Tumor Necrosis Factor-Alpha(TNF-Alpha) Antagonists and the Increased Risk of Tuberculosis

What is tumor necrosis factor-alpha (TNF-alpha)?

A potent cytokine that is an important mediator of the body's response to infection
Promotes inflammation and tissue destruction in rheumatic/immune mediated diseases.
Plays a central role in the initial host response to infection and granuloma formation.

What are TNF-alpha antagonists?

Medications that work to oppose the tissue's destructive effects of TNF-alpha
They are used to treat diseases such as rheumatoid arthritis, Crohn's disease, psoriatic
arthritis, juvenile rheumatoid arthritis and ankylosing spondylitis.
TNF-alpha antagonists often provide an impressive improvement (in treated diseases).

Which TNF-alpha antagonists are used in the U.S.?




Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's
Disease, ulcerative colitis


Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's


Rheumatoid arthritis, Crohn's Disease


Rheumatoid arthritis, psoriatic arthritis, psoriasis, sarcoidosis


Rheumatoid arthritis, Crohn's Disease


Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis

Why do they increase the risk of TB?

Granuloma formation is crucial to the host's ability to contain and control TB infection.

In tuberculosis, these drugs inhibit macrophage activation, recruitment of inflammatory cells,
granuloma formation, and maintenance of the granuloma integrity.

Antibodies against TNF-alpha cause increased susceptibility to M. tuberculosis in mouse
models. Patients treated with TNF–alpha antagonists have an increased risk of tuberculosis.

Epidemiological data
indicate that the risk of
active TB is greatest with

TB rates of 53.8/100,000
with Infliximab and
28.3/100,000 with
Etanercept vs. US rate
of 5/100,000 (Wallis, et
al. Clin Inf Dis 2004; 39:

Possible increased risk of
reactivation of latent
tuberculosis infection
(LTBI) with Infliximab
than Entercept (Wolfe,
Arthritis and Rheumatism
2004; 50: 372-379).

Risk of new infections
progressing directly to
active disease appears
to be similar for both
drugs. (Wallis, The
Lancet 2008; 8: 601-611).

What can be done to decrease the risk of TB when using
these agents?

Carefully screen all candidates prior to prescribing TNF-alpha antagonists
Identify risk factors for TB exposure
Screen for evidence of LTBI, and exclude active TB

Educate patients about the risk of opportunistic infections, especially TB

Instruct patients to report symptoms of an infectious disease:
Fever, malaise, cough, local or generalized pain

Consult a physician knowledgeable about the risk of infections in patients receiving these and other
immunosuppression regimens

Be aware the onset of TB may be subtle, but disease can escalate and disseminate quickly.
A routine chest radiograph may appear normal; miliary infiltrates may only be visible on chest CT.

What does CDC recommend before starting?

Screen for TB risk factors

Test for LTBI and TB disease

Treat those with TB risk factors for LTBI even if TST or IGRA negative

Treat LTBI and TB disease according to published guidelines

What additional recommendations are there?

An interferon gamma release assay (IGRA) QuantiFEROn-Gold Intube or the TSpot TB can be
used to screen perspective TNF-alpha antagonist recipients
See MMWR 2010: 59 (RR-5); 1-25 for guidelines

Two step TST testing at baseline has not been specifically recommended by CDC; although
recent case reports and post-licensure surveillance in Spain note improved accuracy (Gomez-
Reino (2007) Arthritis and Rheumatism 57(5):576-761)

Repeat testing periodically for TB infection even if TST or IGRA is initially negative

Starting TNF-alpha antagonist therapy may improve immune response

Some patients may acquire tuberculosis infection after TNF-alpha therapy is initiated (Fuchs,
Clin Rheum 2008)

When can TNF-alpha antagonists be started after a diagnosis of latent TB infection?

Treatment for LTBI (e.g. Isoniazid for nine months) should start BEFORE TNF-alpha
antagonist treatment is initiated.

CDC recommends considering postponing TNF-alpha antagonist treatment until completion of
LTBI treatment (MMWR 2004: 53 (RR-30))

More recent publications suggest delaying TNF-alpha antagonist treatment until one month
after the start of LTBI treatment (Furst, Annals of the Rheumatic Diseases, 66 (Suppl 3): ii2-22)

What if a patient who is on one of these agents develops signs or symptoms of an infectious disease?

Evaluate thoroughly for both routine and opportunistic infectious disease processes
If a plain radiograph is normal in a patient with cough, shortness of breath or unexplained
fever, a chest CT should be strongly considered.
Collect sputum for mycobacterial smear and culture as well as for other opportunistic
pathogens including fungi.

Stop the TNF-alpha antagonist therapy until a diagnosis is made
Most TB experts prefer that TB be treated until it is under control, cultures are negative, and
patients are tolerating their TB medicines prior to reintroducing the TNF-alpha antagonist

What is the typical course of TB in patients taking these agents?

TB progresses rapidly in TNF-alpha antagonist recipients
Median duration of onset was 12 weeks after initiating TNF-alpha antagonist treatment in the
initial 57 patients reported.
TB is much more likely to be extrapulmonary and disseminated.
In the initial 70 reports to the FDA Adverse Reporting System, 56% of the TB cases were
extrapulmonary and 24% were disseminated disease (Keane, NEJM 345 (15) 1098).
For patients not receiving TNF-alpha antagonists extrapulmonary is reported in only 15-20%
and disseminated in 1-2% of TB cases reported annually (CDC Surveillance Reports 2009).

TB is more likely to result in death.
12/17patients (70%) died (Keane)
<5% of TB cases reportedly annually are diagnosed at death or died during treatment (CDC Surveillance Reports 2009)

Are there concerns other than the risk of TB?

Yes, other opportunistic infections have also been reported including viral, bacterial, fungal
and protozoal infection

The increased risk of fungal infections seems to be of extra concern

Immune Reconstitution Inflammatory Syndrome (IRIS) reactions may occur with improvement
in immune function when the TNF-alpha antagonist is stopped and TB therapy started
IRIS reactions may be especially severe
IRIS reaction may improve with reinstitution of the TNF-alpha antagonist (Wallis, CID 2009,
48:1429), steroid, or anti-inflammatory agents

How should patients taking these agents be monitored?

All TNF-alpha antagonist recipients should be monitored carefully for any signs or symptoms
of infectious disease.

Pursue TB diagnosis as the potential cause of any febrile or respiratory illness (CDC 2005).

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