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We have identified a subset of Crohn's Disease (CD) patients with neutralizing antibodies to Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF Ab) who exhibit increased risk for stricturing ileal disease. We have developed a novel murine model of ileitis involving Card15 deficient mice (C15KO) with GM-CSF neutralization and non-steroidal exposure. However, the reason for ileal specificity with loss of GM-CSF bioactivity was not known. It is known that CCL25 and CCR9 are important in trafficking immune cells to the small intestine, and that antibody blockade of this pathway can ameliorate spontaneous ileitis in the Samp1/YitFc mouse. A clinical trial of a CCR9 antagonist is currently underway. To determine if loss of GM-CSF bioactivity is associated with alterations in CCR9 or CCL25 in human CD and murine ileitis. Ileal biopsies from pediatric patients undergoing diagnostic endoscopy were obtained and immunohistochemistry was performed for CCL25 and CCR9. Blood samples obtained from pediatric patients with CD or healthy controls (HC) were analyzed for GM-CSF Ab and the frequency of CCR9+ lymphocytes. CD patients were classified as Ab+ if their GM-CSF Ab level was above the cut-point of 1.6 mcg/mL which we have previously defined. For our murine studies, C57Bl/6J wild type (WT) or C15KO mice were injected with IgG or neutralizing gm-csf Ab. Two weeks later, mice were placed on piroxicam (NSAID) chow for 1 week before sacrifice. Spleens, mesenteric lymph nodes (MLN) and ileum was harvested for flow cytometric analysis. Ileal biopsies and/or peripheral blood samples were obtained from 45 subjects. Age, gender, disease duration, and clinical disease activity did not differ between Ab+ and Ab- CD patients. There was a trend towards a higher ileal CD histological index of severity score in Ab+ patients compared to Ab- patients. Ab+ patients had a higher frequency of CCL25+ epithelial cells compared to either HC or Ab- patients (1.4 ± 0.1% vs. 0.6 ± 0.2% and 0.6 ± 0.4%, respectively). Ab+ patients also had a higher number of ileal CCR9+ cells/hpf compared to either HC or Ab- patients (16±5/hpf vs. 5±3/hpf and 7±1/hpf). For the peripheral blood studies, medication exposure was similar except that a lower frequency of Ab+ patients were on a 5-ASA compared to Ab- patients (15% vs.78%). The frequency of CD4+ cells that were CCR9+ was significantly higher in Ab+ patients compared to HC or Ab- patients (14±9% vs. 6±5% and 7±6%, respectively). In our murine studies, transmural ileitis developed in C15KO mice following gm-csf neutralization and NSAID exposure. Flow cytometric analysis demonstrated an expansion of CD4+CCR9+ lymphocytes in the affected ileum (41±10% vs. 24±6% in WT mice with GM-CSF neutralization and NSAID exposure), MLN (49±10% vs. 32±8%), and spleen (49±14% vs. 26±5%). CD patients with increased GM-CSF Ab have increased CCL25+ and CCR9+ cells within the affected ileum and increased circulating CCR9+ lymphocytes. Our novel animal model of ileitis is also associated with an up-regulation of CCR9+ lymphocytes. Patients with decreased GM-CSF bioactivity may particularly benefit from therapeutic blockade of this pathway.
Antitumor necrosis factor alpha (aTNF) therapies are commonly used in the treatment of pediatric inflammatory bowel disease (IBD). However, inhibition of the TNF-alpha pathway predisposes to serious infections, including histoplasmosis, which is the most common invasive fungal infection in individuals on aTNF therapy and carries a high mortality rate when associated with delayed diagnosis. Few data exist on the frequency, presentation, and appropriate treatment of pediatric patients with histoplasmosis on aTNF therapy.Following Institutional Review Board approval, cases were identified then reviewed with their primary gastroenterologist and infectious disease specialists.Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area.Histoplasmosis is an important complication of treatment with TNF-alpha neutralizing agents. Children with IBD treated with aTNF therapy who develop the infection may present with minimal pulmonary symptoms. While discontinuation of aTNF therapy is important initially, few data exist to determine when and how aTNF therapy can be reinstituted. Recognition of Histoplasma capsulatum is often delayed due to the overlap of symptoms with some of the extraintestinal manifestations of IBD and other more prevalent infectious complications.
Objectives: Adalimumab is an effective treatment for Crohn’s disease but antibody development may cause loss of response. Concomitant use of an immunomodulator reduces the development of antibodies. We performed a 5- year cross-sectional study of variation in use of adalimumab and concomitant therapy in a large pediatric population.Methods: We identified patients with Crohn’s disesae aged <18 years in the ImproveCareNow registry who received adalimumab between June 2010 through May 2015, and determined the rates of treatment with adalimumab and concomitant therapy with thiopurine or methotrexate, including variation by age, sex, geographical region and annual change. Chi-square tests compared percentages and the Cochran Armitage Trend Test tested percentages over time and across age groups.Results: Of 7,271 patients, adalimumab treatment occurred in 1,009 (14%), more likely with increasing age (p<0.001), in females (p<0.001), and in the West than the Northeast US (p<0.001). From year 1 to year 5, the use of adalimumab increased from 7% to 13% (p<0.001) and concomitant therapy increased from 25% to 47% (p<0.001). Of patients treated with adalimumab, 47% received concomitant therapy with thiopourine (19%) or methotrexate (28%). Concomitant therapy occurred more commonly in younger patients (p<0.01) but frequencies by sex were not significantly different (p=0.17).Conclusions: In pediatric Crohn’s disease there is increasing use of both adalimumab and concomitant therapy, including both thiopurine and methotrexate, with significant variation by age, sex and region of the US. Further study is needed to determine the effectiveness of and indications for concomitant therapy with adalimumab treatment.
Su1752 Comparison of Colonoscopy Preparations in a Pediatric Population Caroline T. Meyer*, Christina a. Hickey, June Y. Hu, Charles M. Samson, Elizabeth C. Utterson Pediatric Gastroenterology, Washington University in St. Louis, Saint Louis, MO; Pediatrics, Washington University in St. Louis, Saint Louis, MO Background: Poor quality colonoscopy preparation in pediatric patients can lead to inadequate visualization of colonic mucosa resulting in missed diagnoses, increased time under anesthesia and the need for repeat procedures. There have been few studies in the literature comparing colonoscopy preparation regimens in pediatric patients. Aims: To compare the efficacy of 2 different colonoscopy preparation regimens in pediatric patients at our institution. Methods: For our institutional quality improvement project, three endoscopists scored the visualization of colonic mucosa based on the Boston Bowel Prep Score (scores 0-9) and time to completion of colonoscopy (measured in!30 minutes, 30 minutes-1 hour, and O1 hour) in patients 8 years and older throughout a six month time period. An adequate cleanout was determined by a score R 5. Patients were prescribed either a regimen of 240 ml of magnesium citrate with two 10mg bisacodyl suppositories (phase 1) or polyethylene glycol (PEG) 3350 (8-12 years old: 119 grams in 960 ml of fluid and O12 years old: 238 grams of PEG 3350 in 1.92 liters of fluid) with oral bisacodyl (8-12 years old: 10mg and O12 years old: 20mg) (phase 2). Both groups were instructed to drink clear liquids the day prior to the procedure. The patients and their families were asked if they had completed all portions of the regimen prior to colonoscopy. Appropriate statistical tests were performed using IBM SPSS. Results: Forty-four patients were scored on the magnesium citrate/bisacodyl suppository prep and fifty patients were scored on the PEG 3350/oral bisacodyl prep. Two patients (one in each group) completed!75% of the regimen. Patients ranged in age from 8-25 years old. There was no significant difference in the mean age (pZ0.29) or the male to female ratio between groups (pZ0.85). The mean bowel prep score of the PEG 3350 group was 6.4 compared to 5.14 in the magnesium citrate group; the distributions of the two groups differed significantly (p!0.001) with statistically different medians (pZ0.03). The proportion of patients in the PEG 3350 group with a bowel prep score R 5 was 76% compared to 59% in patients receiving magensium citrate (pZ0.08) The percent of patients where the colonscopy was completed in less than 30 minutes was significantly higher in the PEG 3350 group (46% vs. 24%, pZ0.03). Conclusions: In our quality improvement project, there was a significant improvement in the efficacy as measured by visualization of colonic mucosa in the PEG 3350/oral bisacodyl treated group and improvement in the percent of colonoscopies completed in less than 30 minutes compared to the magnesium citrate/bisacodyl suppository group. Future studies utilizing patient questionnaire data and larger prospective blinded trials would provide additional information on tolerance and efficacy of bowel preparatory regimens in pediatric patients.
