91 results on '"Joshua D. Noe"'
Search Results
2. Antibodies‐to‐infliximab accelerate clearance while dose intensification reverses immunogenicity and recaptures clinical response in paediatric Crohn’s disease
- Author
-
Ruben J. Colman, Ye Xiong, Tomoyuki Mizuno, Jeffrey S. Hyams, Joshua D. Noe, Brendan Boyle, Geert R. D’Haens, Johan van Limbergen, Kelly Chun, Jane Yang, Michael J. Rosen, Lee A. Denson, Alexander A. Vinks, Phillip Minar, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Paediatric Gastroenterology
- Subjects
Crohn Disease ,Gastrointestinal Agents ,Hepatology ,Gastroenterology ,Humans ,Tumor Necrosis Factor Inhibitors ,Pharmacology (medical) ,Prospective Studies ,Inflammatory Bowel Diseases ,Child ,Article ,Antibodies ,Infliximab - Abstract
BACKGROUND: Antibodies to infliximab (ATI) are associated with secondary loss of response and increased risk for drug reactions. Limited studies have associated ATI with increased infliximab clearance. AIMS: We assessed the impact of ATI on infliximab clearance and loss of response in an inception paediatric Crohn’s disease cohort with 1-year follow-up. METHODS: This multi-centre prospective cohort study collected peak and trough serum infliximab/ATI concentrations from 660 infusions (78 patients) during the first year of therapy. Clinicians were blinded to these research labs. The primary outcome was the difference in infliximab clearance between ATI-positive (ATI) and ATI-negative (no-ATI) patients. Secondary outcomes included pre-treatment predictors of ATI (including HLA-DQA1 genotyping). Clinical remission, loss of response and infliximab clearance were compared between pre-ATI, during ATI and following ATI resolution with MANOVA. Time to ATI was calculated by Cox proportional Hazards model. RESULTS: ATI were detected in 68% (53/78) patients with a median concentration of 76 ng/mL (range 23–1828). Maximum ATI concentration was 6 and starting dose
- Published
- 2021
- Full Text
- View/download PDF
3. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
- Author
-
David R. Mack, Jarod Prince, Susan S. Baker, Brendan M. Boyle, Rebekah Karns, Suresh Venkateswaran, Subra Kugathasan, Talin Haritunians, Dermot P.B. McGovern, Mamta Giri, James Markowitz, Nai Yun Hsu, Melvin B. Heyman, Lee A. Denson, Ling-Shiang Chuang, Mayte Suárez-Fariñas, Greg Gibson, Jeffrey S. Hyams, Neal S. LeLeiko, Andrew Kasarskis, Kyle Gettler, Bruce J. Aronow, Cary G. Sauer, Yael Haberman, Carmen Argmann, Anne M. Griffiths, Joel R. Rosh, Nathan Gotman, Angela Mo, Dalia Arafat, Sapana Shah, Paul A. Rufo, Thomas D. Walters, Marian Pfefferkorn, Ashish S. Patel, Sonia Davis Thomas, Judy H. Cho, Robert N. Baldassano, Emebet Mengesha, Joshua D. Noe, and Sini Nagpal
- Subjects
Oncology ,Multifactorial Inheritance ,medicine.medical_treatment ,Datasets as Topic ,Ulcerative ,Disease ,Medical and Health Sciences ,cell-type-specific gene expression ,Cohort Studies ,Crohn Disease ,Colectomy ,Genetics (clinical) ,Biological Specimen Banks ,Genetics & Heredity ,Framingham Risk Score ,eQTLs ,Biological Sciences ,Colitis ,Prognosis ,Ulcerative colitis ,transcriptome-wide association studies ,Disease Progression ,Patient Safety ,predicted polygenic transcriptional risk scores ,Biotechnology ,medicine.medical_specialty ,Colon ,Quantitative Trait Loci ,Quantitative trait locus ,Autoimmune Disease ,Risk Assessment ,Article ,Clinical Research ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic association ,business.industry ,Prevention ,Gene Expression Profiling ,Human Genome ,Inflammatory Bowel Disease ,medicine.disease ,United Kingdom ,Gene expression profiling ,transcriptional risk scores ,prediction of disease progression ,Expression quantitative trait loci ,Colitis, Ulcerative ,Generic health relevance ,Digestive Diseases ,Transcriptome ,business ,Genome-Wide Association Study - Abstract
Summary An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
- Published
- 2021
- Full Text
- View/download PDF
4. Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance
- Author
-
Ruben J. Colman, Tomoyuki Mizuno, Keizo Fukushima, David B. Haslam, Jeffrey S. Hyams, Brendan Boyle, Joshua D. Noe, Geert R. D'Haens, Johan Van Limbergen, Kelly Chun, Jane Yang, Lee A. Denson, Nicholas J. Ollberding, Alexander A. Vinks, Phillip Minar, Graduate School, Paediatric Gastroenterology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology
- Subjects
Hepatology ,Gastroenterology ,Pharmacology (medical) - Abstract
Background: Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. Aims: To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. Methods: The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure–response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. Results: A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml. Conclusions: This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.
- Published
- 2022
5. Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn's Disease
- Author
-
David M. Lubman, Ryan W. Stidham, Anne M. Griffiths, Lee A. Denson, Joel R. Rosh, Joshua D. Noe, Jeffrey S. Hyams, Ajay S. Gulati, Shervin Rabizadeh, Wallace Crandall, Marla Dubinsky, Jing Wu, Robert N. Baldassano, Subra Kugathasan, and Peter D.R. Higgins
- Subjects
Male ,Proteomics ,medicine.medical_specialty ,Proteomics methods ,Pediatric Crohn's disease ,Serum protein ,Constriction, Pathologic ,Disease ,Risk Assessment ,Article ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Fibrosis ,Internal medicine ,medicine ,Humans ,Child ,Inflammation ,Extracellular Matrix Proteins ,Hepatology ,business.industry ,Disease progression ,Gastroenterology ,medicine.disease ,Intestines ,Multicenter study ,030220 oncology & carcinogenesis ,Risk stratification ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,business ,Biomarkers - Abstract
Avoiding fibrostenotic complications is of paramount concern in the management of Crohn's disease (CD). We sought to investigate the association of candidate biomarkers of fibrosis collected at diagnosis with the future development of fibrostenotic CD.Using the Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort, a multicenter prospective observational pediatric inception cohort, subjects with an inflammatory phenotype (B1) at diagnosis who later converted to a stricturing phenotype (B2) within 3 years were compared with those who remained B1. Serum collected at diagnosis underwent both parallel reaction monitoring-targeted proteomic analysis and conventional enzyme-linked immunosorbent assay for 10 candidate biomarkers of intestinal fibrosis. Cox proportional hazard regression was used for multivariable analysis of time-dependent outcomes.In 116 subjects 58 subjects with verified B1 phenotype at diagnosis who later converted to B2 disease were compared with 58 subjects who remained B1 over 3 years of follow-up. Extracellular matrix protein 1 (ECM1) levels in the upper quartile (hazard ratio [HR] 3.43, 95% confidence limit [CL] 1.33, 8.42) were associated with future fibrostenotic disease. ASCA IgA (HR 4.99, 95% CL 1.50, 16.68) and CBir levels (HR 5.19, 95% CL 1.83, 14.74) were also associated with future intestinal fibrostenosis, although ECM1 continued to demonstrate independent association with conversion to B2 even with adjustment for serologies in multivariable analysis (HR 5.33, 95% CL 1.29, 22.13).ECM1 and other biomarkers of fibrosis may aid in determining the risk of uncomplicated inflammatory disease converting to B2 stricturing phenotypes in children with CD. Prospective validation studies to verify test performance and optimize clinical utilization are needed before clinical implementation.
- Published
- 2019
- Full Text
- View/download PDF
6. Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets
- Author
-
Judy H. Cho, Ephraim Kenigsberg, Wallace Crandall, Ling-Shiang Chuang, Subra Kugathasan, Clara Abraham, Lee A. Denson, Joshua D. Noe, Nai Yun Hsu, Anne M. Griffiths, Jeffrey S. Hyams, Kyle Gettler, Mamta Giri, Richard Kellermayer, Jerome Martin, David R. Mack, and Gabriel E. Hoffman
- Subjects
0301 basic medicine ,Sequence analysis ,Immunology ,Locus (genetics) ,Genome-wide association study ,Disease ,Computational biology ,Biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Gene expression ,Genetics ,Epigenetics ,Gene ,Genetics (clinical) ,030215 immunology ,Genetic association - Abstract
Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.
- Published
- 2019
- Full Text
- View/download PDF
7. Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression
- Author
-
Suresh Venkateswaran, Melvin B. Heyman, Neal S. LeLeiko, Judy H. Cho, Robert N. Baldassano, T Walters, Ashish S. Patel, Brendan M. Boyle, Andrew Kasarskis, Ling-Shiang Chuang, Emebet Mengesha, Greg Gibson, Talin Haritunians, Nai Yun Hsu, Joshua D. Noe, Cary G. Sauer, David R. Mack, Yael Haberman, Jarod Prince, Susan S. Baker, Marian Pfefferkorn, Sini Nagpal, Mayte Suárez-Fariñas, Subra Kugathasan, Lee A. Denson, Anne M. Griffiths, James Markowitz, Bruce J. Aronow, Dalia Arafat, Sonia Davis Thomas, Rebekah Karns, Joel R. Rosh, Nathan Gotman, Angela Mo, Sapana Shah, Paul A. Rufo, Mamta Giri, Kyle Gettler, Dermot P.B. McGovern, Jeffrey S. Hyams, and Carmen Argmann
- Subjects
Oncology ,medicine.medical_specialty ,Framingham Risk Score ,business.industry ,medicine.medical_treatment ,Genome-wide association study ,Disease ,medicine.disease ,Ulcerative colitis ,Clinical trial ,Gene expression profiling ,Internal medicine ,medicine ,business ,Colectomy ,Genetic association - Abstract
SUMMARYAn important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn’s disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.
- Published
- 2021
- Full Text
- View/download PDF
8. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease
- Author
-
Scott B. Snapper, Anil G. Jegga, Nicholas J Ollberding, Marla Dubinsky, Marian D. Pfefferkorn, James Markowitz, Jason Shapiro, Robert Baldassano, Lee A. Denson, Jonathan R Dillman, Subra Kugathasan, Maria Oliva-Hemker, Adina Alazraki, David Hercules, Anthony R. Otley, Melvin B. Heyman, Ramnik J. Xavier, Allison Ta, Rebekah Karns, Yael Haberman, Jeffrey S. Hyams, Joshua D. Noe, Sandra C. Kim, Barbara S. Kirschner, Shervin Rabizadeh, and Richard Kellermayer
- Subjects
medicine.medical_specialty ,16S ,Myeloid ,Aggregatibacter ,Clinical Sciences ,microbiome ,Gene Expression ,Constriction, Pathologic ,Gastroenterology ,transmural healing ,Autoimmune Disease ,Oral and gastrointestinal ,Serology ,Cohort Studies ,Crohn Disease ,Internal medicine ,RNA, Ribosomal, 16S ,Gene expression ,medicine ,Genetics ,Immunology and Allergy ,Humans ,Child ,Pathologic ,Ribosomal ,Pediatric ,Wound Healing ,magnetic resonance enterography ,biology ,Gastroenterology & Hepatology ,business.industry ,Lachnospiraceae ,Inflammatory Bowel Disease ,Area under the curve ,Odds ratio ,Gene signature ,biology.organism_classification ,Constriction ,medicine.anatomical_structure ,RNA ,luminal narrowing ,Leading Off ,business ,Digestive Diseases - Abstract
Background Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. Materials and Methods Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. Results After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. Conclusions Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
- Published
- 2021
9. Su1585: BIOMARKERS OF DRUG CLEARANCE IN PEDIATRIC IBD – A REAL-WORLD VEDOLIZUMAB PHARMACOKINETIC STUDY
- Author
-
Ruben J. Colman, Tomoyuki Mizuno, Jeffrey S. Hyams, Joshua D. Noe, Brendan M. Boyle, Lee A. Denson, Alexander A. Vinks, and Phillip P. Minar
- Subjects
Hepatology ,Gastroenterology - Published
- 2022
- Full Text
- View/download PDF
10. Real-World Infliximab Pharmacokinetic Study Informs an Electronic Health Record-Embedded Dashboard to Guide Precision Dosing in Children with Crohn's Disease
- Author
-
Kimberly Jackson, Yi-Ting Tsai, Jeffrey S. Hyams, Lee A. Denson, Tomoyuki Mizuno, Ye Xiong, Alexander A. Vinks, Michael J. Rosen, Phillip Minar, Ruben J. Colman, Nieko Punt, Brendan M. Boyle, Joshua D. Noe, and Min Dong
- Subjects
medicine.medical_specialty ,Neutrophils ,Population ,Blood Sedimentation ,030226 pharmacology & pharmacy ,Gastroenterology ,Antibodies ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Crohn Disease ,Gastrointestinal Agents ,Internal medicine ,medicine ,Electronic Health Records ,Humans ,Pharmacology (medical) ,Dosing ,education ,Child ,Serum Albumin ,Pharmacology ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Receptors, IgG ,Area under the curve ,Infliximab ,Therapeutic drug monitoring ,030220 oncology & carcinogenesis ,Erythrocyte sedimentation rate ,Area Under Curve ,Calprotectin ,business ,Biomarkers ,medicine.drug - Abstract
Standard-of-care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn’s disease (CD) are common. The primary aim was to conduct a real-world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic. In a multicenter observational study, 671 peak and trough infliximab concentrations from 78 patients with CD were analyzed with a drug-tolerant assay (Esoterix; LabCorp, Calabasas, CA). Individual area under the curve (AUC) estimates were generated as a measure of drug exposure over time. Population PK modeling (nonlinear mixed-effect modeling) identified serum albumin, antibody to infliximab, erythrocyte sedimentation rate (ESR), and neutrophil CD64 as biomarkers for drug clearance. Week 14 and week 52 biochemical remitters (fecal calprotectin < 250 μg/g) had higher infliximab exposure (AUC) throughout induction. The optimal infliximab AUC target during induction for week 14 biochemical remission was 79,348 μg*h/mL (area under the receiver operating characteristic curve (AUROC) 0.77, [0.63–0.90], 85.7% sensitive, and 64.3% specific) with those exceeding the AUC target more likely to achieve a surgery-free week 52 biochemical remission (OR 4.3, [1.2–14.6]). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64 > 6 (OR 4.5, [1.4–17.8]), ESR > 30 mm/h (OR 3.8, [1.4–11]), age < 10 years old (OR 4.2, [1.2–20]), and weight < 30 kg (OR 6.6, [2.1–25]). We created a decision-support PK dashboard with an iterative process and embedded the modeling program within the electronic health record. Model-informed precision dosing guided by real-world PKs is now available at the bedside in real-time.
- Published
- 2020
11. Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease
- Author
-
Susan S. Baker, David R. Mack, Phillip Minar, Ashish S. Patel, Neal S. Leleiko, Jennifer L. Dotson, Bruce J. Aronow, Suresh Venkateswaran, Samuel Tegge, Marla Dubinsky, Brianne Shuler, Scott B. Snapper, Dedrick E. Moulton, Yael Haberman, Robert Baldassano, Jeffrey S. Hyams, Ajay S. Gulati, Daniel Shapiro, David Ziring, Michael C. Stephens, Rebekah Karns, Richard Kellermayer, Ranjana Gokhale, Stanley A. Cohen, Thomas D. Walters, Sudhir Ghandikota, Maria Oliva-Hemker, Anthony R. Otley, Joshua D. Noe, Sandra C. Kim, Lee A. Denson, Tzipi Braun, Jonathan R. Dillman, Joel R. Rosh, Subra Kugathasan, Greg Gibson, Anne M. Griffiths, Melvin B. Heyman, Allison Ta, Phillip J. Dexheimer, James Markowitz, Anil G. Jegga, Stephen L. Guthery, and Steven J. Steiner
- Subjects
0301 basic medicine ,medicine.medical_specialty ,pediatric Crohn Disease ,Clinical Sciences ,small molecule ,Crohn's Disease ,Disease ,Gastroenterology ,Transcriptome ,surgery ,03 medical and health sciences ,0302 clinical medicine ,Paediatric Crohn disease ,Clinical Research ,Internal medicine ,Gene expression ,medicine ,Genetics ,Gene ,Pediatric ,Crohn's disease ,Gastroenterology & Hepatology ,business.industry ,Inflammatory Bowel Disease ,Mucous membrane ,Original Articles ,General Medicine ,Gene signature ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,medicine.anatomical_structure ,030211 gastroenterology & hepatology ,ileum ,business ,Digestive Diseases ,transcriptome - Abstract
Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease [CD]. We aimed to define ileal gene programmes present at diagnosis and linked with future stricturing behaviour during 5-year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicentre paediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing behaviour. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results A total of 19 of the 249 patients developed isolated B2 stricturing behaviour during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our previous report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix [ECM] gene expression, in those who developed stricturing complications. We further computationally prioritise small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by Year 5 after diagnosis {AUC (area under the curve) (95th CI [confidence interval]) = 0.82 [0.7–0.94)}. Conclusions An ileal gene programme for macrophage and fibroblast activation is linked to stricturing complications in treatment of naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
- Published
- 2020
12. Endoscopic Removal of a Single, Painless, Juvenile Polyp in the Small Intestine Causing Anemia
- Author
-
Amornluck Krasaelap, Diana G. Lerner, Joshua D. Noe, James F. Southern, and Ankur Chugh
- Subjects
Enteroscopy ,medicine.medical_specialty ,Anemia ,Gastroenterology ,Capsule Endoscopy ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Capsule endoscopy ,law ,030225 pediatrics ,Internal medicine ,Intussusception (medical disorder) ,Intestine, Small ,otorhinolaryngologic diseases ,medicine ,Humans ,Gastrointestinal Polyp ,neoplasms ,business.industry ,Juvenile Polyp ,Intestinal Polyps ,pathological conditions, signs and symptoms ,medicine.disease ,digestive system diseases ,Small intestine ,Hematochezia ,surgical procedures, operative ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Intussusception - Abstract
Juvenile polyps are the most common gastrointestinal polyps in childhood. Typically, they are located in the colon and present with intermittent and painless hematochezia. A few case reports have described juvenile polyps in the small intestine, all presenting as intussusception requiring surgery. We report an isolated juvenile polyp in the small intestine presenting with painless anemia, identified using video capsule endoscopy, and removed via enteroscopy.
- Published
- 2020
13. Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children
- Author
-
Joel R. Rosh, Susan S. Baker, Alison Marquis, David R. Mack, Anne M. Griffiths, Melvin B. Heyman, Sonia M. Thomas, Brendan M. Boyle, Ashish S. Patel, Steve Steiner, Thomas D. Walters, Joshua D. Noe, Lee A. Denson, Robert Baldassano, David Keljo, Paul A. Rufo, Neal S. LeLeiko, Subra Kugathasan, James Markowitz, Cary G. Sauer, Bradley Saul, and Jeffrey S. Hyams
- Subjects
Male ,medicine.medical_specialty ,Colonoscopy ,Disease ,macromolecular substances ,Blood Sedimentation ,Gastroenterology ,Severity of Illness Index ,Article ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,030225 pediatrics ,White blood cell ,Internal medicine ,Severity of illness ,medicine ,Humans ,Colitis ,Child ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Ulcerative colitis ,medicine.anatomical_structure ,Erythrocyte sedimentation rate ,Pediatrics, Perinatology and Child Health ,Cohort ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,Female ,business - Abstract
OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (
- Published
- 2020
14. Achieving Target Infliximab Drug Concentrations Improves Blood and Fecal Neutrophil Biomarkers in Crohn's Disease
- Author
-
Phillip Minar, Johan Van Limbergen, Brendan M. Boyle, Geert R. D'Haens, Michael J. Rosen, Lee A. Denson, Joshua D. Noe, Jeffrey S. Hyams, Kimberly Jackson, Ruben J. Colman, Yi-Ting Tsai, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatric Gastroenterology, APH - Digital Health, and APH - Health Behaviors & Chronic Diseases
- Subjects
medicine.medical_specialty ,Neutrophils ,Gastroenterology ,Inflammatory bowel disease ,pediatric Crohn's disease ,Cohort Studies ,03 medical and health sciences ,Feces ,0302 clinical medicine ,Crohn Disease ,Gastrointestinal Agents ,Reference Values ,Clinical Research ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,Child ,Crohn's disease ,Receiver operating characteristic ,biology ,business.industry ,Lactoferrin ,Receptors, IgG ,medicine.disease ,fecal lactoferrin ,Infliximab ,fecal calprotectin ,neutrophil CD64 expression ,Pharmacodynamics ,biology.protein ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,Calprotectin ,business ,Leukocyte L1 Antigen Complex ,Biomarkers ,medicine.drug - Abstract
Background The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations. Methods We analyzed FCP, LCT, and nCD64 before and after IFX induction in a pediatric Crohn’s disease (CD) cohort study. Week-14 FCP biomarker remission was defined as FCP 17.5 improvement. Predictive outcomes were calculated by receiver operating characteristics (ROCs). Results Among 56 CD patients, ROC analysis identified an infusion 4 LCT 9.4 µg/mL (AUROC, 0.799, P = 0.002) and >11.5 µg/mL (AUROC, 0.835, P = 0.003) were associated with a FCP 5 µg/mL had a median FCP improvement (dose 1 to dose 4) of 90% compared with a median of 35% with levels Conclusions This study establishes cut points in neutrophil stool and blood biomarkers for both biochemical remission and therapeutic trough levels following induction therapy. Further studies that evaluate pharmacodynamic biomarker targets for endoscopic and histologic healing are warranted.
- Published
- 2020
15. Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study
- Author
-
Ying Lu, Joel R. Rosh, Helen M. Pappa, Marisa G. Stahl, Joseph A. Galanko, Alka Goyal, Karoline Fiedler, Michael D. Kappelman, Jeffrey S. Hyams, Eileen Crowley, Michael C. Stephens, Jennifer A. Strople, Johan Van Limbergen, Melvin B Heyman, Ross M Maltz, A. Muise, Eric I Benchimol, Joshua D. Noe, Anthony L. Guerrerio, Mark Deneau, Lina Karam, Marian Pfefferkorn, Neal S. Leleiko, Raza Alkhouri, Judith R. Kelsen, Scott B. Snapper, Anne M. Griffiths, Leah Siebold, Dedrick Mouton, Keith J. Benkov, Basavaraj Kerur, Paediatric Gastroenterology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, and APH - Health Behaviors & Chronic Diseases
- Subjects
Pancolitis ,medicine.medical_specialty ,Pediatrics ,medicine.medical_treatment ,Constriction, Pathologic ,Inflammatory bowel disease ,surgery ,Crohn Disease ,Interquartile range ,Epidemiology ,medicine ,Immunology and Allergy ,Humans ,Child ,VEOIBD ,Colectomy ,Retrospective Studies ,Crohn's disease ,business.industry ,Gastroenterology ,Retrospective cohort study ,medicine.disease ,Ulcerative colitis ,Child, Preschool ,Chronic Disease ,North America ,epidemiology ,Colitis, Ulcerative ,medicine.symptom ,Leading Off ,business - Abstract
Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9–5.2). Most (94%) Crohn’s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%–15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.
- Published
- 2020
16. The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children
- Author
-
Marla Dubinsky, Melvin B. Heyman, Ashwin N. Ananthakrishnan, Scott B. Snapper, Anne M. Griffiths, Joel R. Rosh, James Markowitz, Livia Lindoso, Thomas D. Walters, Michael C. Stephens, Susan S. Baker, David R. Mack, Jeffrey S. Hyams, Dedrick E. Moulton, Ajay S. Gulati, Marian D. Pfefferkorn, Kajari Mondal, Maria Oliva-Hemker, Stephen L. Guthery, Suresh Venkateswaran, Anthony R. Otley, Cortney R. Ballengee, David J. Keljo, Jonathan Evans, Robert N. Baldassano, Ashish S. Patel, Lee A. Denson, Hari K. Somineni, Subra Kugathasan, Barbara S. Kirschner, Shervin Rabizadeh, Wallace Crandall, Joshua D. Noe, David Ziring, Stanley N. Cohen, Richard Kellermayer, and Neal S. LeLeiko
- Subjects
Male ,0301 basic medicine ,Time Factors ,Adolescent ,Colon ,Constriction, Pathologic ,Disease ,Severity of Illness Index ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Pregnancy ,Risk Factors ,Severity of illness ,medicine ,Humans ,Longitudinal Studies ,Prospective Studies ,Microbiome ,Child ,Immunologic Tolerance ,Crohn's disease ,Hepatology ,business.industry ,Smoking ,Infant, Newborn ,Gastroenterology ,Environmental Exposure ,medicine.disease ,Phenotype ,Hospitalization ,Breast Feeding ,030104 developmental biology ,Prenatal Exposure Delayed Effects ,North America ,Immunology ,Disease Progression ,Female ,Tobacco Smoke Pollution ,030211 gastroenterology & hepatology ,business ,Follow-Up Studies - Abstract
Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype.We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates.Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03).Early life environmental factors influence the eventual phenotypes and disease course in CD.
- Published
- 2018
- Full Text
- View/download PDF
17. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease
- Author
-
Scott B. Snapper, Anne Dodd, Anne M. Griffiths, Michael E. Zwick, Marla Dubinsky, Wallace Crandall, Ingrid Jurickova, Jeffrey S. Hyams, David T. Okou, Yael Haberman, Aaron Linn, Stephen L. Guthery, Melvin B. Heyman, Subra Kugathasan, Lee A. Denson, Christine Stevens, David J. Cutler, Robert N. Baldassano, Rebekah Karns, Ramnik J. Xavier, Bruce J. Aronow, Anthony R. Otley, Ramona Bezold, Neal S. Leleiko, Barbara S. Kirschner, Mark J. Daly, Kajari Mondal, Kathleen Lake, Kimberly Jackson, Kelly A Shaw, Thomas D. Walters, C. Alexander Valencia, Adam Price, and Joshua D. Noe
- Subjects
Adult ,Male ,0301 basic medicine ,Macrophage colony-stimulating factor ,Adolescent ,Neutrophils ,Neutrophil granulocyte ,medicine.medical_treatment ,Mutation, Missense ,STAT5B ,Inflammatory bowel disease ,Cytokine Receptor Common beta Subunit ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,medicine ,Humans ,Immunology and Allergy ,Missense mutation ,Child ,STAT5 ,biology ,business.industry ,Gastroenterology ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,Prognosis ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Granulocyte macrophage colony-stimulating factor ,Cytokine ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,Case-Control Studies ,Child, Preschool ,Immunology ,biology.protein ,Female ,030211 gastroenterology & hepatology ,Original Clinical Articles ,Transcriptome ,business ,Follow-Up Studies ,medicine.drug - Abstract
Author(s): Denson, Lee A; Jurickova, Ingrid; Karns, Rebekah; Shaw, Kelly A; Cutler, David J; Okou, David; Valencia, C Alexander; Dodd, Anne; Mondal, Kajari; Aronow, Bruce J; Haberman, Yael; Linn, Aaron; Price, Adam; Bezold, Ramona; Lake, Kathleen; Jackson, Kimberly; Walters, Thomas D; Griffiths, Anne; Baldassano, Robert N; Noe, Joshua D; Hyams, Jeffrey S; Crandall, Wallace V; Kirschner, Barbara S; Heyman, Melvin B; Snapper, Scott; Guthery, Stephen L; Dubinsky, Marla C; Leleiko, Neal S; Otley, Anthony R; Xavier, Ramnik J; Stevens, Christine; Daly, Mark J; Zwick, Michael E; Kugathasan, Subra | Abstract: BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P l 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.
- Published
- 2018
- Full Text
- View/download PDF
18. Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn’s Disease
- Author
-
Ramona Bezold, Anne Dodd, Rebekah Karns, Yael Haberman, David J. Cutler, Ramnik J. Xavier, Scott B. Snapper, Neal S. Leleiko, Ingrid Jurickova, Michael E. Zwick, Christine Stevens, Anne M. Griffiths, Anthony R. Otley, Aaron Linn, Jeffrey S. Hyams, Robert N. Baldassano, David T. Okou, Kathleen Lake, Thomas D. Walters, Adam Price, Subra Kugathasan, Wallace Crandall, Marla Dubinsky, Joshua D. Noe, Stephen L. Guthery, Kathryn Quinn, Melvin B. Heyman, Kajari Mondal, Kimberly Jackson, Lee A. Denson, Kelly A Shaw, Barbara S. Kirschner, Mark J. Daly, and Bruce J. Aronow
- Subjects
Male ,0301 basic medicine ,Neutrophils ,Crohn's Disease ,Gene mutation ,Inflammatory bowel disease ,Whole Exome Sequencing ,Cohort Studies ,Chronic granulomatous disease ,Crohn Disease ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Pediatric ,Crohn's disease ,NADPH oxidase ,biology ,Gastroenterology ,Up-Regulation ,Phenotype ,Child, Preschool ,Genetic Variant ,WES ,Female ,Tumor necrosis factor alpha ,Sequence Analysis ,Adolescent ,Neutrophil Oxidative Burst ,IBD ,Clinical Sciences ,Mutation, Missense ,Down-Regulation ,Autoimmune Disease ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Clinical Research ,Exome Sequencing ,Genetics ,medicine ,Humans ,CYBB ,Preschool ,Gene ,Alleles ,Gastroenterology & Hepatology ,Hepatology ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,Inflammatory Bowel Disease ,Neurosciences ,Infant ,NADPH Oxidases ,medicine.disease ,Glucose ,030104 developmental biology ,Mutation ,Immunology ,biology.protein ,RNA ,Missense ,Reactive Oxygen Species ,Digestive Diseases ,business - Abstract
Background & aimsIndividuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients.MethodsWe performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.ResultsWe identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P= .0008) and stricturing complications (P= .002) than children with CD without these mutations. Among patients withCD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P=.0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P= .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P= .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses.ConclusionsWe identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.
- Published
- 2018
- Full Text
- View/download PDF
19. Evolution of Pediatric Inflammatory Bowel Disease Unclassified (IBD-U): Incorporated With Serological and Gene Expression Profiles
- Author
-
Joel R. Rosh, Anne M. Griffiths, James Markowitz, Kajari Mondal, Suresh Venkateswaran, Madeline Bertha, Marla Dubinsky, Cary G. Sauer, Shervin Rabizadeh, Joshua D. Noe, Raguraj Chandradevan, Hari K. Somineni, Nusrat Harun, Subra Kugathasan, Scott B. Snapper, Cortney R. Ballengee, Wallace Crandall, Neal S. Leleiko, Lee A. Denson, Thomas D. Walters, Jeffrey S. Hyams, Tatyana Hofmekler, and Mi-Ok Kim
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Disease ,digestive system ,Inflammatory bowel disease ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Prospective Studies ,Child ,Prospective cohort study ,Irritable bowel syndrome ,business.industry ,Infant, Newborn ,Gastroenterology ,Infant ,Inflammatory Bowel Diseases ,Prognosis ,medicine.disease ,Ulcerative colitis ,digestive system diseases ,Natural history ,030104 developmental biology ,Child, Preschool ,Cohort ,Female ,030211 gastroenterology & hepatology ,Transcriptome ,business ,Biomarkers ,Immunosuppressive Agents ,Follow-Up Studies - Abstract
Background Inflammatory bowel disease (IBD) mainly consists of Crohn's disease (CD) and ulcerative colitis (UC). About 10%-15% of patients with IBD cannot be firmly diagnosed with CD or UC; hence, they are initially diagnosed as inflammatory bowel disease unclassified (IBD-U). Having a firm diagnosis is clearly preferred to guide treatment choices, and better understanding of the nature of IBD-U is required. Methods We performed an analysis of a subset of pediatric subjects from an inception IBD cohort of patients initially enrolled in a prospective multicenter study (the RISK study). Initial diagnosis and 2-year follow-up data from the subjects diagnosed with IBD-U were analyzed. An expert panel verified final diagnosis using predefined criteria as a guide. Serological and disease-relevant ileal and rectal tissue gene expression profiles were investigated. The use and the time to initiate anti-TNFα treatment was analyzed among the outcome groups. Results A total of 1411 subjects were enrolled with initial diagnosis of IBD, and among them, 136 subjects were initially diagnosed as IBD-U at enrollment. And 26% were reclassified as UC and 14% as CD within 2 years of diagnosis, while 60% remained as IBD-U. Of those who were reclassified, there was a 2:1 ratio, UC (n = 35) to CD (n = 19). The molecular and serological features of IBD-U at the end of follow-up were very similar to UC and very different from CD. There was less likelihood of receiving anti-TNFα agents if the diagnosis was IBD-U compared with CD (P < 0.0001). Conclusions In our cohort, 60% of the IBD-U subjects remained as unclassified at 2 years; of those subsequently classified, a higher percentage followed a course more similar to UC. Most of the IBD-U subjects at diagnosis had serological and molecular signatures that are very similar to UC. Although the atypical presentations made the clinician to make an interim diagnosis of IBD-U, results of the molecular and serological factors performed at the time of diagnosis suggests that they were very similar to UC. However, long-term studies are needed to better understand the natural history and molecular characterization of pediatric onset IBD-U. 10.1093/ibd/izy136_video1Video 1.Video 1. Watch now at https://academic.oup.com/ibd/article-lookup/doi/10.1093/ibd/izy136izy136.video15791389938001.
- Published
- 2018
- Full Text
- View/download PDF
20. Moving On: Transition Readiness in Adolescents and Young Adults With IBD
- Author
-
Diana G. Lerner, Rachel Neff Greenley, Amitha Prasad Gumidyala, Natasha Poulopoulos, Steven L. Werlin, Jose Cabrera, Dorota Walkiewicz, Stacy A. Kahn, Joshua D. Noe, and Jill M. Plevinsky
- Subjects
Male ,Gerontology ,Health Knowledge, Attitudes, Practice ,Transition to Adult Care ,Adolescent ,Cross-sectional study ,Severity of Illness Index ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Patient Education as Topic ,Health care ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Young adult ,Disease management (health) ,Self-efficacy ,Self-management ,business.industry ,Medical record ,digestive, oral, and skin physiology ,Gastroenterology ,Disease Management ,Inflammatory Bowel Diseases ,Prognosis ,Self Efficacy ,humanities ,Self Care ,Cross-Sectional Studies ,Needs assessment ,Regression Analysis ,Female ,030211 gastroenterology & hepatology ,business ,Needs Assessment - Abstract
Background Inflammatory bowel diseases (IBD) often begins early in life. Adolescents and young adults (AYA) with IBD have to acquire behaviors that support self-care, effective healthcare decision-making, and self-advocacy to successfully transition from pediatric to adult health care. Despite the importance of this critical time period, limited empirical study of factors associated with transition readiness in AYA exists. This study aimed to describe transition readiness in a sample of AYA with IBD and identify associated modifiable and nonmodifiable factors. Methods Seventy-five AYA (ages 16-20) and their parents participated. AYA and parents reported on demographics, patient-provider transition-related communication, and transition readiness. AYA self-reported on disease self-efficacy. Disease information was abstracted from the medical record. Results Deficits in AYA responsibility were found in knowledge of insurance coverage, scheduling appointments, and ordering medication refills. Older AYA age, higher AYA disease-management self-efficacy, and increased patient-provider transition communication were each associated with higher overall transition readiness and AYA responsibility scores. Regression analyses revealed that older AYA age and increased patient-provider transition-related communication were the most salient predictors of AYA responsibility for disease management and overall transition readiness across parent and AYA reports. Conclusions AYA with IBD show deficits in responsibility for their disease management that have the potential to affect their self-management skills. Findings suggest provider communication is particularly important in promoting transition readiness. Additionally, it may be beneficial to wait to transition patients until they are older to allow them more time to master skills necessary to responsibly manage their own healthcare.
- Published
- 2018
- Full Text
- View/download PDF
21. MACHINE LEARNING FOR CROHN’S DISEASE PHENOTYPE MODELING USING BIOPSY IMAGES
- Author
-
Scott B. Snapper, Joel R. Rosh, Shervin Rabizadeh, Ashish S. Patel, Christopher A. Moskaluk, Anne M. Griffiths, Stanley N. Cohen, Erin Bonkowski, Maria Oliva-Hemker, Joshua D. Noe, Dedrick E. Moulton, Richard Kellermayer, Jeffrey S. Hyams, Barbara S. Kirschner, Susan S. Baker, David R. Mack, David Ziring, Lee A. Denson, Sandra C. Kim, Ajay S. Gulati, Lubaina Ehsan, Anthony R. Otley, Subra Kugathasan, Thomas D. Walters, Jennifer L. Dotson, Marian D. Pfefferkorn, Jason Shapiro, Robert N. Baldassano, Saurav Sengupta, Stephen L. Guthery, James Markowitz, Melvin B. Heyman, and Sana Syed
- Subjects
Crohn's disease ,Pathology ,medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Biopsy ,Gastroenterology ,Medicine ,Immunology and Allergy ,business ,medicine.disease ,Phenotype - Abstract
Background Predicting Crohn’s disease (CD) phenotype development has proven challenging due to difficulties in biopsy image interpretation of histologically similar yet biologically distinct phenotypes. At initial diagnosis, mostly CD patients are classified as B1 (inflammatory behavior), they typically either retain B1 phenotype or develop more complicated B2 (stricturing), B3 (internal penetrating), or B2/B3 phenotypes (defined by Montreal Classification). Prediction of phenotype development based on baseline biopsies can radically improve our clinical care by altering disease management. Biopsy-based image analysis via Convolutional Neural Networks (CNNs) has been successful in cancer detection, but investigation into its utility for CD phenotypes is lacking. We applied a machine learning CNN model to classify CD phenotypes and histologically normal ileal controls. Methods Baseline hematoxylin & eosin (H&E) stained ileal biopsy slides were obtained from the Cincinnati Children’s Hospital Medical Center’s RISK validation sub cohort. At University of Virginia, biopsy slides were digitized, and a ResNet101 CNN model was trained. High resolution images were patched into 1000x1000 pixels with a 50% overlap and then resized to 256x256 pixels for training (80-20 split was kept between training and testing sets to ensure same patient patches were not mixed). Gradient Weighted Activating Mappings (GradCAMs) were used to visualize the model’s decision making process. Results We initially trained the model for CD vs. controls where it achieved 97% accuracy in detecting controls. We further trained it for classifying CD phenotypes (n=16 B1, n=16 B2, n=4 B3, n=13 B2/B3; phenotype decision at 5 year). It displayed a higher accuracy in detecting B2 (85%) while there were overlaps in the detection of other phenotypes (Figure 1). For B2, Grad-CAM heatmaps highlighted central pink areas within the lamina propria as the model’s regions of interests which were present when other phenotypes were misclassified as B2 (Figure 2). Conclusions: Here we highlight the potential utility of a machine learning image analysis model for describing CD phenotypes using H&E stained biopsies. Previous studies have shown B2 to be associated with increased activation for extracellular matrix genes (connective tissue component). Our GradCAM results support this finding as the pink central areas utilized by the model for classifying B2 could be connective tissue. Further confirmation via molecular phenotyping including Sirius Red immunohistochemistry is underway. Our work supports prediction of CD phenotypes using baseline biopsies at diagnosis and has potential to influence individualized care for children with CD.
- Published
- 2021
- Full Text
- View/download PDF
22. Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis
- Author
-
David Ziring, Stanley N. Cohen, Scott B. Snapper, Melvin B. Heyman, David J. Keljo, Jonathan Evans, Bruce J. Aronow, Richard Kellermayer, Dedrick E. Moulton, Steven J. Steiner, Mi-Ok Kim, Susan S. Baker, David R. Mack, Melanie Schirmer, Thomas D. Walters, Curtis Huttenhower, Joshua D. Noe, Barbara S. Kirschner, Phillip Dexheimer, Maria Oliva-Hemker, Lee A. Denson, Wallace Crandall, Ajay S. Gulati, Joel R. Rosh, James Markowitz, Yael Haberman, Robert N. Baldassano, Tzipi Braun, Stephen L. Guthery, Anne M. Griffiths, Ramnik J. Xavier, Jeffrey S. Hyams, Neal S. Leleiko, Marla Dubinsky, Subramaniam Kugathasan, Rebekah Karns, Anthony Otley, and Ashish S. Patel
- Subjects
0301 basic medicine ,Male ,Aging ,Disease ,Medical and Health Sciences ,Alpha defensin ,immune response ,Pathogenesis ,Cohort Studies ,Peyer's Patches ,0302 clinical medicine ,Crohn Disease ,Immunology and Allergy ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Pediatric ,Age Factors ,Biological Sciences ,medicine.anatomical_structure ,Pediatric age-of-diagnosis ,Child, Preschool ,mucosal microbial profile and transcriptome ,Female ,Risk ,alpha-Defensins ,Adolescent ,Immunology ,digestive system ,Article ,03 medical and health sciences ,Immune system ,Ileum ,Clinical Research ,medicine ,Genetics ,Humans ,Preschool ,business.industry ,Prevention ,Lachnospiraceae ,Puberty ,Inflammatory Bowel Disease ,Gene signature ,Th1 Cells ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Paneth cell ,Dysbiosis ,business ,Digestive Diseases ,030215 immunology - Abstract
Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.
- Published
- 2019
23. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
- Author
-
Susan S. Baker, Melanie Schirmer, Alison Marquis, Joel R. Rosh, Cary G. Sauer, Laura Bauman, Mason Nistel, Phillip J. Dexheimer, James Markowitz, Kevin P. Mollen, Sapana Shah, Neal S. Leleiko, Anne M. Grifiths, Paul A. Rufo, Robert N. Baldassano, Rebekah Karns, Elizabeth Novak, Ashish S. Patel, Melvin B. Heyman, Judith Somekh, Yael Haberman, Erin Bonkowski, Ingrid Jurickova, Thomas D. Walters, Brendan M. Boyle, Tzipi Braun, Nathan Gotman, Angela Mo, Jeffrey S. Hyams, Curtis Huttenhower, Sonia Davis Thomas, Subra Kugathasan, Ramnik J. Xavier, Lee A. Denson, Marian D. Pfefferkorn, Greg Gibson, Joshua D. Noe, Bruce J. Aronow, Michael J. Rosen, Shai S. Shen-Orr, Margaret H. Collins, and David R. Mack
- Subjects
Male ,0301 basic medicine ,Integrins ,Mitochondrial Diseases ,Anti-Inflammatory Agents ,General Physics and Astronomy ,Ulcerative ,02 engineering and technology ,Severity of Illness Index ,Oral and gastrointestinal ,Pathogenesis ,Feces ,2.1 Biological and endogenous factors ,Medicine ,Prospective Studies ,Intestinal Mucosa ,Precision Medicine ,Aetiology ,lcsh:Science ,Mesalamine ,Child ,Prospective cohort study ,screening and diagnosis ,Multidisciplinary ,Microbiota ,Anti-Inflammatory Agents, Non-Steroidal ,Remission Induction ,Colitis ,021001 nanoscience & nanotechnology ,Ulcerative colitis ,Mitochondria ,Mitochondrial ,3. Good health ,Detection ,Genes, Mitochondrial ,Treatment Outcome ,Adenocarcinoma ,Female ,Non-Steroidal ,0210 nano-technology ,Sequence Analysis ,Biotechnology ,Adult ,Adolescent ,Science ,Autoimmune Disease ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Clinical Research ,Severity of illness ,Genetics ,Humans ,Glucocorticoids ,Nutrition ,Sequence Analysis, RNA ,Tumor Necrosis Factor-alpha ,business.industry ,Gene Expression Profiling ,Inflammatory Bowel Disease ,Rectum ,General Chemistry ,Gene signature ,medicine.disease ,4.1 Discovery and preclinical testing of markers and technologies ,Gene expression profiling ,Good Health and Well Being ,030104 developmental biology ,Genes ,Immunology ,RNA ,Colitis, Ulcerative ,lcsh:Q ,Transcriptome ,Digestive Diseases ,business - Abstract
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches., The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.
- Published
- 2019
- Full Text
- View/download PDF
24. Variation in care in the management of children with Crohn's disease: Data from a multicenter inception cohort study
- Author
-
Lee A. Denson, Joshua D. Noe, Susan S. Baker, David R. Mack, David Keljo, Chenthan Krishnakumar, Anne M. Griffiths, Joel R. Rosh, Dedrick E. Moulton, Ranjana Gokhale, Marla Dubinsky, Stanley A. Cohen, Subra Kugathasan, Jeffrey S. Hyams, Maria Oliva-Hemker, Anthony R. Otley, Michael D. Kappelman, Marian D. Pfefferkorn, Mi-Ok Kim, David Ziring, Robert N. Baldassano, Richard Kellermayer, Shervin Rabizadeh, Jonathan Evans, Scott B. Snapper, Wallace Crandall, Chunyan Liu, Kajari Mondal, T Walters, Ashish S. Patel, Neal S. Leleiko, Cortney R. Ballengee, James Markowitz, Stephen L. Guthery, and Melvin B. Heyman
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Colonoscopy ,Disease ,Severity of Illness Index ,Diagnostic modalities ,03 medical and health sciences ,0302 clinical medicine ,Outcome variable ,Crohn Disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Immunology and Allergy ,Practice Patterns, Physicians' ,Child ,Crohn's disease ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,Antibodies, Monoclonal ,Prognosis ,medicine.disease ,INCEPTION COHORT ,030104 developmental biology ,Variation (linguistics) ,Cohort ,Female ,030211 gastroenterology & hepatology ,Patient Care ,business ,Follow-Up Studies - Abstract
Background: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). Methods: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. Results: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P < 0.01) within 90 days, but variation was not significant over a 3-year period (P = 0.13). Early anti-tumor necrosis factor (anti-TNF) exposure (within 90 days) varied from 2.1% to 65.7% (P < 0.01), but variation was not significant over a 3-year period (P > 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. Conclusions: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care.
- Published
- 2019
- Full Text
- View/download PDF
25. Su519 SHOTGUN METAGENOMICS IDENTIFIES MICROBIAL SIGNATURE CHANGES ASSOCIATED WITH INDUCTION INFLIXIMAB CLEARANCE IN CROHN'S DISEASE
- Author
-
Jeffrey S. Hyams, Lee A. Denson, Phillip Minar, David B. Haslam, Ruben J. Colman, Geert R. D'Haens, Brendan M. Boyle, Johan Van Limbergen, Joshua D. Noe, Michael J. Rosen, Nicholas J. Ollberding, Dawit Tadesse, Ye Xiong, and Alexander A. Vinks
- Subjects
Crohn's disease ,Hepatology ,business.industry ,Immunology ,Gastroenterology ,medicine ,medicine.disease ,business ,Shotgun metagenomics ,Infliximab ,medicine.drug - Published
- 2021
- Full Text
- View/download PDF
26. 728 PLASMA PROTEOMIC RESPONSE SIGNATURE FOR CHILDREN RECEIVING INFLIXIMAB FOR CROHN'S DISEASE
- Author
-
Phillip Minar, Brendan M. Boyle, Jeffrey S. Hyams, Sudhir Ghandikota, Michael J. Rosen, Joshua D. Noe, Anil G. Jegga, Rebekah Karns, and Lee A. Denson
- Subjects
Crohn's disease ,medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,medicine ,medicine.disease ,business ,Infliximab ,medicine.drug - Published
- 2021
- Full Text
- View/download PDF
27. 935 PRE-TREATMENT MUCOSAL INFLAMMATORY AND WOUND HEALING GENE PROGRAMS REVEAL MECHANISMS ASSOCIATED WITH FUTURE STRICTURING BEHAVIOR DURING FIVE YEAR FOLLOW-UP IN PEDIATRIC CROHN'S DISEASE
- Author
-
Robert N. Baldassano, Greg Gibson, David Ziring, Lee A. Denson, Michael C. Stephens, Rebekah Karns, Susan S. Baker, David R. Mack, Phillip Minar, Anne M. Griffiths, Ajay S. Gulati, Dedrick E. Moulton, Melvin B. Heyman, Jeffrey S. Hyams, Daniel Shapiro, Richard Kellermayer, Scott B. Snapper, Anthony R. Otley, Joshua D. Noe, Bruce J. Aronow, Marla Dubinsky, Ashish Patel, Neal S. Leleiko, Yael Haberman, Jennifer L. Dotson, Anil G. Jegga, Sudhir Ghandikota, Maria Oliva-Hemker, Ranjana Gokhale, Stephen L. Guthery, Sandra C. Kim, Steven J. Steiner, Stanley A. Cohen, Phillip J. Dexheimer, James Markowitz, Suresh Venkateswaran, Subra Kugathasan, Thomas D. Walters, Samuel Tegge, Brianne Shuler, and Tzipi Braun
- Subjects
Pre treatment ,medicine.medical_specialty ,Hepatology ,Pediatric Crohn's disease ,business.industry ,Internal medicine ,Gastroenterology ,Five year follow up ,medicine ,business ,Wound healing - Published
- 2020
- Full Text
- View/download PDF
28. 613 ANTIBODIES TO INFLIXIMAB ACCELERATE DRUG CLEARANCE WHILE INTENSIFICATION STRATEGIES REVERSE IMMUNOGENICITY AND RECAPTURE CLINICAL RESPONSE
- Author
-
Ruben J. Colman, Joshua D. Noe, Jeffrey S. Hyams, Jane M. Yang, Michael J. Rosen, Lee A. Denson, Ye Xiong, Alexander A. Vinks, Phillip Minar, Kelly Y. Chun, Tomoyuki Mizuno, and Brendan M. Boyle
- Subjects
Antibodies to infliximab ,Hepatology ,business.industry ,Immunogenicity ,Immunology ,Gastroenterology ,Medicine ,business ,Clearance - Published
- 2020
- Full Text
- View/download PDF
29. 22 CHANGE IN FECAL CALPROTECTIN AND LACTOFERRIN PREDICT CLINICAL REMISSION FOLLOWING INDUCTION THERAPY WITH INFLIXIMAB IN PEDIATRIC CROHN’S DISEASE (CD)
- Author
-
Phillip Minar, Brendan M. Boyle, Joshua D. Noe, Jeffrey S. Hyams, and Ruben J. Colman
- Subjects
medicine.medical_specialty ,Hepatology ,biology ,Lactoferrin ,business.industry ,medicine.medical_treatment ,Gastroenterology ,medicine.disease ,Inflammatory bowel disease ,Infliximab ,Induction therapy ,Internal medicine ,medicine ,biology.protein ,Mucositis ,Calprotectin ,business ,Feces ,Neoadjuvant therapy ,medicine.drug - Published
- 2020
- Full Text
- View/download PDF
30. Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity of Intestinal Inflammation
- Author
-
Thomas D. Walters, Wallace Crandall, Karen N. Conneely, Judy H. Cho, Robert N. Baldassano, Kajari Mondal, Anne M. Griffiths, Melvin B. Heyman, David T. Okou, Susan S. Baker, David R. Mack, Joshua D. Noe, Lee A. Denson, Urko M. Marigorta, Hari K. Somineni, Subra Kugathasan, Joel R. Rosh, Angela Mo, Suresh Venkateswaran, Greg Gibson, Marla Dubinsky, James Markowitz, Alicia K. Smith, Richard Kellermayer, Varun Kilaru, Jeffrey S. Hyams, Michael C. Stephens, David J. Cutler, and Dawayland O. Cobb
- Subjects
0301 basic medicine ,Male ,Crohn's Disease ,Disease ,Inflammatory bowel disease ,Severity of Illness Index ,Oral and gastrointestinal ,0302 clinical medicine ,Crohn Disease ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Children ,Pediatric ,Crohn's disease ,biology ,Gastroenterology ,Age Factors ,Methylation ,Editorial Commentary ,CpG site ,Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease (RISK) Study ,Child, Preschool ,DNA methylation ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Adolescent ,Genotype ,Clinical Sciences ,Single-nucleotide polymorphism ,Autoimmune Disease ,Risk Assessment ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Sex Factors ,Clinical Research ,medicine ,Genetics ,Humans ,Preschool ,Inflammation ,Hepatology ,Gastroenterology & Hepatology ,business.industry ,C-reactive protein ,Inflammatory Bowel Disease ,Human Genome ,Neurosciences ,Infant ,DNA Methylation ,Mendelian Randomization Analysis ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Case-Control Studies ,Immunology ,North America ,biology.protein ,Epigenetic Alteration ,business ,Digestive Diseases ,Follow-Up Studies ,Genome-Wide Association Study - Abstract
Background & Aims Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. Methods We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. Results We identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. Conclusions Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
- Published
- 2018
31. Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis
- Author
-
Susan S. Baker, David R. Mack, James Markowitz, Marian Pfefferkorn, Suresh Venkateswaran, David J. Cutler, Jarod Prince, Neal S. Leleiko, Melvin B. Heyman, Greg Gibson, Sonia M. Davis, Urko M. Marigorta, David J. Keljo, Michael E. Zwick, Joshua D. Noe, Maria Oliva-Hemker, Jeffrey S. Hyams, David T. Okou, Sampath Prahalad, Ashish S. Patel, Anne M. Griffiths, Subra Kugathasan, Robert N. Baldassano, Anthony R. Otley, Lee A. Denson, Brendan M. Boyle, Cary G. Sauer, Thomas D. Walters, Joel R. Rosh, and Paul A. Rufo
- Subjects
0301 basic medicine ,Male ,Ulcerative ,Genome-wide association study ,Inflammatory bowel disease ,0302 clinical medicine ,2.1 Biological and endogenous factors ,GWAS ,Immunology and Allergy ,Medicine ,Aetiology ,Child ,HLA-DRB1 ,Pediatric ,Gastroenterology ,Single Nucleotide ,Colitis ,Child, Preschool ,030211 gastroenterology & hepatology ,Female ,Adolescent ,IBD ,Clinical Sciences ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Pediatric UC ,Autoimmune Disease ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetics ,Ulcerative Colitis ,SNP ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Allele ,Preschool ,Alleles ,Gastroenterology & Hepatology ,business.industry ,Human Genome ,Inflammatory Bowel Disease ,Odds ratio ,medicine.disease ,United Kingdom ,030104 developmental biology ,Case-Control Studies ,Immunology ,Colitis, Ulcerative ,Digestive Diseases ,business ,Basic Science Research ,Genome-Wide Association Study ,HLA-DRB1 Chains - Abstract
BACKGROUND: The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84–1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). METHOD: To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. RESULTS: HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10(-8) to 5 x 10(-10)). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10(–13)) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10(–9)) and another SNP rs17188113 (OR = 0.48, p = 7.56*10(–9)). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10(-10)) and female gender (OR = 8.85, p = 4.82x10(-13)). CONCLUSION: In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.
- Published
- 2018
32. Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease
- Author
-
Iris Barshack, Batia Weiss, Lee A. Denson, Joel R. Rosh, Anne M. Griffiths, Stephen L. Guthery, Melvin B. Heyman, Dedrick E. Moulton, Anthony R. Otley, David Keljo, David Ziring, Yair Anikster, Robert N. Baldassano, Ayelet Di Segni, Marina BenShoshan, Phillip J. Dexheimer, Maria Oliva-Hemker, Joshua D. Noe, James Markowitz, Ashish S. Patel, Scott B. Snapper, Thomas D. Walters, Wallace Crandall, Tzipi Braun, Steven J. Steiner, Stanley A. Cohen, Susan S. Baker, David R. Mack, Camila Avivi, Yael Haberman, Bruce J. Aronow, Ajay S. Gulati, Jeffrey S. Hyams, Richard Kellermayer, Barbara S. Kirschner, Subra Kugathasan, and Neal S. LeLeiko
- Subjects
0301 basic medicine ,Male ,Myeloid ,Messenger ,Crohn's Disease ,Gastroenterology ,Crohn Disease ,Gene expression ,Immunology and Allergy ,2.1 Biological and endogenous factors ,Gene Regulatory Networks ,Aetiology ,Child ,Oligonucleotide Array Sequence Analysis ,RNA expression ,RNAseq ,3. Good health ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Hepatocyte Nuclear Factor 4 ,RNA, Long Noncoding ,Female ,Long Noncoding ,Biotechnology ,Cell type ,medicine.medical_specialty ,Adolescent ,Clinical Sciences ,Down-Regulation ,long ncRNA ,In situ hybridization ,Biology ,Autoimmune Disease ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Ileum ,Internal medicine ,medicine ,Genetics ,Humans ,RNA, Messenger ,Gene ,Neoplastic ,Gastroenterology & Hepatology ,Gene Expression Profiling ,Prevention ,Inflammatory Bowel Disease ,Human Genome ,RNA ,Gene signature ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,Cancer research ,Colitis, Ulcerative ,Caco-2 Cells ,Digestive Diseases ,Basic Science Research - Abstract
Background Long noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA. Methods Using RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes. Results We characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury. Conclusions We systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.
- Published
- 2018
33. Trajectories of oral medication adherence in youth with inflammatory bowel disease
- Author
-
Jennifer G. Walter, Steven L. Werlin, Rachel Neff Greenley, Amitha Prasad Gumidyala, Eve Nguyen, Joshua D. Noe, Jennifer Verrill Schurman, Stacy A. Kahn, Molly Mishler Thomason, and Bryan T. Karazsia
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Thiopurine methyltransferase ,biology ,business.industry ,Medical record ,MEDLINE ,Disease ,Inflammatory Bowel Diseases ,medicine.disease ,Inflammatory bowel disease ,Medication Adherence ,Psychiatry and Mental health ,Regimen ,Pharmacotherapy ,biology.protein ,Humans ,Medicine ,Female ,Child ,business ,Applied Psychology ,Irritable bowel syndrome - Abstract
Objective To examine longitudinal trajectories of oral thiopurine adherence over a 180-day interval in a sample of youth with inflammatory bowel disease (IBD) and to identify the role of disease activity, length of time since diagnosis, and regimen complexity in predicting adherence trajectory class membership. Method Participants included 96 adolescents (M age = 14.32 years) with IBD. Oral medication adherence was assessed via MEMS Track Caps (i.e., an electronic monitor that allows for real-time assessment of adherence) for 6 months, after which time devices were collected and data were downloaded. Medical record reviews provided information about participants' disease activity, length of time since diagnosis, and regimen complexity (including both medications and supplements) at the time of study enrollment. Results Two distinct adherence trajectory classes emerged: Group 1 represented those with consistently near-perfect adherence, whereas Group 2 represented those with mild nonadherence that increased with time. Complexity of medication regimen emerged as the only predictor of trajectory class, with adolescents whose regimen involved more than 1 daily medication administration time being more likely to be classified in Group 2 (i.e., the consistently near-perfect adherence group) than those whose regimen involved only 1 daily medication administration time. Conclusions Distinct classes of adherence trajectories in pediatric IBD can be identified with longitudinal data collection approaches; however, disease and regimen factors offered limited value in predicting adherence trajectory class. Future research should utilize longitudinal conceptualizations of adherence and examine alternative predictors of declining adherence over time.
- Published
- 2015
- Full Text
- View/download PDF
34. Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study
- Author
-
Joel R. Rosh, Nathan Gotman, Neal S. Leleiko, Vin Tangpricha, Francisco A. Sylvester, Marian Pfefferkorn, Jessie Wang, Jeffrey S. Hyams, Paul A. Rufo, Krista Spada, Keith J. Benkov, Michael D. Kappelman, Subra Kugathasan, David R. Mack, Jennifer A. Strople, David Ziring, Susan S. Baker, Anthony Otley, Robert N. Baldassano, Jose Serrano, Dedrick E. Moulton, Marla Dubinsky, Stephen L. Guthery, Brendan M. Boyle, Margaret H. Collins, Cary G. Sauer, David J. Keljo, Joshua D. Noe, Melvin B. Heyman, Jonathan Evans, Anne M. Griffiths, Maria Oliva-Hemker, Prateek Wali, Alison Marquis, Ashley Britt, Ashish S. Patel, Boris Sudel, James Markowitz, Thomas D. Walters, Suresh Venkateswaran, Sonia M. Davis, Lee A. Denson, and Bradley Saul
- Subjects
0301 basic medicine ,Male ,medicine.medical_treatment ,Psychological intervention ,Anti-Inflammatory Agents ,Administration, Oral ,Ulcerative ,Logistic regression ,Oral and gastrointestinal ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Adrenal Cortex Hormones ,Child ,Mesalamine ,Colectomy ,Pediatric ,Anti-Inflammatory Agents, Non-Steroidal ,Remission Induction ,Gastroenterology ,Colitis ,Ulcerative colitis ,3. Good health ,Treatment Outcome ,6.1 Pharmaceuticals ,Child, Preschool ,Administration ,030211 gastroenterology & hepatology ,Administration, Intravenous ,Female ,Non-Steroidal ,Intravenous ,Cohort study ,Oral ,medicine.medical_specialty ,Adolescent ,Autoimmune Disease ,03 medical and health sciences ,Mesalazine ,Clinical Research ,Internal medicine ,medicine ,Humans ,Preschool ,Hepatology ,business.industry ,Evaluation of treatments and therapeutic interventions ,Retrospective cohort study ,medicine.disease ,Surgery ,030104 developmental biology ,chemistry ,Colitis, Ulcerative ,business ,Digestive Diseases - Abstract
BackgroundPrevious retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis.MethodsThe PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI ≥65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor α (TNFα) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535.FindingsPatients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31·1 (SD 13·3) in children initiating with mesalazine, 50·4 (13·8) in those initiating oral corticosteroids, and 66·9 (13·7) in those initiating intravenous corticosteroids (p
- Published
- 2017
35. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study
- Author
-
Francisco A. Sylvester, Joel R. Rosh, Jason Shapiro, Michael D. Kappelman, David Keljo, Lee A. Denson, Urko M. Marigorta, Scott B. Snapper, Dedrick E. Moulton, Marla Dubinsky, Anne M. Griffiths, Chunyan Liu, Susan S. Baker, David R. Mack, Thomas D. Walters, Judy H. Cho, Wallace Crandall, Joshua D. Noe, Anthony R. Otley, Robert N. Baldassano, Subra Kugathasan, Barbara S. Kirschner, Curtis Huttenhower, Maria Oliva-Hemker, Steven J. Steiner, Greg Gibson, Bruce C. Trapnell, Shervin Rabizadeh, David Ziring, Kajari Mondal, Stanley N. Cohen, Richard Kellermayer, Jonathan Evans, Bruce J. Aronow, Michael C. Stephens, Ramnik J. Xavier, Jeffrey S. Hyams, Ashish S. Patel, Melanie Schirmer, Melvin B. Heyman, Stephen L. Guthery, James Markowitz, and Mi-Ok Kim
- Subjects
0301 basic medicine ,Male ,Anti-Inflammatory Agents ,Severity of Illness Index ,Medical and Health Sciences ,Cohort Studies ,0302 clinical medicine ,Crohn Disease ,Prospective Studies ,Prospective cohort study ,Child ,Crohn's disease ,screening and diagnosis ,Hazard ratio ,Anti-Inflammatory Agents, Non-Steroidal ,General Medicine ,Prognosis ,Detection ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Non-Steroidal ,medicine.drug ,Cohort study ,4.2 Evaluation of markers and technologies ,medicine.medical_specialty ,Adolescent ,Risk Assessment ,Autoimmune Disease ,03 medical and health sciences ,Clinical Research ,Internal medicine ,General & Internal Medicine ,medicine ,Adalimumab ,Genetics ,Humans ,Propensity Score ,business.industry ,Tumor Necrosis Factor-alpha ,Prevention ,Inflammatory Bowel Disease ,Gene signature ,medicine.disease ,Infliximab ,Surgery ,Gastrointestinal Microbiome ,030104 developmental biology ,Complication ,business ,Digestive Diseases ,Intestinal Obstruction - Abstract
Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.
- Published
- 2017
36. 27 CLINICAL AND GENOMIC CORRELATES OF NEUTROPHIL GRANULOCYTE-MACROPHAGE COLONY STIMULATING FACTOR SIGNALING IN PEDIATRIC CROHN DISEASE
- Author
-
Thomas D. Walters, Adam Price, Kajari Mondal, Christine Stevens, Michael E. Zwick, Anne M. Griffiths, Rebekah Karns, Kathleen Lake, Jeffrey S. Hyams, Anne Dodd, Ramona Bezold, Barbara S. Kirschner, Scott B. Snapper, Bruce J. Aronow, Stephen L. Guthery, Mark J. Daly, Kimberly Jackson, Aaron Linn, David J. Cutler, Yael Haberman, Robert N. Baldassano, Anthony R. Otley, David T. Okou, Kelly A Shaw, Subra Kugathasan, Marla Dubinsky, Ramnik J. Xavier, Neal S. Leleiko, Lee A. Denson, Wallace Crandall, Ingrid Jurickova, Joshua D. Noe, and Melvin B. Heyman
- Subjects
Macrophage colony-stimulating factor ,medicine.anatomical_structure ,Hepatology ,Crohn disease ,business.industry ,Neutrophil granulocyte ,Immunology ,medicine ,Gastroenterology ,Immunology and Allergy ,business - Published
- 2018
- Full Text
- View/download PDF
37. Tu1756 – The Treatment Naive Rectal Transcriptome Identifies Pathways Underlying Response to Induction Corticosteroid Therapy in Ulcerative Colitis
- Author
-
Greg Gibson, Anne M. Griffiths, Melanie Schirmer, Alison Marquis, Thomas D. Walters, Curtis Huttenhower, Kevin P. Mollen, Joshua D. Noe, Sonia Davis Thomas, Margaret H. Collins, Paul A. Rufo, Brendan M. Boyle, Phillip J. Dexheimer, Cary G. Sauer, James Markowitz, Ashish S. Patel, Sapana Shah, Bruce J. Aronow, Melvin B. Heyman, Michael J. Rosen, Nathan Gotman, Angela Mo, Yael Haberman, Rebekah Karns, Lee A. Denson, Susan S. Baker, David R. Mack, Ingrid Jurickova, Subra Kugathasan, Ramnik J. Xavier, Marian D. Pfefferkorn, Joel R. Rosh, Neal S. Leleiko, Erin Bonkowski, Robert N. Baldassano, and Jeffrey S. Hyams
- Subjects
Therapy naive ,Transcriptome ,Hepatology ,Corticosteroid therapy ,business.industry ,Immunology ,Gastroenterology ,medicine ,medicine.disease ,business ,Ulcerative colitis - Published
- 2019
- Full Text
- View/download PDF
38. 204 – Surgery in Very Early Onset Inflammatory Bowel Disease (Veoibd): Results from a Large, Multi-Center North American Cohort
- Author
-
Ying Lu, Leah Siebold, Joseph A. Galanko, Mel Heyman, Alka Goyal, Michael D. Kappelman, Aleixo M. Muise, Judith R. Kelsen, Joshua D. Noe, Dedrick E. Moulton, Razan Alkhouri, Jennifer A. Strople, Mark Deneau, Karoline Fiedler, Joel R. Rosh, Ross M Maltz, Jeffrey S. Hyams, Anne M. Griffiths, Michael C. Stephens, Johan Van Limbergen, Scott B. Snapper, Lina Karam, Helen M. Pappa, Marisa L. Gallant, Eric I Benchimol, Neal S. Leleiko, Eileen Crowley, Marian D. Pfefferkorn, Anthony L. Guerrerio, Basavaraj Kerur, and Keith J. Benkov
- Subjects
Pediatrics ,medicine.medical_specialty ,Hepatology ,business.industry ,Cohort ,Gastroenterology ,Medicine ,Center (algebra and category theory) ,business ,medicine.disease ,Inflammatory bowel disease ,Very early onset - Published
- 2019
- Full Text
- View/download PDF
39. Su1795 – Utilization of Anti-TNF Therapy (BIOLOGICS) in Children with Very Early Onset Inflammatory Bowel Disease (Veoibd) in a Large North American Cohort
- Author
-
Anthony L. Guerrerio, Alka Goyal, Lina Karam, Basavaraj Kerur, Neal S. Leleiko, Michael D. Kappelman, Ross M Maltz, Razan Alkhouri, Joshua D. Noe, Eric I Benchimol, Jeffrey S. Hyams, Mark Deneau, Jennifer A. Strople, Johan Van Limbergen, Ying Lu, Anne M. Griffiths, Marisa L. Gallant, Leah Siebold, Joseph A. Galanko, Helen M. Pappa, Mel Heyman, Dedrick E. Moulton, Aleixo M. Muise, Marian D. Pfefferkorn, Joel R. Rosh, Michael C. Stephens, Judith R. Kelsen, Eileen Crowley, Scott B. Snapper, Keith J. Benkov, and Karoline Fiedler
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Cohort ,Gastroenterology ,medicine ,Anti-TNF therapy ,business ,medicine.disease ,Very early onset ,Inflammatory bowel disease - Published
- 2019
- Full Text
- View/download PDF
40. Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients
- Author
-
Phillip Minar, Ramona Bezold, Jeffrey S. Hyams, Rebekah Karns, Melvin B. Heyman, Anne M. Griffiths, Jefferson E. Vallance, Robert N. Baldassano, Thomas D. Walters, Joshua D. Noe, Dedrick E. Moulton, Neal S. Leleiko, Margaret H. Collins, Amanda Waddell, James Markowitz, Subra Kugathasan, Wallace Crandall, Michael J. Rosen, Keith T. Wilson, Michael D. Kappelman, Susan S. Baker, David R. Mack, Simon P. Hogan, Lee A. Denson, Yael Haberman, Richard Kellermayer, and Joel R. Rosh
- Subjects
0301 basic medicine ,Male ,Messenger ,Gene Expression ,Ulcerative ,Crohn's Disease ,Inflammatory bowel disease ,Interleukin-23 ,Oral and gastrointestinal ,Type 2 immune response ,Immune Regulation ,0302 clinical medicine ,Intestinal mucosa ,Crohn Disease ,Prospective Studies ,Intestinal Mucosa ,Child ,Cancer ,Pediatric ,Crohn's disease ,Mucosal ,Interleukin-13 ,AUROC ,Prognostic Factor ,Interleukin-17 ,Gastroenterology ,Colitis ,Prognosis ,Ulcerative colitis ,Colo-Rectal Cancer ,Up-Regulation ,Area Under Curve ,030211 gastroenterology & hepatology ,Female ,Adolescent ,Colon ,Clinical Sciences ,Autoimmune Disease ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Immune system ,Clinical Research ,Predictive Value of Tests ,medicine ,Genetics ,Humans ,RNA, Messenger ,Immunity, Mucosal ,Hepatology ,Gastroenterology & Hepatology ,business.industry ,Interleukins ,Inflammatory Bowel Disease ,Case-control study ,Immunity ,Gene Expression Profile ,Neurosciences ,Rectum ,medicine.disease ,030104 developmental biology ,ROC Curve ,Case-Control Studies ,Immunology ,Interleukin-13 Receptor alpha2 Subunit ,RNA ,Colitis, Ulcerative ,Interleukin-5 ,business ,Digestive Diseases ,Transcriptome - Abstract
Background & Aims There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)—few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. Methods We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. Results We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13 , and IL13RA2 ) and a type 17 immune response ( IL17A and IL23 ) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD ( P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553–26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330–28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132–25.12). Conclusions In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
- Published
- 2016
41. Paneth cell defects in Crohn’s disease patients promote dysbiosis
- Author
-
Megan T. Baldridge, Mary L. Holtz, Michael Hayward, Michael C. Stephens, Vincent Biank, Joshua D. Noe, Vy Lam, Thaddeus S. Stappenbeck, Pavlos Bousounis, Nita H. Salzman, Dermot P.B. McGovern, Chengwei Luo, Ramnik J. Xavier, Diana G. Lerner, Ta-Chiang Liu, Pippa Simpson, Yumei Cao, Bhaskar Gurram, Curtis Huttenhower, Jose Cabrera, and Richard D. Head
- Subjects
0301 basic medicine ,Paneth Cells ,Adolescent ,Context (language use) ,Biology ,digestive system ,Proinflammatory cytokine ,Transcriptome ,03 medical and health sciences ,Crohn Disease ,Ileum ,medicine ,Humans ,Microbiome ,Intestinal Mucosa ,Child ,Crohn's disease ,Gastrointestinal Microbiome ,General Medicine ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Paneth cell ,Immunology ,Dysbiosis ,Clinical Medicine - Abstract
BACKGROUND. Paneth cell dysfunction has been implicated in a subset of Crohn’s disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients. METHODS. Pediatric CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome. RESULTS. The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome. CONCLUSION. Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop. FUNDING. The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn’s and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).
- Published
- 2016
- Full Text
- View/download PDF
42. Feeling Fine: Anxiety and Depressive Symptoms in Youth with Established IBD
- Author
-
Stacy A. Kahn, Rachel Neff Greenley, Steven A. Miller, Jennifer Verrill Schurman, Jennifer G. Walter, and Joshua D. Noe
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,media_common.quotation_subject ,Disease ,Anxiety ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Risk Factors ,Surveys and Questionnaires ,Severity of illness ,medicine ,Immunology and Allergy ,Humans ,Psychiatry ,Child ,Depression (differential diagnoses) ,media_common ,business.industry ,Depression ,Medical record ,Gastroenterology ,Inflammatory Bowel Diseases ,Prognosis ,Feeling ,030220 oncology & carcinogenesis ,Quality of Life ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,business ,Psychosocial ,Follow-Up Studies - Abstract
Background Previous research is discrepant with respect to the prevalence of internalizing symptoms (i.e., depressive and anxiety symptoms) in pediatric inflammatory bowel disease (IBD) samples. Moreover, few studies have examined the combined influence of demographic and disease-related risk factors for internalizing symptoms. This study described rates of depressive, anxiety, and overall internalizing symptomatology in a multisite sample of youth with established IBD diagnoses. Additionally, the study examined risk factors for elevated depressive, anxiety, and internalizing symptoms, including those in demographic (i.e., family income and sex) and disease (i.e., disease activity and functional disability) domains. Methods One hundred sixty-one youth (aged 11-18 yr) with established IBD diagnoses, primarily inactive disease, prescribed oral medications, and who were not taking corticosteroids were recruited from outpatient Gastroenterology Clinics at 3 children's hospitals. This article reflects a secondary analysis of data collected from 2 larger studies examining oral medication adherence and psychosocial functioning in pediatric IBD. After providing written consent/assent, participants completed questionnaires assessing demographics, functional disability, and internalizing symptoms. Medical records were reviewed for disease information and clinical disease activity ratings. Results Only 13% of the sample reported clinically elevated anxiety or depressive symptoms. Perceived functional disability, but not clinical disease activity, was associated with higher depressive and anxiety symptoms, and higher overall internalizing symptomatology. Conclusions Current results highlight the need to look beyond disease severity and examine the perception of functional disability of patients with IBD when seeking to identify youth at risk for internalizing symptoms such as depression and anxiety.
- Published
- 2016
43. Identifying Youth Nonadherence in Clinical Settings: Data-based Recommendations for Children and Adolescents with Inflammatory Bowel Disease
- Author
-
Alfonso Martinez, Rachel Neff Greenley, Steven L. Werlin, Vincent Biank, Jennifer Hauser Kunz, Joshua D. Noe, Grzegorz Telega, Adrian Miranda, Neelesh A. Tipnis, and Michael C. Stephens
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,MEDLINE ,Medication adherence ,Clinical settings ,Inflammatory bowel disease ,Medication Adherence ,Surveys and Questionnaires ,Humans ,Immunology and Allergy ,Medicine ,Family ,Child ,Psychiatry ,Thiopurine methyltransferase ,biology ,Mercaptopurine ,business.industry ,Gastroenterology ,Inflammatory Bowel Diseases ,Monitoring system ,Prognosis ,medicine.disease ,Caregivers ,Practice Guidelines as Topic ,biology.protein ,Patient Compliance ,Female ,Self Report ,Drug Monitoring ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Background: To examine the validity of patient self-report of thiopurine adherence in pediatric inflammatory bowel disease (IBD) against an objective electronic monitoring adherence measure, and to investigate the role of youth and maternal involvement in remembering to take daily medications as predictors of medication adherence. Methods: Fifty-one youths with IBD, ages 11–18 years, participated. Youths completed questionnaire assessments of their own and their maternal caregiver's involvement in remembering to take daily medications at baseline, completed monthly interviews assessing thiopurine adherence over the past week for a period of 6 months, and utilized a Medication Events Monitoring System (MEMS) electronic monitor for their thiopurine medication for 6 months. Participants were grouped into adherent (at least 80% of doses taken based on objective MEMS caps) or nonadherent for analyses. Results: Youths who were nonadherent based on electronic monitoring overestimated their adherence by 23%, whereas adherent youths overestimated their adherence by only 2%, and as such patient self-report offered little utility in identifying youths who were nonadherent. Youths who reported high levels of involvement in remembering to take their medications were nearly eight times less likely to be nonadherent. Conclusions: The current findings provide evidence that clinicians who work with children and adolescents with IBD may benefit from modifying their approach to nonadherence screening. Asking about youth involvement in remembering daily medications may be more informative than asking them to recall their medication-taking behavior over the last week in identifying those at highest risk for nonadherence. (Inflamm Bowel Dis 2011;)
- Published
- 2012
- Full Text
- View/download PDF
44. Microbial Dysbiosis Associated with Disease Severity in Treatment Naive Pediatric Patients with New-Onset Ulcerative Colitis
- Author
-
Melanie Schirmer, Dedrick E. Moulton, Ashish S. Patel, Ramnik J. Xavier, Boris Sudel, Neal S. Leleiko, Prateek Wali, Anne M. Griffiths, Maria Oliva-Hemker, Joel R. Rosh, Jennifer A. Strople, Keith J. Benkov, Jeffrey S. Hyams, David Ziring, Marian D. Pfefferkorn, Stephen L. Guthery, Paul A. Rufo, Robert N. Baldassano, Joshua D. Noe, David J. Keljo, Susan S. Baker, David R. Mack, Hera Vlamakis, James Markowitz, Brendan M. Boyle, Subra Kugathasan, Melvin B. Heyman, Cary G. Sauer, Thomas D. Walters, Curtis Huttenhower, Anthony R. Otley, Lee A. Denson, and Sonia M. Davis
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Gastroenterology ,Microbial dysbiosis ,medicine.disease ,Ulcerative colitis ,New onset ,Therapy naive ,Disease severity ,Internal medicine ,Medicine ,business - Published
- 2017
- Full Text
- View/download PDF
45. Predicting Response to Mesalamine Induction Therapy in Children Newly Diagnosed with Mild-to-Moderate Ulcerative Colitis: The Protect Study
- Author
-
Nathan Gotman, Joel R. Rosh, Paul A. Rufo, Lee A. Denson, Anne M. Griffiths, Marian D. Pfefferkorn, James Markowitz, Sonia M. Davis, Ashish S. Patel, Jeffrey S. Hyams, Cary G. Sauer, Melvin B. Heyman, Brendan M. Boyle, Marla Dubinsky, Susan S. Baker, David R. Mack, Anthony R. Otley, Robert N. Baldassano, Neal S. Leleiko, Maria Oliva-Hemker, Joshua D. Noe, David J. Keljo, Alison Marquis, Subra Kugathasan, and Thomas D. Walters
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Induction therapy ,Gastroenterology ,medicine ,Newly diagnosed ,medicine.disease ,business ,Ulcerative colitis - Published
- 2017
- Full Text
- View/download PDF
46. Predicting Response to Oral Corticosteroid Induction Therapy in Children Newly Diagnosed with Moderately Active Ulcerative Colitis: The Protect Study
- Author
-
Robert N. Baldassano, Joshua D. Noe, Thomas D. Walters, Anne M. Griffiths, Melvin B. Heyman, Alison Marquis, Maria Oliva-Hemker, Anthony R. Otley, Ashish S. Patel, James Markowitz, Neal S. Leleiko, Cary G. Sauer, Marian D. Pfefferkorn, Subra Kugathasan, David J. Keljo, Brendan M. Boyle, Jeffrey S. Hyams, Marla Dubinsky, Joel R. Rosh, Nathan Gotman, Sonia M. Davis, Lee A. Denson, Paul A. Rufo, Susan S. Baker, and David R. Mack
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,medicine.drug_class ,Gastroenterology ,Newly diagnosed ,medicine.disease ,Ulcerative colitis ,Induction therapy ,Internal medicine ,Immunology ,Medicine ,Corticosteroid ,business - Published
- 2017
- Full Text
- View/download PDF
47. Corticosteroids Increase Protein Breakdown and Loss in Newly Diagnosed Pediatric Crohn Disease
- Author
-
Scott C. Denne, Joshua D. Noe, and Steven J. Steiner
- Subjects
Blood Glucose ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Phenylalanine ,Protein metabolism ,Newly diagnosed ,Protein kinetics ,Gastroenterology ,Gas Chromatography-Mass Spectrometry ,chemistry.chemical_compound ,Crohn Disease ,Leucine ,Internal medicine ,medicine ,Humans ,Urea ,In patient ,Child ,Crohn disease ,business.industry ,Proteins ,digestive system diseases ,Protein catabolism ,Endocrinology ,chemistry ,Isotope Labeling ,Proteolysis ,Pediatrics, Perinatology and Child Health ,Body Composition ,Prednisone ,Tyrosine ,Corticosteroid ,Abdominal symptoms ,business - Abstract
Children with Crohn disease have altered growth and body composition. Previous studies have demonstrated decreased protein breakdown after either corticosteroid or anti-TNF-α therapy. The aim of this study was to evaluate whole body protein metabolism during corticosteroid therapy in children with newly diagnosed Crohn disease. Children with suspected Crohn disease and children with abdominal symptoms not consistent with Crohn disease underwent outpatient metabolic assessment. Patients diagnosed with Crohn disease and prescribed corticosteroid therapy returned in 2 wk for repeat metabolic assessment. Using the stable isotopes [d5] phenylalanine, [1-(13)C] leucine, and [(15)N(2)] urea, protein kinetics were determined in the fasting state. Thirty-one children (18 controls and 13 newly diagnosed with Crohn disease) completed the study. There were no significant differences in protein breakdown or loss between patients with Crohn disease at diagnosis and controls. After corticosteroid therapy in patients with Crohn disease, the rates of appearance of phenylalanine (32%) and leucine (26%) increased significantly, reflecting increased protein breakdown, and the rate of appearance of urea also increased significantly (273%), reflecting increased protein loss. Whole body protein breakdown and loss increased significantly after 2 wk of corticosteroid therapy in children with newly diagnosed Crohn disease, which may have profound effects on body composition.
- Published
- 2011
- Full Text
- View/download PDF
48. Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
- Author
-
Cary G. Sauer, David R. Mack, Susan S. Baker, Ashish S. Patel, Nathan Gotman, Robert N. Baldassano, Jeffrey S. Hyams, Ramnik J. Xavier, Sonia Davis Thomas, Subra Kugathasan, Thomas D. Walters, Curtis Huttenhower, Melanie Schirmer, Paul A. Rufo, Neal Leleiko, David J. Keljo, Lee A. Denson, James Markowitz, Anne M. Griffiths, Marian D. Pfefferkorn, Joel R. Rosh, Joshua D. Noe, Maria Oliva-Hemker, Melvin B. Heyman, Hera Vlamakis, Brendan M. Boyle, Anthony R. Otley, and Eric A. Franzosa
- Subjects
Male ,0301 basic medicine ,Time Factors ,medicine.medical_treatment ,Anti-Inflammatory Agents ,gut microbiome ,Ulcerative ,Gastroenterology ,Oral and gastrointestinal ,corticosteroids ,Cohort Studies ,Feces ,0302 clinical medicine ,Adrenal Cortex Hormones ,Longitudinal Studies ,Mesalamine ,Child ,Colectomy ,Pediatric ,Clostridiales ,pediatric ulcerative colitis ,disease course ,Anti-Inflammatory Agents, Non-Steroidal ,treatment-naive ,Colitis ,Ulcerative colitis ,5.1 Pharmaceuticals ,Medical Microbiology ,Child, Preschool ,Disease Progression ,Female ,030211 gastroenterology & hepatology ,Development of treatments and therapeutic interventions ,Non-Steroidal ,medicine.medical_specialty ,Adolescent ,Immunology ,Pediatric ulcerative colitis ,host-microbial interactions ,Biology ,Autoimmune Disease ,Microbiology ,Article ,Disease course ,03 medical and health sciences ,response to therapy ,Clinical Research ,Virology ,Internal medicine ,medicine ,Humans ,Microbiome ,Preschool ,Nutrition ,Inflammatory Bowel Disease ,5ASA ,medicine.disease ,Gut microbiome ,Gastrointestinal Microbiome ,serological markers ,030104 developmental biology ,Colitis, Ulcerative ,Parasitology ,Digestive Diseases ,Leukocyte L1 Antigen Complex - Abstract
Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for one year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care.
- Published
- 2018
- Full Text
- View/download PDF
49. 378 - Genomic Correlates of Reduced Neutrophil Granulocytemacrophage Colony Stimulating Factor Signaling in Stricturing Pediatric Crohn Disease
- Author
-
Lee A. Denson, Scott B. Snapper, Rebekah Karns, David J. Cutler, Aaron Linn, David T. Okou, Jeffrey S. Hyams, Barbara S. Kirschner, Mark J. Daly, Anthony R. Otley, Kathleen Lake, Subra Kugathasan, Marla Dubinsky, Anne M. Griffiths, Ann Dodd, Michael E. Zwick, Ingrid Jurickova, Stephen L. Guthery, Melvin B. Heyman, Bruce J. Aronow, Ramnik J. Xavier, Neal S. Leleiko, Christine Stevens, Ramona Bezold, Yael Haberman, Thomas D. Walters, Wallace Crandall, Adam Price, Kajari Mondal, Kimberly Jackson, Robert N. Baldassano, and Joshua D. Noe
- Subjects
Hepatology ,business.industry ,Crohn disease ,Immunology ,Gastroenterology ,Medicine ,business ,Colony-stimulating factor - Published
- 2018
- Full Text
- View/download PDF
50. Su2018 - Longitudinal Adherence to Mesalamine in Pediatric Ulcerative Colitis: Results from the Protect Study
- Author
-
Cary G. Sauer, David J. Keljo, Anne M. Griffiths, Debra Lobato, Jill M. Plevinsky, Lee A. Denson, Joshua D. Noe, Susan S. Baker, David R. Mack, Anthony R. Otley, Robert N. Baldassano, Joel R. Rosh, James Markowitz, Marian D. Pfefferkorn, Julia K. Carmody, Jeffrey S. Hyams, James Peugh, Neal S. Leleiko, Brendan M. Boyle, and Kevin A. Hommel
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,medicine ,Pediatric ulcerative colitis ,business - Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.