Pediatric IBD 101: A Primer for the Pediatrician

1. Pediatric IBD 101: A Primer for the Pediatrician Sandra C. Kim, M.D. Dept. of Pediatrics, Div. of Gastroenterology and The Center for Gastrointestinal Biology and Disease University of North Carolina at Chapel Hill I have the following financial relationship to disclose: a research grant (including funding to an institution for contracted research) – from Abbott. I do not intend to discuss an unapproved/investigative use of a commercial product/device.

2. Disclosure • I have the following financial relationship to disclose: a research grant (including funding to an institution for contracted research) – from Abbott. • I do not intend to discuss an unapproved/investigative use of a commercial product/device.

3. Objectives • Definitions of IBD • Epidemiology • Genetics • Clinical issues • Presentation in children and adolescents • Nutritional and skeletal health issues • Diagnostic evaluation • Principles of treatment • Adolescent transitioning and psychosocial issues

4. What are Inflammatory Bowel Diseases (IBD)? Ulcerative Colitis Crohn’s disease Strictures Ulcers, inflammation (continuous) Ileitis/ileo - colonic (most common) Images removed. “Skip lesions” • Inflammation and ulceration of the intestinal lining (mucosa) • Involves the rectum/colon • Inflammation involving all layers of the intestinal wall • Affects any part of the GI tract

5. Incidence of Pediatric IBD Image removed.

6. Incidence of Pediatric IBD • Increased annual incidence: Crohn’s disease 2.2 to 4.3 for CD; UC 1.8 to 4.9 • Trend towards greater UC cases in Hispanic/Asian populations and greater CD cases in African-American. Image removed.

7. The Cost Of Disease In Pediatric IBD • Annual disease-attributable costs for IBD: $6.3 billion • Overall per patient costs greater in children vs. adults Image removed.

8. IBD

9. Genetic Contribution to Disease Adult onset diabetes Inflammatory bowel disease Cystic fibrosis AIDS Lung cancer Sickle cell anemia Genetic component Environmental component

10. What Do We Know About Genes in IBD? Genetic influences are important in Crohn’s disease and ulcerative colitis Pediatric IBD susceptibility genes Loci on multiple chromosomes (Kugathasan et al. 2008. Nature Genetics) (Imielinskiet al. 2009. Nature Genetics) Multiple IBD - associated-genes (>120) found by genome-wide meta-analyses Wellcome Trust Case Control Consortium; NIH (Hampe et al. 2007. Nature Genetics; Riouxet al. 2007. Nature Genetics; Franke et al. 2010. Nature Genetics; Anderson et al. 2011. Nature Genetics)

11. Pediatric IBD Has Unique Characteristics Similarities between pediatric and adult IBD GI symptoms Extra-intestinal manifestations Presentation is more severe in children (Vernier-Massouille et al. 2008. Gastroenterology; Van Limbergen et al. 2008. Gastroenterology) UC: Higher incidence of pancolitis (>80%) Crohn’s disease: ~20% risk of surgery/complicated disease within 3 years of diagnosis Delay in growth, skeletal development, puberty Psychosocial impact of disease

12. Symptoms in Pediatric Crohn’s Image removed.

13. Symptoms in Pediatric Crohn’s Image removed.

14. IBD: Clinical Manifestations Image removed

15. Crohn’s vs. UC: Gastrointestinal Image removed.

16. Growth and Nutritional Status in IBD Image removed

17. How Prevalent is Growth Failure in Crohn’s Disease? Images removed. • N = 989 patients (male=566; female=423) • 9.8% with growth failure by 10 yrs • Boys > Girls

18. Growth Issues in Pediatric IBD • More common in Crohn’s vs ulcerative colitis; • Issues are noted both pre-and post-diagnosis • Decreased height percentiles in 36-39%; adult height compromised (Sawczenko, et al. 2006. Pediatrics; Motil 1985. Ped Clinic Am) • Decreased height velocity (Walters, et al. 2008. Inflamm Bowel Dis; Kanof, et al. 1988. Gastroenterology) • Crohn’s disease: 32% - 88% • UC: 9% - 34% • *“Growth window” crucial • *Growth good marker for disease activity

19. Factors Affecting Growth • Disease severity/degree of inflammation • Inflammatory cytokines (IL-6, TNF) • Corticosteroid therapy • Inadequate oral intake • Malabsorption • Interval from onset of symptoms to diagnosis • *Disease location: small intestinal/jejunal • Timing of surgery

20. Pubertal Delay in IBD • Impact both medically and psychologically • Similar factors affecting growth affect onset of puberty • Poor nutrition • Pro-inflammatory cytokines • May or may not be made up later in life • Delayed age of peak height velocity (middle of puberty) in Crohn’s disease, but not UC (Hildebrand, et al. 1994. JPGN) • ~1/4 children with Crohn’s • Delay usually 6-12 months

21. Overall Principles in Managing Growth Failure • *Timing is key-intervene before puberty starts • Optimize nutrition • Caloric and vitamin/mineral deficiencies • Re-assess disease activity • Consultation with endocrinologist • *Minimize corticosteroids! • Enteral nutrition • Maintenance medications (Biologics/Immunomodulators) • Surgery timed/used judiciously

22. Bone Health In Children And Teens Decreased bone mineral density common in children and adolescents with IBD Poor calcium absorption/intake; vitamin D deficiency Decreased physical activity Inflammation Maximum accumulation of calcium in your bones occurs in mid-teen years Steroid use increases short - and long -term risk

23. Images removed.

24. Differential Diagnosis • Infectious • Bacterial • Viral • Parasitic • Rheumatological disorders • Immune – mediated/immunodeficiency disease • Other GI illnesses • Psychological/Irritable Bowel Syndrome

25. Diagnostic Studies • Laboratory tests • CBC - differential • Inflammatory markers: ESR; C-reactive protein • Nutritional: Serum albumin, tot. protein, iron panel, Ca++ Mg+, zinc, alkaline phosphatase, folate, transthyretin • Liver profile: AST/ALT, bilirubin, GGT • Stool studies: Leukocytes, guaiac, calprotectin, lactoferrin C. difficile toxin, routine cx, O&P • Serologic studies • *IBD diagnostic panel: ASCA, pANCA, c-OMP,Cbir flagellin, fliC, I2 (Prometheus™) • TPMT pathway

26. Diagnostic Testing • Radiographic evaluation • UGI/SBFT • Abdominal plain films • Abdominal CT scan • MRI enterography • Endoscopy • Colonoscopy • Upper endoscopy (EGD) • Video capsule endoscopy

27. Treatment Goals for Pediatric IBD • Immediate goals • Suppress inflammation to heal mucosa • Decrease/alleviate symptoms • Continued goals • Prevent disease relapse • Avoid complications • Restore normal growth, nutritional status • Ultimate goals • Treatment should be reasonable, cost-effective • Improve quality of life • Alter the natural history of disease favorably • Immediate goals • Suppress inflammation to heal mucosa • Decrease/alleviate symptoms • Continued goals • Prevent disease relapse • Avoid complications • Restore normal growth, nutritional status • Ultimate goals • Treatment should be reasonable, cost-effective • Improve quality of life • Alter the natural history of disease favorably

28. Treatment Efficacy in Pediatric IBD Limited data in pediatric IBD therapy Treatment extrapolated from adult studies Similar/greater efficacy in inducing remission Sample sizes smaller in pediatric studies Toxicity: similar AE but longer drug exposures Impact of lifetime therapy duration Outcomes for clinical trials needs to consider pediatric – specific outcomes Growth parameters Markers of bone metabolism

29. Corticosteroids in Pediatric IBD Initially effective in inducing remission but concerns of dependency Debilitating effect on pediatric patients Psychosocial impact Neurological changes Physical appearance Negative impact on growth and bone metabolism *Absence of GI symptoms not acceptable if the child is stunted, cushingoid

30. Thiopurine Metabolism Images removed.

31. Thiopurines and Pediatric Crohn’s Prospective, double-blind, placebo-controlled study evaluating whether 6-MP decreased need for corticosteroids (Markowitz et al. 2000. Gastroenterology) Children with Crohn’s disease N = 55 (mean age: 13 ± 2 yrs) Diagnosed within 8 wks of study randomization Results: Total steroids: Significantly less by 6 months Relapse: 9% 6MP vs. 47% placebo *Key: Steroid-sparing regimen

32. Thiopurines and Pediatric Crohn’s Images removed.

33. 6-MP Delays Surgery in Pediatric CD Images removed.

34. Methotrexate in Pediatric Crohn’s Retrospective, longitudinal cohort study in children started on MTX after failed 6-MP/ AZA therapy (Turner et al. 2007. AJG) Children with Crohn’s disease N = 60 (mean 14 ± 2 yrs) Intolerant / failed 6MP/AZA; infliximab-naive Results: 12 months: 53% steroid-free remission 36 months: 35% steroid-free remission *Key points Alternative immunomodulator Improved growth velocity

35. Growth Velocity Improved with MTX Images removed. Turner, et al. 2007. AJG

36. Budesonide in Pediatric Crohn’s Low remission rates (47-55%) Randomized, controlled, double-blind study (Levine et al. 2009. IBD Journal) Children with mild-to-moderate Crohn’s N = 70 with ileal +/- colonic involvement Group 1: 9 mg qd (7 wks)  6 mg qd (3 wks) Group 2: Induction 12 mg qd (4 wks)  Grp 1 Results Response : 51.4% (Grp 1) vs. 74.3% (Grp 2) Remission: 42.9% (Grp 1) vs. 65.7% (Grp 2) *Key: Improved remission (induction) without increased side effects

37. “Top-down” Therapy Anti-TNF • Will this reverse the natural history of the disease? • Who would benefit the most? • Risk of infection and malignancy? Immunomodulators, Growth Factors, Nutrition

38. Anti-TNF Therapy Debate between top-down vs. bottom-up Not as applicable for children Benefits of anti-TNF therapy Steroid-sparing Mucosal healing Reversal of growth failure / nutritional status Concerns with anti-TNF therapy Adverse events ― infections *Long-term sequelae: malignancies

39. What is Remicade (infliximab)? • Chimeric monoclonal antibody • Murine (variable regions) • Human (IgG1 constant) “Achilles heel”: Murine component Image removed.

40. Infliximab in Pediatric Crohn’s Disease (REACH) Multicenter, randomized, open-label study (Hyamset al. 2007. Gastroenterology) Children with Crohn’s disease on stable doses of medications / immunomodulator N = 112 (6 - 17 yrs) Results Week 10: 88% with response; 59% remission Week 54: 64% with response; 56% remission *Key points: Steroid-sparing regimen Positive effect on growth

41. Infliximab Reduces Risk for Surgery Images removed.

42. Infliximab and Growth Velocity (REACH) Images removed. Hyams et al. 2007. Gastroenterology

43. Infliximab and Bone Density Biochemical markers of bone metabolism measured from patients in REACH study Bone formation markers increased, while bone resorption measures decreased Images removed.

44. Therapeutic Approaches in the Future for Pediatric IBD… “IBD Panel” Serology Genetics Microbial IBD Subtype Disease Prognosis Patient-specific treatment plan Targeted-specific therapy

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46. Psychological Challenges Facing Children with IBD Greater risk of low self-esteem, poor social functioning, and depression Specific issues facing patients Stress of being a teen and having IBD Defining what it means to have a chronic illness Coping with procedures, frequent clinic visits, and hospitalizations Adhering to complicated medical and dietary regimens

47. Depression and Self-Image Depression present in children with IBD(Szigethyet al. 2004. JPGN) Increased disease activity and corticosteroid treatment correlates with depression Children manifest depression symptoms Quality of life and social interactions impacted ~1/3 – 1/2 children with limitations in ADL Parental perceptions of children with IBD Body image and disordered eating patterns also prevalent

48. Nonadherence in Pediatric IBD Image removed.

49. CD-ROM to Improve Teen Knowledge Images removed. • Self-directed learning led to improved knowledge: • Medications • Disease complications • GI function

50. Self-Management Milestones Images removed.