Stanley A. Cohen

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

BACKGROUND & AIMS We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC). METHODS 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. RESULTS 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. CONCLUSIONS 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.

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.

Increased Effectiveness of Early Therapy With Anti-Tumor Necrosis Factor-α vs an Immunomodulator in Children With Crohn's Disease

BACKGROUND & AIMS Standard therapy for children newly diagnosed with Crohns disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. METHODS We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. RESULTS Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval [CI], 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group. CONCLUSIONS In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.

ImproveCareNow: The development of a pediatric inflammatory bowel disease improvement network

&NA; There is significant variation in diagnostic testing and treatment for inflammatory bowel disease. Quality improvement science methods can help address unwarranted variations in care and outcomes. Methods: The ImproveCareNow Network was established under the sponsorship of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the American Board of Pediatrics as a prototype for a model of improving subspecialty care that included three components: 1) creating enduring multicenter collaborative networks of pediatric subspecialists, 2) sharing of performance data collected in patient registries, and 3) training in quality improvement. The network began with a focus on improving initial diagnostic testing and evaluation, the classification of the severity and extent of disease, the detection and treatment of inadequate nutrition and growth, and the appropriate dosing of immunomodulator medications. Changes are based on an evidence‐based model of chronic illness care involving the use of patient registries for population management, previsit planning, decision support, promoting self‐management, and auditing of care processes. Results: Currently, patients are being enrolled at 23 sites. Through 2009, data have been analyzed on over 2500 patients from over 7500 visits. Initial results suggest improvements in both care processes (e.g., appropriate medication dosing and completion of a classification bundle that includes the patients diagnosis, disease activity, distribution and phenotype, growth status, and nutrition status) and outcomes (e.g., the percentage of patients in remission). Conclusions: These improvements suggest that practice sites are learning how to apply quality improvement methods to improve the care of patients. (Inflamm Bowel Dis 2011;)

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.

Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease.

Objective: The aim of the study was to prospectively evaluate clinical and mucosal responses to the specific carbohydrate diet (SCD) in children with Crohn disease (CD). Methods: Eligible patients with active CD (Pediatric Crohns Disease Activity Index [PCDAI] ≥ 15) underwent a patency capsule and, if passed intact, capsule endoscopy (CE) was performed. Patients taking SCD were monitored for 52 weeks while maintaining all prescribed medications. Demographic, dietary, and clinical information, PCDAI, Harvey-Bradshaw Index (HBI), and Lewis score (LS) were collected at 0, 12, and 52 weeks. CEs were evaluated by an experienced reader blinded to patient clinical information and timing. Results: Sixteen patients were screened; 10 enrolled; and 9 completed the initial 12-week trial—receiving 85% of estimated caloric needs before, and 101% on the SCD. HB significantly decreased from 3.3 ± 2.0 to 0.6 ± 1.3 (P = 0.007) as did PCDAI (21.1 ± 5.9 to 7.8 ± 7.1, P = 0.011). LS declined significantly from 2153 ± 732 to 960 ± 433 (P = 0.012). Seven patients continued the SCD up to 52 weeks; HB (0.1 ± 0.4) and PCDAI (5.4 ± 5.5) remained improved (P = 0.016 and 0.027 compared to baseline), with mean LS at 1046 ± 372 and 2 patients showed sustained mucosal healing. Conclusions: Clinical and mucosal improvements were seen in children with CD, who used SCD for 12 and 52 weeks. In addition, CE can monitor mucosal improvement in treatment trials for pediatric CD. Further studies are critically needed to understand the mechanisms underlying SCDs effectiveness in children with CD.

Measuring Quality of Life in Pediatric Patients With Inflammatory Bowel Disease: Psychometric and Clinical Characteristics

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.