Charles M. Samson

Outcome Following Thiopurine Use in Children With Ulcerative Colitis: A Prospective Multicenter Registry Study

OBJECTIVES:Despite little supporting data, thiopurine use is common in pediatric ulcerative colitis (UC). Our aim was to determine outcome following thiopurine use in a multicenter inception cohort of children diagnosed with UC.METHODS:Data were obtained from a prospective observational study of newly diagnosed children <16 years of age. Data are recorded at diagnosis, 30 days, and quarterly. Patients are managed by physician dictates not protocol. Disease activity is classified by physician global assessment. The primary outcome was corticosteroid (CS)-free inactive UC at 1 year following thiopurine initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy).RESULTS:Of 1,490 patients in our registry, 394 have UC (mean age at diagnosis 11.3±3.7 years); 197 (50%) received thiopurine (49% ≤3 months from diagnosis). Also, 84% were receiving CSs and 60% 5-aminosalicylates at thiopurine start. Of the 197 patients, there was insufficient follow-up (41), previous or concomitant use of infliximab (16), or calcineurin inhibitor (7), leaving 133 patients evaluable at 1 year. Of these, 65 (49%) had CS-free inactive UC without rescue therapy. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤3 months vs. >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan–Meier analysis showed that the likelihood of remaining free of rescue therapy in the thiopurine-treated patients was 73% at 1 year.CONCLUSIONS:Approximately 50% of children with UC starting thiopurine without previous or concomitant biologic or calcineurin inhibitor therapy have CS-free inactive disease 1 year later without the need for rescue therapy.

Presentation and Outcome of Histoplasmosis in Pediatric Inflammatory Bowel Disease Patients Treated with Antitumor Necrosis Factor alpha Therapy: A Case Series

Background: 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. Methods: Following Institutional Review Board approval, cases were identified then reviewed with their primary gastroenterologist and infectious disease specialists. Results: Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area. Conclusions: 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. (Inflamm Bowel Dis 2011;)

Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease.

Objectives: Variations in chronic illness care are common in our health care system and may lead to suboptimal outcomes. Specifically, inconsistent use and suboptimal medication dosing have been demonstrated in the care of patients with inflammatory bowel disease (IBD). Quality improvement (QI) efforts have improved outcomes in conditions such as asthma and diabetes mellitus, but have not been well studied in IBD. We hypothesized that QI efforts would lead to improved outcomes in our pediatric IBD population. Methods: A QI team was formed within our IBD center in 2005. By 2007, we began prospectively capturing physician global assessment (PGA) and patient-reported global assessment. Significant QI interventions included creating evidence-based medication guidelines, joining a national QI collaborative, initiation of preclinic planning, and monitoring serum 25-hydroxyvitamin D. Results: From 2007 to 2010, 505 patients have been followed at our IBD center. During this time, the frequency of patients in clinical remission increased from 59% to 76% (P < 0.05), the frequency of patients who report that their global assessment is >7 increased from 69% to 80% (P < 0.05), and the frequency of patients with a Short Pediatric Crohns Disease Activity Index (sPCDAI) <15 increased from 60% to 77% (P < 0.05). The frequency of repeat steroid use decreased from 17% to 10% (P < 0.05). We observed an association between the use of a vitamin D supplement (P = 0.02), serum 25-hydroxyvitamin D (P < 0.05), and quiescent disease activity. Conclusions: Our results show that significant improvements in patient outcomes are associated with QI efforts that do not rely on new medication or therapies.

Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury

Background Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) relieves symptoms in Crohns disease (CD). It has been reported that reduced GM-CSF bioactivity is associated with more aggressive ileal behaviour and that GM-CSF-null mice exhibit ileal barrier dysfunction and develop a transmural ileitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs). STAT5 signalling is central to GM-CSF action. It was therefore hypothesised that GM-CSF signalling in non-haematopoietic cells is required for ileal homeostasis. Methods Bone marrow (BM) chimeras were generated by reconstituting irradiated GM-CSF receptor (gm-csfr) β chain or GM-CSF (gm-csf) deficient mice with wild type BM (WTBM→GMRKO and WTBM→GMKO). Intestinal barrier function and the response to NSAID-induced ileal injury were examined. Expression of gm-csf, gm-csfr or stat5 in Caco-2 and HT-29 intestinal epithelial cell (IEC) lines was knocked down and the effect of GM-CSF signalling on IEC survival and proliferation was determined. Results Elevated levels of GM-CSF autoantibodies in ileal CD were found to be associated with dysregulation of IEC survival and proliferation. GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras exhibited ileal hyperpermeability. NSAID exposure induced a transmural ileitis in GM-CSF receptor-deficient mice and WTBM→GMRKO chimeras. Transplantation of wild type BM into GM-CSF-deficient mice prevented NSAID ileal injury and restored ileal barrier function. Ileal crypt IEC proliferation was reduced in WTBM→GMRKO chimeras, while STAT5 activation in ileal IEC following NSAID exposure was abrogated in WTBM→GMRKO chimeras. Following knock down of gm-csf, gm-csfr α or β chain or stat5a/b expression in Caco-2 cells, basal proliferation was suppressed. GM-CSF normalised proliferation of Caco-2 cells exposed to NSAID, which was blocked by stat5a/b RNA interference. Conclusions Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury; furthermore, GM-CSF signalling in non-haematopoietic cells regulates ileal epithelial homeostasis via the STAT5 pathway. The therapeutic use of GM-CSF may therefore be beneficial in chronic ileitis associated with CD.

Granulocyte‐macrophage colony stimulating factor blockade promotes ccr9+ lymphocyte expansion in Nod2 deficient mice

Background: Ileal involvement in Crohns disease (CD) is associated with NOD2 mutations and granulocyte‐macrophage colony stimulating factor autoantibodies (GM‐CSF Ab), and GM‐CSF blockade promotes ileitis in Nod2/Card15‐deficient (C15KO) mice. RALDH2‐expressing dendritic cells (DC) and IL‐4 promote CCR9 imprinting and small bowel homing of T lymphocytes, in conjunction with CCL25 expression by ileal epithelial cells (IEC). We hypothesized that GM‐CSF neutralization promotes ileal disease by modulating expression of CCL25 by IEC and CCR9 by T lymphocytes via Nod2‐dependent and independent pathways. Methods: CCL25 and CCR9 expression were determined in pediatric CD patients stratified by GM‐CSF Ab. Ileitis was induced in C15KO mice via GM‐CSF Ab administration followed by nonsteroidal antiinflammatory drug (NSAID) exposure, and expression of CCL25, CCR9, FOXP3, intracellular cytokines, and RALDH2 was determined in IEC and immune cell populations. Results: The frequency of CCL25+ IEC and CCR9+ T lymphocytes was increased in CD patients with elevated GM‐CSF Ab. In the murine model, GM‐CSF blockade alone induced IEC CCL25 expression, and reduced the frequency of mesenteric lymph node (MLN) CD4+FOXP3+ cells, while Card15 deficiency alone enhanced MLN DC RALDH2 expression. Both GM‐CSF neutralization and Card15 deficiency were required for downregulation of MLN DC IL‐10 expression; under these conditions NSAID exposure led to an expansion of IL‐4+ and IL‐17+ CCR9+ lymphocytes in the ileum. Conclusions: GM‐CSF prevents ileal expansion of CCR9+ lymphocytes via Nod2‐dependent and independent pathways. CCR9 blockade may be beneficial in CD patients with elevated GM‐CSF Ab.

Remission in Pediatric Inflammatory Bowel Disease Correlates with Prescription Refill Adherence Rates.

Objectives: The aim of the study was to use pharmacy benefit management (PBM) prescription claims data to assess refill adherence in pediatric inflammatory bowel disease (IBD) and correlate adherence with clinical outcomes in pediatric IBD. Methods: We identified 362 pediatric patients with IBD seen at Washington University from 9/1/2012 to 8/31/2013 and matched them within Express Scripts’ member eligibility files for clients allowing use of prescription drug data for research purposes. Maintenance IBD medication possession ratios (MPR) were determined through PBM prescription claims data and chart review. Demographic and prospectively captured physician global assessments (PGA) were retrospectively extracted from the medical record. MPR was analyzed as continuous data and also dichotomized as greater or less than 80%. Results: Among our 362 patients, we matched 228 (63%) within Express Scripts’ eligibility data files. Of those, 78 patients were continuously eligible for benefits and had at least one outpatient prescription IBD medication prescribed. Their mean MPR was 0.63 ± 0.31 (standard deviation) and 40% had an MPR ≥80%. Patients in clinical remission had a higher mean MPR than those with an active PGA (0.72 ± 0.28 vs 0.51 ± 0.32, P = 0.002) and patients whose MPR were ≥80% were more likely to have a PGA of remission than those with whose MPR were <80% (84% vs 43%, P = <0.001). Conclusions: We found a significant association between refill adherence and clinical remission. Nonadherence was common and was more common in adolescents. Use of PBM databases to identify and intervene on patients with poor adherence may improve outcomes in pediatric IBD.

Budesonide use in pediatric Crohn disease.

Background and Aim: Budesonide (BUD) is being used in pediatric Crohn disease (CD) because it is believed to have the potential to reduce corticosteroid-related toxicity; however, few data are available describing its use. The aim of the present study was to describe BUD use in an inception cohort of pediatric patients with CD. Methods: Data were derived from the prospective Pediatric IBD Collaborative Research Group Registry established in 2002 in North America. Use of BUD in children with CD was examined. Results: BUD was used in 119 of 932 (13%) of children with newly diagnosed CD, with 56 of 119 (47%) starting BUD ⩽30 days of diagnosis (26/56 with ileum and/or ascending colon [IAC] disease). BUD was used as monotherapy (9%), in combination with 5-aminosalicylates (77%), or in combination with immunomodulators (43%). Forty-three percent (24/56) went on to receive conventional corticosteroid at some point following their first BUD course. For the 63 of 119 (53%) who started BUD beyond the diagnosis period, 51 of 63 (81%) also received prednisone, with BUD used as a means of weaning from prednisone in 17 of 63 (27%). Patients with IAC disease who received BUD ⩽30 days of diagnosis were just as likely to have received conventional corticosteroids by 1 year as were those who did not receive BUD ⩽30 days of diagnosis. Two-thirds (77/119) of patients received BUD for ⩽6 months. Conclusions: BUD is being used among pediatric patients newly diagnosed as having CD, although the majority does not have disease limited to the IAC. BUD monotherapy was rare, and further data are required to better define the role of BUD in the treatment of pediatric CD.

Serologic Evidence of Gut-driven Systemic Inflammation in Juvenile Idiopathic Arthritis

Objective. Accumulating evidence links juvenile idiopathic arthritis (JIA) to nonhost factors such as gut microbes. We hypothesize that children with new-onset JIA have increased intestinal bacterial translocation and circulating lipopolysaccharide (LPS). Methods. We studied systemic treatment-naive patients with JIA [polyarticular JIA, n = 22, oligoarticular JIA, n = 31, and spondyloarthropathies (SpA), n = 16], patients with established inflammatory bowel disease–related arthritis (IBD-RA, n = 11), and 34 healthy controls. We determined circulating IgG reactivity against LPS, LPS-binding protein (LBP), α-1-acid glycoprotein (α-1AGP), and C-reactive protein (CRP) in plasma or serum from these patients and controls. Juvenile Arthritis Disease Activity Score (JADAS-27) was calculated for patients with JIA. Results. Circulating anticore LPS antibody concentrations in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.024), and SpA (p = 0.001) were significantly greater than in controls, but there were no significant intergroup differences. Circulating LBP concentrations were also significantly greater in patients with polyarticular JIA (p = 0.001), oligoarticular JIA (p = 0.002), and SpA (p = 0.006) than controls, as were α-1AGP concentrations (p = 0.001, 0.001, and 0.003, respectively). No differences were observed between controls and patients with IBD-RA in any of the assays. Circulating concentrations of LBP and α-1AGP correlated strongly with CRP concentrations (r = 0.78 and r = 0.66, respectively). Anticore LPS antibody levels and CRP (r = 0.26), LBP (r = 0.24), and α-AGP (r = 0.22) concentrations had weaker correlations. JADAS-27 scores correlated with LBP (r = 0.66) and α-1AGP concentrations (r = 0.58). Conclusion. Children with polyarticular JIA, oligoarticular JIA, and SpA have evidence of increased exposure to gut bacterial products. These data reinforce the concept that the intestine is a source of immune stimulation in JIA.

Accuracy of the medication list in the electronic health record—implications for care, research, and improvement

Objective Electronic medication lists may be useful in clinical decision support and research, but their accuracy is not well described. Our aim was to assess the completeness of the medication list compared to the clinical narrative in the electronic health record. Methods We reviewed charts of 30 patients with inflammatory bowel disease (IBD) from each of 6 gastroenterology centers. Centers compared IBD medications from the medication list to the clinical narrative. Results We reviewed 379 IBD medications among 180 patients. There was variation by center, from 90% patients with complete agreement between the medication list and clinical narrative to 50% agreement. Conclusions There was a range in the accuracy of the medication list compared to the clinical narrative. This information may be helpful for sites seeking to improve data quality and those seeking to use medication list data for research or clinical decision support.

The Use of Concomitant Immunomodulators with Adalimumab Therapy in Pediatric Crohn’s Disease

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.