Transcript Tuberculosis in the Era of Anti-Tumor Necrosis Factor (TNF) Therapy

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)
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Immune dysregulation
Upregulation of CD4 T-cells
Pro-inflammatory cytokine cascade
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Tumor necrosis factor–alpha (TNF-)
Interleukin-1 (IL-1)
B-cell activation and auto-antibody production
TNF-
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Primarily expressed by activated macrophages,
T and B cells
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Biological effects are numerous
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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
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TB, Histoplasma, Listeria, Klebsiella,
S. pneumoniae
Overexpression of TNF-
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Inflammation and tissue destruction
Important in pathogenesis
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Crohn’s, rheumatoid arthritis, psoriasis,
ankylosing spondylitis, others
Inhibition of TNF- highly successful in treatment
of these conditions
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Infliximab, adalimumab (monoclonal
antibodies)
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Etanercept (soluble p75 receptor)
RA Biologic Therapies
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Widespread use
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Newly approved
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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
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Inhibition of IL-1: anakinra
TNF- Antagonist Therapy
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Often used in combination with methotrexate
and/or prednisone
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Many patients have co-morbidities
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Chronic lung disease, diabetes
Off-label use frequent
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Wegener’s granulomatosis, uveitis, Bechet’s,
dermatomyositis, polymyositis, sarcoidosis,
giant cell arteritis, others
Prednisone and Tuberculosis
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Risk of reactivation TB poorly defined
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CDC 2000 TB statement
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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
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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)
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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
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9000 patients, followed Dec 2001-Sept 2005.
19 intracellular infections (200/100,000 person-yr)
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All in anti-TNF treated (none in non-biologic
group)
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TB (n=10), NTM (n=1), Listeria (n=3), Salmonella
(n=3), Legionella (n=3)
More TB with monoclonals
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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
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69 TB cases over 3 years
SIR compared to background French population
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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
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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
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20
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60
Number of Infections Reported
CMV, cytomegalovirus; NTM, nontuberculous mycobacteria; TB, tuberculosis.
Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740.
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Nontuberculous (NTM) Disease
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Environmental mycobacteria emergence
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Lung, skin/soft tissue, disseminated disease
Surveyed IDSA EIN
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¼ of US infectious disease specialists
Mycobacterial (tuberculosis/NTM) infections in
last 6 months
Response = 426 (48.9%) EIN members
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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
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Associated biologics
TB (n = 17)
NTM (n = 32)
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INF
ETN
ADA
RTX
ABA
Unspecified
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11
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21 (42%) with concurrent prednisone/MTX
8 patients (16%) died
Biologic stopped in 43 (86%)
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Only 2 with IRIS
ADA, adalimumab.
Winthrop KL et al. Clin Infect Dis. 2008;46:1738-1740.
Preliminary US populationbased Data
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KNPC and VA (NW VISN) 2000-2008
TNF users over 9 year time period (n=4,524)
TB (n=14) among TNF users
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34/100,000
NTM (n=20) among TNF users
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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
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Atypical clinical presentation
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50% extrapulmonary
15%–20% disseminated
Median time to onset
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Infliximab (INF) = 12 weeks
(range, 1–52 weeks)1
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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?
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Infliximab drug mechanism differs
Greater TNF- binding
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Transmembrane and soluble TNF-
Forms stable complex
Longer half-life
Apoptosis of monocytes and T lymphocytes
Downregulates interferon-gamma
Interferon- Story
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Saliu et al. compared monoclonal antibodies and
etanercept
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In vitro whole blood culture exposed to TB
culture-filtrate
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Exposed to anti-TNF drugs in typical
concentrations of body
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Measured t-cell responses, TB growth,
cytokine production, apoptosis
Saliu et al. JID 2006
Interferon- Downregulation
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Adalimumab and infliximab similar
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Suppressed TB antigen induced INF-
production at 5 days
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Decreased T-cell activation at 24 hrs
No difference in TB growth at 24 and 96 hrs
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Bacilli grow slowly (doubling in 15-24 hrs)
Saliu et al. JID 2006
*Granuloma Penetration of
TNFis
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Acute TB infection (mouse)
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No difference between anti-TNFs
Chronic TB infection (mouse)
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Large bacillary load and death
Monoclonal antibodies = death (1 month)
Etanercept = 60% alive at 6 months
Lung pathology
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Etanercept with less penetration of lung
granulomas
*Plessner et al JID 2007
Screening for Latent
Tuberculosis Infection (LTBI)
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Screen before patient is immunocompromised
History of TB risk factors
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Foreign birth or extended living abroad
Previous contact with TB case
Previous LTBI diagnosis or treatment
Incarceration, homelessness, IV drug use
IGRAs
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QuantiFERON-TB Gold® test (Cellestis, Australia)
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Detects cell-mediated immunity
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IFN- released from sensitized lymphocytes
QFT-In Tube (IT)®
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Whole blood incubated with tubercular antigens
(ESAT-6/CFP-10)
Added third antigen (7.7)
T-SPOT.TB® assay (Oxford, UK)
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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
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Greater specificity for tuberculosis than TST
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aP
Does not cross-react with BCG or most environmental
mycobacteria
Relative sensitivity with TST for LTBI?
Matulis et al, 20071
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Patients with inflammatory rheumatic conditions treated with
anti-TNF or non-biologic treated (n = 126)
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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
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Anergy with TST and IGRAs
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False negative with IGRA in patients already
receiving anti-TNF therapy1
Indeterminate results2
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IGRAs less affected by prednisone
QFT-IT and T-SPOT.TB < QFT-Gold
LTBI sensitivity2
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QFT-IT similar to T.SPOT.TB (and probably similar
to or greater than TST)
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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
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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
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Rituximab
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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
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8 TB/NTM cases with rituximab
All cases also on prednisone
*Maglione et al. J Immunol 2007
Abatacept
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Tuberculosis risk unknown
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Screened in clinical trials
Should screen in practice
Murine chronic TB not affected by abatacept*
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Mortality, T cell, B cell, INF-γ production in
lung, and bacillary load
*Bigbee et al. Arth Rheum 2007
Tocilizumab
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10 cases TB in 10,000 patients
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5 pulmonary
Should we be screening?
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YES
Conclusions
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Anti-TNF–associated mycobacterial cases
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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
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Chest CT?
Sputum when appropriate
CT, computed tomography.
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Patients Receiving TNF-
Antagonists
Physicians should maintain high index of
suspicion for TB disease
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If TB diagnosed
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Febrile or respiratory illness
Begin anti-TB treatment
Stop anti-TNF therapy immediately?
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Immune reconstitution inflammatory syndrome
(IRIS)
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Unclear when to re-start anti-TNF therapy
Needed Research
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Studies to assess the infectious risk of therapy in
the U.S.
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Biologics, MTX/prednisone, combination
Ongoing surveillance for TB with newer
biologics
Utility of INF- release assays in screening anti-TNF
candidates for LTBI
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Sensitivity in inflammatory disease patients
Next Steps
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Current ATS/IDSA/CDC joint task force
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Review and propose research
Further refine and issue U.S. screening and
treatment guidelines
• Clarify role of IGRAs
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Creation of a biologic post-marketing surveillance
system
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European luxury
Risk of rituximab, abatacept, others to come
Acknowledgments
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U.S. Centers for Disease Control and Prevention
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US Food and Drug Administration
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Zach Taylor, Michael Iademarco,
John Jereb, Ken Castro
Jeffrey Siegel
National Jewish Medical Center
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Chuck Daley