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.

British Biologic RegistryBritish Biologic Registry

Dixon WG et al. Ann Rheum Dis 2010:69:522-528

British Biologic RegistryBritish Biologic Registry

Dixon WG et al. Ann Rheum Dis 2010:69:522-528

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

AcknowledgmentsAcknowledgments

• 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