1. How Should the Risk of Malignant and Infectious Complications Influence My Treatment Choice Meenakshi Bewtra, MD, MPH, PhD University of Pennsylvania Division of Gastroenterology Center for Clinical Epidemiology & Biostatistics CCEB

2. Outline: Risks of immunosuppressant therapy* Benefits of immunosuppressant therapy* Putting it all together Conclusion Immunosuppressant therapy: thiopurine analogs, biologics, calcineurin inhibitors, methotrexate

3. RISKSESTIMATE Serious/Opportunistic Infections Lymphoma Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML) Risks in Immunosuppressant Therapy

4. STUDYREPORTED INFECTION RISK Grijalva CG et al, JAMA 201110 / 100-person-years Colombel JF et al, NEJM 2010 (SONIC) 4-5% at 54 weeks (mono and combination therapy) Toruner M et al, Gastro 20083.3-4.4 times increased odds (mono) 14.5 times increased (combination therapy) Peyrin-Biroulet L et al, CGH 2008no increased risk Colombel JF et al, Gastro 20042.8%/year Feagan et al, NEJM 2013 (GEMINI 1) Sands et al, Gastro 2014 (GEMINI 3) 9-13%/year Risks in Immunosuppressant Therapy

5. RISKSESTIMATE Serious/Opportunistic Infections 3% per year (monotherapy) 5% per year (combination therapy) Lymphoma Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML) Risks in Immunosuppressant Therapy

6. MEDICATIONREPORTED LYMPHOMA RISK THIOPURINES Kandiel, Gut 2005 (meta-analysis) Beaugerie, Lancet 2009 (CESAME) SIR 4.06 (2.01-7.28) SIR 6.5 (3.5-11.2) ANTI-TNFs Siegel CA, CGH 2009 (meta-analysis) Anderson NN, JAMA 2014 SIR 3.23 (1.5-6.9) RR 1.07 (0.85-1.36) THIOPURINES + ANTI-TNFs Herrinton Am J Gastro 2011 Beaugerie, Lancet 2009 (CESAME): SIR 6.6 (4.4-8.8) SIR 10.2 (1.2-36.9) Risks in Immunosuppressant Therapy

7. RISKSESTIMATE Serious/Opportunistic Infections 3% per year (monotherapy) 5% per year (combination therapy) Lymphoma 4x increased risks (monotherapy) 8x increased risk (combination therapy) Hepatosplenic T-Cell Lymphoma (HSTCL) Progressive Multifocal Leukoencepholapthy (PML) Risks in Immunosuppressant Therapy

8. STUDYREPORTED HSTCL RISK Herrinton L et al, Pharmacoepi Drug Safety 2012 Baseline population risk IBD population risk 0.3 per million-person-years 48 per million-person-years Beaugerie, Lancet 2009 (CESAME):0 per 16,659 person-years Risks in Immunosuppressant Therapy

9. RISKSESTIMATE Serious/Opportunistic Infections 3% per year (monotherapy) 5% per year (combination therapy) Lymphoma 4x increased risks (monotherapy) 8x increased risk (combination therapy) Hepatosplenic T-Cell Lymphoma (HSTCL) 160 times increased risk Progressive Multifocal Leukoencepholapthy (PML) Risks in Immunosuppressant Therapy

10. STUDYREPORTED PML RISK Singh S et al, IBD 2012: JC Ab negative, +/- prior immunosuppressant therapy 1:7,099 – 1:28,397 Bloomgren G et al. NEJM 2012 JC Ab negative; +/- prior immunosuppressant therapy 1:7094 Risks in Immunosuppressant Therapy

11. RISKSESTIMATE Serious/Opportunistic Infections 3% per year (monotherapy) 5% per year (combination therapy) Lymphoma 4x increased risks (monotherapy) 8x increased risk (combination therapy) Hepatosplenic T-Cell Lymphoma (HSTCL) 160 times increased risk Progressive Multifocal Leukoencepholapthy (PML) 1 out of every 7000 (infinitely increased compared to general population) Risks in Immunosuppressant Therapy

12. RISKSESTIMATE Serious/Opportunistic Infections 30/1000 annual incidence (monotherapy) 50/1000 annual incidence (combo therapy) Lymphoma 0.8/1000 annual incidence (monotherapy) 1.6/1000 annual incidence (combo therapy) Hepatosplenic T-Cell Lymphoma (HSTCL) 0.0034/1000 annual incidence Progressive Multifocal Leukoencepholapthy (PML) 0.14/1000 (not annual incidence) Risks in Immunosuppressant Therapy

13. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together Conclusion

14. Untreated IBD:

15. Medication Efficacy: Mesalamine Mild-Moderate UC – Response: 50-70% – Remission: 15-40% Remission rates vary by definition of remission – Complete resolution (stool freq, bleeding, endo, pt & physician assessment): 22% – UCDAI ≤ 1, rectal bleeding/stool freq = 0; ≥ 1pt decrease in baseline endo score: 28% – Mayo score ≤ 2: 40% Hanauer SB et al. Ann Intern Med 1996;124-204Hanauer SB et al. Am J Gastro 1993;88:1188 Hanauer SB et al. Am J Gastro 2005;100:2478Levine et al. Am J Gastro 2002;97:1398 Sninsky CA et al. Ann intern Med 1991;115-350 Sandborn WJ et al. Gastro 2009;Epub ahead of print 6 weeks

16. Risk of medication cessation: Azathioprine Trenton X et al. Clin Gastroenterol Hepatol 2009;7:80-5

17. Risk of medication cessation: Infliximab Intra-abdominal surgeriesCD-related hospitalizations Rutgeerts P et al. Gastroenterology 2004;126(2):402

18. Monotherapy vs. Combination Therapy Colombel JF et al. NEJM 2010;362(15):1383

19. Monotherapy vs. Combination Therapy Scott FI et al. CGH 2014

20. Risk of medication cessation: Cessation of anti-TNF therapy when on combination therapy Louis E et al. Gastroenterology 2012;142(1):63-70

21. Elective colectomy in UC: Mortality HR (95% CI) for Elective Colectomy Compared to Medical Therapy matched patients; adjusted for comorbidities Overall0.67 (0.52-0.87) Age ≥ 500.62 (0.47-0.82) Bewtra M et al. Ann Int Med 2015 Aug 18;163(4):262-70

22. In UC…. ACT 1 GEMINI 1 52 weeks in Week 6 Responders (47%) 47% x 21% = 10%

23. Corticosteroids: Fluid retention CHF Metabolic abnormalities Hypertension Muscle weakness Loss of muscle mass Osteoporosis Compression fractures (spine) Aspectic necrosis (femoral/humeral head) Pathologic fractures Tendon rupture Hyperglycemia cataracts Gastric ulcers Pancreatitis Impaired wound healing Bruising Pseudotumor cerebri Emotional disturbances Menstrual irregularities Cushingoid features Growth suppression (children) Secondary adrenocortical /pituitary unresponsiveness Diabetes mellitus Glaucoma Weight gain are bad

24. STUDYREPORTED INFECTION RISK Lichtenstein et al Clin Gastro Hep 2006 Serious Infections Adj OR 2.2 (1.5-3.3), p=0.001 Toruner et al. Gastro 2008Opportunistic Infections OR 3.3 (1.8-6.1), p<0.001 Aberra et al. Gastro 2003Post-operative infections: elective surgery Any infection: OR 3.7 (1.2-11.0) Major infection: OR 5.5 (1.1-27.3) Corticosteroids: Infection risk

25. STUDYMORTALITY RISK Lichtenstein et al. Clin Gastro Hep 2006 (TREAT registry) OR 2.1 (1.1–3.8) p=.016 Lewis et al. Am J Gastro 2008 (GPRD Database) CD: HR 2.48 (1.85-3.31) UC: HR 2.81 (2.26-3.50) Corticosteroids: risk of mortality

26. STUDYMORTALITY RISK Lewis et al. Am J Gastro 2008 (GPRD Database) CD: HR 2.44 (1.84-3.25) UC: HR 1.67 (1.34-2.09) Untreated/Active IBD: risk of mortality

27. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together Conclusion

28. How do these risks stack up? Adapted from:Lewis JD et al, Am J Gastro 2008Lichtenstein G et al. CGH 2006 Kandiel A et al. Gut 2005 Siegel C. et al. CGH 2006Herrinton L et al Pharm Drug Safe 2012 Trenton X et al. CGH 2009 Rutgeerts P et al. Gastro 2004Singh S et al, IBD 2012 Toruner M et al, Gastro 2008Grijalva CG et al, JAMA 2011Bloomgren G et al NEJM 2012 Immunosuppressant therapy Corticosteroids /Active Disease Number needed to treat to cause one additional lymphoma per year with therapy 4357 (age 20-29; AZA) 355 (age > 65; AZA) 2380 (infliximab) 714 (combo therapy) Number needed to treat to cause one additional HSTCL per year with therapy 20,964 Number needed to cause one additional relapse per year by stopping therapy 3 Number needed to cause one additional hospitalization per year with episodic therapy 7 Number needed to cause one additional abdominal surgery per year with episodic therapy 14 Number needed to treat to cause one additional death146 (steroids) Number needed not to treat to cause one additional death 21 (active disease) Number needed to treat to cause one additional PML per year with therapy 7,000 Number needed to treat to cause one additional serious infection per year with therapy 483 (monotherapy) 276 (combo therapy) 483 (steroids)

29. Why do we fear medications? How one perceives risk: – Epidemiologist: risk is a measured property of a group of people – Physician/patient: risk is a specific property of ME Perception becomes reality: – Reject statistical reasoning in favor of anecdotal reasoning – Accept common risks we “know” in favor of uncommon risks we “fear”

30. Outline: Risks of immunosuppressant therapy Benefits of immunosuppressant therapy Putting it all together Conclusion

31. Conclusions: There are documented risks with immunosuppressant therapy – The absolute risks are low The absolute risks of active/untreated disease and/or corticosteroid therapy are high

32. Thank you