James Markowitz, MD Professor of Pediatrics Hofstra North Shore – LIJ School of Medicine

1. DEBATE: What should be our end-points of therapy?Pro: The only end-points of therapy that matter are clinical symptoms and quality of life James Markowitz, MD Professor of Pediatrics Hofstra North Shore – LIJ School of Medicine Division of Pediatric Gastroenterology Cohen Children’s Medical Center of NY New Hyde Park, NY

2. Disclosures • Janssen Pharmaceuticals – Consultant • Abbvie – Consultant • UCB – Consultant • Soligenix – Consultant

4. Case: P.T. March 2011 • 13 yo Tanner I boy with short stature (50→10%), referred from Peds Endo after neg GH testing • Mild daily cramps, loose nonbloody stools bid • ESR 22, CRP 0.5, albumin 3.2 • Dx: Mild granulomatous inflammation in TI and cecum on ileocolonoscopy; small bowel aphthae on VCE • Rx: Enteral feeds supplying 85% of RDA x 3mos, then prn • Outcome: Asymptomatic with improved weight gain, growth, normalization of labs

5. May 2013 (15 yrs old) • Asymptomatic, hgt 50%, Tanner IV • Gluten free, dairy free diet; resumes NG feeds for episodes of pain or diarrhea • Routine labs: ESR 15, CRP 0.3, albumin 3.8, calprotectin 1380 • VCE: scattered aphthous ulcerations throughout the small bowel

6. How to treat? • Primarily small bowel CD in an asymptomatic adolescent • 5ASA • No significant benefit • Antibiotics • Mom afraid – mat GF had been hospitalized with severe C diff • Immunomodulators, Biologics • Parents very worried about cancer • Parents and patient not interested in issues related to mucosal healing and its role in potentially decreasing risk of future complications • Opted to accept no new therapy

7. The only end-points of therapy that matter….. Matter To Whom??

8. Patient/Parent Concerns Day to day symptoms • Loss of energy • Loss of control • Body image • Isolation and fear • Not reaching full potential • Feeling dirty Drug induced toxicities • Infection • Cancer • Fertility • Teratogenicity Casati J, et al. Dig Dis Sci 2000 Jan;45(1):26-31

9. PROs: Patient Reported Outcomes Measures • Recognized as a critical, necessary and now required aspect of new drug development • The patient perspective: “How does it make me feel?” • FDA: always relevant and should be assessed in all pivotal clinical trials • Recognizes that biologic effects alone are not adequate to judge the overall effect of a treatment http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf Basch E. Value in Health 2012;15(3):401-3

10. Psychological factors influence health-related quality of life in outpatients with IBD • 72 adults with IBD • Standardized survey: Rating Form of IBD Patients' Concerns (RFIPC) Results • HRQOL affected at least as much by psychological characteristics as by IBD activity • “Depressive coping” associated with: • more psychological distress • worse self-rated health status • increased somatic complaints nonspecific to IBD Mussell M, et al. Eur J Gastroenterol 2004;16(12):1273-80

11. Potential mechanisms by which stress can worsen tissue inflammation and clinical course of IBD • Increase gut permeability • Promote immune reactivity • Affect luminal flora • Promote maladaptive behaviors • Sleeplessness • Smoking • Adherence to medical regimens Soderholm JD, et al. Am J PhysiolGastrointest Liver Physiol 2001; 280:G7–G13 Qiu BS, et al. Nat Med 1999; 5:1178–1182 Lyte M, et al. J Lab Clin Med 1996; 128:392–398 Nigro G. et al. J ClinGastroenterol 2001; 32:66–68

12. Do we change the natural history of IBD with medical therapies?

13. Striving for mucosal healing may increase toxicity risk