Trudy Lerer

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.

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.

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.

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)

Dyspepsia in children and adolescents: a prospective study.

BACKGROUND Dyspepsia is poorly characterized in the pediatric population. The goal of the current study was to describe the clinical constellation and natural history of dyspepsia in children and adolescents seen in a pediatric gastroenterology practice. METHODS A standardized questionnaire was administered by a pediatric gastroenterologist to all subjects 5 or more years of age (and their parents or guardians) treated in a referral pediatric gastroenterology practice for 1 month or more of abdominal pain or discomfort, nausea, or vomiting. Subjects with dyspepsia and dyspepsia subtypes (ulcer-like, dysmotility-like) were identified by using previously defined adult criteria. Evaluation and treatment were performed at the discretion of the attending pediatric gastroenterologist. RESULTS During a 1-year period, 257 patients were screened with 127 subjects fulfilling criteria for dyspepsia (59% girls, 85% white; median age, 11.7 years; median duration of symptoms, 8 months). Symptoms were ulcer-like in 26% and dysmotility-like (nausea predominance) in 15% of subjects. In those with dyspepsia, irritable bowel syndrome and gastroesophageal reflux were noted in 24% and 43%, respectively. Esophagogastroduodenoscopy and biopsy were performed in 56 subjects with 21 (38%) having mucosal inflammation (Helicobacter pylori in 5). The remaining 35 subjects (62%) were considered to have functional dyspepsia. Duration of symptoms less than 1 year and vomiting were risk factors for mucosal inflammation. Follow-up at 6 months to 2 years revealed 70% of subjects were either asymptomatic or much improved regardless of the cause of dyspepsia. CONCLUSION Most children and adolescents with dyspepsia do not have serious disease. In our referral population H. pylori infection was unusual, and no peptic ulceration was found. Most subjects with functional dyspepsia have improvement of symptoms over time.

Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease.

Background: In children with inflammatory bowel disease (IBD) it is not known whether reductions in bone mineral density (BMD) are a consequence of bone turnover alterations and if BMD improves with treatment. Methods: In a cohort of children with IBD, we prospectively measured indicators of bone remodeling, body mass index (BMI), disease activity, intact parathyroid hormone, serum IL‐6, and insulin‐like growth factor‐I at diagnosis and then every 6 months for 2 years. BMD was determined annually using dual x‐ray absorptiometry (DXA). BMD Z‐scores were calculated using height/age. Baseline measurements and calcium intake were compared with a group of age‐ and sex‐matched healthy children. Results: We observed that at diagnosis total body BMD Z‐score (mean ± SD) was −0.78 ± 1.02 for Crohns disease (CD, n = 58), −0.46 ± 1.14 for ulcerative colitis (UC, n = 18), and −0.17 ± 0.95 for control (CL, n = 49) (P < 0.01, CD versus CL). In CD, a BMD Z‐score <−1.0 was associated with lower BMI and higher serum IL‐6. Patients with CD and UC had low bone turnover. Activation of bone formation paralleled clinical improvement, but BMC gain was less than expected over the 2‐year study period, especially in CD. Prednisone use did not correlate with low BMD. Conclusions: Decreased bone turnover occurs in children newly diagnosed with IBD. Although indicators of osteoblast activity increase with clinical improvement, bone mineral accrual does not accelerate. Children with low BMI may be considered for BMD screening, since they are at risk for low bone mass.

Effect of early immunomodulator use in moderate to severe pediatric Crohn disease

Background: The immunomodulators (IMs) 6‐mercaptopurine and azathioprine decrease corticosteroid dependence and maintain remission in Crohns disease (CD). We describe IM use in newly diagnosed pediatric CD, comparing outcomes of “early” versus “late” initiation of therapy. Methods: Data were obtained from pediatric CD patients enrolled in a prospective, multicenter observational study. Moderate/severe disease patients treated with IM were compared for outcomes of remission, corticosteroid use, infliximab therapy, hospitalizations, and CD‐related surgery based on timing of initiation of IM therapy. Results: In all, 247 children met the criteria (60% male, mean age 11.9 years); 199 were treated with IM within 1 year of diagnosis; 150 between 0–3 months (early), 49 between 3–12 months (late). Both groups showed a decrease in corticosteroid use by 12 months, at which time proportionately fewer early group patients had received corticosteroids in the preceding quarter (22%) than late groups patients (41%)(P = 0.013). The number of hospitalizations per patient was also noted to be significantly lower in the early group over the 2‐year follow‐up (P = 0.03). No difference was noted in the rates of remission, infliximab use over time, or surgery. Conclusions: 80% of children with newly diagnosed moderate to severe CD are treated with IM within 1 year. Early IM use is associated with reduced corticosteroid exposure and possibly fewer hospitalizations per patient.

Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in Pediatric Crohn’s Disease

OBJECTIVES:Adalimumab, an anti-tumor necrosis factor immunoglobulin-1 antibody, is increasingly being reported as a potential treatment option for children with moderate-to-severe Crohn’s disease (CD). The aim of this study was to characterize common indications, safety, tolerability, and clinical response to adalimumab in pediatric CD in a large, multicenter, patient cohort.METHODS:Data were obtained using a retrospective, uncontrolled chart review at 12 sites of the Pediatric Inflammatory Bowel Disease Collaborative Research Group. Clinical, laboratory, and demographic data were obtained for CD patients who received at least one dose of adalimumab. Indication for adalimumab, concomitant medications, and clinical outcome at 3, 6, and 12 months for each patient were recorded using physician global assessment (PGA) and Pediatric CD Activity Index scores. Serious adverse events were identified.RESULTS:A total of 115 patients (54% female) received at least one dose of adalimumab. The mean age at the diagnosis of CD was 11.1±3.1 years, with the first adalimumab dose administered at 4.7±2.8 years after diagnosis. The most common dosing frequency was every other week with induction doses of 160/80 mg in 19%, 80/40 mg in 44%, and 40/40 mg in 15% of patients. Maintenance dosing was 40 mg every other week in 88% of patients. Mean follow-up after initial adalimumab dose was 10±8.6 months. Infliximab treatment preceded adalimumab in 95% of patients, with a mean of 12 infliximab infusions (range: 1–44). Infliximab discontinuation was due to loss of response (47%), infusion reaction or infliximab intolerance (45%), or preference for a subcutaneous medication (9%). Concomitant medications at the commencement of adalimumab were corticosteroids (38%), azathioprine/6-mercaptopurine (41%), and methotrexate (23%). Clinical response measured by PGA at 3, 6, and 12 months was 65, 71, and 70%, respectively, with steroid-free remission at 3, 6, and 12 months of 22, 33, and 42%, respectively. There were no malignancies, serious infections, or deaths in the study subjects.CONCLUSIONS:Adalimumab was a well-tolerated and effective rescue therapy for moderate-to-severe pediatric CD patients previously treated with infliximab. Adalimumab demonstrated a steroid-sparing effect, and >70% of patients achieved rapid response that was sustained through 12 months.

Laboratory Values for Children With Newly Diagnosed Inflammatory Bowel Disease

OBJECTIVE. The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease. METHODS. Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included hemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorized by physician global assessment. RESULTS. A total of 526 children (mean age: 11.6 years; 58% male; 392 with Crohn disease and 134 with ulcerative colitis) were studied. All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50%, and albumin levels for 60%. There was no clear association between Crohn disease location and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis disease severity and both the extent of bowel inflammation and the number of abnormal laboratory tests. CONCLUSION. The presence of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of inflammatory bowel disease.

Outcome following infliximab therapy in children with ulcerative colitis

OBJECTIVES:Infliximab is effective in treating moderate/severe ulcerative colitis (UC) in adults. The aim of this study was to determine the outcome after treatment with infliximab in pediatric UC.METHODS:We performed a multicenter cohort study of 332 pediatric patients with UC enrolled in the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry. Children ≤16 years of age and newly diagnosed with UC are enrolled in the registry. Disease and medication information are collected prospectively from the treating physician at diagnosis, 30 days, and quarterly thereafter. No interventions were specified, per protocol.RESULTS:Of 332 patients, 52 (16%) received infliximab (23% <3 months from diagnosis, 38% 3–12 months, 38% >12 months). Mean age at infliximab initiation was 13.3±2.6 (range 6–17) years; 87% of patients had pancolitis. Median follow-up was 30 months. Continuous maintenance (CM) therapy was given in 65%, episodic in 21%, episodic converted to CM in 6%, and insufficient data in 8% of patients. Sixty-three percent of patients were corticosteroid refractory, and 35% were corticosteroid dependent. Concomitant medications at first infliximab infusion included corticosteroids (87%), thiopurines (63%), and 5-aminosalicylates (51%). Corticosteroid-free inactive disease by physician global assessment was noted in 12/44 (27%), 15/39 (38%), and 6/28 (21%) patients at 6, 12, and 24 months, respectively. Kaplan–Meier analysis showed that the likelihood of remaining colectomy free after treatment with infliximab was 75% at 6 months, 72% at 12 months, and 61% at 2 years.CONCLUSIONS:In this cohort of children with UC receiving infliximab, corticosteroid-free inactive disease was observed in 38 and 21% of patients at 12 and 24 months, respectively. By 24 months, 61% of patients had avoided colectomy.