Robert N. Baldassano, MD Colman Family Chair in Pediatric IBD Professor of Pediatrics

1. The only end-points of therapy that matter are mucosal healing, normal blood work, andnegative radiologic studies. Robert N. Baldassano, MD Colman Family Chair in Pediatric IBD Professor of Pediatrics University of Pennsylvania School of Medicine Director, Center for Pediatric IBD The Children's Hospital of Philadelphia

2. 1978-82 1983-87 1988-92 1993-97 1998-2002 Are we changing the Natural History by using clinical symptoms as our end-point?? Intestinal Resection in Different Cohorts Treat the patient not the lab tests No change in operative rates 60 P = 0.81 40 % of Patients 20 0 0 12 24 36 48 60 Months After Diagnosis 6MP was standard therapy at this time Cosnes J, et al. Gut. 2005;54:237.

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

4. Shifting CD Therapeutic Goals • ADDED GOALS • Heal the mucosa • Modify the natural history of disease Prevent complications!! • PREVIOUS GOALS • Induce & maintain clinical remission • Improve quality of life • Minimize drug toxicity • Optimize surgical outcomes

5. Does good symptom control mean good disease control?

6. Cannabis induces a clinical response in patients with CD • 21 patients randomized to placebo vs. cannabis with THC • Significant “response” in CDAI in THC group (90% vs. 40%) at 8 weeks • NO change in HCT or CRP • Conclusion: getting high lowers your CDAI. Naftali, et al. CGH 2013

7. The CDAI- Subjective and Non-Specific (p=0.1) 183 91 consecutive patients with CD or IBS Higher CDAIs in IBS patients Pain scores higher Mean CDAI Score 157 Lahiff C. et al. Aliment PharmacolTher. 2013; 37(8):786- 94

8. Relationship Between Clinical Symptoms and Endoscopic Indices at Presentation of Acute CD 600 500 400 Crohn’s Disease Activity Index ( CDAI ) 300 200 100 R=0.13; NS 0 10 15 20 25 30 35 0 5 Crohn’s Disease Endoscopic Index of Severity (CDEIS) Modigliani R et al. Gastroenterology. 1990;98:811.

9. Lack of Correlation Between Endoscopyand Clinical Symptoms(Which One is Really Measuring the Disease?) • Endoscopy is not a biomarker, endoscopy is physical (visual) examination of the ileum and colon • Analogies • Psoriasis – physical (visual) examination showing presence and severity of typical skin lesions • Rheumatoid arthritis – physical examination showing swollen and tender joints + biomarkers • Clinical symptoms are a surrogate for endoscopy findings, not the other way around

10. MR Enterography • 50 CD patients • Ileocolonoscopy and MRE • Strong correlation between CDEIS and wall thickness, ulceration, enhancement, edema • R=0.82 for MRE score and CDEIS • MRE highly accurate for assessment of active disease Rimola et al Gut 2009

11. Treat-to-TargetIBD • This strategy requires a new treatment target. • Clinical remission • Control of inflammation (mucosal healing) Deep Remission

12. Treat-to-Target • This approach is taken with other chronic, progressive diseases where there are clearly defined treatment targets • Hypertension, Diabetes and Rheumatoid Arthritis • No longer sufficient to aim to treat to symptom control

13. Deep Remission • Goals • Prevention of bowel damage • Reduction of long-term disability • Maintenance of good quality of life

14. Deep Remission after 1 year of treatment for UC is predictive of a decreased rate of colectomy Froslie KF, et al. Gastro 2007

15. EXTEND Study Time to Loss of Response at week 52 with and without Deep Remission (DR) at week 12 Colombel JF, et al. Clin Gastro Hep; 2014 (in press)

16. EXTEND Study Quality of life and Productivity at week 52 with and without Deep Remission (DR) at week 12 Colombel JF, et al. Clin Gastro Hep ; 2014 (in press)

17. Meaningful Response: The clinician’s perspective Spryliving.com March 2012 http://spryliving.com/articles/8-ways-to-a-hassle-free-colonoscopy/ This is not the only reason for a colonoscopy.