Infectious Complications of Biologic Therapies: Preventive and Therapeutic Strategies Kevin L....
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Infectious Complications of Biologic Therapies:
Preventive and Therapeutic Strategies
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
• 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)Rheumatoid Arthritis (RA)
TNF- 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- 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 TherapiesRA 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
TNF- Antagonist TherapyTNF- 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 TuberculosisPrednisone 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
Prednisone and TuberculosisPrednisone 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 RegistryBritish 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.
French Active Surveillance for Tuberculosis
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
US Reported Infections Associated With Biologic Drugs
0 20 40 60 80
Number of Infections Reported
SalmonellosisCoccidioidomycosis
BlastomycosisLegionellosis
ListeriosisParasitic Infections
AspergillosisCMV
Severe Pneumococcal DiseaseHistoplasmosis
Invasive Staphylococcus aureusTB/NTM
CMV, cytomegalovirus; NTM, nontuberculous mycobacteria; TB, tuberculosis.Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740.
Nontuberculous (NTM) Disease 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 ResultsEIN 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
Preliminary US population-based Data
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
Risk factors for TB in RA patients who use anti-TNFRisk 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
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?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- StoryInterferon- 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
• 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- DownregulationInterferon- Downregulation
Saliu et al. JID 2006
*Granuloma Penetration of TNFis
*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
Screening for Latent Tuberculosis Infection (LTBI)
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
IGRAsIGRAs
• 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.
IGRAs in Anti-TNF CandidatesIGRAs 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, 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
aP < .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%)
IGRAs in the Immunocompromised
IGRAs in the Immunocompromised
• Anergy with TST and IGRAs
– IGRAs less affected by prednisone
– False negative with IGRA in patients already receiving anti-TNF therapy1
• Indeterminate results2
– 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 TreatmentLTBI 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 MTXMTX, methotrexate.1. Carmona L et al. Arthritis Rheum. 2005;52:1766-1772.
New Biologics for RANew 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
AbataceptAbatacept• 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
TocilizumabTocilizumab
• 10 cases TB in 10,000 patients
– 5 pulmonary
• Should we be screening?
– YES
ConclusionsConclusions
• 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
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
Needed ResearchNeeded 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 StepsNext 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