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.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Isolated Terminal Ileitis in Children.

Isolated terminal ileitis in adults is a well described entity that rarely progresses to Crohn disease (CD), and pediatric literature on this topic is very limited. We describe the prevalence, clinical, endoscopic, histologic, and radiological features, along with long-term outcome of isolated terminal ileitis in our institution. We reviewed charts of 956 children who underwent colonoscopy from 2013 to 2017. Thirty-three children had isolated histologically-defined terminal ileitis. Seventeen children were diagnosed with CD and 16 children had idiopathic terminal ileitis. Children with CD had higher prevalence of abnormal C-reactive protein levels, severe inflammation, and radiological evidence of bowel wall thickening compared with children with idiopathic ileitis. Children with idiopathic ileitis did not develop CD over a follow-up period of 83 months. In contrast to adults, CD is common in children with isolated terminal ileitis and those with idiopathic ileitis do well over long-term.

Complementary and Alternative Medicine Use in Children With Inflammatory Bowel Disease.

Complementary and alternative medicine (CAM) consists of products and practices that are not considered to be a part of conventional medicine. This article reviews pediatric studies on CAM in inflammatory bowel disease (IBD) along with relevant adult studies. Prevalence of CAM use ranges from 22% to 84% in children with IBD all over the world. CAM use in IBD includes diet changes, supplements, herbals, botanicals, and mind-body therapies. Common reasons for using CAM include severe disease and concern for adverse effects of conventional medicines. Despite widespread use, there are limited studies on efficacy and safety of CAM in children. Small studies suggest a favorable evidence for use of probiotics, fish oil, marijuana, and mind-body therapy in IBD. Adverse effects of CAM are reported but are rare. The article provides current state of knowledge on the topic and provides guidance to physicians to address CAM use in pediatric patients with IBD.

Prevalence of Anti-tissue Transglutaminase Antibodies and Celiac Disease in Children With Inflammatory Bowel Disease.

OBJECTIVES: Celiac disease can occur in children with inflammatory bowel disease (IBD) and poses a diagnostic challenge. We evaluated the presence of anti-tissue transglutaminase (tTG) antibodies and celiac disease among children with IBD. METHODS: In a retrospective chart review, we assessed the prevalence of tTG antibodies and celiac disease and compared with a control group of children with gastrointestinal symptoms without IBD. RESULTS: Study population included 130 children with IBD and 257 in the control group. Abnormal tTG levels were found in 6 and 20 patients, respectively (4.6% vs 7.8%, P = 0.24). One patient with IBD and 12 in the control group had celiac disease (0.8% vs 4.7%, P = 0.07). CONCLUSIONS: False-positive tTG can occur in children with IBD. The prevalence of celiac disease is not increased in children with IBD compared with non-IBD children with gastrointestinal symptoms and is similar to that in the general population.

Correlation of Erythrocyte Sedimentation Rate and C-Reactive Protein With Pediatric Inflammatory Bowel Disease Activity.

We aimed to examine correlation of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) with diagnosis of inflammatory bowel disease and with clinical, endoscopic, histological, and radiographic disease activity during follow-up. We reviewed charts of 135 children with inflammatory bowel disease and correlated their ESR and CRP values with disease activity in various encounters during 5 years. Normal ESR and CRP values were observed in up to 28% of children with Crohn disease and 42% of children with ulcerative colitis at diagnosis, respectively. Correlation of ESR and CRP with Crohn disease clinical, endoscopic, and histologic activity during follow-up depended on their value at diagnosis and mode of analysis (continuous or dichotomous). Both markers were not useful in predicting clinical, endoscopic, or histologic ulcerative colitis disease activity and radiographic small bowel Crohn disease during follow-up.

Prevalence and Patterns of Marijuana Use in Young Adults With Inflammatory Bowel Disease.

OBJECTIVES: Recent studies in adults report symptom relief with marijuana use in patients with inflammatory bowel disease (IBD). We assessed the prevalence, pattern, effects, and adverse effects of marijuana use in young adults with IBD. METHODS: We conducted a prospective questionnaire survey study at a pediatric IBD clinic. All patients (18-21 years of age) answered anonymous questionnaires about demographics, IBD, medications, and marijuana use. RESULTS: Fifty-three patients (mean age 18.7 years, 32 boys) were enrolled. Thirty-seven patients (70%) reported using marijuana currently or in the past. There was no statistically significant difference between the users and nonusers of marijuana regarding demographics, disease activity, or medications. Despite prolonged use of marijuana, 70% of patients did not discuss it with their gastroenterologists. Twenty-four patients used marijuana medicinally for IBD symptoms in addition to medical therapy. Although majority found marijuana to be moderately/very helpful, complete relief of symptoms such as abdominal pain, poor appetite, nausea, and diarrhea was seen in 29%, 37%, 14%, and 10% of patients, respectively. Only half of patients reported knowledge of possible adverse effects of marijuana and 19% of patients reported mild neuropsychiatric adverse effects. Overall, 98% of patients supported legalization of marijuana and 85% were interested in using medical marijuana if it became legally available. CONCLUSIONS: We found a high rate of marijuana use in our cohort of young adults with IBD. Majority of users report symptom improvement but do not inform physicians. Future well-controlled studies are necessary to assess role of marijuana in IBD therapy.

Prevalence and Clinical, Endoscopic, and Pathological Features of Duodenitis in Children.

OBJECTIVES: Although gastritis and esophagitis are well studied in children, there is very limited literature on duodenitis in children. We aimed to assess the prevalence, etiology, clinical, endoscopic, and pathological features in a large cohort of unselected children with duodenitis. METHODS: We reviewed the pathology reports of all the upper endoscopies performed at our institution during 5 years to identify children with duodenitis. Biopsy sections were reviewed to confirm the diagnosis of duodenitis. Demographic, clinical, endoscopic data, and the presence of associated gastritis and esophagitis were noted in all of the children with duodenitis. The etiology of duodenitis was correlated with the patients' clinical diagnosis. RESULTS: Out of 2772 children who had endoscopy, 352 had duodenitis with the prevalence rate of 12.7%. Gastritis was seen in 64% of children with duodenitis compared with 46% of children without duodenitis (P < 0.001). Common indications for endoscopy in children with duodenitis were abdominal pain, positive celiac serology, and diarrhea. The most common etiology was celiac disease (32%), followed by Crohn disease (13%), ulcerative colitis (3%), and Helicobacter pylori infection (6%). In 63% of cases, the endoscopic appearance of duodenum was normal. Cryptitis, villous changes, and cellular infiltration were noted on histology. CONCLUSIONS: Prevalence of duodenitis is 12.7% in children undergoing endoscopy. Celiac disease and inflammatory bowel disease are common causes of duodenitis. Associated gastritis is common in children with duodenitis, and the correlation of endoscopic appearance with histology is poor.

Obesity and gastrointestinal disorders in children.

Obesity in children has become a global pandemic during the last decade. Recent studies have reported an association between obesity and functional gastrointestinal (GI) disorders. In addition, obesity is also becoming increasingly recognized at diagnosis of organic GI diseases such as celiac disease and inflammatory bowel disease. An awareness of all possible complications and associations of obesity by the practicing physician is crucial to provide comprehensive care to obese children. This article reviews the present data on the association between obesity and various common GI disorders. The possible mechanisms and the clinical significance of this association are also discussed.

Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.

BACKGROUND & AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology. METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months. RESULTS: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations. CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

Acute necrotizing pancreatitis in children.

OBJECTIVE: To describe the etiologic factors, course, and outcome of acute necrotizing pancreatitis in children. STUDY DESIGN: We performed a retrospective study of children with necrotizing pancreatitis diagnosed during the last 21 years at Yale-New Haven Children's Hospital. Computed tomography (CT) criteria were used to diagnose necrotizing pancreatitis and to assess severity index. Charts were reviewed to collect demographics, etiology, details of hospital stay, complications, and outcome. RESULTS: Seven children (mean age, 11.6 years; range, 4-17.8 years) had necrotizing pancreatitis. Etiologic factors were medications, diabetes, and gallstones. All had prolonged hospitalization (9-40 days; mean, 20 days) and 5 patients required admission to the pediatric intensive care unit. During the hospital stay, patients developed complications involving the respiratory, hematologic, renal, metabolic, and circulatory systems. All patients had aggressive supportive medical therapy, and none required surgery. There were no deaths attributable to pancreatitis. Late complications after hospital discharge occurred in 5 patients and included pseudocysts, transient hyperglycemia, diabetes, and pancreatic exocrine insufficiency. The CT severity index correlated with the risk of complications. CONCLUSIONS: A cute necrotizing pancreatitis has a variable etiology in children. CT scan is useful in the diagnosis and assessment of severity. Necrotizing pancreatitis in children is associated with severe acute and late complications and requires intensive medical therapy.

Celiac disease in a child with ulcerative colitis: a possible genetic association.

Celiac disease and inflammatory bowel disease including ulcerative colitis (UC) and Crohn's disease are both immune-mediated enteropathies. It is rare for both celiac disease and inflammatory bowel disease to occur together in an individual patient. This association has been reported in adults, however, very rarely in children. Here, we report an unusual case of an 8-year-old child with a history of anemia and failure to thrive who presented with bloody diarrhea. His evaluation showed anemia, elevated inflammatory markers, and positive celiac antibodies. Endoscopic evaluation revealed partial duodenal villous atrophy and pancolitis. He was diagnosed with celiac disease and UC and responded well to a gluten-free diet and steroid/mesalamine therapy. The patient's genetic testing revealed markers showing susceptibility for both celiac disease and UC. It is important to be aware of this association as both conditions can present with similar clinical features, however, require different therapeutic approaches.

Polyethylene glycol: a game-changer laxative for children.

Constipation is a common problem in children worldwide. It can also be a chronic problem persisting for many months to years. Successful treatment of constipation requires long-term use of laxatives. Commonly used laxatives in children include milk of magnesia, lactulose, mineral oil, and polyethylene glycol. Compared with other laxatives, polyethylene glycol (with and without electrolytes) is a relatively new laxative used during the last decade. Recent studies report excellent efficacy and safety of polyethylene glycol for the long-term treatment of constipation in children. Because of excellent patient acceptance, polyethylene glycol has become a preferred choice of laxative for many practitioners. This article reviews the recently published pediatric literature on biochemistry, efficacy, safety, patient acceptance, and pharmacoeconomics of polyethylene glycol.

Risk factors associated with biliary pancreatitis in children.

OBJECTIVES: Little is known about risk factors for biliary pancreatitis in children. We characterized cases of pediatric biliary pancreatitis, compared biliary with nonbiliary cases, examined differences in presentation between younger and older children, and studied features distinguishing gallstone- from sludge-induced pancreatitis. METHODS: We evaluated 76 episodes of biliary pancreatitis from 271 cases of acute pancreatitis in children admitted to a tertiary care hospital from 1994 to 2007. RESULTS: Of the 76 cases, 55% had gallstones, 21% had sludge, and 24% had structural defects. Hispanic children had 2.85 (P = 0.01) and 5.59 (P = 0.003) times higher probability for biliary pancreatitis than white and black children, respectively. Median serum amylase and lipase in children with biliary pancreatitis were 64% and 49% higher, respectively, compared with other causes (P < 0.05). In multiple logistic regression, aspartate aminotransferase was an independent predictor of biliary pancreatitis (odds ratio 6.69, P = 0.001). When comparing gallstone- with sludge-induced causes, obesity was an independent predictor (38% more prevalent, P < 0.01) of gallstone cases. CONCLUSIONS: Hispanic ethnicity is a risk factor and aspartate aminotransferase is a biomarker for biliary pancreatitis over other causes. Furthermore, obesity can distinguish gallstone- from sludge-induced pancreatitis. These findings may spur prospective studies to determine the optimal evaluation and management of children with biliary pancreatitis.

Sustained Improvement in Patient Experience by Optimizing Patient Flow in Ambulatory Settings.

Patient experience has become a priority for healthcare institutions as it affects clinical quality of care, financial reimbursement, provider, and patient satisfaction. We report our experience of improving patient experience measured by Press Ganey surveys in a busy multidisciplinary clinic over 65 months. We optimized patient flow in the clinic by technology-facilitated communication among the clinic staff and by a modest space redesign. We noted a significant improvement in "clinic visit" scores from baseline of 82.1 to 84.6 at year 1, 86.1 at year 2, 88.7 at year 3, and 88.9 at year 4 (P < .001). In comparison with previous short-term studies, we were able to sustain improvement in patient experience scores over 4 years due to optimized patient flow and monitoring of clinic operations. A similar approach can be implemented in other ambulatory settings and is likely to cause a long-term positive impact on patient experience.

Jejunal adaptation in a prepubertal boy after total ileal resection and jejunostomy placement: a four-year follow-up.

Intestinal adaptation is the process that attempts to restore total gut absorption after intestinal resection. In humans, the ileum and the colon can undergo adaptation without the jejunum. However, there is little evidence for the jejunum to undergo adaptation in the absence of the ileum. Here, we report the unusual case of a prepubertal boy who underwent total ileal resection, right hemicolectomy, and jejunostomy after a motor vehicle accident. Despite ileal resection, he showed evidence of successful structural and functional jejunal adaptation.

Two-day bowel preparation with polyethylene glycol 3350 and bisacodyl: a new, safe, and effective regimen for colonoscopy in children.

OBJECTIVES: To assess the safety, efficacy, and acceptance of a 2-day bowel preparation with polyethylene glycol (PEG) 3350 without electrolytes and bisacodyl for colonoscopy in children. PATIENTS AND METHODS: In a prospective study, 111 children of mean age 11.9 years were given 2 g/kg of PEG and a 5-mg tablet of bisacodyl daily for 2 days before colonoscopy. Stool frequency, consistency, and adverse effects were monitored for the duration of the bowel preparation. Compliance and quality of colonic preparation were assessed on the day of the colonoscopy. RESULTS: The average daily stool frequency increased from a baseline of 2, to 4* on day 1, and 6.5* on day 2 of the bowel preparation (*P < 0.001 for difference vs baseline). The colonic preparations were rated as excellent or good in 92% and 93% of the patients in the right and left colon, respectively. Adverse effects were mild nausea (19%), abdominal pain (11%), and vomiting (4%). The compliance was rated as excellent in 95% of the patients. CONCLUSIONS: A 2-day bowel preparation with PEG and bisacodyl is safe, effective, and well accepted for colonoscopy in children without any major adverse effects.