Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Differential expression of small bowel TGFß1 and TGFß3 characterizes intestinal strictures in patients with fibrostenotic Crohn's disease.

Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFß has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFß isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFß's role in stricture formation. The mucosa of strictures was characterized by higher TGFß1 while the stricture submucosa showed higher TGFß3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFß3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFß1 and/or TGFß3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease.

A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.

AIMS: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters. METHODS: A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationships for infliximab. RESULTS: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric cohorts (n = 141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. CONCLUSION: The paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Clinical Practice Survey of Repeat Endoscopy in Pediatric Inflammatory Bowel Disease in North America.

OBJECTIVES: Endoscopic remission has become a standard treatment target in inflammatory bowel disease (IBD). It is unclear how widely this practice has been adopted amongst pediatric gastroenterology providers. This study determines the frequency of repeat endoscopy in pediatric IBD and evaluates for predictive baseline characteristics of providers. METHODS: We developed a cross-sectional survey, which was distributed via 3 national email listservs to pediatric gastroenterology providers. We obtained baseline characteristics of respondents and assessed motivations and barriers for the practice of repeat endoscopy compared with none. RESULTS: Two hundred and thirty-eight unique respondents completed the online survey. Response rate was 11% (238 of 2300 possible participants). The majority practice in an academic setting (77%) and reported participation in ImproveCareNow (63%). Overall, 65% of respondents perform repeat endoscopy to assess for endoscopic remission in pediatric IBD as part of routine clinical practice. Fifty-six percent reported repeat endoscopy as individuals in the absence of a departmental protocol. "Symptoms are not sufficient to follow IBD patients" was reported by 82% of those who repeat endoscopy; conversely, "I perform endoscopy based on clinical, biomarker, and/or imaging trends" was reported by 81% of those who do not repeat endoscopy. The establishment of a pediatric-specific guideline was most commonly reported to change current practice, based on rank-order scoring. CONCLUSIONS: A majority of representative providers repeat endoscopy to assess for endoscopic remission in pediatric IBD. Fewer years in practice favored repeating endoscopy. The need for North American pediatric guidelines with pediatric-specific evidence to support the long-term benefits of endoscopic remission are highlighted in this study.

Proteomic Discovery of Stool Protein Biomarkers for Distinguishing Pediatric Inflammatory Bowel Disease Flares.

Fecal calprotectin, the heterodimer of S100A8/S100A9, makes up ∼60% of neutrophil cytoplasmic protein content and is a canonical clinical biomarker of gut inflammation.1,2 Fecal calprotectin is commonly used to diagnose inflammatory bowel disease (IBD) and has an average sensitivity of 93% and specificity of 96%.1 For diagnosing pediatric IBD, calprotectin fecal tests have similar sensitivity (92%) but substantially less specificity (76%).1 Low specificity, especially in pediatric patients, means a high likelihood of false negative diagnoses, suggesting that a substantial number of active IBD cases remain undiagnosed and untreated. To improve on calprotectin as an effective IBD monitoring tool in pediatric populations, specificity must be increased. To develop an assay with higher specificity in pediatric patients, we identified a panel of multiple proteins that are present in both IBD flare and remission but have distinct abundance ranges between each condition. From a pilot cohort of 10 pediatric patients in states of either active disease or remission, we discovered and relatively quantified hundreds of stool proteins. Of these, our mass spectrometry-based study prioritized at least 5 that have potential to augment negative predictive power of mucosal-level inflammation alongside fecal biomarkers such as calprotectin.

Home Infliximab Infusions Are Associated With Suboptimal Outcomes Without Cost Savings in Inflammatory Bowel Diseases.

INTRODUCTION: Biologic agents including infliximab are effective but costly therapies in the management of inflammatory bowel disease (IBD). Home infliximab infusions are increasingly payer-mandated to minimize infusion-related costs. This study aimed to compare biologic medication use, health outcomes, and overall cost of care for adult and pediatric patients with IBD receiving home vs office- vs hospital-based infliximab infusions. METHODS: Longitudinal patient data were obtained from the Optum Clinformatics Data Mart. The analysis considered all patients with IBD who received infliximab from 2003 to 2016. Primary outcomes included nonadherence (≥2 infliximab infusions over 10 weeks apart in 1 year) and discontinuation of infliximab. Secondary outcomes included outpatient corticosteroid use, follow-up visits, emergency room visits, hospitalizations, surgeries, and cost outcomes (out-of-pocket costs and annual overall cost of care). RESULTS: There were 27,396 patients with IBD (1,839 pediatric patients). Overall, 5.7% of patients used home infliximab infusions. These patients were more likely to be nonadherent compared with both office-based (22.2% vs 19.8%; P = .044) and hospital-based infusions (22.2% vs 21.2%; P < .001). They were also more likely to discontinue infliximab compared with office-based (44.7% vs 33.7%; P < .001) or hospital-based (44.7% vs 33.4%; P < .001) infusions. On Kaplan-Meier analysis, the probabilities of remaining on infliximab by day 200 of therapy were 64.4%, 74.2%, and 79.3% for home-, hospital-, and office-based infusions, respectively (P < .001). Home infliximab patients had the highest corticosteroid use (cumulative corticosteroid days after IBD diagnosis: home based, 238.2; office based, 189.7; and hospital based, 208.5; P < .001) and the fewest follow-up visits. Home infusions did not decrease overall annual care costs compared with office infusions ($49,149 vs $43,466, P < .001). DISCUSSION: In this analysis, home infliximab infusions for patients with IBD were associated with suboptimal outcomes including higher rates of nonadherence and discontinuation of infliximab. Home infusions did not result in significant cost savings compared with office infusions.

Nationwide Trends in Acute and Chronic Pancreatitis Among Privately Insured Children and Non-Elderly Adults in the United States, 2007-2014.

BACKGROUND & AIMS: Epidemiologic analyses of acute pancreatitis (AP) and chronic pancreatitis (CP) provide insight into causes and strategies for prevention and affect allocation of resources to its study and treatment. We sought to determine current and accurate incidences of AP and CP, along with the prevalence of CP, in children and adults in the United States. METHODS: We collected data from the Truven MarketScan Research Databases of commercial inpatient and outpatient insurance claims in the United States from 2007 through 2014 (patients 0-64 years old). We calculated the incidences of AP and CP and prevalence of CP based on International Classification of Diseases, 9th Revision diagnosis codes. Children were defined as 18 years or younger and adults as 19 to 64 years old. RESULTS: The incidence of pediatric AP was stable from 2007 through 2014, remaining at 12.3/100,000 persons in 2014. Meanwhile, the incidence for adult AP decreased from 123.7/100,000 persons in 2007 to 111.2/100,000 persons in 2014. The incidence of CP decreased over time in children (2.2/100,000 persons in 2007 to 1.9/100,000 persons in 2014) and adults (31.7/100,000 persons in 2007 to 24.7/100,000 persons in 2014). The prevalences of pediatric and adult CP were 5.8/100,000 persons and 91.9/100,000 persons, respectively, in 2014. Incidences of AP and CP increased with age. We found little change in incidence during the first decade of life but linear increases starting in the second decade. CONCLUSIONS: We performed a comprehensive epidemiologic analysis of privately insured, non-elderly adults and children with AP and CP in the United States. Changes in gallstone formation, smoking, and alcohol consumption, along with advances in pancreatitis management, may be responsible for the stabilization and even decrease in the incidences of AP and CP.

Gender difference in the impact of coexisting diabetes mellitus on long-term clinical outcome in people with heart failure: a report from the Korean Heart Failure Registry.

AIM: Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure. METHODS: A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission. RESULTS: People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P < 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P > 0.05). CONCLUSIONS: In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.

Sex Differences in Treatment Strategies Among Patients With Ulcerative Colitis: A Retrospective Cohort Analysis of Privately Insured Patients.

BACKGROUND: Sex-based treatment disparities occur in many diseases. Women undergo fewer procedural interventions, and their care is less consistent with guideline-based therapy. There is limited research exploring sex-based differences in ulcerative colitis treatment. We hypothesized that women are less likely to be treated with strategies consistent with long-term disease remission, including surgery and maintenance medications. OBJECTIVE: The aim of this study was to determine if patient sex is associated with choice of treatment strategy for ulcerative colitis. DESIGN: This is a retrospective cohort analysis. SETTING: Data were gathered from a large commercial insurance claims database from 2007 to 2015. PATIENTS: We identified a cohort of 38,851 patients newly diagnosed with ulcerative colitis, aged 12 to 64 years with at least 1 year of follow-up. MAIN OUTCOME MEASURES: The primary outcomes measured were the differences between male and female patients in 1) rates and types of index ulcerative colitis operations, 2) rates and types of ulcerative colitis medication prescriptions, and 3) rates of opioid prescriptions. RESULTS: Men were more likely to undergo surgical treatment for ulcerative colitis (2.94% vs 1.97%, p < 0.001, OR 1.51, p < 0.001). The type of index operation performed did not vary by sex. Men were more likely to undergo treatment with maintenance medications, including biologic (12.4% vs 10.2%, p < 0.001, OR 1.22, p < 0.001), immunomodulatory (16.3% vs 14.9%, p < 0.001, OR 1.08, p = 0.006), and 5-aminosalicylate medications (67.0% vs 63.2%, p < 0.001, OR 1.18, p < 0.001). Women were more likely to undergo treatment with rescue therapies and symptomatic control with corticosteroids (55.5% vs 54.0%, p = 0.002, OR 1.07, p = 0.002) and opioids (50.2% vs 45.9%, p < 0.001, OR 1.17, p < 0.001). LIMITATIONS: Claims data lack clinical characteristics acting as confounders. CONCLUSIONS: Men with ulcerative colitis were more likely to undergo treatment consistent with long-term remission or cure, including maintenance medications and definitive surgery. Women were more likely to undergo treatment consistent with short-term symptom management. Further studies to explore underlying mechanisms of sex-related differences in ulcerative colitis treatment strategies and disease trajectories are warranted. See Video Abstract at http://links.lww.com/DCR/A943.

Patient decision-making in severe inflammatory bowel disease: the need for improved communication of treatment options and preferences.

AIM: Patients with inflammatory bowel disease and their physicians must navigate ever-increasing options for treatment. The aim of this study was to elucidate the key drivers of treatment decision-making in inflammatory bowel disease. METHODS: We conducted qualitative semi-structured in-person interviews of 20 adult patients undergoing treatment for inflammatory bowel disease at an academic medical centre who either recently initiated biologic therapy or underwent an operation or surgical evaluation. Interviews were audio-recorded, transcribed verbatim, iteratively coded, and discussed to consensus by five researchers. We used thematic analysis to explore factors influencing decision-making. RESULTS: Four major themes emerged as key drivers of treatment decision-making: perceived clinical state and disease severity, the patient-physician relationship, knowledge, attitudes and beliefs about treatment options, and social isolation and stigma. Patients described experiencing a clinical turning point as the impetus for proceeding with a previously undesired treatment such as infusion medication or surgery. Patients reported delays in care or diagnosis, inadequate communication with their physicians, and lack of control over their disease management. Patients often stated that they considered surgery to be the treatment of last resort, which further compounded the complexity of making treatment decisions. CONCLUSION: Patients described multiple barriers to making informed and collaborative decisions about treatment, especially when considering surgical options. Our study reveals a need for more comprehensive communication between the patient and their physician about the range of medical and surgical treatment options. We recommend a patient-centred approach toward the decision-making process that accounts for patient decision-making preferences, causes of social stress, and clinical status.

Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis.

OBJECTIVE: To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC). STUDY DESIGN: We performed a prospective observational cohort study in infants with a birth weight of <1500 g without existing bowel disease at a level IV neonatal intensive care unit from October 2015 to September 2016. Stools were collected once daily for 30 days or until 32 weeks postmenstrual age and processed using the Fecal Calprotectin High Range Quantitative Quantum Blue assay. RESULTS: In 64 preterm infants, during the first week after birth, 62% of infants had an initial stool sample with high baseline calprotectin levels (≥200 µg/g). In assessment of maternal and neonatal risk factors, maternal etiology for preterm birth (ie, eclamplsia or preeclampsia) was the only significant factor associated with high baseline calprotectin level. Two patients in the cohort developed NEC. Calprotectin levels for the entire cohort fluctuated during the observed period but generally increased in the third and fourth weeks after birth. CONCLUSIONS: At-risk infants had highly variable fecal calprotectin levels, with maternal causes for preterm birth associated with higher baseline levels. More longitudinal data in infants with NEC are necessary to determine whether acute rises in fecal calprotectin levels prior to clinical diagnosis can be confirmed as a diagnostic or prognostic biomarker.

Competitively Selected Donor Fecal Microbiota Transplantation: Butyrate Concentration and Diversity as Measures of Donor Quality.

In this prospective cohort study, we examine the feasibility of a protocol to optimize microbiota for fecal microbiota transplantation (FMT). Donor stool metrics generally accepted as markers of gut health were used to select a stool donor based on superior microbial diversity, balanced constitution of Bacteroidetes versus Firmicutes and high concentration of fecal butyrate. Selected donor microbiota was then administered via FMT. A total of 10 patients with median age of 12 years with recurrent Clostridium difficile infection received the intervention. The rate of recurrence-free resolution with 1-2 FMTs was 100% at Week 10. With a single FMT, 80% of patients cleared Clostridium difficile infection without recurrence, whereas 20% of patients required a single re-treatment. No serious adverse events occurred. Microbiota sequencing revealed that recipients' gut microbiota phylogenic diversity increased by 72-hours post-transplantation, with sustainment over 10-week follow-up. This study highlights the feasibility of purposefully selecting the most ideal microbiota for transplantation.

The Role of Combination Therapy in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

The treatment goal for children suffering from inflammatory bowel disease has been evolving with biologic therapies like anti-tumor necrosis factor agents assuming a more central role in treatment of more aggressive and extensive phenotype. Earlier introduction of anti-tumor necrosis factor agents have shown to be more effective and may even alter the natural history of inflammatory bowel disease. Development of anti-drug antibodies, however, limits long-term usage and leads to dose adjustment in almost half of patients treated with these medications. One of the strategies to minimize the development of anti-drug antibodies has been concomitant use of immunomodulator medications, resulting in fewer infusion reactions and sustained trough levels, potentially lowering the need for dose adjustments. Balanced with these benefits of optimized dosing and likely more sustained response, however, is the concern about increased risk of complications, such as infections and malignancies. The current manuscript reviews the available pediatric literature regarding efficacy, safety, and side effect profile of combination (immunomodulator and biologics) therapy in pediatric Crohn disease and ulcerative colitis, with particular emphasis on cost constraints, and recommendations for selection of patients who would benefit most from combination therapy.

Assuring Quality for Non-hospital-based Biologic Infusions in Pediatric Inflammatory Bowel Disease: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

The primary aim of this Clinical Report by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition is to provide formal guidance to pediatric gastroenterologists and clinicians, health systems, and insurance payers regarding home- and office-based infusions for biologic therapies in pediatric inflammatory bowel disease. Patients in North America are increasingly denied coverage by payers based on "place of service" codes at hospital-based infusion units where the treating clinicians primarily provide care. A task force with topic expertise generated 8 best practice recommendations to ensure quality of care for pediatric patients with inflammatory bowel disease receiving non-hospital-based biologic infusions. Pragmatic considerations discussed in this report include patient safety, pediatric-trained nurse availability, care coordination, patient-centeredness, shared liability, administrative support, clinical governance, and costs of care.

Text Message Intervention (TEACH) Improves Quality of Life and Patient Activation in Celiac Disease: A Randomized Clinical Trial.

OBJECTIVE: To determine the impact of the Text Message Educational Automated Compliance Help (TEACH) text message intervention as a pragmatic approach for patient engagement among adolescents with celiac disease (CD) as measured by gluten-free diet (GFD) adherence, patient activation, and quality of life (QOL). STUDY DESIGN: Randomized controlled trial with patient recruitment at a pediatric, university-based hospital and through social media; 61 participants ages 12-24 years with CD diagnosed at least 1 year were enrolled. The TEACH intervention cohort received 45 unique text messages over a 3-month study period while the control group received standard of care treatment. Primary outcome measures included objective markers of GFD adherence included serum tissue transglutaminase IgA and deamidated gliadin peptide IgA levels. Secondary patient-reported outcomes collected via online survey included the Celiac Dietary Adherence Test, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Global Short Form measure of QOL, Celiac Symptom Index, and Patient Activation Measure. All measures were assessed at enrollment and after the 3-month study period. Statistical analysis performed using the 2-tailed paired Student t test. RESULTS: Among the TEACH intervention group, there was significant improvement comparing enrollment scores with 3-month follow-up scores in patient activation (Patient Activation Measure score 63.1 vs 72.5, P?=?.01) and QOL (NIH PROMIS Global Mental Health 50.8 vs 53.3, P?=?.01 and NIH PROMIS Global Physical Health 50.8 vs 57.7, P?=?.03). There was no statistically significant difference in patient-reported or objectively measured GFD adherence. CONCLUSIONS: TEACH is an effective intervention among patients with CD to improve patient activation and QOL, even among a cohort with GFD adherence at baseline. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02458898.

Frequency of Severe Infusion Reactions Associated With Outpatient Infusion of Infliximab Without Premedications.

In this report, we describe incremental changes, during a 2-year period at a single center with the administration of maintenance infliximab infusions. Given practice-driven changes consisting of 1-hour infusions and omission of premedications, we aimed to investigate if these changes contributed to severe infusion reactions. We reviewed approximately 900 infliximab infusions in a pediatric ambulatory infusion center from January 1, 2014, to December 31, 2015, for severe adverse reactions requiring either rescue epinephrine or a code blue or "rapid response" activation. In 2015, these practice changes resulted in a 51% decrease in total infusion hours (1281 to 630 infusion hours), despite a 9% increase in total number of infusions. No increase in severe adverse events associated with either rapid 1-hour infusion or omission of premedications. Our findings highlight a quality-improvement opportunity to standardize infliximab infusions to streamline care in an ambulatory setting.

Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease.

OBJECTIVES: The pharmacokinetics of infliximab (IFX) is highly variable in children with Crohn disease (CD), and a one-size-fits-all approach to dosing is inadequate. Model-based drug dosing can help individualize dosing strategies. We evaluated the predictive performance and clinical utility of a published population pharmacokinetic model of IFX in children with CD. METHODS: Within a cohort of 34 children with CD who had IFX trough concentrations measured, the pharmacokinetics of each patient was estimated in NONMEM using a published population pharmacokinetic model. Infliximab concentrations were then predicted based on each patient's dosing history and compared with actual measured concentrations (n = 59). In addition, doses 5 to 10 mg/kg and dosing intervals every 4 to 8 weeks were simulated in each patient to examine dose-trough relationships. RESULTS: Predicted concentrations were within ±1.0 µg/mL of actual measured concentrations for 88% of measurements. The median prediction error (ie, measure of bias) was -0.15 µg/mL (95% confidence interval -0.37 to -0.05 µg/mL) and absolute prediction error (ie, measure of precision) was 0.26 µg/mL (95% confidence interval 0.15 to 0.40 µg/mL). At standard maintenance dosing of 5 mg/kg every 8 weeks, a trough >3 µg/mL was predicted to be achieved in 32% of patients. To achieve a trough >3 µg/mL, a dosing interval ≤every 6 weeks was predicted to be required in 29% of patients. CONCLUSIONS: A published IFX population pharmacokinetic model demonstrated accurate predictive performance in a pediatric CD population. Individualized IFX dosing strategies in children with CD will be critical to consistently achieve trough concentrations associated with optimal outcomes.

Donor Considerations in Fecal Microbiota Transplantation.

PURPOSE OF REVIEW: Tremendous acceleration has been made in understanding the gut microbiota in the past decade and, with it, further understanding of the pathologic role of dysbiosis and the use of fecal microbiota transplantation (FMT) as therapy. FMT has been studied in many disease states including the most common indication of Clostridium difficile infection (CDI), though many questions regarding stool donor selection remain. RECENT FINDINGS: Though traditionally, one donor has provided stool for one patient, research is underway to explore many donor selection considerations from the use of pooled donor stool to selection of a high diversity donor. It is well-known that dietary intake shapes the gut microbiota and the potential implications of this on FMT donor selection are being explored. Though further high-quality research is needed, optimizing the fecal microbiota inoculum holds great promise.

Health Insurance Paid Costs and Drivers of Costs for Patients With Crohn's Disease in the United States.

OBJECTIVES: The cost of medical care for Crohn's disease (CD) and comorbidities in the era of biologics is unclear. We examined insurance claims data from US health plans to understand this relationship. METHODS: Longitudinal CD patient data and reimbursement information from 11 health plans engaged with Accordant Health Services between 2011 and 2013 were analyzed. The analysis considered data for all CD patients and for the patient subgroup ≤20 years and >20 years of age. Descriptive statistics measured the mean health-plan paid costs per patient, the relative cost contribution of anti-tumor necrosis factor (TNF) agents, and health care costs for 31 specific comorbid conditions among CD patients. RESULTS: Overall, there were 5,090 CD patients (57% women) of which 587 CD patients were ≤20 years of age. The mean health-plan paid cost per member per year was $18,637 (s.d. $32,023) for all CD patients, $22,796 (s.d. $ 41,905) for CD patients ≤20 years, and $18,095 (s.d. $30,065) for patients >20 years of age. Twenty-eight percent of CD patients accounted for 80% of total costs. No differences were found in costs based on gender. Increased health-plan paid costs were significantly correlated with the number of comorbid conditions across all ages. Pharmacy utilization costs account for nearly one-half (45.5%) of the total CD-attributable costs, exceeding inpatient care costs. Anti-TNF agents alone comprised nearly one-third (29.5%) of total costs. Aside from anti-TNF costs, other major categories of expense were as follows: inpatient 23.1%, outpatient hospital setting 15.7%, and MD office 8.2%. CONCLUSIONS: Total health-care costs in CD exceed previous estimates, with the majority of costs being allocated to a relatively small subgroup of patients. Pharmacy utilization costs, owing to anti-TNF use, result in increasing total health-care costs and currently exceed costs for inpatient care. Pragmatic strategies to encourage gastroenterologists in the best clinical practice of optimizing anti-TNF use-in particular for younger age patients and those with multiple comorbidities-are necessary to reduce avoidable pharmacy utilization and inpatient care costs.

Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease.

OBJECTIVES: Standard infliximab maintenance dosing of 5 mg/kg every 8 weeks may be inadequate to consistently achieve sufficient drug exposure to minimize loss of response or treatment failure in pediatric Crohn disease (CD). We aimed to determine the predicted infliximab trough concentrations in children with CD during maintenance therapy and the percentage of patients achieving target trough concentration >3 µg/mL. METHODS: A Monte Carlo simulation analysis was constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial. We assessed maintenance dosing strategies of 5, 7.5, and 10 mg/kg at dosing intervals of every 4, 6, and 8 weeks for children that differed by age, weight, albumin level, and concomitant immunomodulator therapy. RESULTS: Based on the index case of a 10-year-old with CD receiving standard infliximab dosing with concomitant immunomodulator therapy, the median (interquartile range) simulated infliximab trough concentration at week 14 was 1.3 (0.5-2.7) µg/mL and 2.4 (1.0-4.8) µg/mL for albumin levels of 3 and 4 g/dL, respectively. Among 1000 simulated children in the model, trough concentration >3 µg/mL at week 14 was achieved 21% and 41% of the time for albumin levels of 3 and 4 g/dL, respectively. CONCLUSIONS: Standard infliximab maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low. Optimized dosing strategies for individual patients are needed to achieve sufficient drug exposure during infliximab maintenance therapy.