Pediatric IBD Research STAKEHOLDER REVIEWER TRAINING PROGRAM Pediatric IBD Research Michael D. Kappelman, M.D.,M.P.H. Pediatric Gastroenterology, and Center for GI Biology and Disease University of North Carolina at Chapel Hill

Children With IBD: Not Small Adults!

Nor large mice!

IBD in Children Everything Dr. Long taught last night applies to children Similarities between children and adults with IBD GI symptoms Extra-intestinal manifestations Diagnostic testing Treatment goals Medical treatments Surgical Treatments

IBD in Children: Unique Issues Presentation is more severe in children Crohn’s disease: ~20% risk of surgery/complicated disease UC: Higher incidence of pancolitis (>80%) Delay in growth and puberty Psychological and emotional impact on children Risks (and benefits) of medications Van Limbergen Gastroenterology 2008

Epidemiology of Pediatric IBD Peak age of onset is between 15-30 yrs. Prevalence = 1.2 million Americans ~50-75K IBD patients are < 18 years (5%) ~25% of patients with IBD will have onset of symptoms under the age of 18 yrs. Annual incidence = 7/100,000 children Kugathasan, et al. 2003. J. Pediatr

Is it 25% or 5%? Incidence: # new cases/time period Prevalence: total # cases at a given time Prevalence = incidence * average duration IBD: No cure (yet), near normal life expectancy Long duration Even if 25% of IBD is diagnosed during childhood, those individuals spend most of their lives as adults

Disease Costs Annual disease-attributable costs for IBD: $6.3 billion Kappelman, et al. 2008. Gastroenterology Annual disease-attributable costs for IBD: $6.3 billion *Costs greater in children vs. adults

Presentation of IBD in Children Crohn’s disease (n=386) Abdominal pain - 86% Diarrhea - 78% Blood in stool - 49% Weight loss – 80% Fever – 38% Perianal lesions – 44% Ulcerative colitis (n=195) Abdominal pain 69% Diarrhea – 93% Blood in stool – 95% Weight loss – 55% Fever – 15% Griffiths and Buller in Walker: Pediatric Gastrointestinal Disease (2000)

The Effect Of IBD On Growth Growth often affected in children with IBD More common in CD than in UC Seen both before and after disease is diagnosed Adult height may be compromised CD: 32-88% UC: 9-34% Growth marker for disease activity

The Effect Of IBD On Growth “Growth window” Pre - pubertal Crucial to minimize time between symptom onset, diagnosis, and treatment

Causes of poor growth Intestinal inflammation Inadequate oral intake Abdominal pain, anorexia, nausea Diarrhea and nutrient losses Steroids Disease location

Pubertal Delay in IBD Similar factors affecting growth affect onset of puberty Poor nutrition Pro-inflammatory cytokines Delayed age of peak height velocity (middle of puberty) in Crohn’s disease, but not UC ~1/4 children with Crohn’s Delay usually 6-12 months

Bone Density in IBD Maximum accumulation of calcium in bone occurs in mid-teen years Decreased bone mineral density common in children and adolescents with IBD Poor calcium absorption/inadequate calcium intake and vitamin D deficiency (~36%) Decreased physical activity Inflammation Steroid use increases short and long term risk Shifts balance between bone formation to bone breakdown and fat cell production

Promoting Growth and Bone Health Control inflammation Induce remission Maintain remission Ensure adequate caloric intake For some, high calorie supplements may be needed Ensure adequate calcium and vitamin D Avoid long-term or repetitive steroid use

Psychological Challenges Specific issues facing patients Being a teen is hard enough! Defining what it means to have a chronic illness Physical symptoms associated with IBD affect patients’ self-image Coping with procedures, frequent clinic visits, and hospitalizations Adhering to complicated medical/dietary regimens Greater risk of low self-esteem, poor social functioning, and depression When a child is faced with a chronic illness he or she may struggle with these issues: review each Being aware of and addressing these challenges early on promotes the best types of adaptation.

Treatment Challenges Limited data Treatment data taken from adult studies Trials do not consider child-specific outcomes Unanswered questions Do medications work as well (or better) in kids? Are there differences in safety? Infections Malignancy *Impact of lifetime therapy duration Practical considerations, not “one size fits all” Swallowing medications Ease of following a regimen

Absolute versus Relative Relative risk (or benefit): Drug A doubles the chances of an outcome (remission, infection) Absolute risk (or benefit): The actual probability that the event will occur. For patients, its absolute risk that matters: Doubling the chances of a rare event = a rare event Important concept in peds, as the baseline risk of malignancy and serious infections is much lower

Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s disease Estimated annual risk = 2 per 10,000 treated patients Courtesy of Corey Siegel

Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s disease receiving 6MP or Azathioprine Estimated annual risk = 4 per 10,000 treated patients Courtesy of Corey Siegel

Towards Personalized Medicine IBD is not two diseases, but dozens Selecting the right treatment for the right patient at the right time is the ultimate goal Balancing risk and benefits Using clinical factors (symptoms, inflammation, growth/skeleton, psychological well-being) Incorporating state of the art science (genetics, immunology, microbiome)

First visit to the clinic… Patient-specific treatment plan IBD 2015 and beyond… First visit to the clinic… IBD Panel Serology Genetics Proteomics IBD Subtype Disease Prognosis Patient-specific treatment plan