Clinical impacts of immunomodulator withdrawal from anti-tumor necrosis factor combination therapy in pediatric inflammatory bowel disease.

OBJECTIVES: Combination therapy consists of both anti-tumor necrosis factor (anti-TNF) and an immunomodulator (IMM) and has been shown to improve outcomes in patients with inflammatory bowel disease (IBD). This study assesses the impacts of IMM withdrawal from combination therapy to anti-TNF monotherapy in children with IBD. METHODS: This single-center retrospective cohort study included children with IBD initiated on combination therapy between 2014 and 2019 who discontinued the IMM. We evaluated whether IMM withdrawal impacts laboratory values and disease activity. Linear mixed effects models with random intercepts were used to compare differences between groups. Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation of therapy. RESULTS: One hundred and fifty-two patients discontinued the IMM which did not significantly affect disease activity. However, 18% of patients escalated therapy after IMM withdrawal, primarily due to low anti-TNF levels. Lower anti-TNF and higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before IMM withdrawal were associated with subsequent escalation of therapy. Overall, there was no statistically significant effect on anti-TNF drug levels. Patients with Crohn's disease (CD) on infliximab (IFX) and methotrexate (MTX) who discontinued the IMM had an increase in mean ESR and CRP (p < 0.05). CONCLUSIONS: IMM withdrawal from anti-TNF combination therapy may be considered safe in the setting of higher anti-TNF levels and normal serum inflammatory markers. Clinicians should consider assessing anti-TNF levels and inflammatory markers after IMM withdrawal, especially in patients with CD receiving IFX who discontinued MTX.

Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease.

OBJECTIVES: Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). METHODS: A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 µg/mL at Week 6 and >12 µg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. RESULTS: Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6 and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 µg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR) rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). CONCLUSION: Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

Clinical outcomes and cost savings of a nonmedical switch to a biosimilar in children/young adults with inflammatory bowel disease.

OBJECTIVES: The safety, efficacy, and cost savings associated with biosimilar medications are well established. However, a lack of pediatric data exists surrounding clinical outcomes when switching from an originator to a biosimilar. Our primary aim is to evaluate clinical outcomes following a nonmedical switch from the infliximab originator to a biosimilar in children and young adults with inflammatory bowel disease (IBD). Our secondary aim is to estimate cost savings associated with this switch. METHODS: A quality improvement project was implemented to establish safe switching protocols, then those patients who underwent a nonmedical switch from the infliximab originator to the biosimilar were retrospectively reviewed. Demographic data, physician global assessments (PGAs), and laboratory values were recorded 1 year pre- and post-switch. Continuation rates on the biosimilar were reported at 6 and 12 months. Cost savings were estimated using two different pricing models. RESULTS: Fifty-three patients underwent a nonmedical switch. Laboratory values including inflammatory markers, infliximab levels, and PGA scores remained similar when assessed pre- and post-switch. No infusion reactions or antidrug antibody development occurred. Two patients reported psoriasis-like rashes. Five patients switched back to the originator during the study period. There were 379 biosimilar infusions completed with an estimated total cost savings of $11,260 (average sales price) and $566,223 (wholesale acquisition cost). CONCLUSIONS: Clinical remission rates, inflammatory laboratory markers, serious adverse events, infliximab levels, and antidrug antibodies remained similar after a one-time nonmedical switch to an infliximab biosimilar. Nonmedical switching to biosimilars resulted in significant cost savings.

Outcomes for Standardized Home and Hospital-Based Infusions of Infliximab for Children With Inflammatory Bowel Disease.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) is commonly treated with infliximab in a hospital setting. Utilization of home infusions (HI) is increasing due to insurance mandates, travel time savings, and convenience. We evaluated adverse outcomes (AOs) of infliximab infusions in children with IBD receiving HI compared to hospital-based infusions. METHODS: Children receiving HI between September 2016 and September 2018 were retrospectively matched based on age, race, ethnicity, sex, and disease type to a cohort receiving infliximab at a hospital-based center. A survival analysis evaluated the hazard ratio for AOs in HI relative to hospital-infused children over 2 years. AOs were defined as discontinuation of therapy for clinically relevant reasons, IBD-related hospitalizations, and emergency department visits. RESULTS: We included 102 children (51 pairs) (63% male, 91% White, 92% Crohn disease). Disease location, behavior, growth status, and disease severity were similar between the 2 cohorts. Quiescent disease increased from 3% to 93% after 2 years without cohort differences. At baseline, 94% of HI patients and 88% of controls were on 5 mg/kg every 8 weeks as standard maintenance therapy. Within 2 years, only 19% remained on 5 mg/kg and the remainder required increased dosing or decreased interval. The HI cohort had fewer labs obtained ( P < 0.001), though laboratory values, number of clinic visits, and frequency of AOs were similar. CONCLUSION: Drug durability, AOs, and laboratory values were similar between HI and hospital-based infusions. These findings suggest HI may be as effective as hospital-based infusions, provided a standardized care approach is utilized.

Biosimilars for Pediatric Patients With Inflammatory Bowel Disease: Pediatric Gastroenterology Clinical Practice Survey.

BACKGROUND: Biosimilars are biological agents that have been demonstrated to have similar safety and efficacy profiles as the originator. The objective of this study was to evaluate the perspectives of pediatric gastroenterologists in the United States (U.S.) toward biosimilar use and to explore factors that impact their comfort level with prescribing infliximab biosimilars. METHODS: A cross-sectional survey was developed and distributed to pediatric gastroenterology physicians from the U.S. via a listserv (Pediatric gastroenterology Bulletin Board). Respondent's demographics were recorded. Using a 6-point Likert scale, the survey assessed the respondent's perceptions toward biosimilars and initiating switches from the originator to biosimilar agent along with factors impacting provider's comfort level. Fischer exact tests were used to detect statistically significant differences in responses for hypotheses of interest. RESULTS: One hundred thirty-nine pediatric gastroenterologists completed the online survey (response rate 5.4%). Eighty-seven percent of respondents reported being comfortable prescribing infliximab biosimilars to anti-tumor necrosis factor naive patients, and 69% reported being comfortable doing a one-time switch if the patient was in clinical remission. Factors that negatively impacted a respondent's comfort level included respondents not practicing at an ImproveCareNow (ICN) center and managing less than 50 patients with inflammatory bowel diseases (IBD). CONCLUSIONS: Nearly 90% of pediatric gastroenterologists felt comfortable prescribing an infliximab biosimilar, and 70% felt comfortable with a one-time switch to the biosimilar if the patient was in clinical remission. Involvement in ICN a learning health system and caring for higher numbers of patients with IBD was associated with increased provider comfort with biosimilar use.

Diagnosis and Treatment of Iron Deficiency and Anemia in Youth With Inflammatory Bowel Disease.

OBJECTIVES: Iron deficiency (ID) with and without anemia is prevalent in children and adults diagnosed with inflammatory bowel disease (IBD), but often goes unrecognized. We hypothesized, quality improvement (QI) methodology could increase the screening for and treatment of ID in children newly diagnosed with IBD. METHODS: We developed and implemented an easy-to-follow algorithm to facilitate screening for and treatment of ID for patients diagnosed with IBD. Through a series of Plan-Do-Study-Act cycles, the approach was modified to increase screening and treatment of ID. Data between January 2019 and July 2021 were assessed using statistical process control. RESULTS: Among patients newly diagnosed with IBD, 298 patients were included (67% Crohn disease, 29% ulcerative colitis, 4% indeterminate colitis, and 56% males). Rates of ID screening increased significantly from a baseline of 20% to >90%. Of the 232 patients screened for ID during the improvement period, 205 (88%) met criteria for either iron deficiency anemia (IDA) or ID at diagnosis, specifically, 151 (65%) met criteria for IDA and 54 (23%) met criteria for ID. CONCLUSIONS: Use of QI methodology to standardize screening assessments for ID among children newly diagnosed with IBD improved screening rates from a baseline of 20% to >90%, with 88% of patients found to have IDA or ID.

Impact of Telemedicine on Delivery of Pediatric Inflammatory Bowel Disease Care.

OBJECTIVES: Outpatient inflammatory bowel disease (IBD) care shifted from office visits (OVs) to a model with integrated telemedicine during the 2020 COVID-19 pandemic. We describe the impact of this shift on delivery of pediatric IBD care. METHODS: We collected electronic medical record data from office and telemedicine visits for pediatric patients with IBD at a single center from April 2019 to December 2020. We compared visit volume, duration, and test ordering between 2019 and 2020, and between OV and telemedicine, and assessed for differences in telemedicine adoption by sociodemographic factors. RESULTS: Visit volume was maintained between 2019 and 2020. Median overall appointment time was shorter for telemedicine versus OV [46 (interquartile range, IQR 35-72) vs 62 (IQR 51-80) minutes; P < 0.001] with no significant difference in time spent with provider [28 (IQR 21-41) vs OV 30 (IQR 24-39) minutes; P = 0.08]. Accounting for drive time, telemedicine visits were 2.6 times shorter than office visits in 2020 ( P < 0.001). In univariate analyses, there was no difference in telemedicine utilization by race or gender. Variables significantly associated with telemedicine were older age, English as primary language, being non-Hispanic, commercial insurance, living in an area of very high opportunity, and having a longer drive time to the office ( P < 0.05 for all comparisons). In multivariate analyses, visits among patients with commercial insurance were significantly more likely to be conducted via telemedicine ( P = 0.02). Among those with a telemedicine visit, multivariate analyses demonstrated multiracial patients were significantly more likely to have video visits (vs audio-only; P = 0.02), while patients with public insurance, no or missing insurance, and whose primary language was Arabic were significantly less likely to have video visits ( P < 0.05 for all comparisons). CONCLUSIONS: Integrated telemedicine allowed for continued delivery of pediatric IBD care and significantly decreased appointment time. While telemedicine may improve access for those who live further from the office, concerns remain about the introduction of disparities.

Similar Growth Outcomes in Children with Inflammatory Bowel Disease Initiated on Infliximab Originator or Biosimilar.

BACKGROUND: Growth is an important clinical outcome, especially in childhood-onset inflammatory bowel disease (IBD). Prior research has demonstrated growth improvements with infliximab therapy. There are limited studies evaluating whether clinical and growth outcomes in children initiated on the infliximab originator and infliximab biosimilar are similar. METHODS: This was a single-center retrospective review of patients with IBD, younger than 17 years old, and initiated on the infliximab originator or biosimilar for at least 12 months between April 2016 and February 2021. Propensity score matching was utilized. Laboratory values, disease activity scores, and growth values were collected at baseline (prior to infliximab initiation), 6 months, and 12 months post initiation. Linear mixed models with random intercepts were used to test differences in measures over time and between study groups. RESULTS: There were 113 patients on the originator and 39 patients on a biosimilar who met eligibility criteria. Propensity score methodology identified 37 dyads (1:1 match). Weight, height, and body mass index z scores increased over time (from baseline to 12 months) for both groups ( P < 0.05) and there was a similar rate of change between study groups. Clinical outcomes of lab values (albumin, C-reactive protein, and hemoglobin) and disease activity scoring were similar from baseline to 12 months between study groups. CONCLUSIONS: There were similar improvements in growth and clinical outcomes in patients initiated on the infliximab originator compared to an infliximab biosimilar agent. This study adds to the limited research evaluating whether infliximab biosimilars have similar growth outcomes in children with IBD.

Risk of Post-Resection Recurrence in Pediatric Crohn Disease.

BACKGROUND: Ileocecectomy related to stricturing, fistula formation, or medically refractory disease is commonly required in patients with Crohn disease (CD). Limited research exists in endoscopic recurrence (ER) in pediatric inflammatory bowel disease (IBD). In this study, we sought to determine ER rates and the impact of therapy duration before surgery in pediatric patients with CD. METHODS: This was a single-center retrospective review of patients with CD between the ages of 2 to 20 years who required ileocecectomy between January 2015 and December 2019 at Nationwide Children's Hospital. Follow-up endoscopies, laboratory values, medications, and sPCDAI scores were recorded at 6, 12, 24, and 36 months post-resection wherever available. Modified Rutgeert scores (mRS) were independently assigned to post-resection colonoscopy images by 3 trained investigators. Post-resection outcomes were compared between patients on CD therapy >30 days before resection (late surgery) to those started on CD therapy <30 days before resection (early surgery). RESULTS: A total of 48 patients underwent ileocecectomy, with a mean age at time of resection of 17 years (+/-2.3). In total, 88% of patients had a post-resection endoscopy and 57% had an endoscopy within 12 months of resection. Twenty-nine percentage had ER with a mRS ≥i2. There was no statistical difference in endoscopic and clinical outcomes after resection between the early and late surgery groups. CONCLUSIONS: Post-resection endoscopic recurrence after ileocecectomy was found in 29% of our center's pediatric CD population based on mRS. Post-resection outcomes were not affected by therapy duration before resection.

Patient and Caregivers' Perspectives on Biosimilar Use in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Studies assessing adult inflammatory bowel disease (IBD) patient perspectives on biosimilar use revealed that most were unfamiliar with biosimilars and had a negative perception. The objective of this study was to evaluate the perspectives of pediatric patients with IBD and their caregivers regarding biosimilar use and non-medical switches. METHODS: A survey was given to a cross section of patients with IBD ages 11-21 years receiving the intravenous anti-tumor necrosis factor originator and caregivers of patients with IBD ages 3-21 years receiving the originator. Recruitment occurred via mail, during clinic visits, and infusions. Fisher exact tests were used to test for statistically significant differences. RESULTS: Response rate amongst caregivers was 49% (n = 98) and among patients was 35% (n = 67). Sixty-four percent of caregivers and 79% of patients had never heard of biosimilars. There was increased discomfort surrounding the use of biosimilars and switching to a biosimilar amongst caregivers who had previously heard of biosimilars compared to caregivers who had not previously heard of biosimilars ( P < 0.05). Similar concerns were not seen in patient respondents. The length of time on the originator had no effect on patient or caregiver concerns related to biosimilar efficacy, adverse effects, or switches. CONCLUSION: The majority of pediatric patients and caregivers had never heard of biosimilars. Caregivers that had heard of biosimilars before the study were more likely to have a negative perception of them. This study highlights the importance of providing thorough and accurate education to pediatric patients and families regarding the safety and efficacy of biosimilars.

6- and 12-Month Outcomes after 90:10 Enteral Nutrition Induction Therapy in Pediatric Crohn's Disease.

OBJECTIVES: Studies describing longer-term outcomes after EEN induction are limited. We describe clinical outcomes during 90:10 EN induction, and 6- and 12- month outcomes among patients that successfully completed EN induction and then continued either EN or immunomodulator (IM) maintenance therapy. METHODS: All children with CD treated with 90:10 EN induction protocol (90% formula:10% regular diet) at our IBD Center from 2013 to 2018 were retrospectively reviewed. Demographic, clinical, and laboratory data were recorded at baseline, 6, and 12 months (± 3 months at each timepoint). Therapy changes after initiation of EN induction through 12 months were recorded. Among patients that successfully completed 90:10 induction, outcomes between EN and IM maintenance groups were compared. RESULTS: In total, 44/105 (42%) patients completed 8-12 weeks of 90:10 EN induction. Sixty-one patients had incomplete EN induction, with 52% requiring corticosteroids and 25% anti-TNF therapy as alternate induction approaches. Forty-four patients completed EN induction (18 continued EN maintenance and 26 IM maintenance therapy). Twenty-seven of these 44 (61%) remained on initial maintenance therapy at 6 months (10/18 (56%) EN and 17/26 (65%) IM). In total, 16/44 (36%) remained on their initial maintenance therapy at 12 months. By 12 months, 10 patients required anti-TNF and 11 corticosteroids after successful completion of induction. CONCLUSIONS: In this retrospective study of short and longer-term outcomes after 90:10 EN induction, the need for an alternate induction therapy was common, most frequently to anti-TNF or corticosteroid therapy. Future studies are needed to evaluate for predictors of long-term success after EN induction.

Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.

BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.

Stressor-Induced Increases in Circulating, but Not Colonic, Cytokines Are Related to Anxiety-like Behavior and Hippocampal Inflammation in a Murine Colitis Model.

Stressor exposure increases colonic inflammation. Because inflammation leads to anxiety-like behavior, we tested whether stressor exposure in mice recovering from dextran-sulfate-sodium (DSS)-induced colitis enhances anxiety-like behavior. Mice received 2% DSS for five consecutive days prior to being exposed to a social-disruption (SDR) stressor (or being left undisturbed). After stressor exposure, their behavior was tested and colitis was assessed via histopathology and via inflammatory-cytokine measurement in the serum and colon. Cytokine and chemokine mRNA levels in the colon, mesenteric lymph nodes (MLNs), hippocampus, and amygdala were measured with RT-PCR. SDR increased anxiety-like behaviors, which correlated with serum and hippocampal IL-17A. The stressor also reduced IL-1ß, CCL2, and iNOS in the colonic tissue, but increased iNOS, IFNγ, IL-17A, and TNFα in the MLNs. A network analysis indicated that reductions in colonic iNOS were related to elevated MLN iNOS and IFNγ. These inflammatory markers were related to serum and hippocampal IL-17A and associated with anxiety-like behavior. Our data suggest that iNOS may protect against extra-colonic inflammation, and when suppressed during stress it is associated with elevated MLN IFNγ, which may coordinate gut-to-brain inflammation. Our data point to hippocampal IL-17A as a key correlate of anxiety-like behavior.

Predicting Suboptimal Transitions in Adolescents With Inflammatory Bowel Disease.

OBJECTIVES: Adolescents and young adults (AYAs) are at risk for disease exacerbations and increased health care utilization around the time of transition to adult care. Our aim was to identify risk factors predictive of a suboptimal transition for AYA with inflammatory bowel disease. MATERIALS AND METHODS: We performed a retrospective chart review of patients with pediatric inflammatory bowel disease transferred to adult care from our institution in 2016 and 2017, recording demographic, psychosocial, and disease-specific data. Post-transfer data were obtained via the health care information exchange from the adult provider within our electronic medical record. We defined suboptimal transition as either a return to pediatric care or requiring care escalation within 1 year of transfer. RESULTS: Out of 104 subjects 37 (36%) were found to have had a suboptimal transition. Our models suggest that a suboptimal transition is associated with several risk factors including any mental health diagnosis (odds ratio [OR] = 4.15; 95% confidence interval [95% CI]: 1.18-14.59), history of medication nonadherence (OR = 5.15 [95% CI: 1.52-17.42]), public insurance (OR = 6.60 [95% CI: 1.25-34.96]), higher Physician Global Assessment score at time of transition (OR = 6.64 [95% CI: 1.60-27.58], and short Pediatric Crohn Disease Activity Index scores (OR = 1.17 [95% CI: 1.03-1.33]). Higher hemoglobin levels at transition were protective (OR = 0.69 [95% CI: 0.48-0.98]). Age at time of transition, disease duration, and medication type at transition were not found to be associated with transition outcomes. CONCLUSION: AYA with public insurance, a mental health history, medication nonadherence, and evidence of active disease may be at greater risk for suboptimal and poor health outcomes at transition.

Polyethylene Glycol 3350 Changes Stool Consistency and the Microbiome but not Behavior of CD1 Mice.

OBJECTIVES: Polyethylene Glycol 3350 (PEG3350) is a laxative commonly used to treat constipation in children. The Food and Drug Administration has received reports of increased anxiety, aggression, and obsessive--compulsive behaviors in children administered PEG3350. Thus, we assessed whether daily administration of PEG3350 leads to anxiety-like behavior in mice. METHODS: Outbred CD-1 IGS mice were administered either a high or a low dose of PEG3350 via daily oral gavage for 2 weeks. As a laxative comparison and control, additional mice were given a high or low dose of magnesium citrate or vehicle (water). Weight and stool consistency were assessed after each gavage to determine laxative effectiveness. Anxiety-like behaviors were assessed using light/dark, open field, and elevated plus maze (EPM) tests at baseline, after 2 weeks of daily gavage, and after a 2 week washout in experiment 1, and after 2 weeks of daily gavage in experiment 2. Stool samples were collected for microbiome analysis in experiment 2 at baseline, after 2 weeks of daily gavage, and after 2 weeks washout. RESULTS: PEG3350 and magnesium citrate significantly changed stool consistency, as well as microbiome alpha and beta diversity. Anxiety-like behaviors were not, however, different in mice administered low or high doses of PEG3350 or magnesium citrate. CONCLUSIONS: Although changes in stool consistency and the gut microbiome occurred, administration of PEG3350 did not alter anxiety-like behaviors.

Single High-dose Vitamin D3 Supplementation in Pediatric Patients With Inflammatory Bowel Disease and Hypovitaminosis D.

OBJECTIVES: The primary aim was to determine the effectiveness of a single high-dose of oral vitamin D3 (stoss therapy) in children with inflammatory bowel disease (IBD) and hypovitaminosis D. Our secondary aim was to examine the safety of stoss therapy. METHODS: We conducted a randomized, prospective study of 44 patients, ages 6 to 21 years, with IBD and 25-hydroxyvitamin D (25-OHD) concentrations <30 ng/mL. Patients were randomized to receive 50,000 IU of vitamin D3 once weekly for 6 weeks (standard of care, SOC group) or 300,000 IU once (stoss group). Serum 25-OHD levels were obtained at baseline, 4 and 12 weeks. Safety monitoring labs were performed at week 4. RESULTS: Thirty-nine of 44 enrolled patients (19 stoss, 20 SOC) completed the study. Baseline vitamin D levels were not significantly different between the groups. Stoss therapy resulted in a substantial rise in 25-OHD levels at week 4, equivalent to the weekly regimen (53.6 ±â€Š17.3 vs 54.6 ±â€Š17.5 ng/mL). At week 12, serum 25-OHD levels decreased in both groups, significantly lower in the stoss group, but remained close to 30 ng/mL (29.8 ±â€Š7.1 vs 40.4 ±â€Š11.9 ng/mL, P = 0.04). A significant interaction with treatment group over time was observed (P = 0.0003). At the week-4 time point, all patients who received stoss therapy had normal serum calcium and PTH levels. Eighty percentage of patients preferred stoss therapy to the weekly regimen. CONCLUSIONS: Stoss therapy was safe and effective in raising 25-OHD in children with IBD commensurate to that of the weekly regimen.

Improving Post-induction Antitumor Necrosis Factor Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Adequate serum drug levels of tumor necrosis factor-alpha inhibitors (anti-TNF) have been shown to improve outcomes in patients with inflammatory bowel disease. We aim to describe the quality improvement (QI) methods used at our institution to improve post-induction therapeutic drug monitoring (TDM) in children initiating anti-TNF therapy (infliximab and adalimumab) and describe the frequency of subtherapeutic anti-TNF levels. METHODS: Beginning in February 2016, all patients initiating anti-TNF therapy were identified and tracked. Interventions to improve TDM, including the initiation of therapy plans for infliximab, real-time reminders for practitioners, and scheduling modifications for those initiating anti-TNF therapies were implemented using the Institute for Healthcare Improvement Plan-Do-Study-Act cycle approach. Statistical process control charts were used to demonstrate improvement over time. Anti-TNF levels and presence of antidrug antibodies were also recorded. RESULTS: Using QI methodology, we improved post-induction anti-TNF TDM from a baseline of 43% in 2015 to >80% by the end of 2017, with sustained improvement. Infliximab post-induction TDM improved from a baseline of 59% to 82%, whereas adalimumab post-induction TDM improved from baseline of 14% to 79%. In total, 36% of all anti-TNF post-induction levels were <5 µg/mL, with nearly 60% of post-induction infliximab levels being <5 µg/mL. CONCLUSIONS: Through incremental QI approaches, we improved the utilization of anti-TNF post-induction TDM with sustained improvement, approaching our goal of 90%. Subtherapeutic post-induction infliximab levels were common, indicating a strong need for anti-TNF TDM and an opportunity for dose optimization.

Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short-chain Fatty Acid Levels and Receptors.

OBJECTIVES: Gastrointestinal disorders, such as inflammatory bowel diseases (IBDs) and functional gastrointestinal disorders (FGIDs), involve disrupted homeostatic interactions between the microbiota and the host. Both disorders are worsened during stress, and in laboratory mice, stress exposure has been shown to change the composition of the gut microbiome. Stress-induced changes to the microbiome exacerbate intestinal inflammation and alter intestinal motility in mice. It is, however, not yet known whether microbiota-derived short-chain fatty acids (butyrate, propionate, and acetate) and their receptors contribute to this effect. METHODS: Mice were exposed to a social disruption stress, or left undisturbed as a control. After the first stress exposure, mice were orally challenged with Citrobacter rodentium or with vehicle. The levels of short-chain fatty acids (SCFAs) were measured using gas chromatography-mass spectrometry. SCFA receptors were measured via real-time polymerase chain reaction. Microbial community composition was assessed using 16S rRNA gene sequencing. RESULTS: Stress exposure reduced colonic SCFA levels. Stress exposure and C rodentium, however, significantly increased SCFA levels and changed the expression of SCFA receptors. The levels of SCFAs did not correlate with the severity of colonic inflammation, but the colonic expression of the SCFA receptor GPR41 was positively associated with inflammatory cytokines and colonic histopathology scores. The relative abundances of several taxa of colonic bacteria were significantly changed by stress exposure, including SCFA producers. CONCLUSIONS: Social stress can have a significant effect on infection-induced colonic inflammation, and stress-induced changes in microbial-produced metabolites and their receptors may be involved.

A Quality Improvement Approach to External Infliximab Infusions in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: We used a quality improvement (QI) approach to improve access and reduce barriers to care by increasing the number of external infliximab infusions at our pediatric inflammatory bowel disease center. METHODS: Using an iterative QI strategy, pediatric patients ≥12 years of age with inflammatory bowel disease were offered the opportunity to receive infliximab infusions at home/an external infusion center. They were required to first have >5 infusions at the hospital without any significant infusion reactions. Data were collected and tracked monthly using P-charts. Comparisons between control chart centerlines were analyzed using the Fisher exact test. RESULTS: Fifty-four patients received external infusions, 87% had Crohn disease, 63% boys, average age 17.6 ±â€Š2.9 years, and 89% with private insurance. From September 2016 to January 2018, the percentage of eligible patients receiving external infusions was approximately 7%, increasing to approximately 30% by January 2018. A centerline shift, representing a statistically significant change, occurred in October 2016 and June 2017 (P < 0.001). No serious safety concerns have occurred. CONCLUSIONS: Through a multidisciplinary team of stakeholders using QI strategies, we now offer external infusion service options to all appropriate patients as routine practice. Home infusions are a viable option to reduce barriers to care, and our patients did not experience any safety events.

Using Quality Improvement to Increase Utilization of Enteral Therapy in Pediatric Crohn Disease: Results and Outcomes.

INTRODUCTION: Exclusive enteral nutrition (EEN) for induction of remission in children with Crohn disease (CD) is recommended as first-line therapy, but underutilized in the United States related to real and perceived barriers. We hypothesized that quality improvement (QI) methodology could increase use of EEN. METHODS: We developed, implemented, and revised an algorithm and a set of tools to facilitate use of EEN. Through a series of Plan Do Study Act cycles, the approach was modified to overcome provider and patient/family barriers. The primary outcome, the percentage of newly diagnosed CD patients who receive EEN per month between July 2013 and October 2015, assessed using statistical process control. Secondary outcomes, including the short pediatric Crohn disease activity index (sPCDAI), body mass index (BMI) z score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, and hemoglobin were compared before and after EEN. RESULTS: Among patients newly diagnosed with CD, 73 patients initiated EEN and were included (mean age 12.7 ±â€Š2.9 years, 49% girls, 86% white). Rates of utilization of EEN increased significantly from a baseline of <5% to an average of approximately 50%. Of the 73 patients who started EEN, 37 (50%) completed a minimum of 8 weeks. Of those completing therapy, 25 (71%) achieved remission, with a significant reduction of sPCDAI (33.6 ±â€Š14.4 to 10.7 ±â€Š12.3, P < 0.0001) CONCLUSIONS:: Use of QI methodology to systematically implement tools designed to improve utilization was effective in increasing the use of EEN. Among those completing therapy, EEN was effective in inducing remission.