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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 Rheumatoid Arthritis (RA) • • • 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 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 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) RA Biologic Therapies • Widespread use – • Newly approved – – – • TNF- inhibition: infliximab, adalimumab, and etanercept, golimumab, certolizumab CD4 co-stimulation modulator: abatacept B-cell (CD20+) antibody: rituximab Anti-IL-6 receptor antibody: tocilizumab Rarely used – Inhibition of IL-1: anakinra 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 Prednisone and Tuberculosis • Risk of reactivation TB poorly defined – • CDC 2000 TB statement – – • • Based on anecdotal reports from 1950-70s >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 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 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]) Adjusted for age, sex, RA severity, extra-articular manifestations, steroids, diabetes, COPD/asthma, smoking. Dixon WG et al. Arthritis and Rheum 2006 British Biologic Registry Dixon WG et al. Ann Rheum Dis 2010:69:522-528 British Biologic Registry Dixon WG et al. Ann Rheum Dis 2010:69:522-528 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) US Reported Infections Associated With Biologic Drugs Salmonellosis Coccidioidomycosis Blastomycosis Legionellosis Listeriosis Parasitic Infections Aspergillosis CMV Severe Pneumococcal Disease Histoplasmosis Invasive Staphylococcus aureus TB/NTM 0 20 40 60 Number of Infections Reported CMV, cytomegalovirus; NTM, nontuberculous mycobacteria; TB, tuberculosis. Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740. 80 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. EIN Survey Results • Associated biologics TB (n = 17) NTM (n = 32) • • • INF ETN ADA RTX ABA Unspecified 7 4 1 3 0 2 11 8 2 5 0 6 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. Preliminary US populationbased 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 Risk factors for TB in RA patients who use anti-TNF TB # (%) (n= 14) Uninfected # (%) (n=4,490) OR (95% CI, p=value) Diabetes 6 (43) 759 (17) 3.7 (1.1- 12.2), p= 0.02 LTBI 7 (50) 274 (6) 15.5 (4.6- 52.1), p< 0.01 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. 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 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 Interferon- Downregulation • • 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) Saliu et al. JID 2006 *Granuloma Penetration of TNFis • Acute TB infection (mouse) – – • No difference between anti-TNFs Chronic TB infection (mouse) – – • Large bacillary load and death 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 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 IGRAs • • QuantiFERON-TB Gold® test (Cellestis, Australia) – – Detects cell-mediated immunity – IFN- released from sensitized lymphocytes QFT-In Tube (IT)® – • Whole blood incubated with tubercular antigens (ESAT-6/CFP-10) 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. IGRAs in Anti-TNF Candidates • Greater specificity for tuberculosis than TST – • • • aP Does not cross-react with BCG or most environmental mycobacteria Relative sensitivity with TST for LTBI? Matulis et al, 20071 – 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, 20082 RA (n = 101) Controls (n = 93) TST+ 27 (27%)a 61 (66%) QFT-IT+ 45 (45%) 55 (59%) < .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. IGRAs in the Immunocompromised • Anergy with TST and IGRAs – – • False negative with IGRA in patients already receiving anti-TNF therapy1 Indeterminate results2 – • IGRAs less affected by prednisone QFT-IT and T-SPOT.TB < QFT-Gold LTBI sensitivity2 – 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. 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 Spain1 – 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. 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 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 Tocilizumab • 10 cases TB in 10,000 patients – • 5 pulmonary Should we be screening? – YES 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. • Patients Receiving TNF- Antagonists Physicians should maintain high index of suspicion for TB disease – • If TB diagnosed – • Febrile or respiratory illness Begin anti-TB treatment Stop anti-TNF therapy immediately? – Immune reconstitution inflammatory syndrome (IRIS) – Unclear when to re-start anti-TNF therapy 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 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 Acknowledgments • U.S. Centers for Disease Control and Prevention – • US Food and Drug Administration – • Zach Taylor, Michael Iademarco, John Jereb, Ken Castro Jeffrey Siegel National Jewish Medical Center – Chuck Daley