1 table omitted
The Food and Drug Administration (FDA) has determined that tuberculosis
(TB) disease is a potential adverse reaction from treatment with the tumor
necrosis factor-alpha (TNF-α) antagonists infliximab (Remicade®),
etanercept (Enbrel®), and adalimumab (Humira®)*; the three products
are labeled accordingly.1,2 These products work by blocking TNF-α,
an inflammatory cytokine, and are approved for treating rheumatoid arthritis
and other selected autoimmune diseases. TNF-α is associated with the immunology
and pathophysiology of certain infectious diseases, notably TB; blocking TNF-α
can allow TB disease to emerge from latent Mycobacterium
tuberculosis infection. In 2002, a California county health department
reported three cases of TB disease occurring in association with infliximab
therapy. This report summarizes those cases and nine subsequently reported
cases and provides interim recommendations for TB prevention and management
in recipients of these blocking agents. Health-care providers should take
steps to prevent TB in immunocompromised patients and remain vigilant for
TB as a cause of unexplained febrile illness.
Case 1. In January 2002, a U.S.-born man aged
55 years with rheumatoid arthritis had pulmonary TB disease diagnosed 17 months
after starting infliximab therapy. In 1995, he had a positive tuberculin skin
test (TST) and reportedly took isoniazid for 12 months; however, his adherence
to therapy was questionable. During September 2000–January 2002, he
received 13 infusions of infliximab, and his arthritic symptoms decreased.
However, in January he had fever and weight loss. Four weeks later, a supraclavicular
lymph node became enlarged, and a chest radiograph revealed a right-upper-lobe
lung cavity with a nodular infiltrate. M. tuberculosis was isolated from sputum and lymph node specimens, and
his condition improved with anti-TB medications. In July 2002, he again lost
weight. He had smoked cigarettes for many years and was found to have lung
cancer; he died in November 2002.
Case 2. A woman aged 64 years with rheumatoid
arthritis had pulmonary and pericardial TB disease diagnosed in June 2002.
She had begun infliximab therapy in September 2001 and received 7 doses before
onset of fever and weight loss in April 2002. Her chest radiograph revealed
a large pericardial effusion and a right-upper-lobe lung infiltrate. M. tuberculosis resistant to isoniazid, rifampin, pyrazinamide,
and ethambutol was isolated from sputum and pericardial fluid. The patient
was born in the Philippines, where TB often is drug resistant.3 In
1999, she was exposed to a person with drug-susceptible TB in the United States
and subsequently had two TSTs with negative results in 2000; however, she
was taking prednisone for her arthritis at the time of the TSTs. After 12
months of therapy with second-line anti-TB medications, her medical condition
Case 3. A U.S.-born woman aged 54 years was
exposed to contagious TB in 1996; she had a positive TST result during the
contact investigation but was not treated for latent TB infection (LTBI).
The patient has Crohn’s disease and received infliximab in February
2001 and June 2002. Two weeks after her second infusion, but 16 months after
her first infusion, she sought care for cough, fever, and abdominal pain.
Her chest radiograph revealed upper-lobe lung nodules with a pleural effusion,
and sputum specimens yielded M. tuberculosis. She
started standard, four-drug anti-TB therapy but experienced gastrointestinal
intolerance. Isoniazid was discontinued, and she was free of TB disease after
treatment with rifampin, pyrazinamide, and ethambutol.
In 2003, the state of California Department of Health Services asked
local jurisdictions to report TB cases associated with TNF-α antagonists
since January 2002. As of September 2003, nine additional reports had been
received, for a total of 12 cases diagnosed during January 2002–August
2003. The median patient age was 54.5 years (range: 23 to 73 years), and eight
(67%) of the patients were female. Eleven of the patients had TB disease after
receiving infliximab. One patient had TB disease while receiving chronic etanercept
Eleven of the patients had at least one risk factor for LTBI (e.g.,
born in countries where TB is prevalent or contact with a person with TB disease).
Eight were taking other immunosuppressive therapies at the time of their TB
diagnoses. Three patients underwent a medical history for TB risk factors
before beginning therapy with a TNF-α antagonist. In addition to the patient
in case 1, a second patient died (from cardiomyopathy) while being treated
for TB disease.
P Costamagna, K Furst, MD, K Tully, San Joaquin County Public Health
Svcs; J Landis, Santa Cruz County Health Svcs; K Moser, MD, San Diego County
Dept of Health; L Quach, J Kwak, County of Orange Health Care Agency; H Calvet,
MD, B Lindsey, Long Beach City Dept of Health and Human Svcs; J Flood, MD,
California Dept of Health Svcs. M Braun, MD, Center for Biologics Evaluation
and Research; J Siegel, MD, Center for Drug Evaluation and Research, Food
and Drug Administration. K Winthrop, MD, J Jereb, MD, Z Taylor, MD, M Iademarco,
MD, K Castro, MD, Div of TB Elimination, National Center for HIV, STD, and
TB Prevention, CDC.
As of January 2004, FDA’s adverse-event reporting system had received
several hundred reports, mostly from outside the United States, of TB disease
in patients who received TNF-α antagonists. Manufacturers of these products
are required to report known cases, but reporting is voluntary for others.
The majority of the cases probably represent progression of LTBI to TB disease,
although the contribution of newly acquired M. tuberculosis infection to the total number of reports is unknown.1 Reports
have included atypical presentations, extrapulmonary and disseminated disease,
In California, after the initial three reports, nine additional cases
of TB disease were reported during January 2002–August 2003 in patients
taking TNF-α antagonists. Although reporting of TB cases is mandatory
in California, reporting the association with TNF-α antagonists was voluntary,
and an underestimate might have resulted.
Eight of the 12 patients in California were born in countries where
TB is prevalent. In certain instances, physicians had not screened for risk
factors for M. tuberculosis infection or tested their
patients for infection before beginning therapy with TNF-α antagonists.
In other instances, testing was performed, but LTBI was not diagnosed, possibly
because of cutaneous anergy. Many patients who receive TNF-α antagonists
already are receiving other immunosuppressive therapies, and certain conditions
such as rheumatoid arthritis also can decrease sensitivity to tuberculin;
therefore, TST results at the time of initiating TNF-α antagonist therapy
might be falsely negative. Some experts advocate treating for presumed LTBI
when a candidate for TNF-α antagonists has risk factors for M. tuberculosis infection but a negative TST result.4,5
TNF-α, an inflammatory cytokine expressed by activated macrophages,
T-cells, and other immune cells, plays a crucial role in the host response
against M. tuberculosis and other intracellular pathogens.
Infliximab and adalimumab are monoclonal antibodies; etanercept is a dimeric
soluble form of the TNF-α receptor. All three products are approved for
the treatment of patients with rheumatoid arthritis. Infliximab also is approved
for Crohn’s disease, and etanercept is approved for specific other arthritides
and for psoriasis. Use of these agents has been associated with other life-threatening
infectious diseases besides TB, including candidiasis, histoplasmosis, aspergillosis,
and listeriosis.1 TNF-α antagonists often are used in conjunction
with other immunosuppressive therapies, particularly glucocorticoids and methotrexate.
Whether the increased rates of TB or other infectious diseases are caused
by interactions among these therapies is unknown.
Diagnosing LTBI in candidates for TNF-α antagonist therapy is challenging
(Box). For patients who undergo treatment
for LTBI, the optimal time for starting TNF-α antagonist therapy is undetermined.
Some experts advocate postponing therapy until LTBI treatment is complete.
However, this delay might be impractical.4,6 The risk for TB relapse
in patients previously cured of TB disease and subsequently treated with TNF-α
antagonists is unknown.
If active TB disease develops during TNF-α antagonist therapy, the
TNF-α antagonist should be discontinued, at least until the anti-TB regimen
has been started and the patient’s condition has improved. The optimal
time for resuming TNF-α antagonist therapy is undetermined. Outcomes with
other immunosuppressive agents during the treatment of TB disease have been
variable. Use of glucocorticosteroids during the treatment of TB disease is
considered safe,7 and studies of TB disease in organ transplant
recipients suggest that survival is not decreased by the use of cyclosporine
or azathioprine.8 Etanercept, administered in a phase-1 clinical
trial along with a standard initial anti-TB regimen, did not delay the resolution
of TB disease markers in a group of patients coinfected with human immunodeficiency
virus in comparison with historical controls; adverse effects were not detected.9 However, use of anti–T-cell agents in transplant recipients
with TB disease is associated with increased mortality; whether this increased
mortality is because of the suppression of immune response or the dysfunction
of the transplanted organ is unclear.8
Practitioners who prescribe TNF-α antagonists should educate their
patients about the symptoms of TB disease, with added emphasis on extrapulmonary
symptoms, which can include fever, malaise, or development of a mass. A patient
with symptoms should undergo diagnostic testing for TB. In addition to following
local reporting requirements, health-care providers should report TB cases
associated with TNF-α antagonists to FDA’s Medwatch system (available
Ongoing clinical trials are using both approved and experimental TNF-α
antagonists in the treatment of additional conditions.4 Novel therapies
that inhibit other related inflammatory cytokines are under development. As
the use of these blocking agents expands, associated cases of TB might increase.
Vigilance for TB in association with these agents is critical to early recognition
and successful treatment.
*Respectively, Centocor, Malvern, Pennsylvania; Immunex Corporation,
Thousand Oaks, California; and Abbott Laboratories, Abbott Park, Illinois.
REFERENCES: 9 available
Tuberculosis Associated With Blocking Agents Against Tumor Necrosis Factor-Alpha—California, 2002-2003. JAMA. 2004;292(14):1676-1678. doi:10.1001/jama.292.14.1676