Corticosteroid therapy has been shown to be effective for symptomatic relief in adult and pediatric Crohn disease (CD), but is limited by adverse effects and dependency. Budesonide (BUD) is a corticosteroid with anti-inflammatory potency but low systemic bioavailability and activity when given orally or rectally because of extensive (90%) first-pass hepatic metabolism (1–5). These properties suggest that BUD may be particularly beneficial for IBD (2). The use of an oral controlled release preparation of BUD, with location-specific delivery (distal small intestine and right colon), was first described in pilot studies in the early 1990s (6). BUD has been shown in multiple meta-analyses to be more efficacious than placebo, but less efficacious than prednisone for the induction of remission in mild-to-moderate active CD in adults (7–10).
The likelihood of adverse events and adrenal suppression is lower with BUD than with conventional corticosteroids (7). Given the growth and osteoporosis concerns associated with the use of prednisone, BUD has the potential of offering significant benefits over prednisone for inducing remission in pediatric CD. There are, however, limited published data on the use of BUD in children with CD (2,11–13).
In January 2002, the Pediatric Inflammatory Bowel Disease Collaborative Research Group established the Pediatric IBD Collaborative Research Group Registry (henceforth the Registry), an observational research program, to examine and characterize clinical, laboratory, and humanistic outcomes associated with present and emerging IBD treatments in newly diagnosed pediatric patients. Subjects enrolled in the Registry are managed according to the dictates of their treating physicians, not by standardized protocol. In this analysis, we have examined prospectively collected data on BUD use in patients enrolled in the Registry. Although we ultimately would like to determine the effectiveness of oral BUD in children with IBD, the goal of this analysis was to understand how practitioners are presently using BUD in pediatric gastroenterology practice in major IBD centers. This information could then be used to design an acceptable controlled trial to determine efficacy. In the course of reviewing our experience with BUD, we were able to examine whether the early use of BUD (within 30 days of diagnosis) altered the overall likelihood that patients with ileum and/or ascending colon (IAC) disease would be exposed to conventional corticosteroids within the first year of their disease.
Subjects for analysis were selected from a prospective database (the Registry) compiled by members of the Pediatric Inflammatory Bowel Disease Collaborative Research Group. The Registry is drawn from 21 North American pediatric gastroenterology centers with active IBD practices. Investigators at each of the collaborating centers prospectively enroll children newly diagnosed as having IBD who have not yet reached their 16th birthday at the time of IBD diagnosis. Subjects’ clinical and demographic characteristics, including type and extent of IBD, disease activity assessment (determined by Physician Global Assessment and Pediatric Crohn Disease Activity Index), treatment, complications, and need for hospitalization or surgery are recorded at the time of initial diagnosis, 30 days after diagnosis and quarterly thereafter. All of the children enrolled in the Registry are managed according to the usual and customary practice of their individual physicians, not by standardized protocols.
For the present study, the database was searched for children with CD who had received BUD at any time during the course of their disease management. Data on other medical therapy, including the use of traditional corticosteroids, immunomodulatory agents including 6-mercaptopurine (6-MP), azathioprine and methotrexate, infliximab, adalimumab, 5-aminosalicylates (5-ASA), enteral nutrition, and surgical procedures related to IBD were prospectively compiled. Frequency of BUD use, duration of therapy, choice of dose, distribution of disease, and clinical setting were evaluated. Except in the instance in which BUD was started and stopped within the first 30 days from diagnosis, duration of individual courses of BUD therapy was defined in 3-month intervals by the quarters during which BUD was initiated and stopped. Because this is an observational cohort, there were no predetermined durations for length of an individual medication course.
BUD is available in the United States as a 3-mg capsule designed to release BUD in the terminal IAC (Entocort, AstraZeneca, Lund, Sweden) or in Canada, as both Entocort and Budenofalk (Dr Falk Pharma, Freiburg, Germany), a pH-dependent release form of BUD. For patients who received BUD, we compared those for whom disease was limited to the IAC with patients with disease not limited to the IAC (these patients may/may not have IAC involvement, but did have an additional site(s) of involvement outside the IAC). For the purposes of defining disease extent, esophageal/gastroduodenal involvement was not included.
Patients with CD with involvement limited to the IAC were compared with respect to their use of BUD within 30 days of diagnosis (early BUD use) or nonuse of BUD in this time period. We examined whether there were differences between key demographic factors (age, sex, Tanner stage, height z score, body mass index z score) or disease activity scores, which may influence the choice of therapy (BUD or other therapy). We also compared the 2 groups at 1 year from diagnosis with respect to whether they had received any conventional corticosteroids.
The present study was approved by the respective institutional review boards of each center. Informed consent was obtained before enrollment of all of the subjects.
SPSS 13.0 (SPSS Inc, Chicago, IL) was used for statistical analysis. Categorical variables were compared between study groups using χ2 or Fisher exact tests. Continuous variables were compared using t tests and Mann-Whitney tests. All of the tests used a significance level of 0.05.
At the time that the database was locked for this analysis, there were 1382 children enrolled in the Registry, 932 of whom had CD. Of the 932, 119 (13%) had received BUD at some point during their course of treatment. The median follow-up for the 119 BUD users was 39 months (range 1–78 months). The mean age ± standard deviation of the group was 12.5 ± 2.1 years. The time to initiation of BUD therapy is listed in Table 1.
Overall, the 119 patients received 148 courses of BUD therapy. Because of the variability and small number of patients who received 2 courses (27/119) or 3 courses (1/119), we limited our analysis to the initial course of BUD therapy for all 119 cases. The duration of these initial courses of BUD therapy is listed in Table 2. In 35% (42/119) of Registry patients, receiving BUD disease was limited solely to the IAC. The remaining 65% (77/119) had CD involvement in sites other than the IAC. In only 6 of 77 patients was there no IAC involvement. Therefore, 95% (113/119) patients had at least IAC involvement.
Each BUD capsule contained 3 mg. The maximum doses prescribed per patient were 12 mg (1 patient), 9 mg (105 patients), 6 mg (10 patients), and 3 mg (9 patients.) When calculated on a per-kilogram basis, the daily dosage ranged from 0.06 to 0.39 mg/kg.
Among the 56 children starting BUD within 30 days of diagnosis, only 5 started taking BUD as monotherapy. For the remainder, concomitant therapies during the BUD course included 5-ASA in 77% (43/56), and immunomodulator (IM) therapy (azathioprine/6-MP or methotrexate) in 36% (20/56). The medications received by these 56 patients subsequent to the discontinuation of their first BUD course are summarized in Table 3. For the 5 patients who initiated BUD as a monotherapy, 3 started taking concomitant 5-ASA within the first 3 months, 1 required step-up therapy to prednisone and was bridged to azathioprine, and 1 had insufficient follow-up data to report outcome.
In the 63 children who initiated BUD beyond 30 days of diagnosis, its use in all but 1 patient was as an adjunct with other therapies to treat active disease. Concomitant treatments in this group of children are summarized in Table 4. As noted in the table, a substantial number of these patients (51/63 or 81%) had been taking prednisone, and for 17 of 63 (27%), BUD was started to wean patients from prednisone.
Medications subsequent to initiating the first course of BUD for the 63 patients who received BUD following the initial diagnosis period are summarized as follows: 2 stepped down to 5-ASA alone and the rest either moved toward conventional steroids (13/63) or required step up therapy to either a biological agent (8/63) or an IM (16/63). After their course of BUD, 21 of 63 (33%) returned to the same medication as they were taking before initiation of the BUD. Overall, 47 of 60 (78%) patients (with sufficient follow-up) did not require conventional corticosteroids during or immediately following their BUD course.
Of the total of 932 children with CD in the Registry database, 178 had disease limited to the IAC. From the 178 patients with CD with IAC involvement, we derived a subgroup of 161 patients, in which 25 of 161 (16%) had early use of BUD (ie, within 30 days of diagnosis) and 136 of 161 (84%) never received BUD. For this analysis, we did not include the 17 IAC-only patients who first received BUD beyond the first 30 days from diagnosis. Within the limits of our retrospective analysis, we attempted to identify factors that may have contributed to the decision to use BUD early (at diagnosis) in patients with disease limited to the IAC; we compared the subgroup who were prescribed BUD in this time period with those with similar disease distribution who were not prescribed BUD (Table 5). There were no differences discernable with respect to disease activity, age, sex, Tanner stage, and height or body mass index z scores at diagnosis between the groups (P > 0.05 for all). Additionally, by the end of year 1, there was no significant difference in the percentage of patients who had received standard corticosteroids when we compared the group that had received BUD early (58%) with those who did not (73%; P = 0.23). The data were not sufficient to be able to determine cumulative corticosteroid exposure in the 2 groups.
No fractures, opportunistic or serious infections were reported in the BUD cohort. During or subsequent to BUD therapy, 32 of 119 patients had ≥1 hospitalizations and 17 of 119 had a major surgical procedure performed. One malignancy occurred in a patient who had been treated with BUD, infliximab, and 6-MP.
BUD monotherapy at or subsequent to diagnosis was uncommon (5%, 6/119 patients) in this large inception cohort. The majority of patients were placed on BUD as an adjunct therapy together with 5-ASA or an IM to treat active disease. For those who initiated BUD beyond the diagnosis period, >80% had a previous prednisone course and in almost 30%, it was used to aid in weaning from this corticosteroid.
In North America, the controlled-ileal release formulation of BUD is licensed for use in adults with CD involving the IAC. It is interesting, therefore, that in only 35% (42/119) of Registry patients receiving BUD was disease limited solely to the IAC; however, in the remaining 65% (77/119) with disease extent beyond the IAC, virtually all (92%) had IAC involvement as well.
The majority of our patients started taking a 9-mg daily dose of BUD for treatment of active disease regardless of their age or body weight. Although BUD at 9 mg/day is less effective at inducing remission of mild to moderate CD limited to the IAC compared with prednisone/prednisolone, it is superior to mesalamine and placebo (7). Pediatric studies have usually reported dosing equivalent to adults, with no clear adjustment for age or body weight (2,11,12). An Israeli group reported a randomized controlled trial in which 1 study arm received a 12-mg daily induction dose for 1 month, compared with the control arm, which received the 9-mg daily dosing more routinely seen (14). No significant difference was noted at 7 weeks in the main outcome measure, although a trend toward a greater remission rate was suggested in the 12-mg daily group. Pharmacokinetic studies comparing adult and pediatric response to oral BUD did not demonstrate clinically important differences (15). With data (15) supporting pharmacokinetic equivalence for children and adults with BUD 9-mg daily dosing, and adult clinical trials showing 9 mg/day as the most effective dose, it would seem that the present practice of North American pediatric gastroenterologists to treat children with BUD 9 mg daily is reasonable.
Our data indicate that physicians are using BUD to induce remission rather than to maintain remission. This is evident because >60% of the cohort have a duration of BUD use during the first course of therapy of ≤6 months, and >90% are receiving concomitant therapy. This is in keeping with the findings of a meta-analysis of the BUD maintenance therapy trials, which did not show efficacy for BUD in maintenance of remission in CD (16). Randomized controlled trials have demonstrated that BUD is not effective in maintaining disease remission (16).
The Pediatric Inflammatory Bowel Disease Collaborative Research Group, through its multicenter, the North American Pediatric IBD Registry, has the strength of being a unique pediatric prospective inception cohort of inflammatory bowel disease patients followed from diagnosis; however, there are obvious limitations to our study. As an observational study, we are limited by small sample size in our ability to detect differences between subgroups within our BUD cohort. Also, because of the observational nature of this cohort whereby patient management is not dictated by protocol, some of the outcomes important in the evaluation of the efficacy and safety of BUD cannot be ascertained directly. Thus, growth parameters, bone density assessments, cortisol levels, or adrenocorticotropic hormone stimulation tests were not performed in sufficient number or in a systematic fashion to allow these to be incorporated in our evaluation of conventional corticosteroid or BUD use. In particular, our data cannot describe the specific effects of BUD on growth in our population. The database does not specifically capture physical signs of steroid toxicity. Similarly, there were no major adverse events readily attributable to BUD therapy. Adverse events have been summarized in other studies involving BUD (17–22).
Given the known toxicities that are associated with the use of conventional corticosteroids, BUD may play a role in the management of pediatric patients with CD. There is clearly a need for additional randomized controlled trials with sufficient follow-up to allow a thorough evaluation of the role of BUD in managing pediatric CD.
The authors acknowledge the hard work and contributions of the following research coordinators, without whom the present study would have been impossible: Miriam Lincoln, Kathleen Grancher, Karen Frost, Shari Huffman, Tara Raboin, Jay Ingram, Ruth Singleton, Lisa Reynolds, Jennifer Haskett, Gail Waltz, Annette Langseder, Kelley Koslasky, Vivian Abadom, Kelly Boyer, Barbara Bancroft, Sarah Bistrick, Kelly Kachelries, and Sandra McRandal.
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