1. Infectious Complications of Biologic Therapies: Preventive and Therapeutic Strategies Kevin L. Winthrop, MD, MPH Assistant Professor, Divisions of Infectious Diseases, Public Health, and Preventive Medicine Oregon Health & Science University

2. Immune dysregulation Upregulation of CD4 T-cells Pro-inflammatory cytokine cascade – Tumor necrosis factor–alpha (TNF-  ) – Interleukin-1 (IL-1) B-cell activation and auto-antibody production Rheumatoid Arthritis (RA)

3. TNF-  Primarily expressed by activated macrophages, T and B cells Biological effects are numerous – Integral to granuloma formation and maintenance – Activates macrophages to ingest and kill mycobacterium and other pathogens Mice deficient in TNF-  /p-55 signaling pathway more susceptible – TB, Histoplasma, Listeria, Klebsiella, S. pneumoniae

4. Overexpression of TNF-  Inflammation and tissue destruction Important in pathogenesis – Crohn’s, rheumatoid arthritis, psoriasis, ankylosing spondylitis, others Inhibition of TNF-  highly successful in treatment of these conditions – Infliximab, adalimumab (monoclonal antibodies) – Etanercept (soluble p75 receptor)

5. RA Biologic Therapies Widespread use – TNF-  inhibition: infliximab, adalimumab, and etanercept, golimumab, certolizumab Newly approved – CD4 co-stimulation modulator: abatacept – B-cell (CD20+) antibody: rituximab – Anti-IL-6 receptor antibody: tocilizumab Rarely used – Inhibition of IL-1: anakinra

6. TNF-  Antagonist Therapy Often used in combination with methotrexate and/or prednisone Many patients have co-morbidities – Chronic lung disease, diabetes Off-label use frequent – Wegener’s granulomatosis, uveitis, Bechet’s, dermatomyositis, polymyositis, sarcoidosis, giant cell arteritis, others

7. Prednisone and Tuberculosis Risk of reactivation TB poorly defined – Based on anecdotal reports from 1950-70s CDC 2000 TB statement – >15mg/day for one month or more – Dose shown to suppress tuberculin skin test reactivity No observational or prospective data to support Retrospective studies in low incidence areas unable to demonstrate any risk of TB

8. Prednisone and Tuberculosis Jick et al. Arthritis Rheum 2006 General Practice Research Database, UK TB cases 1990-2001 and controls † Current glucocorticoid use *OR 4.9 (2.9-8.3) <15mg/day *OR 2.8 (1.0-7.9) >15mg/day *OR 7.7 (2.8-21.4) – Causal versus severity of underlying disease *Adjusted for smoking, BMI, lung disease, diabetes, anti-rheumatic therapy, other TB risk factors † Controls matched for age, sex, residence, time clinically followed

9. British Biologic Registry 9000 patients, followed Dec 2001-Sept 2005. 19 intracellular infections (200/100,000 person-yr) – All in anti-TNF treated (none in non-biologic group) – TB (n=10), NTM (n=1), Listeria (n=3), Salmonella (n=3), Legionella (n=3) More TB with monoclonals – Infliximab (adj. IRR 4.9 [.5-49.8]) – Adalimumab (adj. IRR 3.5 [.3-47.3]) Dixon WG et al. Arthritis and Rheum 2006 Adjusted for age, sex, RA severity, extra-articular manifestations, steroids, diabetes, COPD/asthma, smoking.

10. British Biologic Registry Dixon WG et al. Ann Rheum Dis 2010:69:522-528

11. British Biologic Registry Dixon WG et al. Ann Rheum Dis 2010:69:522-528

12. French Active Surveillance for Tuberculosis 69 TB cases over 3 years SIR compared to background French population – Adalimumab 29.3 (20.3-42.4) – Infliximab 18.6 (13.4-25.8) – Etanercept 1.8 (0.7-4.3) Case-control with etanercept as reference – Adalimumab OR 17.1 (3.6-80.6) – Infliximab OR 13.3 (2.6-69.0)

13. US Reported Infections Associated With Biologic Drugs Number of Infections Reported Salmonellosis Coccidioidomycosis Blastomycosis Legionellosis Listeriosis Parasitic Infections Aspergillosis CMV Severe Pneumococcal Disease Histoplasmosis Invasive Staphylococcus aureus TB/NTM CMV, cytomegalovirus; NTM, nontuberculous mycobacteria; TB, tuberculosis. Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740.

14. Nontuberculous (NTM) Disease Environmental mycobacteria emergence – Lung, skin/soft tissue, disseminated disease Surveyed IDSA EIN – ¼ of US infectious disease specialists – Mycobacterial (tuberculosis/NTM) infections in last 6 months Response = 426 (48.9%) EIN members – 49 (2.6%) of 1876 associated with biologics – 32 cases NTM vs 17 TB – Mycobacterium avium complex most common (n = 16) EIN, Emerging Infections Network; IDSA, infectious Diseases Society of America.

15. EIN Survey Results Associated biologics 21 (42%) with concurrent prednisone/MTX 8 patients (16%) died Biologic stopped in 43 (86%) – Only 2 with IRIS ADA, adalimumab. Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740. INF ETN ADA RTX ABA Unspecified TB (n = 17) 7 4 1 3 0 2 NTM (n = 32) 11 8 2 5 0 6

17. Preliminary US population- based Data KNPC and VA (NW VISN) 2000-2008 TNF users over 9 year time period (n=4,524) TB (n=14) among TNF users – 34/100,000 NTM (n=20) among TNF users – 49/100,000 – 7/20 died during study time-period

18. Risk factors for TB in RA patients who use anti-TNF

20. TNF-  Antagonist Therapy and TB Atypical clinical presentation – 50% extrapulmonary – 15%–20% disseminated Median time to onset – Infliximab (INF) = 12 weeks (range, 1–52 weeks) 1 – Etanercept (ETN) = 11.5 months (range, 1–20 months) 2 TNF, tumor necrosis factor. 1. Keane J et al. N Engl J Med. 2001;345:1098-1104. 2. Mohan AK et al. Clin Infect Dis. 2004;39:295-299.

21. More TB Risk with Infliximab? Infliximab drug mechanism differs Greater TNF-  binding – Transmembrane and soluble TNF-  – Forms stable complex Longer half-life Apoptosis of monocytes and T lymphocytes Downregulates interferon-gamma

22. Interferon-  Story Saliu et al. compared monoclonal antibodies and etanercept In vitro whole blood culture exposed to TB culture-filtrate – Exposed to anti-TNF drugs in typical concentrations of body – Measured t-cell responses, TB growth, cytokine production, apoptosis Saliu et al. JID 2006

23. Adalimumab and infliximab similar – Suppressed TB antigen induced INF-  production at 5 days – Decreased T-cell activation at 24 hrs No difference in TB growth at 24 and 96 hrs – Bacilli grow slowly (doubling in 15-24 hrs) Interferon-  Downregulation Saliu et al. JID 2006

24. *Granuloma Penetration of TNFis Acute TB infection (mouse) – Large bacillary load and death – No difference between anti-TNFs Chronic TB infection (mouse) – Monoclonal antibodies = death (1 month) – Etanercept = 60% alive at 6 months Lung pathology – Etanercept with less penetration of lung granulomas *Plessner et al JID 2007

25. Screening for Latent Tuberculosis Infection (LTBI) Screen before patient is immunocompromised History of TB risk factors – Foreign birth or extended living abroad – Previous contact with TB case – Previous LTBI diagnosis or treatment – Incarceration, homelessness, IV drug use

26. IGRAs QuantiFERON-TB Gold ® test (Cellestis, Australia) – Detects cell-mediated immunity – Whole blood incubated with tubercular antigens (ESAT-6/CFP-10) – IFN-  released from sensitized lymphocytes QFT-In Tube (IT) ® – Added third antigen (7.7) T-SPOT.TB ® assay (Oxford, UK) – Measures number of reactive lymphocytes CFP-10, culture filtrate protein–10 kDa; ESAT-6, early secreted antigenic target–6 kDa.

27. IGRAs in Anti-TNF Candidates Greater specificity for tuberculosis than TST – Does not cross-react with BCG or most environmental mycobacteria Relative sensitivity with TST for LTBI? Matulis et al, 2007 1 – Patients with inflammatory rheumatic conditions treated with anti-TNF or non-biologic treated (n = 126) – 12% QFT positive vs 40% TST positive – QFT-IT more closely associated with LTBI risk factors than TST Ponce de Leon et al, 2008 2 a P <.05 for comparisons. BCG, bacille Calmette-Guérin; RA, rheumatoid arthritis. 1. Matulis G et al. Ann Rheum Dis. 2008;67:84-90; 2. Ponce de Leon D et al. J Rheumatol. 2008;35:776-781. RA (n = 101)Controls (n = 93) TST+ 27 (27%) a 61 (66%) QFT-IT+ 45 (45%) 55 (59%)

28. IGRAs in the Immunocompromised Anergy with TST and IGRAs – IGRAs less affected by prednisone – False negative with IGRA in patients already receiving anti-TNF therapy 1 Indeterminate results 2 – QFT-IT and T-SPOT.TB < QFT-Gold LTBI sensitivity 2 – QFT-IT similar to T.SPOT.TB (and probably similar to or greater than TST) – QFT-Gold is less sensitive 1. Hamdi H et al. Arthritis Res Ther. 2006;8:R114. 2. Lalvani A, Millington KA. Autoimmun Rev. 2008. Epub ahead of print.

30. LTBI Treatment Begin treatment before starting anti-TNF therapy – 9 months isoniazid (INH) preferred in US – 4 months rifampin is alternative Start INH 1 month prior to anti-TNF initiation – 83% reduction in INF-associated cases in Spain 1 – Ensure INH compliance and tolerance Liver function testing – Many patients taking MTX MTX, methotrexate. 1. Carmona L et al. Arthritis Rheum. 2005;52:1766-1772.

31. New Biologics for RA Rituximab – CD20+ B-cell antibody – Depletes peripheral B cells – No TB in RA clinical trials or in lymphoma use – B cell importance to granuloma/survival in murine model of TB* EIN Survey – 8 TB/NTM cases with rituximab – All cases also on prednisone *Maglione et al. J Immunol 2007

32. Abatacept Tuberculosis risk unknown – Screened in clinical trials – Should screen in practice Murine chronic TB not affected by abatacept* – Mortality, T cell, B cell, INF-γ production in lung, and bacillary load *Bigbee et al. Arth Rheum 2007

33. Tocilizumab 10 cases TB in 10,000 patients – 5 pulmonary Should we be screening? – YES

34. Conclusions Anti-TNF–associated mycobacterial cases – NTM likely more common than TB in US – M. avium complex is most common – High mortality – Severe lung destruction despite anti-NTM therapy Screening and prevention – Chest CT? – Sputum when appropriate CT, computed tomography.

35. Patients Receiving TNF-  Antagonists Physicians should maintain high index of suspicion for TB disease – Febrile or respiratory illness If TB diagnosed – Begin anti-TB treatment Stop anti-TNF therapy immediately? – Immune reconstitution inflammatory syndrome (IRIS) – Unclear when to re-start anti-TNF therapy

36. Needed Research Studies to assess the infectious risk of therapy in the U.S. – Biologics, MTX/prednisone, combination – Ongoing surveillance for TB with newer biologics Utility of INF-  release assays in screening anti-TNF candidates for LTBI – Sensitivity in inflammatory disease patients

37. Next Steps Current ATS/IDSA/CDC joint task force – Review and propose research – Further refine and issue U.S. screening and treatment guidelines Clarify role of IGRAs Creation of a biologic post-marketing surveillance system – European luxury – Risk of rituximab, abatacept, others to come

38. Acknowledgments U.S. Centers for Disease Control and Prevention – Zach Taylor, Michael Iademarco, John Jereb, Ken Castro US Food and Drug Administration – Jeffrey Siegel National Jewish Medical Center – Chuck Daley