Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

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.

Major basic protein is a useful marker to distinguish eosinophilic esophagitis from IBD-associated eosinophilia in children.

OBJECTIVES: The incidence of eosinophilic esophagitis (EoE) is 3-5 times greater in patients with inflammatory bowel disease (IBD) compared with the general population. This study aimed to differentiate true EoE from esophageal eosinophilia in IBD patients by evaluating expression of major basic protein (MBP) and interleukin-13 (IL-13) in esophageal biopsies. METHODS: This retrospective study included subjects who had an esophagogastroduodenoscopy with esophageal biopsies for IBD work up or suspicion for EoE. Patients were classified into 5 groups: EoE with ≥15 eosinophils per high power field (eos/hpf), EoE-IBD with ≥15 eos/hpf, IBD eosinophilia with 1-14 eos/hpf, IBD and control groups. Biopsies were stained with MBP and IL-13 antibodies and the results (% staining/total tissue area), demographic, and clinical findings were compared among the groups. RESULTS: The median for MBP staining levels in EoE-IBD was 3.8 (interquartile range 1.3-23), significantly lower than in EoE at 52.8 (8.3-113.2), but higher than in IBD eosinophilia at 0.2 (0-0.9; p < 0.001) and negligible in the IBD and control groups. IL-13 expression in EoE was significantly higher only compared with IBD and controls not with EoE-IBD or IBD eosinophilia. MBP predicted EoE with 100% sensitivity and 99% specificity while IL-13 had 83% sensitivity and 90% specificity using cutoff point from the cohort without EoE-IBD patients. Based on MBP cutoff point that distinguished EoE from non EoE, 56% in EoE-IBD were MBP-positive whereas 100% in EoE group (p < 0.05). CONCLUSIONS: MBP may be an excellent marker in distinguishing true EoE from eosinophilia caused by IBD. Our data implied that MBP together with endoscopic and histologic changes can assist EoE diagnosis in IBD patients.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Oncostatin-M Does Not Predict Treatment Response in Inflammatory Bowel Disease in a Pediatric Cohort.

OBJECTIVES: This study aimed to determine whether mRNA expression of oncostatin-M (OSM) and its receptor (OSMR) in initial, pre-treatment intestinal biopsies is predictive of response to tumor necrosis factor antagonists (anti-TNF) in a pediatric inflammatory bowel disease (IBD) cohort. Secondary outcomes correlated OSM and OSMR expression with demographic variables; IBD type, extent, phenotype, and severity; laboratory values; and endoscopic findings. METHODS: A retrospective chart review was conducted on 98 pediatric patients. Patients' clinical courses were stratified as follows: failed anti-TNF (n = 14), quiescent on anti-TNF (n = 36), anti-TNF naïve (n = 19), and age-matched non-IBD controls (n = 29). The mRNA from each patient's pre-treatment ileal or colonic biopsy was isolated, and expression of OSM and OSMR was analyzed. RESULTS: There was no difference in OSM or OSMR expression among the three IBD groups; however, expression was significantly higher in patients with IBD than non-IBD controls (P < 0.001). OSM and OSMR were more highly expressed in patients with ulcerative colitis (UC) with a Mayo score of 3 (P = 0.0092 and P = 0.0313, respectively). High OSM expression correlated with severe disease activity indices at diagnosis (P = 0.002), anemia at diagnosis (P = 0.0236), and need for immunomodulators (P = 0.0193) and steroids (P = 0.0273) during patients' clinical courses. CONCLUSIONS: OSM and OSMR expression were not predictive of response to anti-TNF in our pediatric cohort. OSM expression did correlate with IBD compared with healthy controls as well as with several clinical indicators of severe IBD.

Underutilization of Bowel Ultrasound in North America in Children with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic relapsing disease that requires evaluation using multiple objective tools. In Europe, bowel ultrasound (US) is a widely accepted modality used for the management of patients with IBD; however, its use in North America has only recently emerged as a potential technique. OBJECTIVES: Our goal was to identify current practice patterns of pediatric gastroenterologists and radiologists using bowel US in patients with IBD and highlight perceived limitations to the widespread adoption of this modality in North America. METHODS: A 14-question survey was e-mailed to the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition internet bulletin board composed of 3,058 subscribers from 51 countries; the Society of Pediatric Radiology listserv composed of 1,917 subscribers worldwide; and the Society of Chairs of Radiology at Children's Hospitals listserv. Descriptive summary statistics was used. RESULTS: In North America, about one-quarter of gastroenterology and radiology participants reported using bowel US for IBD; over 3-fourths expressed an interest in using US more often. Bowel US was performed more frequently for Crohn's disease. Both groups agreed the main limitation to using bowel US was concern for inter-observer variability and operator-dependent factors; radiologists reported that other modalities are more effective to assess IBD, whereas gastroenterologists reported unfamiliarity with bowel US indications and techniques. CONCLUSIONS: Our data show there is significant interest among both radiologists and gastroenterologists in using bowel US. However, lack of education, insufficient training, and perceived high inter-observer variability among US technologists are limitations preventing the widespread adoption of US for IBD in North America.

Salivary pepsin A detection related to gastro-oesophageal reflux episodes in children undergoing impedance probe monitoring.

AIM: Gastro-oesophageal reflux is routinely diagnosed with invasive intraluminal impedance pH probe monitoring. This study aimed to determine whether gastric pepsin A detected in saliva of children correlates with gastro-oesophageal reflux. METHODS: Patients undergoing probe monitoring were prospectively recruited between 2014 and 2016 at a paediatric hospital. Standard impedance and demographic data were obtained from electronic medical records. Salivary samples were collected during impedance and measured for gastric pepsin A with an enzyme-linked immunosorbent assay. Impedance probe and pepsin data were analysed and compared for correlation. RESULTS: From 52 enrolled subjects, 28 males and 24 females with mean age 8.0 ± 5.9 and range 0.58-18.0 years, 417 salivary samples were collected. Positive pepsin was found in 14% of samples and 48% patients. The sensitivity of pepsin A in predicting an abnormal impedance was 43% and specificity, 50%. Among pepsin A positive samples, 72% corresponded with a gastro-oesophageal reflux episode. Pepsin peak levels significantly correlated with acidic reflux. CONCLUSION: Pepsin A was presented in saliva of children undergoing gastro-oesophageal reflux disease investigation. Positive pepsin A was associated with a gastro-oesophageal reflux episode, and its peak value correlated with acidic reflux. Salivary pepsin as a marker for gastro-oesophageal reflux needs further investigation.

Delayed Diagnosis of X-linked Lymphoproliferative Syndrome Type 2 in a 17-year-old Male With Severe Crohn's Disease and Recurrent Skin Infections.

X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn's disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.

Branched-chain Amino Acids and Relationship With Inflammation in Youth With Obesity: A Randomized Controlled Intervention Study.

CONTEXT: Elevated concentrations of branched-chain amino acids (BCAA) are strong predictors of type 2 diabetes mellitus (T2DM). Their association with cardiovascular disease (CVD) remains uncertain, particularly in youth. OBJECTIVE: We investigated the role of BCAA and aromatic amino acids (AAA) in obesity, their relationships with novel biomarkers of CVD, and response to a physical activity-based lifestyle intervention (PAL-I) in a randomized controlled study in youth with normal weight (NW) and obesity (OB). METHODS: Age (14-18 years) and Tanner stage (≥IV) matched youth (OB, n = 15 and NW, n = 6) were studied; the 15 participants with OB underwent a 3-month randomized controlled PAL-I. Circulating amino acid profile, glucose, insulin, lipids, adiponectin, retinol binding protein-4, fibrinogen, high-sensitivity C-reactive protein, interleukin-6, and 25-hydroxy vitamin-D, along with body composition, were measured at baseline and after PAL-I. Independent t tests, analysis of covariance, and mixed-effect models were used for analysis of the data. RESULTS: Compared with NW, the concentration of various amino acids, including BCAA and AAA, were altered in OB (P < 0.05). BCAA and AAA showed baseline correlations with body composition and novel biomarkers of CVD, particularly inflammatory factors (all P < 0.05). The PAL-I produced only negligible effects (P > 0.05) on BCAA and AAA. Glutamine, glycine, and aspartic acid decreased with PAL-I (all P < 0.05). CONCLUSION: The novel finding of the BCAA-inflammation relationship, along with strong correlations with nontraditional biomarkers of CVD, may raise the prospect of BCAA as a biomarker of CVD and evoke a potential link between obesity, T2DM, and CVD.

The PNPLA3 rs738409 Variant but not MBOAT7 rs641738 is a Risk Factor for Nonalcoholic Fatty Liver Disease in Obese U.S. Children of Hispanic Ethnicity.

PURPOSE: The rs641738 C>T in membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) is implicated, along with the rs738409 C>G polymorphism in patatin-like phospholipase domain-containing protein 3 (PNPLA3), in nonalcoholic fatty liver disease (NAFLD). The association of these polymorphisms and NAFLD are investigated in Hispanic children with obesity. METHODS: Obese children with and without NAFLD were enrolled at a pediatric tertiary care health system and genotyped for MBOAT7 rs641738 C>T and PNPLA3 rs738409 C>G. NAFLD was characterized by the ultrasonographic presence of hepatic steatosis along with persistently elevated liver enzymes. Genetic variants and demographic and biochemical data were analyzed for the effects on NAFLD. RESULTS: Among 126 enrolled subjects, 84 in the case group had NAFLD and 42 in the control group did not. The two groups had similar demographic distribution. NAFLD was associated with abnormal liver enzymes and elevated triglycerides and cholesterol (p<0.05). Children with NAFLD had higher percentage of PNPLA3 GG genotype at 70.2% versus 31.0% in non-NAFLD, and lower MBOAT7 TT genotype at 4.8% versus 16.7% in non-NAFLD (p<0.05). PNPLA3 rs738409 C>G had an additive effect in NAFLD; however, MBOAT7 rs641738 C>T had no effects alone or synergistically with PNPLA3 polymorphism. NAFLD risk increased 3.7-fold in subjects carrying PNPLA3 GG genotype and decreased in MBOAT7 TT genotype. CONCLUSION: In Hispanic children with obesity, PNPLA3 rs738409 C>G polymorphism increased the risk for NAFLD. The role of MBOAT7 rs641738 variant in NAFLD is less evident.

Report on the Short Endoscopic Exocrine Pancreatic Function Test in Children and Young Adults.

OBJECTIVES: Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testing since the 1990s. In patients, short ePFT assesses acinar function, unlike the longer version for ductal function in adults. The present study summarizes characteristics of 1913 short ePFTs (S-ePFT) performed at 2 centers since 2001. METHODS: The main indications in patients presenting at ages infancy to 24.3 years, for the S-ePFT were failure to thrive, weight loss, diarrhea, and abdominal pain with bloating. Secretin was administered as bolus, and 4 aliquots of fluid were collected between 4 and 10 minutes after administration. Amylase, lipase, trypsin, and chymotrypsin activities were measured in the laboratory. RESULTS: The pH of consecutive samples increased by 0.3 to 0.7. Overall, 36.7% had abnormal S-ePFT with selective amylase deficiency (9.5%) and generalized enzyme deficiency (8.9%) being the most frequent. Retest reproducibility, repeatability, and clinical validity were high. By adding S-ePFT to endoscopy for the suspicion of malabsorption, the abnormal findings increased by 36.9%. CONCLUSIONS: Short ePFT assesses pancreatic acinar function in a reliable and clinically meaningful way in patients. Diagnostic yield of endoscopy increased substantially albeit with increased sedation time. By S-ePFT ductal function, cytokines and proteomics can also be assessed.

Use of Electronic Health Record Tools to Facilitate and Audit Infliximab Prescribing.

OBJECTIVES: The objective of this project was to assess a pediatric institution's use of infliximab and develop and evaluate electronic health record tools to improve safety and efficiency of infliximab ordering through auditing and improved communication. METHODS: Best use of infliximab was defined through a literature review, analysis of baseline use of infliximab at our institution, and distribution and analysis of a national survey. Auditing and order communication were optimized through implementation of mandatory indications in the infliximab orderable and creation of an interactive flowsheet that collects discrete and free-text data. The value of the implemented electronic health record tools was assessed at the conclusion of the project. RESULTS: Baseline analysis determined that 93.8% of orders were dosed appropriately according to the findings of a literature review. After implementation of the flowsheet and indications, the time to perform an audit of use was reduced from 60 minutes to 5 minutes per month. Four months post implementation, data were entered by 60% of the pediatric gastroenterologists at our institution on 15.3% of all encounters for infliximab. Users were surveyed on the value of the tools, with 100% planning to continue using the workflow, and 82% stating the tools frequently improve the efficiency and safety of infliximab prescribing. CONCLUSIONS: Creation of a standard workflow by using an interactive flowsheet has improved auditing ability and facilitated the communication of important order information surrounding infliximab. Providers and pharmacists feel these tools improve the safety and efficiency of infliximab ordering, and auditing data reveal that the tools are being used.

Safety of Secretin Administration in Children.

OBJECTIVE: The aim of this study was to compare the hemodynamic parameters from the anesthesia records of children who underwent upper gastrointestinal endoscopy (esophagogastroduodenoscopy [EGD]) with and without secretin pancreatic function tests (sPFTs). METHODS: The hemodynamic parameters were retrieved from an electronic anesthesia database. The secretin group consisted of 186 children, and the age- and sex-matched control group included 136 patients who did not have sPFTs. RESULTS: There was no difference in the demographic parameters (age and sex) between the 2 groups. The secretin group had a lower height and body mass index. The sPFT resulted in an average 3-minute extension of the endoscopic procedure. The heart rate increased during the EGD in both groups and was higher (averaged 7 beats per minute) in the secretin group than the EGD-only group. There were mild elevations on the systolic and diastolic blood pressures. None of these changes were clinically significant. There were no complications reported during the anesthesia and procedures in the 2 groups. CONCLUSIONS: Secretin PFT is a safe procedure. It only slightly prolongs the total procedure and anesthesia time. There were no clinically significant changes in the vital parameters in the secretin group, and there were no adverse effects recorded.

Spontaneous Gastric Perforation in Two Adolescents.

BACKGROUND Spontaneous gastric perforation is a rare clinical disorder. The majority of the available data have been reported in the neonatal age group. There are a few cases of spontaneous gastric perforation in preschool children. To our knowledge, there is no published information on spontaneous gastric perforation in older children and adolescents. CASE REPORT We describe the presentation and clinical course of two adolescent children who presented with spontaneous gastric perforation. Both children presented with acute onset abdominal pain, which progressively worsened. In both cases, the patient were taken urgently to the operating room after imaging studies had shown pneumoperitoneum. In both cases, surgery revealed gastric perforation with no obvious etiology, specifically no -ulcer, inflammation, or other pathology. CONCLUSIONS These two cases highlight the importance of including spontaneous gastric perforation, not just the typical duodenal/gastric ulcer, in the differential of a patient with severe abdominal pain and distension, who has imaging showing pneumoperitoneum.