George D. Ferry

Common variants at five new loci associated with early-onset inflammatory bowel disease

The inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohns disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

A randomized, double-blind trial of lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease

&NA; Probiotics are widely used by patients with Crohns 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.

Rising incidence of inflammatory bowel disease among children: a 12-year study.

Objective: Data suggest an increase in the incidence of pediatric inflammatory bowel disease (IBD). We examined the trend of the incidence of IBD in children. Patients and Methods: A retrospective investigation was conducted on a cohort of children diagnosed with IBD between 1991 and 2002 who were registered in the IBD center at Texas Childrens Hospital. The diagnosis of IBD was based on clinical, radiological, endoscopic, and histological examinations. Results: There were 272 children eligible for the analysis; 56% diagnosed with Crohn disease (CD), 22% with ulcerative colitis (UC), and 22% with indeterminate colitis. The male-to-female ratio was 1.2:1 in CD, 0.6:1 in UC, and 0.8:1 in indeterminate colitis. From 1991 to 2002, the incidence rate has doubled from 1.1/100,000/year (95% confidence interval [CI] 0.85–1.36) to 2.4/1001,000/year (95% CI 2.10–2.77). This trend was valid for CD but not for UC. Whites had higher incidence rate of IBD than African Americans or Hispanics: 4.15/100,000/year (95% CI 3.48–4.82) versus 1.83/100,000/year (95% CI 1.14–2.51), and 0.61/100,000/year (95% CI 0.33–0.89), respectively. African Americans were predominantly diagnosed with CD. Conclusions: The results demonstrate the rising incidence of IBD among children with evidence of more CD than UC. Recognition of these results will have important implications for diagnosis and management of IBD in children.

Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c‐Jun

Background: Differential immunoregulatory capabilities of probiotic Lactobacillus were explored in the context of pediatric Crohns disease. Experimental strategies addressed molecular mechanisms of tumor necrosis factor (TNF) suppression in activated macrophages by transcriptional regulation. Methods: Secreted factors produced by probiotic Lactobacillus reuteri strains were harvested and tested with human monocytes and macrophages. Quantitative immunoassays and real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) were used to examine relative quantities of human cytokines and TNF mRNA, respectively, and reporter assays assessed transcriptional regulation of TNF by probiotics. DNA‐protein macroarrays interrogated probiotic‐mediated effects on transcription factor activation. Finally, enzyme‐linked immunosorbent assays (ELISAs) and immunoblots examined the involvement of the specific transcription factor AP‐1 and its components. Results: Probiotic L. reuteri strain ATCC PTA 6475 demonstrated the ability to potently suppress human TNF production by lipopolysaccharide‐activated monocytes and primary monocyte‐derived macrophages from children with Crohns disease. Quantities of the chemokine MCP‐1/CCL2 were also reduced by probiotic L. reuteri strain ATCC PTA 6475 in macrophages of children in remission. Quantitative real‐time RT‐PCR and luciferase reporter assays showed that transcriptional regulation of human TNF was a primary mechanism of probiotic‐mediated immunomodulation. Probiotic L. reuteri suppressed TNF transcription by inhibiting activation of MAP kinase‐regulated c‐Jun and the transcription factor, AP‐1. Conclusions: Human TNF and MCP‐1 suppression by probiotic L. reuteri was strain‐dependent, and the activation of c‐Jun and AP‐1 represent primary targets for probiotic‐mediated suppression of TNF transcription. This report emphasizes the clonal nature of immunoprobiosis and delineation of a specific immunomodulatory mechanism for probiotic strain selection in future inflammatory bowel disease‐oriented clinical trials.

Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease.

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 Crohns 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.

Transition of the patient with inflammatory bowel disease from pediatric to adult care: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Children with inflammatory bowel disease (IBD) should be cared for by a physician trained to manage issues unique to pediatric patients. Pediatric gastroenterologists have the expertise to address a multitude of important problems that occur during childhood, particularly growth and development. Internist– gastroenterologists have a different set of skills that are necessary to provide optimal care to adult patients with IBD. The passage from adolescence to adulthood is a time of internal turmoil and intense examination of personal goals and wishes. In a few short years, the growing adolescent must shed the sheltered environment of childhood and achieve self-reliance and independent living. This time of growth and change causes frustration about the present and anxiety about the future even in the healthiest of children. For chronically ill adolescents, the transition to adulthood is additionally stressful not only for the child, but also for the family and healthcare providers because of the issues surrounding the transfer of care to an adult internist–gastroenterologist (1–6). During the transition to an internist–gastroenterologist, adolescent patients, their parents, and other family members may feel threatened by changes in the pattern of care and resentful of the effort required to adjust to a new setting with new staff. Patients and families have weathered many crises and made vital decisions with the support of their pediatric team and have come to regard this strong source of advocacy as a permanent arrangement. In contrast, they may perceive the internist–gastroenterologist, whose patients usually function independently, as less involved or less sensitive to developmental and social needs. Healthcare providers may also feel ambivalent during this period of change and may find it difficult to relinquish the patient to another physician whose style of practice is not well known. OBSTACLES TO TRANSITION

Presentation and Disease Course in Early- Compared to Later-Onset Pediatric Crohn’s Disease

BACKGROUND:The relationship between the age at diagnosis and disease course is poorly defined in children with Crohns 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.

Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn’s disease in children: REACH open-label extension

Abstract Objective: Assess long-term effects of maintenance infliximab therapy in children with moderately-to-severely active Crohn’s disease. Research design and methods: One hundred twelve patients with a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6 in the REACH study. Patients considered responders at week 10 were randomized to infliximab 5 mg/kg every 8 (q8w) or 12 (q12w) weeks. Patients who completed treatment through week 46, and who the investigator believed would benefit from continued treatment, could enter the open-label extension (OLE) and receive up to three additional years of infliximab. No hypothesis testing was performed. Clinical trial registration: www.clinicaltrials.gov, identifier: NCT0020767. Results: Sixty children entered the OLE: 33, 12, and 15 patients were receiving infliximab 5 mg/kg q8w, 5 mg/kg q12w, and 10 mg/kg q8w, respectively, at extension entry. Patients receiving infliximab for up to 3 years during the OLE maintained clinical benefit, with approximately 80% of patients consistently having no to mild disease activity per the physician’s global assessment and very good to fair health in the past 2 weeks per the patient and parent/guardian global assessments. Patients with ≥1-year delay in bone age at baseline trended toward improvement in height during the OLE. Respiratory system disorders, most commonly upper respiratory infections, were the most prevalent adverse events reported; six (10%) patients had serious infections. Conclusions: Among children with moderately-to-severely active Crohn’s disease who received infliximab for 46 weeks in REACH and then for up to 3 additional years in the REACH OLE, infliximab was effective in maintaining clinical benefit and was generally well-tolerated.

Gender Differences in Presentation and Course of Disease in Pediatric Patients With Crohn Disease

OBJECTIVE. The objective of this study was to determine gender differences in pediatric patients with Crohn disease. METHODS. We conducted a retrospective cohort study of 989 consecutive pediatric patients (566 boys, 423 girls) who had Crohn disease (aged 0 to 17 years at diagnosis) by using the Pediatric IBD Consortium Registry. Uniform data were analyzed to compare the presentation and course of disease according to gender. RESULTS. Median follow-up time was 2.8 years. Mean ± SD age at diagnosis of inflammatory bowel disease (11.5 ± 3.8 years) did not differ by gender. Compared with boys, girls had a higher prevalence of mouth sores at symptom onset and a higher prevalence of hypoalbuminemia at the time of diagnosis. Location of disease did not differ by gender. A higher proportion of girls had abnormal anti–outer membrane porin of Escherichia coli levels compared with boys. Girls were at increased risk for erythema nodosum/pyoderma gangrenosum and decreased risk for growth failure compared with boys. CONCLUSIONS. Girls appear to have an overall more severe course of disease; however, boys are at increased risk for developing growth failure. Disease course and the impact of disease severity on growth according to gender in pediatric Crohn disease require prospective study.

Premedication and infusion reactions with infliximab: Results from a pediatric inflammatory bowel disease consortium

Background: Infusion reactions (IRs) are the most common adverse events associated with the use of infliximab for inflammatory bowel disease (IBD). Antipyretics, antihistamines, and corticosteroids have been used to prevent the development of IRs, but their efficacy is not known. We studied the proportion of pediatric patients receiving infliximab for IBD that developed IRs and the potential effects of premedication on IR. Methods: Uniformly collected data from a cohort of pediatric patients with IBD enrolled between January 2000 and May 2003 at 6 pediatric centers were analyzed. Data were retrospectively reviewed and analyzed. Results: A total of 1652 infusions given to 243 patients in 6 centers was analyzed. Overall, 60 IRs were recorded in 40 patients (3.6% of infusions, 16.5% of patients). Thirty‐three of 243 patients received premedication before the first IR (group 1). Two hundred ten patients did not receive premedication until the development of IRs, if at all (group 2). IRs were more common among patients in group 1 than in group 2 (12/33 versus 28/210, P < 0.01). Of the 28 patients in group 2 with IRs, 10 began receiving premedication with each subsequent infusion, 12 continued without premedications, and 6 had no further infusions recorded. Two of 10 who began receiving premedication had a subsequent IR versus 6 of 12 who did not receive premedication (P = 0.15). Conclusions: IRs occur in a small proportion of infusions among pediatric patients receiving infliximab for IBD. Premedication does not seem to prevent the development of IRs; however, once an IR has occurred, premedication may be indicated to prevent subsequent IRs.