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Pediatric Crohn's Disease (pediatric + crohn's_disease)
Selected AbstractsLipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis,INFLAMMATORY BOWEL DISEASES, Issue 5 2010Brad A. Pasternak MD Abstract Background: Systemic exposure to lipopolysaccharide (LPS) has been linked to clinical disease activity in adults with inflammatory bowel disease (IBD). We hypothesized that markers of LPS exposure and the acute phase response (APR) would be increased in pediatric IBD patients with growth failure, and that LPS signaling would be required for induction of the APR in murine colitis. Methods: Serum markers of LPS exposure, endotoxin core IgA antibody (EndoCAb), and the APR, LPS binding protein (LBP) were quantified in pediatric IBD patients and controls. LBP and cytokine production were determined after administration of trinitrobenzene sulfonic acid (TNBS) enemas to mice with genetic deletion of Toll-Like receptor 4 (TLR4), and wildtype (WT) controls. Results: Serum EndoCAb and LBP were significantly elevated in patients with Crohn's disease (CD), compared to disease controls with ulcerative colitis (UC) and healthy controls (P < 0.001). This was independent of disease activity or location. CD patients with elevated serum EndoCAb and LBP exhibited linear growth failure which persisted during therapy. Serum LBP increased in WT mice following TNBS administration, in conjunction with increased serum TNF-,, IL-6, and IL-10, and expansion of regulatory T-cell numbers. Both the APR and expansion of foxp3+ T cells were abrogated in TLR4-deficient mice, in conjunction with a reduction in acute weight loss. Conclusions: LPS exposure and a persistent APR are associated with growth failure in pediatric CD. LPS signaling is required for the APR in murine colitis. Therapies targeting this pathway may benefit the subset of patients with refractory growth failure. (Inflamm Bowel Dis 2010) [source] Pediatric Crohn's disease activity at diagnosis, its influence on pediatrician's prescribing behavior, and clinical outcome 5 years laterINFLAMMATORY BOWEL DISEASES, Issue 11 2009Tamara Mesker MD Abstract Background: No studies have been performed in which therapeutic regimens have been compared between mild and moderate-to-severe pediatric Crohn's disease (CD) at diagnosis. The aim was to analyze pediatric CD activity at diagnosis, its influence on pediatrician's prescribing behavior, and clinical outcome 5 years later. Methods: In a retrospective multicenter study we divided pediatric CD patients at diagnosis into mild or moderate-severe disease. We compared initial therapies, duration of first remission, number of exacerbations, height-for-age and weight-for-height evolvement, and cumulative duration of systemic steroid use in a 5-year follow-up period. Results: Forty-three children were included (25 with mild and 18 with moderate-severe disease). Aminosalicylate monotherapy was more frequently prescribed in the mild group (40% versus 17%; P < 0.01). The median duration of systemic steroid use was 18.3 months in the mild group and 10.4 months in the moderate-severe group (P = 0.09). Duration of first remission was 15.0 months in the mild group and 23.4 months in the moderate-severe group (P = 0.16). The mean number of exacerbations was 2.2 in the mild group and 1.8 in the moderate-severe group (P = 0.28). Conclusions: CD patients with mild disease were treated with aminosalicylate monotherapy more frequently. These patients, however, tend to have more exacerbations, shorter duration of first remission, and longer total duration of systemic steroid use. Our data support the concept that severity of disease at diagnosis does not reliably predict subsequent clinical course. This study suggests that there is no indication that children with mild CD should be treated differently compared to children with moderate-severe disease. (Inflamm Bowel Dis 2009) [source] Efficacy of infliximab in pediatric Crohn's disease: A randomized multicenter open-label trial comparing scheduled to on demand maintenance therapyINFLAMMATORY BOWEL DISEASES, Issue 3 2009Frank M. Ruemmele MD Abstract Background: Infliximab (IFX) is efficacious in inducing remission in severe forms of pediatric Crohn's disease (CD). Adult studies indicate that IFX is also safe and well tolerated as maintenance therapy. The present study aimed to evaluate in a prospective manner the efficacy and safety of IFX as maintenance therapy of severe pediatric CD comparing scheduled and "on demand" treatment strategies. Methods: Forty children with CD (nonpenetrating, nonstricturing as well as penetrating forms, mean age: 13.9 ± 2.2 years) with a severe flare-up (Harvey,Bradshaw Index [HBI] ,5, erythrocyte sedimentation rate [ESR] >20 mm/h) despite well-conducted immunomodulator therapy (n = 36 azathioprine, n = 1 mercaptopurine, n = 3 methotrexate) combined with steroids were included in this randomized, multicenter, open-label study. Three IFX infusions (5 mg/kg) were administered at week (W)0/W2/W6. At W10, clinical remission (HBI <5) and steroid withdrawal were analyzed and IFX responders were randomized to maintenance therapy over 1 year: group A, scheduled every 2 months; group B, "on demand" on relapse. Results: In all, 34/40 children came into remission during IFX induction therapy (HBI: 6.7 ± 2.5 (WO) vs. 1.1 ± 1.5 (W10); P < 0.001). At the end of phase 2, 15/18 (83%) patients were in remission in group A compared to 8/13 (61%) children in group B (P < 0.01), with a mean HBI of 0.5 versus 3.2 points (group A versus B, P = 0.011). In group A, 3/13 (23.1%) children experienced a relapse compared to 11/12 (92%) children in group B. No severe adverse event occurred during this trial. Conclusions: IFX is well tolerated and safe as maintenance therapy for pediatric CD, with a clear advantage when used on a scheduled 2-month basis compared to an "on demand" basis. (Inflamm Bowel Dis 2009) [source] Mucosal NOD2 expression and NF-,B activation in pediatric Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2008Laura Stronati PhD Abstract Background: Recent advances in the pathogenesis of Crohn's disease (CD) have suggested that an aberrant innate immune response initiates the cascade of events leading to T-cell activation and to disease development. NOD2 protein, which is mainly expressed by innate immunity cells, appears to play a key role against bacteria by triggering a host defense response through the activation of the transcriptor factor NF-,B and a consequent proinflammatory cytokine production. The present study was aimed at investigating the expression and activity of NOD2, NF-,B, and of 2 proinflammatory cytokines, TNF, and IL-1,, in mucosal biopsies of CD affected children compared to healthy controls. Methods: In all, 22 children with active CD and 10 matched controls were entered in the study. mRNA and protein expressions were detected using reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot; NF-,B binding activity was assessed by electromobility gel shift assay (EMSA). Results: NOD2 and IL-1, mRNAs were upregulated in CD children. Protein levels of NOD2, TNF,, and nuclear NF-,B, as well as the binding activity of NF-,B to a consensus DNA sequence, were significantly increased in inflamed mucosa of patients as compared to controls. Moreover, NF-,B activity was strongly upregulated in patients also when bound to the NOD2 promoter site. No difference was seen between patients and controls when NF-,B binding activity was determined in the uninflamed tissue. Conclusions: This study suggests that altered mechanisms regulating NOD2 induction, NF-,B activation and cytokine production may contribute to dysregulate the innate immune response underlying pediatric CD. (Inflamm Bowel Dis 2007) [source] IL-23 receptor (IL - 23R) gene protects against pediatric Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2007Marla C. Dubinsky MD Abstract Background: The IL-23 receptor (IL - 23R) has been found to be associated with small bowel Crohn's disease (CD) in a whole genome association study. Specifically, the rare allele of the R381Q single nucleotide polymorphism (SNP) conferred protection against CD. It is unknown whether IL - 23R is associated with IBD in children. The aim was to examine the association of IL - 23R with susceptibility to IBD in pediatric patients. Methods: DNA was collected from 609 subjects (151 CD and 52 ulcerative colitis [UC] trios). Trios were genotyped for the R381Q SNP of the IL-23R gene and SNP8, SNP12, SNP13, of the CARD15 gene using Taqman. The transmission disequilibrium test (TDT) was used for association to disease using GENEHUNTER 2.0. Results: The rare allele of R381Q SNP was present in 2.7% of CD and 2.9% UC probands. The CARD15 frequency was 31.5% (CD) and 18% (UC). The IL - 23R allele was negatively associated with inflammatory bowel disease (IBD): the R381Q SNP was undertransmitted in children with IBD (8 transmitted [T] versus 27 untransmitted [UT]; P = 0.001). This association was significant for all CD patients (6 T versus 19 UT; P = 0.009), especially for non-Jewish CD patients (2 T versus 17 UT; P = 0.0006). TDT showed a borderline association for UC (2 T versus 8 UT; P = 0.06). As expected, CARD15 was associated with CD in children by the TDT (58 T versus 22 UT P = 0.00006), but not with UC. Conclusions: The protective IL - 23R R381Q variant was particularly associated with CD in non-Jewish children. Thus, the initial whole genome association study based on ileal CD in adults has been extended to the pediatric population and beyond small bowel CD. (Inflamm Bowel Dis 2007) [source] Azathioprine Maintains first remission in newly diagnosed pediatric Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2006Gerald J. Jaspers Abstract 6-Mercaptopurine (6-MP) maintains remission in pediatric Crohn's disease (CD). Azathioprine, a prodrug of 6-MP, is used for maintenance of remission of CD in Europe. We evaluated to what extent azathioprine is used in newly diagnosed pediatric CD patients and whether maintenance of remission differed between patients using azathioprine or not. Charts of children (diagnosed 1998-2003, follow-up , 18 mo) were reviewed. Active disease was defined as Pediatric Crohn's Disease Activity Index (PCDAI) greater than 10 or systemic corticosteroid use. Remission was defined as PCDAI 10 or less without use of corticosteroids. Eighty-eight children (55M/33F, age 12 ± 3 yr) were included. Seventy-two (82%) patients received azathioprine during the follow-up period (38 ± 17 mo). Patients diagnosed after 2000 received azathioprine significantly earlier during the course of disease compared with those diagnosed earlier (median, at 233 vs. 686 days; P < 0.05). At initial presentation, moderate-severe disease activity and prescription of corticosteroids were more prevalent in patients using azathioprine compared with nonazathioprine patients (75% vs. 52%; P < 0.05; and 89% vs. 58%; P < 0.005, respectively). Duration of corticosteroid use was longer in patients receiving azathioprine (232 vs. 168 days; P < 0.005). Median maintenance of first remission in patients who initially used corticosteroids, however, was longer in patients receiving azathioprine compared with nonazathioprine patients (PCDAI, 544 vs. 254 days, P = 0.08; corticosteroid free, 575 vs. 259 days, P < 0.05, respectively). We conclude that, since 2000, azathioprine is being introduced earlier in the treatment of newly diagnosed pediatric CD patients. The use of azathioprine is associated with prolonged maintenance of the first remission. [source] Infliximab improves inflammation and anthropometric measures in pediatric Crohn's diseaseJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2010Daniel M Sinitsky Abstract Background and Aim:, Infliximab (IFX) is a monoclonal antibody licensed to treat medically refractory Crohn's disease (CD). Our aim was to elucidate the effects of IFX therapy on clinical, growth and serum parameters in children with CD in a single pediatric center in Sydney, Australia. Methods:, A retrospective case series review of children treated with IFX for CD at Sydney Children's Hospital, Australia was undertaken, with a review of outcomes after starting IFX. Main outcome measures were response and remission (as measured according to improvements in Pediatric Crohn's Disease Activity Index scores and Physician Global Assessment), laboratory markers (C-reactive protein, erythrocyte sedimentation rate, hemoglobin, white cell count, lymphocytes, neutrophils, platelets, albumin) and growth (Z scores). Results:, The 16 patients included had a mean age at first infusion of 13.0 years (1.25,17.5 years). Six of 12 patients (with adequate data available) were in remission at 2 weeks following the first infusion. At 1 year, 10 of 12 patients (83%) were in remission. Mean C-reactive protein and erythrocyte sedimentation rate had fallen significantly (P < 0.05) at 2 weeks (from 29 to 7 mg/L and 40 to 19 mm/h, respectively). Positive trends were observed for all other parameters, excluding lymphocytes and white cell count. At 1 year, mean Z score for body mass index improved significantly from ,0.9 to ,0.1 (P < 0.01). Conclusions:, Disease activity subsides in most children treated with IFX for CD. IFX therapy also improves some growth parameters. The pattern of improvement requires further elucidation, as the results in the present study suggest differing dosing frequency of infusion may achieve better efficacy. [source] Zoledronic acid for the treatment of osteopenia in pediatric Crohn's diseasePEDIATRICS INTERNATIONAL, Issue 5 2010Anne Marie Sbrocchi Abstract Background:, Pediatric patients with Crohn's disease often have low bone mass (osteopenia) for age. No randomized, placebo-controlled trials using zoledronic acid have ever been performed in this population. The objective of this study was to assess the efficacy of zoledronic acid in children with Crohn's disease and osteopenia. Methods:, A double-blind, randomized, placebo-controlled design was used. Thirteen adolescents received either a single intravenous dose of zoledronic acid (0.066 mg/kg, max 4 mg, n= 7) or saline placebo (n= 6). The primary outcome was change in lumbar spine bone mineral density (LSBMD) z-score at 6 months. Secondary outcomes included bone markers and adverse events. Results:, At 6 months, the change in LSBMD z-score was significantly higher in the zoledronic acid group compared to placebo (0.7 vs 0.1, P < 0.001). Volumetrically adjusted LSBMD z-score also significantly increased in the treated group. This significant difference persisted until 12 months. With zoledronic acid, urinary C-telopeptide excretion decreased by 50% at 6 months and remained suppressed at 12 months (P= 0.02), but no changes were observed with placebo. Both groups had similar adverse events which included transient fever, arthralgias, and nausea (3/7 treated, 2/6 placebo, P= NS). Conclusions:, In this study, zoledronic acid demonstrated a significant increase in LSBMD at 6 and 12 months following a well-tolerated infusion. [source] | ||||||||||