Opioid use in children with inflammatory bowel disease-related arthritis.

OBJECTIVES: Concomitant arthritis may increase risk of chronic opioid use in youngsters with IBD. We aimed to assess trends and clinical features associated with opioid use in children with IBD-related arthritis. METHODS: Adolescents under 18 years of age with IBD-related arthritis, at least 1 year of continuous enrolment, and at least 1 pharmacy claim in the Truven Health MarketScan Claims and Encounter Database were included. Subjects were identified using previously validated algorithms consisting of ICD codes, pharmacy claims and procedure codes. The primary outcome was chronic opioid exposure. Temporal trends in opioid exposure were tested using the Cuzick-Wilcoxon test. The association of chronic opioid use and baseline covariates in the IBD and IBD-arthritis cohorts were examined using multivariable logistic regression models. RESULTS: 14,943 adolescents with IBD, 480 of whom had arthritis, were included. Chronic opioid use was non-trivial in youngsters with IBD-related arthritis, higher than that of total IBD cohort (12.3% vs. 5%) and remained stable over the years of study. Using multivariable regression, joint pain and arthritis were significantly associated with chronic opioid exposure in young people with IBD. Among IBD-related arthritis patients older age, public insurance, gastrointestinal surgery, hospitalisation and psychiatric comorbidities were significantly associated with chronic opioid use. CONCLUSIONS: Chronic opioid use in adolescents with IBD-related arthritis was higher than that of total IBD cohort but stable over the years of study. Future study is needed to explore ways to optimise non-narcotic pain management strategies and ensuring appropriate use of opioids when necessary.

Psoriasis Associated With Tumor Necrosis Factor Inhibitors in Children With Inflammatory Diseases.

OBJECTIVE: To estimate the incidence rate (IR) of psoriasis in children with inflammatory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and chronic noninfectious osteomyelitis (CNO) with tumor necrosis factor inhibitor (TNFi) exposure as compared to children without TNFi exposure and to the general pediatric population. METHODS: This was a single-center retrospective cohort study of children with IBD, JIA, or CNO from 2008 to 2018. TNFi exposure was defined as a prescription for adalimumab, etanercept, infliximab, certolizumab, or golimumab, and the primary outcome was incident psoriasis. IRs and standardized incidence ratios (SIRs) were calculated. Cox proportional hazards models were used to assess the association of psoriasis with TNFi exposure and other risk factors. RESULTS: Of the 4,111 children who met inclusion criteria, 1,614 (39%) had TNFi exposure and 2,497 (61%) did not, with 4,705 and 6,604 person-years of follow-up, respectively. There were 58 cases (IR 12.3 per 1,000 person-years) and 25 cases (IR 3.8 per 1,000 person-years) of psoriasis in children with and without TNFi exposure, respectively. The SIR was 18 (95% confidence interval [95% CI] 15-22) overall, 30 (95% CI 23-39) for children with TNFi exposure, and 9.3 (95% CI 6.3-14) for children without TNFi exposure. The hazard ratio of psoriasis comparing TNFi exposure to no TNFi exposure was 3.84 (95% CI 2.28-6.47; P < 0.001). CONCLUSION: Children with IBD, JIA, and CNO had an increased rate of psoriasis compared to the general pediatric population, with the highest rate in those with TNFi exposure.

Utilization of an Electronic Medical Record-integrated Dashboard Improves Identification and Treatment of Anemia and Iron Deficiency in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Iron deficiency (ID) and anemia are one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD), usually complicating the course both in ulcerative colitis and Crohn's disease. Despite their high prevalence and significant impact on patients, this particular aspect is still underestimated by clinicians. Although guidelines have been recently published to address this problem, these recommendations do not address pediatric specific concerns and do not provide guidance as to how implement these guidelines in clinical practice. The aims of this quality improvement (QI) initiative were to improve the rates of detection and treatment of anemia in children with IBD. METHODS: After the creation of a multidisciplinary team of skateholders in IBD and anemia, we launched a multifaceted QI strategy that included the development of a pediatric evidence-based care pathway, utilization of an electronic medical record (EMR)-integrated dashboard to track patients, and generation of an automated provider-based monthly report. Data were collected and graphed into statistical process control charts. RESULTS: These key strategies resulted in improved rates of ID screening from 31.7% to 63.6%, in increased treatment rates from 38.2% to 49.9%, and in decreased prevalence of anemia from 35.8% to 29.7%, which was reflected by a greater decline in patients with quiescent disease. CONCLUSIONS: Quality improvement strategies incorporating the creation of a pediatric evidence-based care pathway with an EMR-supported electronic dashboard were the foundation of a successful intervention in the management of ID and anemia in pediatric IBD. Our positive results demonstrate the potential of QI initiatives using automated technology to assist clinicians in their commitment to provide evidence-based IBD care and enhance patient outcomes.

Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease.

BACKGROUND: Recent studies have shown that oral combination antibiotics may improve disease course in refractory inflammatory bowel disease (IBD). Here, we describe the use of combination oral antibiotics as salvage therapy in refractory ulcerative colitis (UC), Crohn's colitis, and IBD-unclassified (IBD-U) at a large pediatric IBD center. METHODS: Clinical response, disease activity indices, adverse events, and clinical outcomes were measured up to 1 year after antibiotic treatment in this retrospective cohort study of children with medically refractory IBD colitis. RESULTS: Sixty-three patients with refractory UC, Crohn's colitis, and IBD-U (median age [interquartile range {IQR}], 15.3 [11.2-16.5] years; median disease duration [IQR], 1.2 [0.41-4.6] years) received a combination of 3 or 4 oral antibiotics (most commonly amoxicillin, metronidazole, and either doxycycline or ciprofloxacin) for a median (IQR) of 29 (21-58) days. Thirty-four patients (54%) were deemed corticosteroid-refractory or -dependent, with the majority (62/63) having a previous or present loss of response or primary nonresponse to anti-tumor necrosis factor alpha (anti-TNFα) therapy. Use of combination antibiotics led to a significant decrease in median Pediatric Ulcerative Colitis Activity Index (PUCAI) score (IQR) from 55 (40-65) to 10 (0-40; P < 0.0001) over 3 ± 1 weeks, with 25/63 (39.7%) patients achieving clinical remission (PUCAI <10 points). The clinical benefits of oral antibiotics were independent of anti-TNFα therapy optimization. Among children entering clinical remission (n = 25), only 1 patient required surgery at 1-year follow-up, vs 10 patients in the nonresponder group. Negative predictors of response to combination antibiotics were exposure to doxycycline (odds ratio [OR], 0.25; 95% CI, 0.08-0.76) and PUCAI ≥65 at baseline (OR, 0.2; 95% CI, 0.05-0.74). CONCLUSIONS: Oral combination antibiotics appears to be an effective rescue and steroid-sparing therapy to induce remission in the short term in patients failing a biologic.

Pediatric Inflammatory Bowel Disease Clinical Innovations Meeting of the Crohn's & Colitis Foundation: Charting the Future of Pediatric IBD.

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure.10.1093/ibd/izy205_video1izy205.video15799266615001.

Biologics Delay Progression of Crohn's Disease, but Not Early Surgery, in Children.

BACKGROUND & AIMS: Up to 30% of patients with Crohn's disease (CD) require surgery within the first 5 years from diagnosis. We investigated the recent risk of bowel surgery in an inception cohort of pediatric patients with CD and whether early use of biologics (tumor necrosis factor antagonists) alters later disease course. METHODS: We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group registry on 1442 children (age, ≤16 y) diagnosed with CD from January 2002 through December 2014. Data were collected at diagnosis, 30 days following diagnosis, and then quarterly and during hospitalizations for up to 12 years. Our primary aim was to determine the 10-year risk for surgery in children with CD. Our secondary aim was to determine whether early use of biologics (<3 mo of diagnosis) affected risk of disease progression. RESULTS: The 10-year risk of first bowel surgery was 26%. The 5-year risk of bowel surgery did not change from 2002 through 2014, and remained between 13% and 14%. Most surgeries occurred within 3 years from diagnosis. The only predictor of surgery was disease behavior at diagnosis. CD with inflammatory behavior had the lowest risk of surgery compared to stricturing disease, penetrating disease, or both. We associated slowing of disease progression to stricturing or penetrating disease (but not surgery) with early use of biologics, but this effect only became evident after 5 years of disease. Our results indicate that biologics slow disease progression over time (hazard ratio, 0.85; 95% CI, 0.76-0.95). CONCLUSIONS: In an analysis of data from a registry of pediatric patients with CD, we found that among those with significant and progressing disease at or shortly after presentation, early surgery is difficult to prevent, even with early use of biologics. Early use of biologics (<3 mo of diagnosis) can delay later disease progression to stricturing and/or penetrating disease, but this affect could become evident only years after initial management decisions are made.

Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees.

Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.

Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease.

BACKGROUND: Vedolizumab is effective for inducing and maintaining remission in adults with inflammatory bowel disease (IBD); however, there is limited pediatric data. This study aimed to describe the adverse events and clinical response to vedolizumab in refractory pediatric IBD. METHODS: Disease activity indices, clinical response, concomitant medication use, and adverse events were measured over 22 weeks in an observational prospective cohort study of children with refractory IBD who had failed anti-tumor necrosis factor therapy and subsequently initiated vedolizumab therapy. RESULTS: Twenty-one subjects, 16 with Crohn disease, received vedolizumab. Clinical response was observed in 6/19 (31.6%) of the evaluable subjects at week 6 and in 11/19 (57.9%) by week 22. Before induction, 15/21 (71.4%) participants were treated with systemic corticosteroids, as compared with 7/21 (33.3%) subjects at 22 weeks. Steroid-free remission was seen in 1/20 (5.0%) subjects at 6 weeks, 3/20 (15.0%) at 14 weeks, and 4/20 (20.0%) at 22 weeks. There was statistically significant improvement in serum albumin and hematocrit; however, C-reactive protein increased by week 22 (P < 0.05). There were no infusion reactions. Vedolizumab was discontinued in 2 patients because of severe colitis, requiring surgical intervention. CONCLUSIONS: There is limited experience with vedolizumab therapy in pediatric IBD. There seems to be a marked number of subjects with clinical response in the first 6 weeks that increases further by week 22 despite the severity of disease in this cohort. Adverse events may not be directly related to vedolizumab. This study is limited by small sample size, and larger prospective studies are warranted.

Efficacy of oral methotrexate in paediatric Crohn's disease: a multicentre propensity score study.

BACKGROUND: Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn's disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD. METHODS: 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and 'doubly robust' weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups. RESULTS: 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test). CONCLUSIONS: In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

Infliximab therapy in pediatric patients 7 years of age and younger.

BACKGROUND: Infliximab (IFX) is efficacious for induction and maintenance of remission in pediatric patients with moderate-to-severe inflammatory bowel disease (IBD). It has, however, not been studied in patients 7 years old and younger. Our aim was to characterize efficacy and safety of IFX therapy in this cohort. METHODS: This was a retrospective study of patients with IBD ages 7 years and younger, treated with IFX between 1999 and 2011. Medical records were reviewed for age of diagnosis, disease phenotype, therapy, surgery, IFX infusion dates, dose, and intervals. Outcome measures included physician global assessment, corticosteroid requirement, and adverse events. RESULTS: Thirty-three children (ages 2.4-7 years) were included. Twenty patients had Crohn disease, 4 had ulcerative colitis, and 9 had indeterminate colitis. Maintenance of IFX therapy at 1, 2, and 3 years was 36%, 18%, and 12%, respectively. Patients of age 5 years and younger had the lowest rates of maintenance of therapy at 25% at year 1, and 10% at years 2 and 3 combined. Nine percent of all of the patients demonstrated response measured by the physician global assessment and were steroid free at 1 year. There were 8 infusion reactions. There were no malignancies, serious infections, or deaths. CONCLUSIONS: IFX demonstrated a modest response rate and a low steroid-sparing effect in patients with IBD 7 years old and younger. Although this is a limited study, there appears to be a trend for decreased sustained efficacy with IFX in this age group, particularly in children 5 years old and younger, when compared with the previously published literature in older children.

Retrospective cohort study of methotrexate use in the treatment of pediatric Crohn's disease.

BACKGROUND: Methotrexate (MTX) use as an alternative to thiopurines in the treatment of Crohn's disease (CD) in children is increasing. This study was undertaken to assess safety and efficacy of MTX in children with CD. METHODS: Patients treated with MTX with a minimum of 1-year follow-up were identified in the Pediatric IBD Collaborative Research Group Registry, a prospective inception cohort study started in 2002. The clinical efficacy and safety of MTX were analyzed retrospectively. RESULTS: Two hundred ninety patients treated with MTX were identified. One hundred seventy-two patients received at least 3 months of MTX without thiopurine or biologicals and had ≥1 year of follow-up. Eighty-one of 172 patients (47%) received MTX as first immunomodulator (IMM), of which 22 (27%) achieved ≥12 months of sustained clinical remission without surgery, thiopurine, biologicals, or corticosteroids. Those receiving MTX as second IMM achieved similar remission rate (35%, P = not significant). Fourteen percent received MTX as first IMM in 2002 and 60% in 2010 (P = 0.005). Disease location did not affect outcomes. MTX doses were equivalent in both groups. Fifteen percent of patients developed an alanine aminotransferase >60 international units/liter and 12% developed a white blood cell <4000 cells per microliter while on MTX. Only 4% of these discontinued MTX completely. A small group of 6 centers, which contributed only about one-third of patients with CD in the registry, contributed nearly two-thirds of the patients receiving MTX (P < 0.001). CONCLUSIONS: MTX use as first choice IMM is increasing in pediatric CD. MTX provided sustained clinical remission in nearly one-third of patients with minimal toxicity. There is large center-to-center variability in its use.

Effectiveness of anti-TNFα for Crohn disease: research in a pediatric learning health system.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20-1.96) for clinical remission and 1.74 (95% CI, 1.33-2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4-11.1) for clinical remission and 5.0 (95% CI, 3.4-10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.

Liver enzyme elevations within 3 months of diagnosis of inflammatory bowel disease and likelihood of liver disease.

BACKGROUND: Inflammatory bowel disease-associated liver diseases (IBD-LDs) include autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and an overlap syndrome. Prospective unbiased multicenter data regarding the frequency of IBD-LD in patients with pediatric inflammatory bowel disease (IBD) are lacking. We examined early alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT) elevations in children diagnosed as having IBD and assessed the likelihood of IBD-LD. METHODS: Data collected from the prospective observational Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry enrolling children of age <16 years within 30 days of diagnosis. AIH, PSC, and overlap syndrome were diagnosed using local institutional criteria. RESULTS: A total of 1569 subjects had liver enzymes available. Of the total, 757 had both ALT and GGT, 800 had ALT only (no GGT), and 12 had GGT only (no ALT). Overall, 29 of 1569 patients (1.8%) had IBD-LD. IBD-LD was diagnosed in 1 of 661 (0.15%) of patients with both ALT and GGT ≤ 50 IU/L compared with 21 of 42 (50%) of patients with both ALT and GGT > 50 (odds ratio 660, P < 0.0001). Of the 29 patients with IBD-LD, 21 had PSC, 2 had AIH, and 6 had overlap syndrome. IBD-LD was more common in patients with ulcerative colitis and IBD-unclassified (indeterminate colitis) than in those with Crohn disease (4% vs 0.8%, respectively, P < 0.001). CONCLUSIONS: Elevation of both ALT and GGT within 90 days after the diagnosis of IBD is associated with a markedly increased likelihood of IBD-LD. Both ALT and GGT levels should be measured in all of the pediatric patients newly diagnosed as having IBD.

A novel enteral nutrition protocol for the treatment of pediatric Crohn's disease.

BACKGROUND: Enteral nutritional therapy (EN) is an effective modality for inducing and maintaining remission in pediatric patients with Crohn's disease (CD). The standard protocol for EN provides patients with 100% of their caloric needs for induction of remission. The aim of this study was to determine the efficacy of delivering 80% to 90% of patient's caloric needs through EN, to induce remission in pediatric patients with CD. This approach allows patients to consume remaining calories from a normal diet. METHODS: A retrospective review of charts from 1998 to 2010 was conducted at The Children's Hospital of Philadelphia. Remission (Pediatric Crohn's Disease Activity Index <10) and response (decrease in Pediatric Crohn's Disease Activity Index score of ≥12.5 points) were calculated before and after treatment with EN. Weight z scores and laboratory parameters were evaluated in all participants. RESULTS: Forty-three charts were evaluated. Mean age of participants was 12.8 years (5.1-17.4), 67% were male and 33% female patients. Remission and response were evaluated in a group of 23 participants, with no missing data. There were reductions in erythrocyte sedimentation rate (P < 0.0001) and C-reactive protein (P < 0.02), and increases in albumin (P < 0.03). Mean Pediatric Crohn's Disease Activity Index score at baseline was 26.9 and was reduced to a score of 10.2 at follow-up (P < 0.0001). Induction of remission was achieved in 65% and response in 87% at a mean follow-up of 2 months (1-4 months). CONCLUSIONS: This novel EN protocol seems to be effective for the induction of remission in pediatric patients with CD and contributes to increasing weight and improving laboratory markers. This protocol may result in improved EN acceptance and compliance and will be evaluated prospectively.

Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease.

BACKGROUND: The thiopurines, azathioprine and 6-mercaptopurine, are traditional first-line immunomodulatory agents in adult and pediatric Crohn's disease, but the comparative efficacy and safety of methotrexate have seldom been examined. We report outcomes with methotrexate treatment in pediatric patients previously refractory to or intolerant of thiopurines. METHODS: In a four-center, retrospective cohort study, efficacy of methotrexate in maintaining remission was assessed by PCDAI measurements, steroid use, and height velocity. Patients served as their own historical controls. Multivariable analysis controlled for route of methotrexate administration, reason for thiopurine discontinuation, baseline disease activity, and disease duration. RESULTS: Forty-two percent of 60 children treated with methotrexate were in clinical remission without steroids at both 6 and 12 months. A strong steroid sparing effect was observed compared with the year prior to methotrexate (P<0.001). Success rates were similar in previously thiopurine-intolerant and refractory patients. Height velocity increased from -1.9 SDS to -0.14 SDS (P=0.004) in the year following therapy. In a median 3-yr follow-up, a third of the patients did not require escalation of therapy; the others required step-up therapy with infliximab or surgery. Eight children (13%) stopped methotrexate due to adverse events, including, most commonly, elevated liver enzymes, and one serious episode of sepsis. CONCLUSION: Methotrexate appears effective in maintaining remission in pediatric Crohn's disease, when thiopurines have failed. Consideration should be given to its use earlier in pediatric treatment algorithms.