Abstract
Treatment with tumor necrosis factor–α (TNF–α) inhibitors increases the risk of tuberculosis (TB) due to reactivation of latent Mycobacterium tuberculosis infection (LTBI). Screening for LTBI is based mainly on the tuberculin skin test (TST), which has several limitations in any patient who is immunosuppressed due to drugs or autoimmune disease. T cell interferon–γ release assays (IGRA) have been shown to be more specific than TST in immunocompetent patients and potentially represent a new approach for the management of patients taking TNF–α blockers. Even if there is no evidence-based literature of IGRA superiority versus TST in this specific clinical setting, some studies suggest blood assays may be helpful in clinical management of these patients, in addition to currently recommended clinical screening for risk factors for LTBI.
- TUBERCULOSIS
- TUMOR NECROSIS FACTOR–α BLOCKER
- INTERFERON–γ RELEASE ASSAYS
Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a pathogenic role in many autoimmune diseases, and that is essential for host defenses against mycobacteria and other intracellular pathogens. The role of TNF–α in the human immune response to Mycobacterium tuberculosis (Mtb) is to promote macrophage phagocytosis and intracellular killing of mycobacteria and to help granuloma formation and function1.
The biologic antagonists of TNF–α, infliximab, etanercept, and adalimumab, are approved for use in treating selected autoimmune diseases that include rheumatoid arthritis, inflammatory bowel diseases, psoriatic arthritis, and ankylosing spondylitis. However, shortly after the licensing of these agents, a risk of serious infections, including tuberculosis (TB), in association with the clinical use of these commercially available TNF–α inhibitors was reported. To date, reactivation of latent TB infection is a major complication of TNF–α antagonists, the prevalence of TB being the highest during therapy with infliximab, due to its ability to inhibit anti-TB T cell responses2–4. In particular, TB associated with TNF–α blockade frequently appears with extrapulmonary manifestations or as disseminated disease5; moreover a case of reactivation of Mycobacterium bovis in a patient treated with infliximab has been reported6.
Screening for latent TB infection (LTBI) and active disease is recommended before treatment is initiated7,8. In 2005 the US Centers for Disease Control and Prevention (CDC) guidelines for the prevention of TB specifically in the setting of TNF blockade suggested taking a careful medical history before starting anti-TNF therapy3. All patients should be questioned regarding their demographic details (i.e., age, country of birth), history of bacillus Calmette Guerin (BCG) vaccination, TB risk factors (i.e., recent close exposure to TB patients, immigration from or recent stay in high TB prevalence countries, radiographic evidence of TB sequelae), and current treatments (i.e., drugs).
Diagnosis of LTBI is based mainly on the tuberculin skin test (TST), which has several limitations9. However, the use of TST is controversial even in patients with TB risk factors due to the high rate of false negative results as a consequence of previous longterm immunosuppressive treatments10.
Negative TST results should be interpreted with caution in any patient who is immunosuppressed by drugs or autoimmune disease.
Innovative blood tests that measure release of interferon–γ (IFN–γ) by T cells stimulated in vitro with Mtb-specific antigens offer new approaches for diagnosing TB infection11,12. To date, 2 tests are commercially available in agency-approved formats. They are T-SPOT.TBTM (TS-TB, Oxford Immunotech, Abingdon, UK) and QuantiFERON In Tube (QFT, Cellestis, Carnegie, Australia). While the test formats are based on different methodologies, respectively, enzyme-linked immunospot assay (ELISPOT) and whole-blood ELISA, both tests rely on the use of the same 2 Mtb-specific antigens, ESAT-6 (early secretory antigen target-6) and CFP-10 (culture filtrate protein-10). The genes encoding for both these antigens have been mapped to a region of the Mtb genome called RD (region of differentiation)-1, which is absent in all BCG vaccine strains and in most environmental mycobacteria13. As a consequence, IFN–γ release assays (IGRA) seem to be more specific than TST. In addition, they are more sensitive in detecting patients with active TB, and their results correlate better with Mtb exposure in people likely affected by latent infection14.
Given the lack of information on the relative sensitivities of IGRA in immunosuppressed populations, the routine use of these tests is not yet currently supported. And, while confirmation of positive-TST results, when BCG vaccination and exposure to non-tuberculous mycobacteria have been excluded, adds no significant clinical information (as this finding does not modify recommended treatment strategies), interpretation of positive blood tests among TST-negative cases is more difficult15.
A recent study, reporting results of the comparison between the IGRA and the TST for the detection of Mtb infection in patients with psoriasis or psoriasis arthritis with no identified TB risk factors who were candidates for biological treatment, suggests that IFN–γ assays may be helpful in clinical management of these patients. Good agreement of both IFN–γ blood tests with TST has been reported: 12 patients (63.2%) had negative TST and IFN–γ assay results. IGRA scored a positive result in 10.54% of cases (all negative TST results)16. A positive result to either an IGRA or TST, in addition to currently recommended clinical screening for risk factors for LTBI, should result in prophylactic treatment because of the high risk of TB in patients on anti-TNF therapy17.
The patients receiving immunosuppressive therapies, including TNF–α antagonists, could benefit from treatment of latent TB infection due to the high-risk of disease progression. According to the guidelines of the British Thoracic Society, a chemoprophylaxis with 6-month isoniazid (isonicotinyl hydrazine, INH) or 3-month isoniazid and rifampicin regimens are recommended in these patients. However, a 9-month regimen with INH or completion of chemoprophylaxis before starting this therapy may have proved more effective18.
Footnotes
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