both dose groups). The effect was most pronounced in anti-TNF Naïve patients and early responders. In all groups, the standard dose group demonstrated slightly more improvement compared to low dose, but differences were not statistically significant. Conclusion: ADA treatment was associated with improved HRQOL in pediatric patients with CD by week 12 and remained over the 52-week study.
Efficacy and Safety of Standard vs Low Dose Adalimumab Maintenance Therapy As a Function of Disease Severity in Pediatric Patients With Crohn's Disease: Subanalysis of Imagine 1 Jeffrey S. Hyams, Wallace Crandall, Joel R. Rosh, Frank Ruemmele, Johanna C. Escher, Andreas Lazar, Yaqin Wang, Roopal Thakkar Aim: Adalimumab (ADA) has been shown to be an effective treatment for inducing and maintaining clinical remission and/or response in children with moderate to severe Crohn's disease (CD)1. Although the standard adult dose (SD) ADA maintenance therapy exhibited generally greater efficacy than low dose (LD)1, the influence of baseline (BL) disease severity on outcomes has not been determined. Methods: In IMAgINE11, patients (pts) aged 6-17 years that had a PCDAI score .30 at BL, with CD resistant or intolerant to conventional therapy, including prior infliximab (IFX), received open-label induction ADA at weeks (wks) 0/2 according to body weight (≥40kg, 160/80mg; ,40kg, 80/40mg). At wk4, 188 randomized pts (ITT population) received either double-blind SD ( ≥40kg, 40mg every other wk (eow); ,40kg, 20mg eow) or LD ( ≥40kg, 20mg eow; ,40kg, 10mg eow) maintenance therapy. After wk12, pts could move to blinded weekly (ew) dosing for disease flare or non-response. Clinical remission (PCDAI≤10) and response (PCDAI decrease ≥15 points from BL) were measured at wk52. Subgroup analyses by disease severity, based on the median BL PCDAI observed for the study population (less severe CD, PCDAI ,40; more severe CD, PCDAI≥40), and also by prior IFX use were performed. Non-responder imputation was used for missing data or after switch to ew therapy. Treatment-emergent adverse events (AE) were reported as events/100pt-years (E/100PY) for any pt receiving at least one dose of ADA. Results: Greater clinical remission and response was achieved with SD ADA therapy compared to LD at wk52 in pts with more severe disease, with the greatest difference between doses occurring in IFX Naïve pts. For pts with less severe CD, similar rates of remission and response were observed between SD and LD ADA (Table). Switch to ew dosing occurred most frequently in pts with more severe CD receiving LD ADA (55.6%) than in pts with less severe CD receiving the same dose (43.9%). For pts receiving SD ADA, escalation to ew dosing occurred in a similar percentage of pts, regardless of BL disease severity (35.9%, less severe; 38.9%, more severe). The overall rate of AEs was similar between dosing groups for either pt population. For pts with less severe CD, serious AEs (SAEs) were higher with SD (32.0 E/100PY) than LD ADA (17.6 E/100PY), whereas a similar rate of SAEs was observed between SD and LD ADA in pts with more severe disease (54.8 vs 64.5 E/ 100PY, respectively). No malignancies, TB, congestive heart failure or deaths were reported. Conclusion: At wk52, SD maintenance ADA was a more effective therapy than LD for children with more severe CD, whereas pts with less severe disease benefitted equally from both doses. The greatest remission and response rates were observed for IFX-Naïve pts. The overall safety profile was similar for SD and LD ADA treatment. 1.Hyams 2012 Gastroenterology;143:365 Clinical outcomes in pediatric CD pts with eow SD vs eow LD ADA (ITT population)
Tu1946 Use of the QuantiFERON-TB Gold in-Tube Test for Latent Tuberculosis Screening in Children With Inflammatory Bowel Disease Treated With Infliximab Eugene Vortia, Victor E. Uko, Belinda Yen-Lieberman, Jill Frawley, Lara Danziger-Isakov, Barbara Kaplan, Lori Mahajan BACKGROUND: Infliximab therapy has been linked with an increased risk of active tuberculosis (TB), mediated by its inhibitory effect on TNF- α. As a result, latent TB screening is recommended prior to initiation of infliximab therapy. The QuantiFERON-TB Gold In-Tube Test (QFT-GIT) (Qiagen/Cellestis, Germantown, Maryland), an interferon gamma release assay, is an alternative to the tuberculin skin test (TST) for latent TB screening. The QFTGIT is specific and performed in one visit. Since immunosuppressants may suppress the mitogen response (positive control) and generate indeterminate test results, there is concern about the usefulness of this test for patients on infliximab. OBJECTIVE: To assess the prevalence of QFT-GIT indeterminate results in children ≥ 5 yrs with inflammatory bowel disease (IBD) treated with infliximab and to evaluate factors that affect mitogen response. METHODS: A single-center prospective study was performed to evaluate 93 children 5-19 yrs of age with IBD receiving infliximab infusions. All subjects had blood drawn for a complete blood count and the QFT-GIT. In addition, data was collected on demographic, anthropometric, and disease factors, as well as medications and risk of TB exposure. RESULTS: The mean age of the 93 enrolled patients was 15.2 (±3.8) yrs. 86% had Crohn's disease and 14% had ulcerative colitis. The mean infliximab dosage was 6.4 ±1.8 mg/kg [range 3.8 -10.2] and mean duration since the prior infliximab infusion was 44.3 (±12.7) days, [range 28-76]. Mean duration since initiation of infliximab therapy was 35.1 (±26.7) months [range 3-119]. In the 31 patients for whom results of TSTs before therapy was available, none had a positive result. The mean mitogen response was 9.3 (±2.2) IU/ml, with the maximum response (10 IU/ml) observed in 82 patients (88 %). The QFT-GIT was negative in 90 patients and positive in 2 patients and both positive patients had a negative initial TST. One patient (1%) had an indeterminate result (95% CI: 0.19 % - 5.84%), which was significantly less than the hypothesized rate of 8% (one-sided non-inferiority test, p = 0.004). None of the 17 patients receiving additional immunosuppression to infliximab had indeterminate QFT-GIT results [prednisone (7), median dose: 0.43 mg/kg, azathioprine (14), median dose: 1.35 mg/kg and 6-mercaptopurine (1), 0.61 mg/kg]. Lower hemoglobin levels were significantly associated with decreased mitogen response in univariable and multivariable regression analyses (P,0.01). CONCLUSION: This is the first prospective study assessing the use of the QuantiFERON-TB Gold In-Tube test in pediatric patients treated with infliximab. The indeterminate rate was 1%, a rate comparable to non-immunosuppressed children of similar age. This study suggests that this test can be a useful tool to screen for latent TB in children on infliximab.
*p≤0.05, **p≤0.01 SD vs LD, p values from Chi-square test or Fisher's exact test; ITT: intent-to-treat Tu1945 Adalimumab Treatment Is Associated With Improved Quality of Life in Pediatric Crohn's Disease Gigi Veereman, Johanna C. Escher, Frank Ruemmele, Wallace Crandall, Andreas Lazar, Martha Skup, Mei Yang, Jingdong Chao, Parvez Mulani, Roopal Thakkar, Jeffrey S. Hyams Background: Adalimumab (ADA) has been shown to induce response and remission in moderate/severe Crohn's disease (CD) in children. Aim: We aimed to assess the effect of ADA treatment on health-related quality of life (HRQOL) in pediatric patients with CD. Methods: IMAgINE 1 was a 52-week, multi-center, double-blind study assessing efficacy and safety of ADA in patients aged 6-17 years with moderate to severe CD (defined as Pediatric CD Activity Index [PCDAI] .30) failing prior therapy, including infliximab. Following 4 weeks of open-label induction (80 mg and 40 mg at weeks 0 and 2, respectively for patients with bodyweight [BW] ,40 kg, or 160 mg and 80 mg for BW ≥40 kg), 188 patients were randomized 1:1 to standard dose (20 mg, BW ,40 kg, or 40 mg, BW ≥40 kg) or low dose (10 mg, BW ,40 kg, or 20 mg, BW ≥40 kg) double-blind ADA every other week. After Week 12, patients who experienced flare or nonresponse could switch to blinded weekly dosing and to standard dose open label therapy. To assess HRQOL, patients ≥10 years (N= 176) completed the IMPACT III, a 35-item questionnaire with scores ranging from 35 (poor) to 175 (best), at baseline and weeks 12, 26, and 52. A change of 10.8 has been shown to indicate clinical improvement. Within group changes from baseline were assessed using paired t-tests at each time point (by group; by group and prior anti-TNF use; by group and Week 4 response). Changes from baseline were compared between dose groups using ANCOVA (with group as factor, adjusting for anti-TNF exposure, Week 4 response, and baseline IMPACT III score). Last-observation-carried-forward was used for patients who discontinued or dose escalated. Results: At baseline, no significant differences were observed between dose groups in demographics, mean PCDAI scores, and prior anti-TNF exposure. The low dose group exhibited higher mean IMPACT III scores at baseline (117.7±15.5 vs. 111.6±18.7, P=.018). Both groups demonstrated significant improvements in mean IMPACT III scores at Weeks 12, 26, and 52 (figure). Improvements were observed in each domain, particularly in the bowel symptoms domain (4.7-4.8 change from baseline by Week 12 in
Tu1947 de novo Expression of the Corticotropin-Releasing Factor (CRF) Receptors in Stomachs of Patients With Gastritis Pallavi Mhaske, Elizabeth A. Garnett, Min Liao, Melvin B. Heyman, Aditi Bhargava Background. Components of the stress hormone system have been implicated in gastrointestinal (GI) diseases. Urocortin 1 (Ucn1) and its two GPCR receptors CRF1 and CRF2 are important mediators of local, peripheral inflammatory responses. Presence of the components of the CRF system in stomachs of pediatric patients has not been reported. Aim. To determine if Ucn1 and CRF receptors are involved in pediatric patients with gastritis. Methods. Pediatric patients who underwent upper endoscopy with biopsies at UCSF were categorized by diagnosis and matched by age and gender. Data collected on all patients included demographics, medical history, presenting symptoms, location of disease, final diagnosis and histological results. The protocol was approved by the UCSF Committee on Human Research. Paraffinembedded sections of the stomachs were immunostained with Ucn1 and CRF1/2 receptor antibodies and sections were analyzed by confocal microscopy. Pre-adsorbed or no primary antibodies were used as negative controls. Results. Parietal cells and a subset of endocrine G cells of the stomachs of normal males (ages 7-15) showed robust immuonreactive Ucn1 (IR-Ucn1), while CRF receptor immunostaining (IR-CRF1/2) was not detected (Fig. 1). IRUcn1 was prominently expressed in the goblet cells and apical lining, while epithelial cells also expressed IR-Ucn1. This is in sharp contrast to both upper and lower GI regions of the same patients, where robust IR-CRF1/2 and Ucn1 is prominently detected in the duodenum, ileum and colon. In patients with gastritis, de novo expression of IR-CRF1/2 was