Anti-Tumour Necrosis Factor Agents and

Review
Anti-TNF and tuberculosis
Anti-tumour necrosis factor agents and

tuberculosis risk: mechanisms of action and
clinical management
Michael A Gardam, Edward C Keystone, Richard Menzies, Steven Manners, Emil Skamene, Richard Long,
and Donald C Vinh
Cases of active tuberculosis have
C: Cytokine and chemokine release
been reported worldwide with the use
Attraction and stimulation of CD4
of therapeutic agents that inhibit
and CD8 lymphocytes, / lymphocytes
Increased T-cell adhesion, antigen presentation
tumour necrosis factor (TNF) . TNF
Proliferation and recruitment of T and B cells
has a central role in mycobacterial
infection and disease. Accordingly,
TNF
progression of recently acquired
Alveolar
tuberculosis infection or reactivation of
macrophage
remotely acquired infection should be
expected with the use of anti-TNF B: TNF release
and autocrine
D: Activated T cells release interferon ,
agents. The available in-vitro and
stimulation
further activating macrophages
epidemiological evidence for the two
Increased antigen presentation
currently approved agents, infliximab
Intracellular killing of bacilli
and etanercept, shows that the risk of
Macrophage apoptosis, granuloma
formation
development of active tuberculosis is
greater with infliximab. Tuberculin skin
A: Phagocytosis
testing (TST) should be undertaken
of bacilli
before any significant immunosuppressive therapy including these Figure 1. Schematic representation of the central role of TNF in the cellular immune response to
agents, though the possibility of M tuberculosis infection.
false-negative reactions in immunocompromised populations must be borne in mind. A positive
2 years owing to inability to control the infection.2 The
TST should be followed by medical assessment and chest remaining 95% of exposed individuals will contain the
radiography, as well as by other tests judged appropriate by organism via an effective cell-mediated immune response.
the physician to identify active disease. Active tuberculosis
However, the ability to contain the organism effectively is a
must be treated appropriately before initiation of treatment dynamic process, and about 5% of those who initially
with an anti-TNF agent. Treatment of latent tuberculosis can control the infection will subsequently develop reactivation
be considered on an individual basis for TST-negative
disease.
patients receiving anti-TNF agents when significant risk
An effective host response depends partly on the ability
factors for infection are present.
to produce an appropriate Th1 cytokine profile, including
tumour necrosis factor (TNF) , which is involved in both

protection against mycobacterial infection and tuberculosis
pathogenesis.3,4
Lancet Infect Dis 2003; 3: 14855
Mycobacterium tuberculosis currently infects about a third

of the worlds population (ie, close to 2 billion people).1
According to a 1997 survey by WHO, there are 63
111 million new cases each year and 121225 million
prevalent cases of tuberculosis.1
In Canada, the annual incidence of new active and
relapsed tuberculosis infection in 1998 was reported to be
59 per 100 000 population.2 Although the incidence has
remained stable for the past two decades, there have been
significant changes in the epidemiology of the disease. In
1981, 38% of tuberculosis cases occurred in foreign-born
patients,2 whereas by 1998 this had increased to 64%.
About 5% of individuals who become infected with
M tuberculosis will develop clinical disease within the first
148
MAG is Director of the Infection Prevention and Control and

Tuberculosis Clinic, Division of Infectious Disease, University Health
Network, Toronto, Ontario, Canada. ECK is Director of the Centre
for Advanced Therapeutics in Arthritis, Mount Sinai Hospital,
Toronto. RM is at the Montreal Chest Institute, Montreal, Quebec.
SM is a medical writer/editor and editorial consultant to Chiron
Corporation, Eli Lilly Canada, Novartis Canada, Pfizer Canada,
Schering Canada, and Teva Neuroscience. ES is Scientific Director
and DCV is a medical resident at the Research Institute of the McGill
University Health Centre, Montreal. RL is at the University of Alberta,
Edmonton, Alberta.
Correspondence: Dr Michael A Gardam, Division of Infectious
Disease, 200 Elizabeth Street, NUW 13-117, Toronto, ON, Canada
M5G 2C4. Tel +1 416 340 3758; fax +1 416 340 5047;
email michael.gardam@uhn.on.ca
THE LANCET Infectious Diseases Vol 3 March 2003
http://infection.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
The advent of chemotherapeutic agents that inhibit

TNF, and reports of tuberculosis in patients receiving these
agents,5,6 have raised concerns about the risk of reactivation
of latent mycobacterial infection and the most appropriate
steps that should be taken to prevent such reactivation.
Role of TNF in M tuberculosis infection and

disease
TNF has a central role both in the host immune response
to M tuberculosis infection and in the immunopathology of
tuberculosis (figure 1). TNF is a proinflammatory cytokine
produced primarily by activated monocytes/macrophages in
response to various stimuli, including lipopolysaccharide,
viral infection, and Gram-negative and Gram-positive
pathogens.7,8 TNF can also be expressed by activated
T cells, B lymphocytes, natural killer cells, and some tumour
cells.7 TNF exists in soluble and transmembrane forms. The
biological effects include antitumour activity, antiviral
activity, and mediation of shock and cachexis. The main
mechanism of action is as a ligand that stimulates apoptosis.
Response to TNF is mediated by its receptors, TNFR1
(55 kDa; p55) and TNFR2 (75 kDa; p75).7 Soluble TNF
mainly binds to TNFR1; the membrane-associated form
of TNF is the prime activating ligand of TNFR2.9
Experiments in animals have shown that TNFR1 is
important in granuloma formation during M tuberculosis
infection10 and in susceptibility to intracellular pathogens.11
TNFR2 seems to have a lesser role in granuloma formation
and mycobacterial immunity.12
The release of TNF in response to mycobacterial
infection has several beneficial effects. In-vitro studies
show that the cytokine increases the ability of macrophages
to phagocytose and kill mycobacteria.13,14 TNF production
is a requirement for formation of granulomas, which
sequester mycobacteria and prevent their dissemination.15
Several studies have shown that granulomatous lesions are
protective and indicate a successful immune response. Roach
and colleagues16 compared the effect of TNF induction in
wild-type and TNF-deficient mice; TNF was required for the
early expression of mRNA encoding chemokines and
leucocyte recruitment. Furthermore, lymphocytes and
macrophages failed to form granulomas and prevent
progressive infection.16 Ehlers and co-workers examined
granuloma formation in mice deficient in TNFR1 (TNFRp55)
infected with M avium strains of high or intermediate
virulence.17 Granulomas underwent progressive necrosis and
infection resulted in death in all TNFR1-deficient mice. In a
murine model of persistent tuberculosis infection,18 blockade
of TNF resulted in fatal reactivation of persistent
tuberculosis associated with an increase in bacillary burden
and augmented production of interleukin 10. In a similar
model, inhibition of TNF synthesis with pentoxifylline
increased macrophage degeneration and tissue destruction,
although bacillary load did not increase.19 In a series of
experiments on TNF depletion in TNFR1-deficient mice or
animals treated with a monoclonal antibody against TNF
(hamster monoclonal antibody TN3-19.12), abnormal
granuloma formation after infection with M tuberculosis or
the avirulent mycobacterial strain bacille Calmette-Gurin
(BCG).20 The number of bacilli was ten times higher than in

controls. Finally, TNF assists in containing mycobacterial
growth by inducing apoptosis of presumably ineffective
macrophages, thus depriving the organism of an intracellular
sanctuary.21,22
These findings suggest that TNF, acting through the
p55 receptor, has an essential role in the coordination and
containment of mycobacterial infection.10,20,22 Thus, TNFinduced granuloma formation, by controlling bacterial
growth and dissemination and limiting tissue damage,
appears as important for survival after M tuberculosis
infection as an effective antigen-specific T-cell response.23
Adequate TNF activity outside the lung cannot
compensate for inadequate intrapulmonary TNF activity.
In a murine model of pulmonary blockade of TNF
(SPCTNFRIIIFc mice), inhibition of TNF production only
in the lung resulted in dysregulation of the granulomatous
response, increased pulmonary inflammation, and early
death.24 These effects were not associated with a significant
increase in the number of bacteria; thus, bacterial load seems
to be only one factor contributing to tuberculosis mortality.
Also noteworthy is that in-vitro studies of TNF with
M tuberculosis or purified protein derivative have shown
rapid apoptosis of neutrophils.25 This process may be a
mechanism for clearing neutrophils; TNF blockade may
therefore result in an accumulation of neutrophils, persistent
inflammation, and pulmonary cell damage.24
In contrast to its protective effects, excessive production
of TNF and increased tissue sensitivity to the cytokine have
been implicated in the immunopathology of tuberculosis,
such as caseous necrotising reactions. For example, excess
TNF (relative to its receptors) in human bronchoalveolarlavage fluid was associated with tissue necrosis and cavity
formation, although a causal relation was not proven.26
TNF mediates systemic inflammation, which manifests
clinically as cachexia,27,28 consistent with its original
designation as cachectin.29 Blockade of excessive TNF
seems to attenuate this effect. In a small study of 30 patients
with tuberculosis, with or without HIV infection, who were
receiving antituberculous therapies, thalidomide lowered
serum concentrations of TNF and produced significant
weight gain compared with placebo;30 these effects ceased or
were reversed at the end of the 14-day treatment cycle.
The beneficial and detrimental effects of TNF in
tuberculosis may be partly dose-dependent. In a study by
Bekker and colleagues, TNF knockout mice were infected
with high or low doses of recombinant BCG that secreted
murine TNF.31 Low doses of BCG-TNF resulted in
controlled bacterial growth, small, well-differentiated
granulomas, and survival. By contrast, high BCG-TNF
inocula produced clearance of the infection, but severe
inflammation in the lungs and spleen resulted in early death.
The amount of biologically active TNF may influence
the duration of tuberculosis. In comparing M tuberculosis with
bacterial meningitis infection, Rydberg and co-workers found
that the ratio between soluble TNF receptor and TNF was
higher in tuberculosis than in meningitis (27 vs 4), indicating
a small biologically active fraction of TNF in tuberculosis.32
This finding suggests that TNF activity differs between
149
Review
chronic and acute infections. Moreover, these researchers

suggested that mycobacteria can modulate the host response.
In-vitro studies have shown that higher TNF production
is induced by avirulent strains of M tuberculosis than by
the virulent strain H37Rv in a mouse model.33 Although
similar amounts of TNF are produced by human alveolar
macrophages infected with virulent and attenuated
M tuberculosis strains, the bioactivity of TNF is lower
in the virulent model owing to a relative increase in soluble
TNFR2 resulting in the formation of TNFTNFR2
complexes.22
Thus, TNF interactions with mycobacteria and the role
of the cytokine in host defence are complex. The precise
mechanisms have not been fully elucidated, but adequate
TNF production seems to be required for an effective
immune response, for granuloma formation, and to inhibit
bacterial dissemination; excessive TNF can produce
substantial damage to host tissues and organs.
Etanercept is a dimeric fusion protein and consists of the

extracellular ligand portion of the human TNFRp75 linked
with the Fc portion of human IgG1. In comparison with
infliximab, etanercept forms less stable complexes with
membrane-bound TNF and monomeric TNF,35 but it
does bind significantly with the trimeric form of soluble
TNF. Unlike infliximab, etanercept also forms stable
complexes with lymphotoxin , which appears to be
involved in the Th1 response to M bovis BCG infection and
in spleen granuloma formation.39
The administration and pharmacokinetics of infliximab
and etanercept differ. Infliximab is given as an intravenous
infusion at weeks 0 and 2 of therapy, followed by a regular
bolus infusion every 8 weeks; it has a half-life of 105 days.40
Etanercept is given twice weekly as a subcutaneous injection
and has a half-life of about 3 days.41
Although both agents interact with TNF in various
forms, there are subtle differences in their mechanisms of
action. In particular, drug-mediated apoptosis and
Anti-TNF therapies
monocytopenia appear to be unique to infliximab. Also,
Several therapeutic agents that neutralise TNF have been infliximab seems to bind more avidly to different forms of
developed; of these, infliximab and etanercept have been TNF. On the basis of these differences, infliximab might be
studied most extensively (figure 2). Infliximab is a human- predicted to have a more significant effect on the hosts ability
murine (25% murine) chimeric monoclonal antibody to suppress M tuberculosis infection. The effect of bolus dosing
with high binding affinity31 and specificity for TNF.34 It of infliximab versus more steady dosing of etanercept may
forms stable complexes with the monomeric and trimeric also affect the hosts ability to control M tuberculosis infection,
forms of soluble TNF and with the transmembrane although this issue has not been studied.
forms of TNF.35 As an antibody, infliximab also has the
The efficacy of infliximab given as an intravenous infusion
ability to cross-link TNF molecules. Binding to in rheumatoid arthritis was demonstrated in a study of
transmembrane TNF results in macrophage and monocyte patients with long-standing refractory disease; four regimens
lysis by cytotoxicity that depends on antibodies and of infliximab (3 mg/kg every 4 weeks or 8 weeks, or 10 mg/kg
complement.3638 Infliximab does not bind to related every 4 weeks or 8 weeks) plus methotrexate provided
cytokines, such as TNF (lymphotoxin ), which is involved additional clinical benefit in patients who had an inadequate
in the Th1 response.33
response to methotrexate alone.42 As a chimeric antibody,
infliximab has to be used in
combination with methotrexate to
prevent an immune response against
the foreign murine protein. It was
TNF
effective in the treatment of patients
TNF
Etanercept
Soluble
with non-fistulising and fistulising
Alveolar
TNF
Infliximab
TNF
macrophage
Crohns disease who showed no
TNF
cell membrane
response to or who could not tolerate
TNF
TNF
conventional therapies,43 and in
TNF
patients with spondyloarthropathies
including ankylosing spondylitis,44 and
in psoriasis.45 Finally, there is
TNF
Transmembrane
preliminary evidence that infliximab
Infliximab
TNF
TNF
Etanercept
may have a therapeutic role in other
TNF
immunological diseases including
sarcoid46,47 and sarcoid arthritis,48
TNF
Etanercept
TNF
Behets disease,4951 and uveitis.52
TNF
Infliximab
The efficacy of etanercept given as
TNF
TNF
a subcutaneous injection was
demonstrated in a population of
Figure 2. Interactions with infliximab and etanercept. Infliximab binds more avidly than etanercept
patients with early rheumatoid
does to transmembrane TNF and forms a more stable complex. More infliximab than etanercept
arthritis, in which 10 mg or 25 mg
binds to transmembrane TNF. Infliximab is more effective at inhibiting transmembrane TNFtwice a week had similar clinical
mediated activation of endothelial cells. Infliximab binds both the monomeric and trimeric form of
efficacy but a more rapid onset of
soluble TNF, whereas etanercept effectively binds only to the trimeric form. EtanerceptTNF
action than methotrexate 20 mg/week
complexes are unstable, resulting in the release of soluble TNF.
150
Review
at 12 months.53 Etanercept also produced significant

improvements in joint damage compared with
methotrexate. In a randomised controlled trial, etanercept at
a dose of 25 mg twice a week was not effective in Crohns
disease.54 Patients with psoriatic arthritis receiving etanercept
for 12 weeks had significant improvement in their disease
compared with patients receiving placebo.55 Finally, in a 4month randomised placebo-controlled trial, etanercept was
effective in treating patients with ankylosing spondylitis.56
The efficacy of etanercept in treating sarcoidosis and
Behets disease is unknown but preliminary data suggest
that it may be effective in uveitis.57,58
Other anti-TNF agents currently in development are
D2E7 (adalimumab), a fully humanised monoclonal
antibody; CDP870, a humanised PEGylated TNF inhibitor;
and a PEGylated recombinant human soluble TNFR1.59 In
addition, thalidomide has been shown to have anti-TNF
activity.60 Preliminary data suggest that D2E7 and CDP870
are effective in rheumatoid arthritis.61,62
As a class, anti-TNF agents have been recommended as
a treatment for patients with moderate to severe rheumatoid
arthritis who do not adequately respond to or who cannot
tolerate methotrexate, or who have not responded to at least
two other disease-modifying agents.63 Given their efficacy
and tolerability, anti-TNF agents are likely to be used to
treat several immunologically mediated diseases in the
future in addition to becoming standard therapy for
refractory rheumatoid arthritis.
Tuberculosis risk with anti-TNF agents

Clinical use of anti-TNF agents has been implicated in the
reactivation of recent or remotely acquired tuberculosis
infection, although the relative proportions of disease due to
recent infection and to reactivation of latent infection are
not known. In a study by Keane and colleagues, 70 cases of
tuberculosis were identified among about 147 000 patients
worldwide who had received treatment with infliximab for
rheumatoid arthritis, Crohns disease, and other illnesses.5
40 patients had extrapulmonary disease, including 17 cases
of disseminated disease. Since more than half of the cases
were extrapulmonary and 25% of the total had disseminated
disease, the preliminary evidence suggests that the
presentation of tuberculosis in this population may be
atypical, which could result in delays in diagnosis. 78% of
cases of active tuberculosis presented within the time of the
first three infusions and 98% within the first six infusions
(about seven months).64
The evidence supporting a causal link between the use of
infliximab and the development of tuberculosis in that study
was: the temporal relation between the development of
active disease and the start of therapy; an estimated rate
of 244 cases per 100 000 in the USA compared with a
background rate of tuberculosis in American patients
with rheumatoid arthritis who had not received the drug of
62 cases per 100 000; and a higher frequency of forms
associated with immunosuppression (eg, extrapulmonary
dissemination). The estimated tuberculosis rate in all
European recipients of infliximab calculated from the
data presented by Keane and colleagues is 173 cases per
100 000several times higher than the background rate in

European countries.
As of March, 2002, 121 000 patients had been treated
with etanercept worldwide,65 with about 94% of the use in
the USA.66 During clinical trials, 19 patients with a history of
tuberculosis and seven with a positive tuberculin skin test
received etanercept but did not develop evidence of
tuberculosis reactivation.67 One etanercept-treated patient
developed a positive tuberculin skin test after 10 months of
therapy and was given concomitant isoniazid.67 In a search
of the US Food and Drug Administration Medwatch
database for adverse events reported up to March, 2002,
Manadan and co-workers detected 25 cases of tuberculosis
that occurred during or after etanercept therapy.6 From these
data and with the assumption that cases reported to the
Food and Drug Administration could have occurred outside
the USA, a crude world tuberculosis rate of 207 cases per
100 000 in patients receiving etanercept can be calculated.
Slightly more than 50% of patients had extrapulmonary
disease, similar to the proportion reported for infliximab.57
In contrast to infliximab, the development of active
tuberculosis in recipients of etanercept generally occurs later
after the start of treatment; the median time from first dose
to the diagnosis of tuberculosis was 115 months (range
120). No consistent temporal relation has been found
between the start of etanercept therapy and the onset of
clinical tuberculosis.6 A crude world tuberculosis rate in
patients receiving infliximab as calculated from the data
presented by Keane and colleagues is 476 cases per 100 000.
Comparisons of the rates of tuberculosis reported with
infliximab and with etanercept need cautious interpretation
for several reasons. The study populations for the two drugs
differed; a large proportion of patients given infliximab had
Crohns disease. Infliximab has been used more than
etanercept in Europe (18% vs 6%),5,6 where the overall
tuberculosis rate is higher than in the USA. The rates do not
factor in the length of treatment for each patient (patients
with Crohns disease typically receive short-course therapy).
The tuberculosis risk factors were not clearly defined for
each population. The etanercept data include patients who
developed tuberculosis after therapy, which could have been
due to recent infection. The distribution process of
infliximab makes accurate estimation of the exact amount
of drug given difficult.
Given these limitations in the available data, the relative
rates of tuberculosis with the two therapies remain
unquantifiable, although most of these limitations would
tend to bias the rates in favour of infliximab (ie, falsely lower
the rate), so the true risk with infliximab is likely to be
higher. The Food and Drug Administration has estimated
the US age-adjusted incidence to be 82 per 100 000 patientyears for all patients (rheumatoid arthritis, Crohns disease,
other illnesses) exposed to anti-TNF agents.68 Thus, the
existing data suggest that both drugs increase the risk of
active tuberculosis. The majority of cases of active
tuberculosis are assumed to result from reactivation of
previous latent infection, but the contribution of recent
infection to the total burden of active disease in this
population is unknown.
151
Review
Another granulomatous disease, disseminated histoplasmosis, has also been reported with these therapies: in a
review of the Food and Drug Administration passive
surveillance database, nine cases of invasive disseminated
histoplasmosis have been reported in patients receiving
infliximab and one case in a patient who had received
etanercept.69 Although these data are preliminary, they again
suggest that this disorder may be a more significant problem
with infliximab.
Risk factors for tuberculosis infection and

progression to active disease
The risk of reactivation from anti-TNF therapy depends on
two variables: the immunomodulating effect of the therapy
and the underlying rate of latent tuberculosis infection or risk
of previous infection in the population. The rate of latent
tuberculosis infection in turn depends on many variables,
including the persons age, country of origin, socioeconomic
status, ethnic origin, travel history to high-prevalence
countries, and occupation (eg, work in a healthcare facility or
shelter for homeless people).2
Investigation for possible infection with M tuberculosis
should begin with an assessment for possible tuberculosis
exposure. High-risk groups include foreign-born individuals
from countries with a high prevalence of tuberculosis,
injection-drug users, and those who have a high risk of
institutional exposure to tuberculosis.2 Elderly people are an
important risk group, even if born in a country currently
judged to have low prevalence, such as the USA or Canada,
because such countries had much higher rates of tuberculosis
in the past. For example, the prevalence in Canada in 1945
was almost 120 cases per 100 000, similar to that reported by
some less developed countries today.70
Groups at high risk of progression to active disease
after infection include people with HIV coinfection, recent
skin-test converters, individuals with a chest radiograph
suggesting old tuberculosis, and patients on immunosuppressive therapy or with certain medical disorders (eg,
diabetes, severe kidney disease, silicosis, some cancers, some
intestinal disorders, and malnutrition [<90% of ideal
bodyweight]).2 In patients with rheumatoid arthritis, the use
of corticosteroids has long been known to increase the risk of
tuberculosis, presumably through the agents effects on cellmediated immunity.71 Accordingly, routine clinical practice
used to be to assess tuberculosis risk when initiating a
therapeutic trial of a corticosteroid. Indeed, in countries with
high rates of tuberculosis, the frequency of active disease in
corticosteroid-treated patients with rheumatoid arthritis
remains a concern; rates of tuberculosis as high as 2000 per
100 000 patient-years have been reported.72 On the basis of
the existing evidence, patients receiving anti-TNF therapies
should also be judged to be at risk of progression to active
disease.
The development of active tuberculosis in this
immunocompromised population is of significant concern:
the diagnosis can be obscured by somewhat atypical
presentations;5,6 long-term treatment may be required and
patients may experience adverse effects of drugs owing to
underlying disease or drug interactions; and there is potential
152
for disease transmission to close contacts, including other

immunocompromised individuals in the healthcare setting.
Management
Tuberculin testing
Tuberculin skin testing (TST) is the standard screening test for

latent tuberculosis infection in high-risk populations. The test
dose is bioequivalent to 5 tuberculin units of standard purified
protein derivative injected intradermally (not subcutaneously)
into the volar surface of the forearm.2,73 In patients previously
exposed to tuberculosis, sensitised T cells are recruited to the
site of injection and release cytokines, which induce a local
induration.73 If given correctly, the injection should raise a
small wheal of 5 mm, which resolves within 1015 min.2
Induration (not erythema) is measured at 4872 h and
recorded in millimetres. One of the more common reasons for
false-negative or false-positive results is misreading of the size
of the induration.2
Assessment for latent tuberculosis infection is
recommended by the manufacturers of the currently approved
anti-TNF medications for all patients before treatment with
these agents.40,41 This recommendation will inevitably lead to
skin testing of some populations at low risk of M tuberculosis
infection. The positive predictive value of the TST in lowfrequency populations is less than 50%, so positive tests must
be interpreted with caution.73 Given the possible risk of the
development of active disease however, erring on the side of
caution is appropriate and false-positive reactors should be
accepted to improve the capture of all those infected. Falsepositive results can occur in people infected with
environmental non-tuberculous mycobacteria and recipients
of the BCG vaccine if the vaccine was given after the first year
of life.2 Although false-positive results can occur in countries
where BCG vaccine is given after infancy, a conservative
approach may be appropriate, disregarding BCG vaccination
as a cause of a positive skin test in the setting of TNF
inhibitors.
The rate of false-negative results increases with the degree
of immunosuppression resulting from poor nutrition or
general health, medications (eg, corticosteroids, ciclosporin),
or coexisting illness (eg, HIV infection, malignant disease,
chronic renal failure).73 In general, all patients about to
embark on immunosuppressive therapy or who have
impaired immunity due to illness should undergo TST before
therapy or as soon as possible after the diagnosis of the
immunosuppressive disease to keep to a minimum the risk of
false-negative reactions due to anergy.
Management algorithm
In general, immunocompromised patients, including those

receiving anti-TNF therapies, should avoid settings with a high
risk of tuberculosis. For example, immunocompromised
healthcare workers should avoid working in inner-city
emergency departments or respiratory-disease clinics, and
should avoid high-risk occupations such as respiratory
therapy. Similarly, the risk of latent tuberculosis infection or
the possibility of new infection must always be considered
when using immunosuppressive agents in high-frequency
settings.
Review
Although existing evidence suggests that the risk of

development of active disease is greater with infliximab
than with etanercept, a conservative approach would be
to consider the two drugs, and other drugs coming onto
the market, as similar in interpretation and management
of positive skin tests. This approach may require
modification as more accurate measurements of the
relative risks become known.
Suggested TST cut-off criteria for patients receiving
anti-TNF therapy are shown in the table. TST-negative
patients who have no epidemiological risk factors for
M tuberculosis infection (induration less than 10 mm) can
receive treatment with an anti-TNF agent without
additional investigation or therapy. However, continuing
vigilance is recommended for the duration of therapy.
TST-positive patients (induration 5 mm or more with
coexisting epidemiological risk factors, and all others with
induration of 10 mm or more) will require further
investigation to rule out active disease. A history should
be taken and physical examination done to assess the
presence of pulmonary or extrapulmonary tuberculosis. An
important point to note is that up to 95% of patients with a
positive Mantoux test will have a normal chest radiograph.
The latter investigation is done not to confirm or exclude
latent infection, but to identify any abnormalities that
would put a person with latent infection at higher risk of
reactivation and to look for active disease.2,73 The presence
of active disease must be ruled out before therapy for latent
tuberculosis infection or anti-TNF therapy can be
considered. TST-positive patients with a normal chest
radiograph or a stable abnormal chest radiograph
compatible with inactive tuberculosis plus negative sputum
cultures should receive treatment for latent tuberculosis
infection. Referral at this stage to a specialist familiar with
the diagnosis and management of tuberculosis may be
appropriate. Patients with active tuberculosis must be
treated with a standard regimen (see Canadian2 or
American Thoracic Society73 standards) and must have
documented completion of therapy before anti-TNF
therapy can be started.
Significantly immunocompromised patients (eg, antiTNF therapy plus other immunosuppressive agents) with
induration on the TST of less than 5 mm may rarely be
considered candidates for preventive therapy in the presence
of several or highly significant risk factors for tuberculosis
infection, however, the decision to provide therapy for latent
infection should be made on an individual basis in
conjunction with a tuberculosis specialist. Individuals who
do not receive preventive therapy should be monitored
closely for signs and symptoms of tuberculosis.
Once active disease has been excluded in TST-positive
patients, treatment of latent tuberculosis should be
recommended. The gold-standard therapy remains isoniazid
300 mg daily for 9 months.2,73 An alternative regimen is
rifampicin 600 mg/day for 4 months. Short-course therapy
with rifampicin plus pyrazinamide is generally discouraged
owing to the risk of hepatotoxicity.74,75
Liver-function tests should be done before the start of
preventive therapy, especially in patients receiving other
Suggested Mantoux skin test criteria for patients receiving

anti-TNF inhibitors (adapted from references 2, 73).
TST
(mm induration)
Patient characteristics for which preventive therapy

is recommended
04 mm*
Major immune suppression (eg, anti-TNF therapy with

other immunosuppressive medications) with additional
significant risk factors for tuberculosis progressioneg,
Fibronodular disease on chest radiograph
Recent household contact of an active case
59 mm
Anti-TNF therapy with epidemiologic risk factorseg,

Foreign born from an endemic country
Likely occupational exposure
(eg, healthcare worker)
Abnormal chest radiograph
Known contact of an active case
10 mm
All others receiving anti-TNF therapy
*The decision to treat latent infection in such cases should be made on an individual
basis in conjunction with a tuberculosis specialist.
hepatotoxic medications such as methotrexate. Isoniazid,

rifampicin, and pyrazinamide have been associated with
hepatoxicity, and close clinical monitoring for the signs
and symptoms of drug-induced hepatitis is required.2,73
Regular monitoring of aminotransferase concentrations is
recommended in these patients because most if not all are
concurrently taking potentially hepatotoxic drugs. Clinical
assessments and liver-function tests every 2 weeks have been
recommended for patients receiving short-course preventive
therapy with pyrazinamide and rifampicin.74 Rifampicin
will cause the urine and saliva to turn orange or red in
colour and is a potent inducer of the cytochrome P450
enzyme pathway. Accordingly, rifampicin will decrease the
circulating concentrations of medications that use the same
metabolic pathway, including exogenous corticosteroids
and ciclosporin. In settings in which rifampicin will
significantly interact with other medications and isoniazid is
contraindicated, rifabutin can be used in place of rifampicin
at a dose of 300 mg daily for 4 months, although it has not
been studied for this indication. Rifabutin is of the rifamycin
class but is a less potent inducer of the cytochrome P450
system. Pyrazinamide can cause non-specific joint pains and
hyperuricaemia, leading to clinical gout, which may
complicate the management of patients with rheumatoid
arthritis.
The duration of prophylaxis before anti-TNF therapy
has not been established. Although a preferable approach is
to wait until a full course of preventive therapy has been
completed, if the clinical condition warrants it, anti-TNF
therapy can be initiated 12 months after the start of
prophylaxis if this therapy is well-tolerated.
Conclusions
Anti-TNF agents are an important addition to treatments for
rheumatoid arthritis and other autoimmune disorders. That
these agents have been suggested to increase the risk of
active tuberculosis is not surprising given the central role
of TNF in the host defence against tuberculosiskilling of
M tuberculosis by macrophages, granuloma formation,
apoptosis, and prevention of dissemination of infection to
other sites. Differences in potency and route of
153
Review
administration as well as differences in the mechanism of

action, such as binding to different forms of TNF or
causing macrophage or monocyte apoptosis, suggest
that infliximab should cause more cases of active
tuberculosis than etanercept. The epidemiological data
also suggest that infliximab therapy may also pose a
greater tuberculosis risk, although the crude rates available
are probably inaccurate for both agents. Preliminary data
also suggest that the relative risk of disseminated
histoplasmosis is higher with infliximab than with
etanercept.
From the existing data, however, a reasonable
assumption is that the development of active tuberculosis
is a class effect that can be expected with the use of
any anti-TNF agent. This assumption may require
modification as more data become available. For example,
an odd observation is that infliximab is effective in the
treatment of a granulomatous immunological disease
(Crohns disease) but etanercept is not. Preliminary
data also suggest that infliximab may have a role in
treatment of sarcoidosis, but the role of etanercept has
not yet been studied. As future research further delineates
the roles of these two drugs and other similar future
agents, it may show that those agents most effective at
treating granulomatous diseases are also those most
likely to result in active tuberculosis. Further study will
also allow a more accurate determination of the relative
risk of active disease attributable to these drugs compared
with other known reactivation risk factors.
Before initiation of infliximab therapy, assessment
of tuberculosis infection risk factors and a TST are
strongly recommended to determine the patients latent
tuberculosis infection status and, thus, the risk of active
disease.40 Although a TST is not required before initiation
of etanercept, the product monograph does warn the
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Search strategy and selection criteria

Data for this review were identified by searches of
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Conflicts of interest
MAG has received honoraria from Schering Canada to educate

rheumatologists about screening for and treatment of latent
tuberculosis infection in patients starting anti-TNF therapy. SM has
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