James Markowitz

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

Background and Objectives: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. Methods: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. Results: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean ± SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 ± 10.4, 32.2 ± 12.7, and 47.8 ± 14.9, respectively (P < 0.001 for all comparisons). Mean ± SD PCDAI for inactive disease after treatment was 5.2 ± 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of ≥30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of ≥12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. Conclusions: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of ≥30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Growth failure in pediatric inflammatory bowel disease.

To assess whether children with inflammatory bowel disease (IBD) develop permanent impairment of linear growth, we analyzed records from 48 young adults who had IBD during childhood or early adolescence (Tanner I-III; 11.8 +/- 2.4 years old at diagnosis). All were fully grown (Tanner V; 21.1 +/- 3.0 years) at last examination. Adult heights were predicted from data obtained at or shortly after the diagnosis of IBD by three methods: height for age percentile, the Bailey-Pinneau (BP), and Roche-Wainer-Thissen (RWT) methods. Predicted adult heights were then compared with the actual ultimate height of each subject. Permanent growth failure occurred in 19-35% of subjects, depending upon the method used to assess growth. Overall, 31% (15 of 48) of the subjects had deficits of adult height identified by two or more methods, including 14 of 38 (37%) of those with Crohns disease but only one of 10 with ulcerative colitis. Age at diagnosis of IBD, age at last examination, age at cessation of linear growth, and site of IBD did not differ between impaired and normal growth groups. Duration of corticosteroid use was longer (p < 0.05) in growth-impaired subjects. In addition, although 60% of all subjects had periods of poor growth that put them in height-for-age percentiles two or more major growth channels below previous percentiles, only 19% remained at these levels upon achieving their final adult heights. Permanent impairment of linear growth leading to clinically meaningful deficits of ultimate adult height is common in patients with IBD in childhood or early adolescence. New therapeutic approaches are needed to address this problem.

Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.

Consensus for Managing Acute Severe Ulcerative Colitis in Children: A Systematic Review and Joint Statement From ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN

OBJECTIVES:Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohns and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN.METHODS:A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature.RESULTS:The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points.CONCLUSIONS:These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.

Long-term outcome of maintenance infliximab therapy in children with Crohn's disease

Background: Infliximab therapy has short‐term benefits in children with moderate‐to‐severe Crohns disease (CD). We assessed the long‐term outcome of infliximab maintenance therapy in children with CD. Methods: We performed a multicenter cohort study of 729 pediatric patients with CD enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children younger than 16 years and newly diagnosed with CD were eligible for this study. Disease and medication information were collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol. Results: In all, 202 of 729 patients received infliximab: 62%, 23%, and 15% within 1, 1–2, and >2 years of diagnosis, respectively. The mean age at infliximab initiation was 12.7 years. A total of 158 infliximab‐treated patients received maintenance therapy, 29 episodic (8 converted to maintenance), and 15 had incomplete follow‐up. Among 128 patients administered maintenance infliximab and followed for ≥1 year, concomitant medications at infliximab initiation included corticosteroids (52%) and immunomodulators (90%). By 1, 2, and 3 years, <10% of patients continuing on maintenance infliximab were receiving corticosteroids (P < 0.001). Following maintenance therapy initiation, 26%, 44%, and 33% of patients continuing on maintenance infliximab over 0–1, 1–2, and 2–3 years, respectively, had clinically inactive disease not requiring corticosteroids or surgery. The likelihood of continuing maintenance infliximab at 1, 2, and 3 years was 93%, 78%, and 67%, respectively. Conclusions: Infliximab maintenance therapy was a durable and effective treatment that was associated with prolonged corticosteroid withdrawal over a 3‐year period in children with CD.

Safety and Efficacy of Adalimumab for Moderate to Severe Crohn's Disease in Children

BACKGROUND & AIMS The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohns disease (CD). METHODS We studied 192 patients with Pediatric Crohns Disease Activity Index (PCDAI) scores >30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or <40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or <40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or <40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran-Mantel-Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety. RESULTS A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected. CONCLUSIONS Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant.

Clinical outcome of ulcerative colitis in children.

OBJECTIVES To characterize the response to current medical therapies in children with ulcerative colitis, and to identify those factors that may predict the need for colectomy. DESIGN Retrospective chart review at two large pediatric inflammatory bowel disease centers. RESULTS We identified 171 subjects ranging in age from 1.5 to 17.7 years at diagnosis (mean 11.2 years). Mean follow-up was 5.1 years. Of these subjects, 43% had mild disease at presentation and 57% had disease that was classified as moderate or severe. After treatment 90% of the former group and 81% of the latter group had resolution of symptoms by 6 months. During any subsequent yearly follow-up interval, approximately 55% of the entire study population was symptom free, 38% had chronic intermittent symptoms, and 7% had continuous symptoms. A significantly lower risk of colectomy was noted for those with initially mild disease compared with those with moderate/severe disease. At 1-year the risk of colectomy was 1% among those with mild disease versus 8% with moderate/severe disease; at 5 years, the risk of colectomy was 9% in the mild disease group versus 26% in the moderate/severe disease group (p <0.03). CONCLUSIONS In the majority of pediatric subjects with ulcerative colitis remission is achieved in the first 6 months after therapy; thereafter disease is inactive in about 50% of patients during any given year of follow-up. Severity of disease at presentation is a significant risk factor for colectomy during the first 5 years of follow-up. Future management protocols with more aggressive initial therapy may be warranted in children with moderate/severe disease.

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.

Appraisal of the pediatric ulcerative colitis activity index (PUCAI)

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

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