled pilot studies suggest that a probiotic preparation (VSL#3) maintains remission in mild to moderate UC and reduces active inflammation in adult patients. Aims of our prospective, 1-year, placebo-controlled, double-blind study were to assess the efficacy of VSL#3 on induction and maintenance of remission and to evaluate the safety and tolerability of the probiotic preparation therapy in children with active UC. METHODS: A total of 29 consecutive patients (mean age: 9.8 years; range: 1.7-16.1 years; female/male: 13/16) with newly diagnosed UC were randomized to receive either VSL#3 (weight-based dose, range: 450-1,800 billion bacteria/day; n=14) or an identical placebo (n=15) in conjunction with concomitant steroid induction and mesalamine maintenance treatment. Children were prospectively evaluated at four time points: within 1 month, 2 months, 6 months, and 1 year after diagnosis or at the time of relapse. Lichtiger colitis activity index and a physician's global assessment were used to measure disease activity. At baseline, within 6 months and 12 months or at the time of relapse, all patients were assessed endoscopically and histologically. RESULTS: All 29 patients responded to the inflammatory bowel disease (IBD) induction therapy. Remission was achieved in 13 patients (92.8%) treated with VSL#3 and IBD therapy and in 4 patients (36.4%) treated with placebo and IBD therapy (P<0.001). Overall, 3 of 14 (21.4%) patients treated with VSL#3 and IBD therapy and 11 of 15 (73.3%) patients treated with placebo and IBD therapy relapsed within 1 year of follow-up (P=0.014; RR=0.32; CI=0.025-0.773; NNT=2). All 3 patients treated with VSL#3 and 6 of 11 (54.5%) patients treated with placebo relapsed within 6 months of diagnosis. At 6 months, 12 months, or at time of relapse, endoscopic and histological scores were significantly lower in the VSL#3 group than in the placebo group (P<0.05). There were no biochemical or clinical adverse events related to VSL#3. CONCLUSIONS: This is the first pediatric, randomized, placebo-controlled trial that suggests the efficacy and safety of a highly concentrated mixture of probiotic bacterial strains (VSL#3) in active UC and demonstrates its role in maintenance of remission.

Heyman MB, Garnett EA, Shaikh N, Huen K, Jose FA, Harmatz P, Winter HS, Baldassano RN, Cohen SA, Gold BD, Kirschner BS, Ferry GD, Stege E, Holland N. · Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143-0136, USA. · Am J Clin Nutr. · Pubmed #19116333 No free full text.

Abstract: BACKGROUND: Folate is postulated to protect against cell injury and long-term risk of cancer. Folate deficiency has been shown to be associated with inflammatory bowel disease (IBD). However, folate concentrations are poorly delineated in children with IBD. OBJECTIVE: The objective was to compare folate concentrations between children with newly diagnosed IBD and healthy controls. DESIGN: Red blood cell folate (RBCF) and whole-blood folate (WBF) concentrations were measured in 78 children (mean age: 12.8 +/- 2.7 y): 22 patients with newly diagnosed untreated Crohn disease, 11 patients with ulcerative colitis, 4 patients with indeterminate colitis, and 41 controls. Vitamin supplementation and dietary intakes determined by food-frequency questionnaire were recorded for 20 IBD patients and 28 controls. RESULTS: RBCF concentrations were 19.4% lower in controls (587.0 +/- 148.6 ng/mL) than in patients (728.7 +/- 185.8 ng/mL; P = 0.0004), and WBF concentrations were 11.1% lower in controls (218.2 +/- 49.7 ng/mL) than in patients (245.3 +/- 59.1 ng/mL; P = 0.031). Total folate intake was 18.8% higher in controls (444.7 +/- 266.7 microg/d) than in IBD patients (361.1 +/- 230.6 microg/d), but this difference was not statistically significant (P = 0.264). Folate intakes were below the Recommended Dietary Allowance (200-400 microg/d), adjusted for age and sex, in 35.4% of study subjects. CONCLUSIONS: In contrast with previous evidence of folate deficiency in adult IBD patients, our data indicate higher folate concentrations in children with newly diagnosed untreated IBD than in controls. This finding was unexpected, especially in light of the higher dietary folate intakes and hematocrit values in children without IBD. The influence of IBD therapy on folate metabolism and the long-term clinical implications of high RBCF and WBF concentrations at the time of IBD diagnosis should be explored further.

White JM, O'Connor S, Winter HS, Heyman MB, Kirschner BS, Ferry GD, Cohen SA, Baldassano RN, Smith T, Clemons T, Gold BD. · Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA. · Clin Gastroenterol Hepatol. · Pubmed #18848910 No free full text.

Abstract: BACKGROUND & AIMS: Few epidemiologic investigations characterize inflammatory bowel disease (IBD) in non-Caucasian children. Our study compared IBD characteristics between African Americans and non-African Americans enrolled in a multicenter pediatric IBD registry with endoscopic- and pathology-based diagnosis. METHODS: The study retrieved data entered from January 2000 to October 2003 on children 1 to 17 years old, inclusive, followed by a consortium of academic and community US pediatric gastroenterology practices. Analyses examined racial/ethnic differences by comparing the proportions of African Americans and non-African Americans in the following categories: each diagnostic disease classification (any IBD, Crohn's disease, ulcerative colitis, indeterminate colitis); age group (<6 y, 6-12 y, or >12 y) at diagnosis or symptom onset; presence of extraintestinal manifestations, Z-scores for height and weight, immunomodulatory therapy, anatomic disease location, and abnormal hemoglobin, albumin, or sedimentation rate at diagnosis. RESULTS: A total of 1406 patients had complete data, 138 (10%) of whom were African American. African Americans more often were older than 12 years of age at diagnosis (52% vs 37%; odds ratio [OR], 1.82; 95% confidence interval [95% CI], 1.28-2.59) and symptom onset (46% vs 30%; OR, 1.99; 95% CI, 1.40-2.84); had Crohn's disease (78% vs 59%; OR, 2.36; 95% CI, 1.56-3.58); and had a low hemoglobin level at diagnosis (39% vs 17%; OR, 3.15; 95% CI, 1.92-5.17). CONCLUSIONS: IBD in African American children and adolescents presents more commonly with Crohn's disease and at older ages compared with non-African Americans. Racial/ethnic differences in the epidemiology of IBD, particularly Crohn's disease, among American youths require further investigation.

Gupta N, Bostrom AG, Kirschner BS, Cohen SA, Abramson O, Ferry GD, Gold BD, Winter HS, Baldassano RN, Smith T, Heyman MB. · UCSF Children's Hospital, University of California, San Francisco, California 94143-0136, USA. · Am J Gastroenterol. · Pubmed #18796101 No free full text.

Abstract: BACKGROUND: The relationship between the age at diagnosis and disease course is poorly defined in children with Crohn's disease (CD). We examined the presentation and course of disease in patients 0-5 compared to 6-17 yr of age at diagnosis. METHODS: We analyzed uniform data from 989 consecutive CD patients collected between January 2000 and November 2003, and stored in the Pediatric IBD Consortium Registry. The statistical tests account for the length of follow-up of each patient. RESULTS: In total, 98 patients (9.9%) were of 0-5 yr of age at diagnosis. The mean follow-up time was 5.6 +/- 5.0 yr in the younger group and 3.3 +/- 2.8 yr in the older group (P < 0.001). Race/ethnicity differed by the age group (P= 0.015); a larger proportion of the younger group was Asian/Pacific Islander or Hispanic, and a larger proportion of the older group was African American. The initial classification as ulcerative colitis or indeterminate colitis was more common among the 0-5 yr of age group (P < 0.001). The 6-17 yr of age patients presented with more abdominal pain (P < 0.001), weight loss (P= 0.001), or fever (P= 0.07), while the 0-5 yr of age patients presented with more rectal bleeding (P= 0.008). The 6-17 yr of age patients were more likely to be treated with antibiotics (P < 0.001), 6-mercaptopurine/azathioprine (P < 0.001), infliximab (P= 0.001), or corticosteroids (P= 0.0006). The 6-17 yr of age patients had a higher cumulative incidence of treatment with 5-aminosalicylates (P= 0.009) or methotrexate (P= 0.04). The risk for developing an abscess (P= 0.001), a fistula (P= 0.02), a stricture (P= 0.05), or a perianal fissure (P= 0.06) was greater in the 6-17 yr of age patients. CONCLUSIONS: The 6-17 yr of age patients with CD appear to have a more complicated disease course compared to 0-5 yr of age children. The 0-5 yr of age group may represent a unique disease phenotype and benefit from different approaches to management. Long-term prospective studies are required to validate these findings.

Kugathasan S, Baldassano RN, Bradfield JP, Sleiman PM, Imielinski M, Guthery SL, Cucchiara S, Kim CE, Frackelton EC, Annaiah K, Glessner JT, Santa E, Willson T, Eckert AW, Bonkowski E, Shaner JL, Smith RM, Otieno FG, Peterson N, Abrams DJ, Chiavacci RM, Grundmeier R, Mamula P, Tomer G, Piccoli DA, Monos DS, Annese V, Denson LA, Grant SF, Hakonarson H. · Department of Pediatrics, Children's Research Institute and Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Nat Genet. · Pubmed #18758464 No free full text.

Abstract: Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

Jose FA, Garnett EA, Vittinghoff E, Ferry GD, Winter HS, Baldassano RN, Kirschner BS, Cohen SA, Gold BD, Abramson O, Heyman MB. · Department of Pediatric Gastroenterology Hepatology and Nutrition, San Francisco, California 94143, USA. · Inflamm Bowel Dis. · Pubmed #18626963 No free full text.

Abstract: BACKGROUND: Extraintestinal manifestations (EIMs) in pediatric patients with inflammatory bowel disease (IBD) are poorly characterized. We examined the prevalence of EIMs at diagnosis, subsequent incidence, and risk factors for EIMs. METHODS: Data for 1649 patients from the PediIBD Consortium Registry, diagnosed with IBD before 18 years of age (1007 [61%] with Crohn's disease, 471 [29%] with ulcerative colitis, and 171 [10%] with indeterminate colitis), were analyzed using logistic regression, Kaplan-Meier, log rank tests, and Cox models. RESULTS: EIMs were reported prior to IBD diagnosis in 97 of 1649 patients (6%). Older children at diagnosis had higher rates compared with younger children, and arthritis (26%) and aphthous stomatitis (21%) were most common. Among the 1552 patients without EIM at diagnosis, 290 developed at least 1 EIM. Kaplan-Meier estimates of cumulative incidence were 9% at 1 year, 19% at 5 years, and 29% at 15 years after diagnosis. Incidence did not differ by IBD type (P = 0.20), age at diagnosis (P = 0.22), or race/ethnicity (P = 0.24). Arthritis (17%) and osteopenia/osteoporosis (15%) were the most common EIMs after IBD diagnosis. CONCLUSIONS: In our large cohort of pediatric IBD patients, 6% had at least 1 EIM before diagnosis of IBD. At least 1 EIM will develop in 29% within 15 years of diagnosis. The incidence of EIMs both before and after diagnosis of IBD differs by type of EIM and may be slightly higher in girls, but is independent of the type of IBD, age at diagnosis, and race/ethnicity.

Hommel KA, Davis CM, Baldassano RN. · Cincinnati Children's Hospital Medical Center, Center for the Promotion of Treatment Adherence and Self Management, Division of Behavioral Medicine and Clinical Psychology, 3333 Burnet Ave. MLC 7039, Cincinnati, OH 45229, USA. · J Pediatr Psychol. · Pubmed #18337262 No free full text.

Abstract: OBJECTIVE: To examine the relationship between medication adherence and quality of life (QOL) in adolescent patients with inflammatory bowel disease (IBD) utilizing a multimethod adherence assessment approach. METHODS: Medication adherence in 36 adolescents with IBD was assessed via interviews, pill counts, and biological assays. QOL was assessed via patient and parent report. Pediatric gastroenterologists provided disease severity assessments. RESULTS: Hierarchical multiple regression analyses revealed that adherence contributed significant variance to patient-reported QOL but not parent-reported QOL. Nonadherence to 6-MP/azathioprine was related to poorer patient-reported physical health QOL. Greater self-reported 5-ASA adherence was related to poorer overall psychological health QOL, and particularly social functioning QOL. CONCLUSIONS: Results provide preliminary support for the negative effects of 6-MP/azathioprine nonadherence on QOL and an inverse relationship between 5-ASA adherence and QOL in this population. Adherence burden in patients and the utility of multimethod adherence assessment in research are discussed.

Perrin JM, Kuhlthau K, Chughtai A, Romm D, Kirschner BS, Ferry GD, Cohen SA, Gold BD, Heyman MB, Baldassano RN, Winter HS. · Department of Pediatrics, MassGeneral Hospital for Children, Boston, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #18223375 No free full text.

Abstract: OBJECTIVE: To extend development of a pediatric inflammatory bowel disease (IBD) health-related quality of life (HRQoL) measure by determining its factor structure and associations of factors with generic HRQoL measures and clinical variables. PATIENTS AND METHODS: Cross-sectional survey of children and adolescents ages 8 years to 18 years and their parents attending any of 6 US IBD centers, recruited from either existing registry of age-eligible subjects or visits to participating centers. The survey included generic (Pediatric Quality of Life Inventory) and IBD-specific (Impact Questionnaire) quality of life measures, disease activity, and other clinical indicators. We carried out factor analysis of Impact responses, comparing resulting factors with results on the generic HRQoL and the clinical measures. RESULTS: We included 220 subjects (161 with Crohn disease and 59 with ulcerative colitis). Initial confirmatory factor analysis did not support the 6 proposed Impact domains. Exploratory factor analysis indicated 4 factors with good to excellent reliability for IBD responses: general well-being and symptoms, emotional functioning, social interactions, and body image. Two items did not load well on any factor. The 4 factors correlated well with the Pediatric Quality of Life Inventory and subscales. Children with higher disease activity scores and other indicators of clinical activity reported lower HRQoL. CONCLUSIONS: This study provides further characteristics of a HRQoL measure specific to pediatric IBD and indicates ways to score the measure based on the resulting factor structure. The measure correlates appropriately with generic HRQoL measures and clinical severity indicators.

Anonymous00166, Anonymous00167, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, Kirschner BS, Kugathasan S, Baldassano RN, Russo PA. · No affiliation provided · J Pediatr Gastroenterol Nutr. · Pubmed #17460505 No free full text.

Abstract: BACKGROUND: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. METHODS: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohn's and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and "backwash ileitis" in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. RESULTS: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. CONCLUSIONS: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms "ulcerative colitis," "Crohn disease," and "indeterminate colitis." The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Reddy KP, Markowitz JE, Ruchelli ED, Baldassano RN, Brown KA. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. · Dig Dis Sci. · Pubmed #17219072 No free full text.

Abstract: Dysregulation of interleukin-8 (IL-8) production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies, which evaluate adult patients with long-standing or steroid-modulated disease, have reported conflicting results regarding the role of IL-8 in IBD pathogenesis. The present study evaluates IL-8 in colonic organ cultures and sera of newly and previously diagnosed pediatric IBD patients with various degrees of histopathologic activity. Colon and terminal ileum biopsies were obtained from 26 patients with Crohn's disease, 12 with ulcerative colitis, 4 with indeterminate colitis, and 12 age-matched normal controls. IBD patients were additionally characterized as newly or previously diagnosed. Supernatants from organ-cultured lamina propria biopsies and sera were evaluated by ELISA for IL-8 protein. IL-8 increased with degree of histologic inflammation regardless of diagnosis (no pathologic diagnosis, 62.6 ng/ml, interquartile range [IQR] 30.4-94.6 ng/ml; mild, 92.0 ng/ml, IQR 21.9-170.0 ng/ml; moderate, 676.2 ng/ml, IQR 46.4-2967.7 ng/ml; severe, 585.6 ng/ml, IQR 149.7-1602.2 ng/ml; P < 0.01). Lamina propria IL-8 was significantly elevated in moderately and severely inflamed tissue segments (603.26 ng/ml; IQR, 72.15-2240.4 ng/ml) compared to noninflamed and mildly inflamed segments (67.70 ng/ml; IQR, 30.38-124.1 ng/ml; P = 0.0009). There was no significant trend in IL-8 concentration when compared by clinical diagnosis. No significant difference was found in IL-8 concentrations in organ cultures from newly diagnosed patients versus those from previously diagnosed patients. There was no significant correlation between serum IL-8 concentration and organ culture IL-8 concentration. We conclude that higher concentrations of IL-8 are found in more histologically inflamed tissue segments from pediatric IBD patients. IL-8 does not appear to be associated with clinical IBD subtype. IL-8 appears to be an integral part of both early and established mucosal inflammation in pediatric IBD patients. These findings suggest that IL-8-specific therapies may universally modify inflammatory activity in IBD patients.

Gupta N, Cohen SA, Bostrom AG, Kirschner BS, Baldassano RN, Winter HS, Ferry GD, Smith T, Abramson O, Gold BD, Heyman MB. · UCSF Children's Hospital, University of California, San Francisco, California 94143-0136, USA. · Gastroenterology. · Pubmed #16618401 No free full text.

Abstract: BACKGROUND & AIMS: The cumulative incidence of surgery ranges from 40%-70% at 10 years from the time of diagnosis of Crohn's disease in adults. We retrospectively determined the cumulative incidence of and risk factors for surgery (intestinal resection) in pediatric patients with Crohn's disease. METHODS: Uniform data from 989 consecutive Crohn's disease patients (age 0-17 years at diagnosis), collected from 6 different pediatric centers between January 2000 and November 2003 and stored in the Pediatric IBD Consortium Registry, were analyzed. RESULTS: Median follow-up time was 2.8 years (range, 1 day to 16.7 years). One hundred twenty-eight patients underwent surgery. Kaplan-Meier survival estimates of the cumulative incidence of surgery were 17% at 5 years and 28% at 10 years from the diagnosis of inflammatory bowel disease. Univariate Cox proportional hazards models showed leukocytosis (2.85 [hazard ratio]; P = .02), hypoalbuminemia (3.41; P = .05), and anti-Saccharomyces cerevisiae antibody (ASCA) positivity (3.43; P = .05) were associated with increased risk for surgery. Multivariate Cox models showed female gender (1.49; P = .03), initial diagnosis of ulcerative colitis (3.63; P < .0001), poor growth at presentation (2.16; P = .007), and abscess (1.90; P = .009), fistula (2.30; P = .0005), or stricture (3.41; P < .0001) development were associated with increased risk for surgery. Age 3-5 years (0.26; P = .01) or 6-12 years (0.62; P = .01) at diagnosis, fever at presentation (0.50; P = .03), and treatment with infliximab (0.36; P = .0005) or 5-aminosalicylic acid (0.44; P < .0001) were associated with decreased risk for surgery. CONCLUSIONS: Risk stratification during the course of Crohn's disease in pediatric patients will help to guide therapy that may improve the natural history of disease and decrease the need for surgery.

Shepanski MA, Hurd LB, Culton K, Markowitz JE, Mamula P, Baldassano RN. · Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · Inflamm Bowel Dis. · Pubmed #15677910 No free full text.

Abstract: PURPOSE: To describe the reported health-related quality of life (HRQOL) in children and adolescents with inflammatory bowel disease (IBD) after attending an IBD summer camp. METHODS: A prospective analysis of quality of life was completed at an overnight camp that was exclusively for patients with IBD, which was sponsored by the Crohn's and Colitis Foundation of America. The IMPACT-II questionnaire (Canada and United States) and the State-Trait Anxiety Inventory for Children were administered to the campers at the beginning and at the end of a 1-week camp to assess HRQOL and anxiety. The IMPACT-II questionnaire consists of 35 questions measuring 6 quality-of-life domains (i.e., bowel domain, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions). The State-Trait Anxiety Inventory for Children consists of 2 different 20-item sets of questions. One set assesses state anxiety, and the other, trait anxiety. A repeated-measures multivariate analysis of variance was performed to determine the differences between scores attained before and after camp on the IMPACT-II questionnaire and in each of its domains. Paired sample t tests were performed on state and trait anxiety before and after camp. RESULTS: A total of 125 individuals consented to participate, but 61 patients (50 girls and 11 boys; age range, 9 to 16 y) completed the IMPACT-II questionnaire in full. Of those 61 patients, 47 had Crohn's disease and 14 had ulcerative colitis. There was statistically significant improvement between the mean (+/-SD) precamp total score (172.95 +/- 36.61) and the mean postcamp total score (178.71 +/- 40.97; P = 0.035), bowel symptoms scores (P = 0.036), social functioning scores (P = 0.022), and treatment interventions scores (P = 0.012). No difference was found between anxiety scores before and after camp on either the state or trait anxiety inventories (n = 55; P > 0.05). CONCLUSIONS: Overall, HRQOL improved in children after attending IBD summer camp. This exploratory study suggests that contributing factors for these improvements may be an increase in social functioning, a better acceptance of IBD symptoms, and less distress regarding treatment interventions, suggesting that a camp that is specifically designed for children with IBD may normalize the chronic illness experience. However, future research using a multimodal measurement approach is warranted to support these conclusions.

Kadivar K, Ruchelli ED, Markowitz JE, Defelice ML, Strogatz ML, Kanzaria MM, Reddy KP, Baldassano RN, von Allmen D, Brown KA. · Division of Gastroenterology & Nutrition, The Children's Hospital of Philadelphia, Pennsylvania, USA. · Inflamm Bowel Dis. · Pubmed #15472520 No free full text.

Abstract: BACKGROUND: Interleukin-13 (IL-13) is a multifunctional cytokine whose net principle action is to diminish inflammatory responses. Dysregulation of IL-13 production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies implicate IL-13 in IBD pathogenesis; however, they fail to accurately reflect in vivo intestinal IL-13 production. We evaluate IL-13, IL-6, and IL-1beta elaborations from colonic organ cultures of pediatric IBD patients METHODS: Endoscopic lamina propria biopsies or surgical specimens from pediatric patients with IBD were organ cultured and supernatants evaluated by enzyme-linked immunosorbent assay for IL-1beta, IL-6, and IL-13. RESULTS: IL-13 concentrations were significantly reduced in ulcerative colitis (UC) patients when compared with normal controls (P = 0.002) and Crohn disease (CD) patients (P = 0.001). End-stage UC patients at colectomy had lower intestinal IL-13 production than all other UC patients (P = 0.002). No significant correlation was found between IL-13 concentration and histologic disease severity (P = 0.134). CONCLUSIONS: Diminished intestinal IL-13 production is present in UC patients and wanes further with clinical disease progression. These findings suggest that UC patients may be differentiated from CD patients by intestinal IL-13 quantitation, and UC patients may benefit from IL-13 enhancing therapies.

Miele E, Markowitz JE, Mamula P, Baldassano RN. · The Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #15097438 No free full text.

Abstract: INTRODUCTION: Pediatric studies on immunogenicity of infliximab have not been published. The aim of the study was to evaluate the prevalence of human antichimeric antibody (HACA), relationship to infusion reactions (IR), and the role of concomitant immunomodulatory therapies. METHODS: An inflammatory bowel disease (IBD) database was queried, and a retrospective review of patients who had HACA performed was undertaken. RESULTS: HACA was conclusively determined in 34 patients with IBD (14 male, Crohn disease/ulcerative colitis: 30/4), median age 14.8 years (range, 6.4-22.5 years). Twenty-nine (85.3%) patients were receiving immunomodulatory therapy. A total of 234 infliximab infusions were administered (mean, 6.9; range, 1-26). HACA was detected in 12 (35.3%) patients. IR occurred in 8 (23.5%) patients. HACA-positive patients had a higher proportion of infusions associated with IR than did HACA-negative patients (P < 0.01). HACA levels > or =8.0 microg/mL were more likely to be associated with IR (P = 0.03). Levels of > or = 8.0 microg/mL were more common in patients who had an average interval between infliximab infusions of 8 weeks or less (P = 0.04). Concomitant immunomodulatory therapy was associated with a lower risk of developing HACA (P = 0.02) and lower titer of HACA (P = 0.04). Patients did not have HACA at a greater rate when there was an extended interval (more than 12 weeks) between infliximab infusions (P = 0.89). CONCLUSIONS: In children and adolescents with IBD, HACA formation is related to IR and to the duration of response to treatment. Immunomodulatory agents seem to have a protective role against development of HACA or high titers of antibodies. The interval between infusions does not influence the development of HACA.

Mamula P, Markowitz JE, Cohen LJ, von Allmen D, Baldassano RN. · Division of GI & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #15076630 No free full text.

Abstract: OBJECTIVES: The role of infliximab in treating pediatric ulcerative colitis (UC) is not defined. The authors previously have described their experience with the open label use of infliximab in nine children with moderate to severe UC. The aim of this study was to describe the outcome of these patients after a minimum 2-year follow-up and to describe the responses of eight additional patients to this medication. METHODS: The authors reviewed all pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia from its first use until February 2003. Tolerance of the infusions and adverse events were recorded. RESULTS: Follow-up information for a minimum of 2 years was reviewed for the nine initial patients. A total of 73 infliximab infusions were administered to these patients. Seven of nine (78%) patients were considered to be responders to the initial dose of infliximab. Two of these patients became nonresponders within 9 months of the first dose of infliximab and underwent colectomy. Of the remaining five (56%) patients with sustained response, two continue to receive infliximab infusions and three are doing well without infliximab. One patient experienced an infusion reaction, and one experienced herpes zoster infection. We have treated eight additional UC patients with infliximab. Seven (88%) patients were considered responders. One responder experienced relapse within 2 months. Overall, a short-term improvement was seen in 14 of 17 (82%) patients, and sustained improvement in 10 of 16 (63%) patients followed up for more than 9 months. All five patients with severe or fulminant UC, unresponsive to 2 weeks of intravenous corticosteroid therapy, experienced improvement with infliximab. Infliximab was well tolerated. CONCLUSION: Infliximab is associated with short- and long-term clinical improvement in children and adolescents with moderate to severe UC.

Brown KA, Back SJ, Ruchelli ED, Markowitz J, Mascarenhas M, Verma R, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · Am J Gastroenterol. · Pubmed #12385446 No free full text.

Abstract: OBJECTIVES: Understanding cytokine production patterns in early mucosal lesions of pediatric patients newly diagnosed with inflammatory bowel disease (IBD) may be critical to understanding IBD pathogenesis. Interleukin-6 (IL-6) has a central role in a multitude of immune system reactions; however, inconsistent lamina propria and serum IL-6 has been reported in IBD patients. Newly diagnosed pediatric IBD patients have not previously been evaluated for lamina propria or serum IL-6. METHODS: Serum and intestinal lamina propria biopsy whole organ culture supernatants were evaluated by ELISA for IL-6 obtained from newly diagnosed IBD patients, before initiation of immunomodulatory therapies. RESULTS: Levels of lamina propria IL-6 demonstrated significant correlation with graded severity of histological inflammation (p < 0.001). Log-transformed serum and organ culture IL-6 levels demonstrated significant correlation (p < 0.0001, R2 = 0.6226). Assigning a demarcation level of >400 pg/ml, serum IL-6 concentrations were a superior marker for the presence of microscopic intestinal inflammation than erythrocyte sedimentation rate (ESR), with a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 82%. When evaluating subtypes of IBD, serum IL-6 levels were correlated more significantly with active disease in ulcerative colitis patients (p = 0.01, R2 = 0.74) than in Crohn's disease patients (p = 0.21, R2 = 0.33). CONCLUSIONS: This study outlines graded production of IL-6 in intestinal lamina propria and serum of newly diagnosed pediatric IBD patients, confirming the presence of IL-6 in early IBD patients. In addition, serum IL-6 may be a good predictor of IBD in pediatric patients with suspected or newly diagnosed IBD.

Duerr RH, Barmada MM, Zhang L, Achkar JP, Cho JH, Hanauer SB, Brant SR, Bayless TM, Baldassano RN, Weeks DE. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Hum Mol Genet. · Pubmed #12354785 links to  free full text

Abstract: Crohn's disease and ulcerative colitis, the two major forms of idiopathic inflammatory bowel disease (IBD), are heritable, complex traits that appear to share some but not all susceptibility loci. We report that transmission/disequilibrium test analysis of a Crohn's disease genome scan dataset has detected an inflammatory bowel disease locus on chromosome 3p26 (nominal P=0.000052 and genome-wide corrected P=0.039 at D3S1297). An allele sharing method shows significant linkage (multipoint lod=3.69) in a larger, independent sample of inflammatory bowel disease-affected sibling pairs. A survey of 16 chromosome 3p26 short tandem repeat polymorphisms in a combined sample of 234 independent nuclear families with 324 IBD-affected sibling pairs shows significant linkage to chromosome 3p26 (multipoint lod=3.78) and significant transmission/disequilibrium test results at two adjacent markers (nominal P values in two different transmission/disequilibrium analysis methods=0.00011 and 0.0011 for the first marker, and 0.00071 and 0.00013 for the second marker). There is highly significant under-transmission of a common allele and modest over-transmission of other alleles at both markers. Families with no transmission to affected individuals of the under-transmitted alleles show significant linkage (multipoint lod=4.50) that is significantly greater in four simulation studies (P=0.0001, 0.0000625, 0.0000625 and 0.0000625, respectively) than the linkage evidence in families with transmission of the under-transmitted alleles (multipoint lod=0.12). Thus, the existence of an inflammatory bowel disease locus on chromosome 3p26 is supported by significant linkage, transmission/disequilibrium and partitioning of linkage evidence.

Mamula P, Telega GW, Markowitz JE, Brown KA, Russo PA, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · Am J Gastroenterol. · Pubmed #12190168 No free full text.

Abstract: OBJECTIVES: Clinicians are becoming increasingly aware that inflammatory bowel disease (IBD) can affect all age groups, although it has not been well described in infants and young children. Our aim was to evaluate early onset IBD in patients 5 yr of age and younger. METHODS: Medical records of patients diagnosed with early onset IBD at The Children's Hospital of Philadelphia between 1977 and 2000 were reviewed. Patients were divided into three categories: those with Crohn's disease (CD), those with ulcerative colitis (UC), and those with indeterminant colitis (IC). RESULTS: A total of 82 patients fulfilled the criteria. In 12 patients (15%), the IBD diagnosis was changed during the course of illness. At the end of the follow-up period, linear growth failure was present in 10 of 35 (29%) children with CD, one of 30 (3%) with UC, and three of 17 (18%) with IC. Failure to thrive was a frequent presenting symptom in children with CD (44%) and IC (39%), whereas in all four patients with UC and failure to thrive the diagnosis was subsequently changed to CD or IC. A high proportion of patients with CD had large bowel (89%), and perianal (34%) disease. None of the tested patients were positive for anti-Saccharomyces cerevisiae antibody (ASCA), and 10 tested positive for perinuclear antineutrophil cytoplasmic antibody (three of five patients with CD, five of seven with UC, and two of three with IC). CONCLUSIONS: Failure to thrive, at the time of presentation, is indicative of a final diagnosis of CD or IC, not UC. Linear growth failure is a common finding in patients with early onset CD. A high proportion of patients with CD have failure to thrive, colonic, and perianal disease. The IBD serology panel is of limited clinical relevance in providing definitive diagnostic information in this pediatric population.

Mamula P, Markowitz JE, Brown KA, Hurd LB, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11964959 No free full text.

Abstract: OBJECTIVES: The role of infliximab (anti-tumor necrosis factor alpha antibody) therapy in ulcerative colitis (UC) is not well defined. There are only two reports published describing its use in UC. The authors describe their experience with open-label use of infliximab in children with moderate to severe UC. METHODS: The authors collected data on all consecutive pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia until July 2001. The primary measured outcome was clinical response at 2 days and 2 weeks after infliximab infusion, as measured by the Lichtiger colitis activity index (LCAI) score and the Physician Global Assessment (PGA). Tolerance of the infusions and adverse events were recorded. RESULTS: Nine patients qualified for clinical response analysis. The median Lichtiger colitis activity index score decreased from 11 before the infusion to 1 at 2 days and 2 weeks after the infusion, respectively (P = 0.01 for 2 days and 2 weeks). Seven of nine (77%) patients had decreased activity of their disease measured by the Physician Global Assessment. Corticosteroid therapy was discontinued in six (66%) patients. An infusion reaction developed (generalized pruritus and facial flushing) in two patients and an elevated anti-nuclear antibody (ANA) titer of 1:1280 developed in one patient. CONCLUSION: Infliximab is associated with short-term clinical improvement in children and adolescents with moderate to severe UC.

Mamula P, Piccoli DA, Peck SN, Markowitz JE, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11964953 No free full text.

Abstract: BACKGROUND: Iron-deficiency anemia is a frequent complication in children with inflammatory bowel disease (IBD). Parenteral iron therapy is rarely prescribed because of concern about potential side effects. The aim of this study was to retrospectively evaluate the safety and efficacy of total dose intravenous (TDI) iron therapy. METHODS: Charts of all the pediatric patients with IBD who received TDI iron therapy between February of 1994 and February of 2000 were reviewed. RESULTS: Seventy patients (20 with ulcerative colitis and 50 with Crohn disease) received a total of 119 TDI iron dextran infusions. Thirty-four patients qualified for the efficacy analysis. The average increase in hemoglobin concentration was 2.9 g/dL, (P < 0.0001). Eleven immediate hypersensitivity reactions developed in 10 patients (9% of the total number of infusions). None of the reactions was life threatening and none required hospitalization. CONCLUSIONS: Total dose intravenous infusion of iron dextran, when appropriately used, is a safe and potentially efficacious treatment for children with inflammatory bowel disease and iron deficiency anemia who are unresponsive to or noncompliant with oral iron therapy.