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Ted Denson, MD

Using the Pediatric RISK and PROTECT Inception Cohorts to Define Important Clinical and Biologic Phenotypes. Ted Denson, MD Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. Disclosures & Objectives. Grant support: NIH & CCFA

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Ted Denson, MD

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  1. Using the Pediatric RISK and PROTECT Inception Cohorts to Define Important Clinical and Biologic Phenotypes Ted Denson, MD Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine

  2. Disclosures & Objectives • Grant support: NIH & CCFA • Describe aims & composition of RISK & PROTECT cohort studies • Share early analyses from RISK cohort • Summarize future goals for using cohorts to refine patient clinical and biologic phenotypes

  3. Enrolling sites • Thomas D. Walters, SickKids, Toronto, Canada • SubraKugathasan, Emory-Children’s Center, Atlanta, GA • CCHMC - GI • Lee Denson • Yael Haberman • CCHMC Bioinformatics core • Bruce J Aronow • Phillip Dexheimer Curtis Huttenhower Ramnik J Xavier Timothy L Tickle Dirk Gevers PRO-KIIDS

  4. Current IBD Clinical Phenotyping • Suspect the diagnosis • History, exam, lab tests • Determine disease location • Upper endoscopy, colonoscopy, CT/MR enterography • Classify as CD, UC, or IBD-U • Montreal or Paris classification for disease location, extent, severity, and complications

  5. Importance of IBD Clinical Phenotypes Louis et al Best Pract & Res Clin Gastro 2011

  6. Crohn’s Disease Progresses on “Conventional Therapy” in Children: 1988-2002 Inflammatory 34% at 5 yrs Stricturing Penetrating Vernier-Massouille et al. Gastroenterology 2008;135:1106

  7. Combined Genetic:Paneth Cell Phenotype Stappenbeck et al Gastro 2013

  8. High Risk CD Patient for Complications: CD1 • NOD2 gene mutation • Ileal location • High titer anti-microbial serologies

  9. CD1: High Risk Anti-TNF Responsive Validate this model in a prospective inception cohort Siegel et al IBD 2011

  10. Clinical use of Gene Expression Panels to Improve Diagnostic or Prognostic Accuracy Several gene expression diagnostics for oncology Afirma Thyroid Cancer test 56,540 thyroid cancer cases per year Indeterminate pathology in 30% Expression of 142 genes in thyroid biopsy 49 site validation in 3789 patients: 92% accuracy Prevent 25,000 thyroid resections per year Charge: $4200, covered by Medicare and third party Alexander et al NEJM 2012

  11. CCFA Sponsored Pediatric Clinical Research Network: PRO-KIIDS RISK Study 1112 children with CD at diagnosis between 2008-2012 Follow-up to 2017 Paris Classification Genotype Environmental Exposures Serology Microbial Community/Gene Expression Define patients with complication / surgery

  12. AIMS OF RISK • Develop and validate a composite risk score for complicating CD based upon age, cytokine and microbial antigen sero-reactivity, and early anti-TNF therapy • Compare the effectiveness of early versus late introduction of anti-TNF upon rates of complicating behavior • Profile host gene expression & the microbial community structure and function in tissue and stool samples • Identify and validate intestinal gene expression and microbial community profiles associated with complicated behavior which will improve the accuracy of a model based upon clinical, genetic, and serologic factors

  13. RISK Cohort

  14. RISK Enrollment Birth & Environmental History

  15. Comparative Effectiveness of Early IM vs anti-TNF for Week 52 SFR in RISK 552 with complete data and 1 yr f/u No early immunotherapy n = 236 Anti-TNFα n = 68 Early IM only n=248 Propensity Score Matching Anti-TNFα n = 68 IM only n = 68 No early immunotherapy n = 68 Hyams et al Gastro 2013

  16. 12 Month Outcomes For The Three Early Therapy Approaches: CS-free, Surgery free (p=0.0003) No difference between early IM and no early IM Hyams et al Gastro 2013

  17. What Does This Mean? • In clinically similar populations of children with Crohn’s disease, early (<3 mon) therapy with anti-TNFα was superior to early IM or no early immunotherapy despite later addition of those agents: PCDAI remission, CRP, growth • There was no particular clinical or laboratory characteristic that helped predict response or non-response to an initial therapeutic decision • It doesn’t mean that everyone should get anti-TNFα therapy, rather that we need to better define further characteristics of patients, such as genetics, serology, microbiome. Confirmatory studies will be required. Hyams et al Gastro 2013

  18. Using Next Gen Sequencing to Classify the Intestinal Microbiome and Genome at Diagnosis • Processed ~ 5300 intestinal biopsies from 950 CD, UC, IBDU patients and non-IBD controls • DNA yield: 10,500 (8,468,12,670) ng • RNA yield: 11,490 (9,351, 13,640) ng • RNA quality sufficient for PCR or RNASeq in >95% • Microbiome: 1000 ng DNA • RNASeq: 1000 ngRNA • Completed ileal & rectal RNASeq for 317 CD, 79 UC, 9 IBDU & 52 non-IBD control • Completed ileal, rectal, and fecal 16S-microbial DNA profile for 477 CD & 221 non-IBD control

  19. Ileal Gene Expression Panel Associated with Complicated Behavior in High Risk Ser2+ Patients

  20. Multivariate Analysis by Linear Models (MaAsLin) • Between: • Genes from the APOA1 module(APOA1, CXCL9) • Genes from DUOX2module (DUOXA2, MUC4, LCT) • Clinical phenotype (Ctl, UC, CD) • endoscopic severity (ileal deep ulcers) • Clinical severity (PCDAI) & • ileal microbial community Controlling for: age, gender, body mass index (BMI), and NOD2, FUT2, and ATG16L1 risk allele carriage. Haberman et al 2013

  21. Host:Microbe Profiles Present at Diagnosis May Define IBD Biologic Phenotypes UC2 CD2 greater clinical severity at diagnosis Lower rate of SFR with conventional therapy Two-fold higher anti-TNF exposure CD1 CD2 UC1 Haberman et al 2013

  22. CD UC Treatment Response Phenotype:“5-ASA Responsive UC” Severe Surgery Biologics Disease Severity Moderate Methotrexate Thiopurines Prednisone Enteral Nutrition Budesonide Antibiotics Aminosalicylates Mild

  23. 1U01 DK 095745-01

  24. AIMS OF PROTECT • Define rates of week 52 steroid-free remission with 5-ASA as sole maintenance therapy in an inception cohort of 430 pediatric UC patients receiving standardized induction therapy with 5-ASA/corticosteroids • Test clinical and biologic predictors of week 52 SFR • Define the host rectal global pattern and of gene expression and rectal and fecal microbial community structure and function • Identify mucosal host and microbial biologic pathways associated with initial treatment response and week 52 SFR

  25. PROTECT Recruitment

  26. Future IBD Phenotyping • RISK & PROTECT cohorts: 2000 CD & UC patients • Prospective clinical course & treatment responses • Genetics & serology in all • Tissue gene expression and microbial community profile in fifty percent • Optimizing technique to isolate RNA & DNA from clinical path specimens in order to perform gene expression and microbial community analysis on all patients • Key to maintain accurate long-term follow-up to link these host and microbial profiles to clinical outcomes • Utilize to define combined clinical/biologic/treatment response phenotypes

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