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 1.Loss of energy 2.Loss of control 3.Body image 4.Isolation and fear 5.Not reaching full potential 6.Feeling dirty Drug induced toxicities 1.Infection 2.Cancer 3.Fertility 4.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 Physiol Gastrointest 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 Clin Gastroenterol 2001; 32:66–68

12. Do we change the natural history of IBD with medical therapies? ThiopurinesAnti-TNF Corticosteroid free maintenance +++ Change from B1 → B2 or B3+++ Risk of 1 st surgery+++ Post-operative recurrence+++ Growth0+

13. Striving for mucosal healing may increase toxicity risk ThiopurinesAnti-TNF Opportunistic infections++ Malignancy Lymphoma++ SkinNonmelanomaMelanoma Immunogenicity/ Autoimmunity 0+