1. ©2010 MFMER | slide-1 Edward V. Loftus, Jr., M.D. Professor of Medicine Mayo Clinic Rochester, Minnesota, U.S.A. Pro: Immunomodulators and Anti- TNFs Must Be Stopped When a Viral, Bacterial, or Fungal Infection Occurs

2. Loftus Disclosures (last 12 months) Consultant AbbVie UCB Janssen Takeda Immune Pharmaceuticals Research support AbbVie UCB Bristol-Myers Squibb Shire Genentech Janssen Amgen Pfizer Braintree Takeda GlaxoSmithKline Robarts Clinical Trials Santarus

3. Case: 26 Year Old Man with Ulcerative Colitis Diagnosed with proctitis 3 years ago Severe flare 1 year ago: now with extensive disease Steroid-dependent Azathioprine 2.5 mg/kg body weight daily Still steroid-dependent after 3 months CXR, PPD negative Infliximab 5 mg/kg started, 3-dose induction and scheduled maintenance Visit at 8 weeks: significant clinical improvement

4. Case: Steroid-Dependent UC Week 10: calls to report 10 days of fever, myalgia, chest discomfort, dry cough Seen urgently that day CXR: “negative” Chest CT: numerous tiny nodules throughout lungs, mediastinal lymphadenopathy ID: consistent with a granulomatous infection such as histoplasmosis Histoplasma serology negative, no clinical response to itraconazole

5. Case: Steroid-Dependent UC Referred to pulmonary Bronchoscopy, transbronchial biopsy/aspirate negative Original induced sputum from 2 weeks ago grew out Mycobacterium tuberculosis Prednisone and infliximab and AZA all held Started on ethambutol, pyrazinamide, rifampin, isoniazid: 9 months Developed arthralgias and fevers 2 weeks after starting antimycobacterial therapy Eventually diagnosed as immune reconstitution syndrome Restarted on low-dose prednisone Serious flare of UC 1 year after TB Hospitalized Colectomy

6. Infection Definitions Opportunistic infection Infection by an organism which has limited pathogenic capacity in ordinary circumstances Serious infection Infection resulting in need for intravenous therapy or hospitalization, or which results in disability or death Not all opportunistic infections are serious and not all serious infections are opportunistic

7. Immunosuppression in IBD Not all IBD patients are immunosuppressed Most important factors Increased age Malnutrition Comorbidities (e.g., COPD, DM) Medications: steroids, immunosuppressives, biologics Hospitalization Interplay of these factors results in variable amounts of immunosuppression with same medications No clinical test available to measure “immunity”

8. Mayo Case-Control Study (n = 100 Trios): Age Associated with Opportunistic Infection Age at IBD diagnosis: Odds Ratio (per 5 years), 1.1 (1.1-1.2) Age at first Mayo visit: 0 – 231.0 (reference) 24 – 36 1.2 (0.5 – 2.8) 37 – 49 1.1 (0.5 – 2.5) ≥ 503.0 (1.2 – 7.2) Toruner M et al, Gastroenterology 2008; 134:929-36.

9. Biologics in the Elderly Adverse Events Older Cohort (n=89) Younger Cohort (n=178) Events N Patients N (%) Events N Patients N (%) Adverse Event6140 (45)6741 (23) Serious Adverse Events3224 (27)2917 (10) Serious Infections2720 (22)2615 (8) Bhushan A et al, DDW Abstract 2010 Older age, HR unadjusted 1.9 (1.2 – 3.1) HR adjusted 1.7 (1.1 – 2.8)

10. Mayo Case-Control Study (n = 100 Trios): Immunosuppressive Medications Were Associated with Increased Risk of Opportunistic Infections Odds Ratio (95% CI)P value Any Medication (5-ASA, AZA/6-MP, steroids, MTX, infliximab) 3.5 (2 - 6.1)<0.0001* 5-ASA1.0 (0.6 - 1.6)0.94 Corticosteroids3.4 (1.8 - 6.2)<0.0001* 6-MP/azathioprine3.1 (1.7 - 5.5)0.0001* Methotrexate4.0 (0.4 - 44.1)0.26 Infliximab4.4 (1.2 - 17.1)0.03 Toruner M et al, Gastroenterology 2008; 134:929-36.

11. Risk Factors for Opportunistic Infections in IBD: A Case-Control Study Odds Ratio (95% CI)P value Odds Ratio (95% CI)P value 1 medication 2.65 (1.45-4.82)0.0014 ≥2 medications 14.5 (4.9-43)<0.0001 Toruner M et al, Gastroenterology 2008; 134:929-36.

12. Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience Lichenstein GR et al, Gastroenterology 2006;130(Suppl 4):A-71. Lichtenstein GR et al, Clin Gastroenterol Hepatol 2006;4:621-30. Multivariate analysis **P<0.0001 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 IFX Odds ratio MortalitySerious infections AZA 6-MP MTX Steroids * IFX AZA 6-MP MTX Steroids ** IFX = infliximab; AZA = azathioprine; MTX = methotrexate *P=0.001

13. Infliximab Dose and Serious Infection: RCT in RA (n = 1084) RCT of placebo vs 2 doses of infliximab in RA Relaxed entry criteria to allow co-morbidities Group 1: placebo to wk 22, then 3 mg/kg q 8 Group 2: 3 mg/kg to wk 22, then escalate by 1.5 mg/kg PRN Group 3: 10 mg/kg throughout Primary endpoint: risk of serious infection at week 22 P = 0.013 Westhovens R et al. Arthritis Rheum. 2006;54:1075-86 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Relative Risk Serious Infection # TB Cases Week 54 Group 1 Group 2Group 3

14. Risk of Hospitalization for Serious Infection After Starting Medication for IBD (n=2,323 Pairs Matched on Propensity Score) Incidence rates: Anti-TNF: 10.9 per 100 PY AZA/6MP: 9.6 per 100 PY Adjusted hazard ratio: 1.1 (0.8-1.5) Grijalva CG et al, JAMA 2011 Online Early

15. Prospective study (n=230) Seksik P et al. Aliment Pharmacol Ther 2009;29:1106-13. AZA Increases the Incidence of Certain Viral Infections Infection/patient-year 2.01.51.00.50 AZA+ n=169 AZA– n=61 AZA+ n=169 AZA– n=61 NS * Upper respiratory tract infections Herpes virus flare-ups AZA+AZA–AZA+AZA– Warts at the entry in the study Appearance of increased number of warts NS * Patients (%) 20181614121086420 NS = not significant

16. Cervical Dysplasia in IBD Some (not all) studies suggest that cervical dypslasia is more common in women with IBD Presumably mediated through HPV reactivation Immunosuppressive medications Cigarette smoking Recommend annual screening for cervical dysplasia in women with IBD, especially those who smoke and are on immunosuppressives Bhatia J et al, World J Gastroenterol 2006;12:6167-71. Kane S et al, Am J Gastroenterol 2008;103:631-6. Singh H et al, Gastroenterology 2009;136:451-8. Lees CW et al, Inflamm Bowel Dis 2009;15:1621-9.

17. ECCO Guidelines for Managing Opportunistic Viral Infections VirusScreen?Vaccinate?Withdraw? HCVNot necessaryN/ANo HBVYes No but treat pre- emptive HIVConsider testingN/ANo if counts OK CMVNoN/AYes HSVNoN/AOnly for severe VZVYes if no hxYesOnly for severe EBVNoN/AOnly for severe HPVCervical caYesOnly for severe JCVYesN/AYes ©2010 MFMER | slide-17 Rahier JF et al, J Crohns Colitis 2009;3:47-91

18. Clostridium difficile Infection and IBD Increasing percentage of C. diff infections are IBD patients Increasing number of hospitalizations in IBD patients with C. diff Issa M, et al. Clin Gastroenterol Hepatol 2007; 5: 345-51. Classic risk factors disappearing Pseudomembranes usually not present Low threshold for checking in IBD patients with flares Should you stop immunosuppression? Conflicting data

19. Granulomatous Infections After TNF Blockade Bacterial Tuberculosis Atypical mycobacterial infection Listeriosis Invasive fungal Histoplasmosis Coccidioidomycosis Candidiasis Aspergillosis Pneumocystosis Others Lee JH et al. Arthritis Rheum. 2002;46:2565-70 Velayos FS et al. Inflamm Bowel Dis. 2004;10:657-60 Bergstrom L et al. Arthritis Rheum. 2004;50:1959-66

20. Geographic Distribution of Histoplasmosis and Coccidioidomycosis in Older Americans, 1999-2008: Medicare Sample Histoplasmosis Coccidiodomycosis Baddley JW et al, Emerging Infect Dis 2011;17:1664-9. Cases per 100,000 person-years

21. Fungal Infections and Anti-TNF Therapy: MEDLINE and PubMed Until 2007 Tsiodras S et al, Mayo Clin Proc 2008;83:181-94.

22. Long-Term Outcome of Patients Treated With IV Cyclosporine for Severe UC (n=86) Aspergillus pneumonia Aspergillus pneumonia 60 yr old man, IV Steroids, AZA, cyclosporine Aspergillus pneumonia Aspergillus pneumonia 57 yr old man, IV Steroids, cyclosporine, surgery Pneumocystis jiroveci Pneumocystis jiroveci 32 yr old man, Steroids, cyclosporine, AZA Arts J et al. Inflamm Bowel Dis 2004;10:73-8.

23. Tuberculosis Screening Average risk: tuberculin test and chest X- ray Residents of endemic areas and/or those who received BCG Interferon gamma release assay (QuantiFERON) Latent infection: INH for 6-9 months, can start anti-TNF after 3 weeks Active infection: do not start or reinitiate anti-TNF until a minimum of 2 months of anti-TB therapy

24. ECCO Guidelines for Managing Fungal Infections, Bacterial Infections and Tuberculosis OrganismScreen?Vaccinate?Withdraw? FungalNoN/AIndividualize TBYesN/ALatent: wait 3 weeks Active: yes wait 2 months C diffScreen at flareN/AIndividualize Various bacterialNoN/AIndividualize ©2010 MFMER | slide-24 Rahier JF et al, J Crohns Colitis 2009;3:47-91

25. Conclusions Serious and opportunistic infections occur in IBD patients Risk factors include older age, hospitalization, corticosteroids, immunosuppressives, anti-TNF agents Overall risk of serious infection with anti-TNF probably no higher than with thiopurines Pay close attention in the elderly Stay vigilant Weigh benefit to risk ratio in each patient Decision to stop immunosuppression in most cases is individualized-get I.D. support