Transcript Infectious Risks in Patients Receiving TNF

Infectious Risks in Patients
Receiving TNF-alpha inhibitors
Michael J. Tan, MD, FACP, FIDSA
Associate Professor of Internal Medicine,
Northeast Ohio Medical University
Summa Health, Akron, OH
Objectives
 Review mechanism of action of TNF-alpha inhibitors
 Understand the role of TNF in the inflammatory
response
 Be familiar with infections associated with TNF
inhibitors
 Review methods to prevent infection in these patients.
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What is a biologic?
 Biologics
 Monoclonal antibodies against specific target cells or cytokines. May
also be receptor constructions
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Two contrasting outcomes of signaling
through tumor necrosis factor receptor 1
(TNFR1). Engagement of TNFR1 by
trimeric tumor necrosis factor- (TNF-)
can trigger apoptosis and/or nuclear
factor B (NF-B) activation. Both
processes involve the adapter protein
TNFR-associated death domain
(TRADD), which associates with
TNFR1 via interactions between "death
domains" (D.D.) on both proteins. For
NF-B activation, TNFR-associated
factor 2 (TRAF2) and receptorinteracting protein (RIP) are required.
Induction of apoptosis occurs when the
death domain-containing protein Fasassociated death domain protein (FADD)
associates with TRADD. FADD also
contains a "death effector domain"
(D.E.D.) that interacts with caspase 8 to
initiate the apoptotic process. Cys =
cysteine. (Adapted from Yuan J:
Transducing signals of life and death.
Curr Opin Cell Biol 9:247, 1997; and
Nagata S: Apoptosis by death factor.
Cell 88:355, 1997.)
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TNF-alpha
 TNF, TNF-alpha, cachectin
 Systemic inflammatory cytokine able to induce
apoptotic cell death
 Produced by macrophages, lymphoid cells, mast cells,
endothelial cells, cardiac myocytes, adipose,
fibroblasts, neuronal tissue.
 Able to induce inflammation
 Able to inhibit tumorigenesis and viral replication
 Acts with other cytokines, including IFN-gamma, to
generate cell-mediate immune response to pathogens
such as M tuberculosis, Listeria sp, Histoplasma sp.
 Lack of TNF prevents formation of granuloma
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TNF
 Acute phase response, associated with fever
 No known human state of TNF deficiency
 1997 “knock-out” mouse model lacking TNF were
markedly more susceptible to mycobacterial infection
and infection with intra-cellular pathogens including
Listeria, Salmonella, some viruses, and pneumococcus
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TNF-alpha antagonists
 Infliximab – Remicade
 Chimeric anti-TNF-alpha monoclonal antibody
 Often given with other immunesuppressants to prevent immune
response to murine protein and may increase risk of infection.
 Etanercept – Enbrel
 Two TNF-alpha receptor domains fused to a portion of human IgG1
 Binds soluble TNF alpha with receptor domains, binds circulating
TNF-alpha but less membrane bound TNF-alpha.
 Adalimumab – Humira
 Fully human anti-TNF alpha monoclonal antibody
 Golimumab – Simponi
 Certolizumab pegol – Cimzia
 Pegylated FAb region, human monoclonal antibody.
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Who uses them?
 Patients with
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Rheumatoid arthritis
Ankylosing spondylitis
Crohn Disease
Psoriasis, psoriatic arthritis
Some use in EtOH associated hepatitis, Behcet, uveitis, pyoderma
gangrenosum, Still’s disease, sarcoidosis, Sjogren, severe
hidradenitis, GVH
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Diseases associated with TNF-alpha
antagonists
 Mycobacterial infections, mostly MTb
 Miliary, disseminated, urinary tract, osteoarticular, tonsillitis, and
peritonitis have been reported.
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Fungi, including endemic mycoses
Viruses
PCP
Listeria
TNF Blocker infections: Intracellular organisms:
Mycobacteria, Histo, Candida, Listeria, Aspergillus,
Cyrptococcus, Nocardia, Salmonella
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Isaacs D. Infectious Risks Associated with Biologics, in Curtis N, et al eds. Hot Topics in Infection and Immunity in Children IX, Advances in
Experimental Medicine and Biology, 2013
Rychly DJ, DiPiro JT. Infections Associated with Tumor Necrosis Factor-alpha Antagonists. Pharmacotherapy 2005; 25(9):1181-1192
Crum NF, Lederman ER, Wallace MR. Infections Associated with Tumor Necrosis Factor-alpha Antagonists. Medicine 2005;84:291-302.
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Case Review
 Crum et al, 2005
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MTb
Cryptococcosis
Coccidioidomycosis
Pneumococcal bacteremia
• Bacterial infections due to Strep, Staph, Moraxella, including pneumonia,
abscess, cellulitis, sinusitis
 Histoplasmosis, Aspergillosis, NTM, Candidiasis, PCP, Listeriosis,
Legionellosis
 Intracellular pathogens such as Salmonella, Toxoplasma, Bartonella,
Leishmania have been reported
 Nocardia, Sporothrix, Zygomycetes
 CMV, HSV, Molluscum contagiosum
 Post-operative infections—little risk
 Are some of these infections due to the TNF or are the patients
naturally at greater risk because of the disease states?
Crum NF, Lederman ER, Wallace MR. Infections Associated with Tumor Necrosis Factor-alpha Antagonists. Medicine 2005;84:291-302.
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What is the risk of Tb?
 Infliximab RCT, case series, case reports reviewed
 3 cases of MTb in 3882 receiving infliximab vs. 0/2430
placebo/control
 Post-licensure Tb rates:
• US with RA 6.2/100k
• RA + inflixumab 24.4/100k
– 4x higher.
 MTb generally developed 12 weeks into therapy.
Rychly DJ, DiPiro JT. Infections Associated with Tumor Necrosis Factor-alpha Antagonists. Pharmacotherapy 2005; 25(9):1181-1192
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What is the risk of Tb?
 Etanercept review
 0 cases in RCT
 2 cases in reviewed that had tonsillitis/enteritis
 January 1998-Sept 2002, 39 cases in surveillance system
 Adalimumab review
 1/1750 vs. 0/832 control. 8/477 (1.7%) in Development trials.
5/1900 in surveillance
 Cases of MTb were reported to have occurred longer
after initiation of therapy than with infliximab (30-46 wks
mean)
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Other infectious risks
 Debatable. May be based on epidemiology
 Recommendation-Prevention is key
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Screens
 Tb
 TST at baseline and every 12 mos, baseline CXR
 Histoplasmosis
 Consider CXR, urine histo ag at baseline and f/u q3-4 mos for those
in endemic areas
 Coccidioidomycosis
 CXR and serolgic testing with IgM/IgG at baseline and f/u q3-4 mos
for those in endemic areas
 Cryptococcus
 No data
 Listeria
 Patient education regarding food prep and safety
Crum NF, Lederman ER, Wallace MR. Infections Associated with Tumor Necrosis Factor-alpha Antagonists. Medicine 2005;84:291-302.
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Prevention
 All patients on TNF
 Screen for MTb with TST or IGRA, baseline and q12mos
 Consider prophlyaxis for Pneumocystis
 Immunization
• Consider pneumococcal conjugate vaccine
• Consider HBV series.
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Prophylaxis?
 Tb
 No/Treat LTBI
 Histoplasmosis
 Itraconazole daily?? Lifestyle modification, avoid high risk activity.
 Coccidioidomycosis
 fluconazole daily? More likely secondary prophy.
 Cryptococcus
 fluconazole? More likely secondary prophy.
 Listeria
 TMP-SMX? Little data, but would help with PCP, nocardia
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Case
 A 60 year old woman with RA presents to your office.
Her rheumatologist would like to start a TNF inhibitor.
A TST was performed and reported to be 12x12mm.
She is sent to you for evaluation.
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An approach to +PPD/IGRA
 Common: Patient with RA to start TNF, but PPD or
IGRA positive
 Ascertain exposure history
 If +PPD, consider getting IGRA due to poor PPD/TST placement or
reading of test. (10mm, but immune compromised consider 5mm).
 Check Chest radiography (PA/LAT) as baseline
• If negative, proceed with LTBI therapy.
 Safest: Initiate INH daily x9 months.
• Check LFT at baseline, 2 weeks, q every other month.
 Generally defer TNF, but if must start, allow 4-6 weeks of INH before
starting TNF
 Check repeat CXR 1-2 months after starting TNF
 Finish INH, and follow CXR. Probably little benefit of repeat TST or
IGRA since positivity will persist.
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Vaccination
 Live, such as HSV or VZV?
 Or… “Help! My RA patient on TNF-inhibitor just got VZV
Vaccination!”
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Vaccinations
DOI: 10.1093/cid/cit684, Rubin, et al 2013 IDSA Clinical Practice Guideline for
Vaccination of the Immunocompromised Host
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Pneumococcus
 Vaccination recommendation:
 Previously vaccinated with PPSV23:
• Dose PCV 13, redose PPSV23 >8 weeks later and >5 years after
previous PPSV23.
 Vaccine naïve:
• Dose PCV13, redose PPSV23 >8 weeks later.
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American College of Rheumatology
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http://www.rheumatology.org/Publications/Hotline/Update_on_Herpes_Zoster_%28Shingles%29_Vaccine_for_Autoimmune_Disease_Patients/
In general, for vaccinations
 Give prior to planned immunesuppression
 Live:
 >=4 weeks of immunesuppression, and avoid within 2 weeks of
initiation of immunesuppression
 On immunesuppression: No live, but perhaps hold for a few weeks,
vaccinate, and restart.
 Inactivated:
 >=2 weeks prior to initiation of immunesuppression
 If one immunesuppression, inactived can be given
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VZV
 Vaccination appropriate >4 weeks prior to
immunesuppression
 Little said about vaccination of someone that is
currently on therapy.
 Some will hold therapy for 4-8 weeks prior to
vaccination, then restart 4 weeks afterward.
 Risk of vaccine acquired VZV and HSV higher with TNFinhibitor patients.
 >100 cases, but VZV severity “acceptable”
 Try not to panic
 No need to use antiviral
 Watch patients closely.
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Do you need to hold therapy prior
to surgery, colonscopy, cataracts?
 What’s the risk?
 Infection
 Impaired wound healing
 Recommendation:
 Hold for 1-2 weeks prior to surgery, resume 1-2 weeks after surgery
or when PO
• How is this impacted by the long effect of the agents?
• Data overall are limited and may not necessarily support holding agents.
– Recommend to hold for at least one dosage cycle.
• HSS J. Sep 2006; 2(2): 141–147.
• BSR/BHPR: doi:10.1093/rheumatology/keq249b
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Medscape’s take
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Does presence of TNF inhibitors need to change
manner of thinking of pathogens for common
infections?
 Common things are still common
 History should be your trigger
 Has there been travel to endemic area?
 Does the patient have epidemiologic risk factors?
 How long have the symptoms been present, and how did they
progress?
 Has the patient had previous treatment for LTBI? Endemic mycosis?
 Vaccinations?
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Questions?
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Suggested Reading
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Isaacs D. Infectious Risks Associated with Biologics, in Curtis N, et al eds. Hot
Topics in Infection and Immunity in Children IX, Advances in Experimental Medicine
and Biology, 2013
Rychly DJ, DiPiro JT. Infections Associated with Tumor Necrosis Factor-alpha
Antagonists. Pharmacotherapy 2005; 25(9):1181-1192
Crum NF, Lederman ER, Wallace MR. Infections Associated with Tumor Necrosis
Factor-alpha Antagonists. Medicine 2005;84:291-302.
2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised
Host. DOI:10.1092/cid/cit684
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