Data for this review were identified by searches of papers published in English on Medline with the key words: “infliximab”, “etanercept”, “tumour necrosis factor alpha inhibitors”, “TNF”, “anti-TNF”, “adalimumab”, “D2E7”, “CDP870”, “PEGylated TNF”, and “PEGylated TNFR1” in association with “tuberculosis”, “Crohn's disease”, “psoriasis”, and “ankylosing spondylitis”. Relevant references were also obtained from articles acquired through the search strategy. Clinical practice guidelines from
ReviewAnti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management
Section snippets
Role of TNF in M tuberculosis infection and disease
TNFα has a central role both in the host immune response to M tuberculosis infection and in the immunopathology of tuberculosis (figure 1). TNFα 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 TNFα can also be expressed by activated T cells, B lymphocytes, natural killer cells, and some tumour cells.7 TNFα exists in soluble and
Anti-TNF therapies
Several therapeutic agents that neutralise TNFα have been developed; of these, infliximab and etanercept have been studied most extensively (figure 2). Infliximab is a human-murine (25% murine) chimeric monoclonal antibody with high binding affinity31 and specificity for TNFα .34 It forms stable complexes with the monomeric and trimeric forms of soluble TNFα and with the transmembrane forms of TNFα.35 As an antibody, infliximab also has the ability to cross-link TNFα molecules. Binding to
Tuberculosis risk with anti-TNF agents
Clinical use of anti-TNFα 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, Crohn's disease, and other illnesses.5 40 patients had
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 person's 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
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
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 TNFα in the host defence against tuberculosis—killing of M tuberculosis by macrophages, granuloma formation, apoptosis, and prevention of dissemination of infection to other sites. Differences in potency and route of administration as well as differences in
Search strategy and selection criteria
References (75)
- et al.
The role of cytokines in the immune response to tuberculosis
Res Immunol
(1996) - et al.
Tumor necrosis factor: biology and therapeutic implications
Gastroenterology
(2000) - et al.
Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L monocytogenes infection
Cell
(1993) - et al.
The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection
Cell
(1989) - et al.
Tumor necrosis factor-α is required in the protective immune response against Mycobacterium tuberculosis in mice
Immunity
(1995) - et al.
Imbalances between tumor necrosis factor-alpha and its soluble receptor forms, and interleukin-1beta and interleukin-1 receptor antagonist in BAL fluid of cavitary pulmonary tuberculosis
Chest
(2000) - et al.
Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages: the role of cachectin (tumor necrosis factor)
Immunol Lett
(1985) - et al.
Differential release of tumor necrosis factor alpha from murine peritoneal macrophages stimulated with virulent and avirulent species of mycobacteria
FEMS Immunol Med Microbiol
(1994) - et al.
Construction and initial characterization of a mouse-human chimeric anti-TNF antibody
Mol Immunol
(1993) - et al.
Chimeric anti-TNF-alpha monoclonal antibody cA2binds recombinant transmembrane TNF-alpha and activates immune effector functions
Cytokine
(1995)
Infliximab induced apoptosis in monocytes from patients with chronic active Crohn's disease by using a Caspase-dependent pathway
Gastroenterology
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial
Lancet
Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial
Lancet
Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial
Lancet
Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial
Gastroenterology
Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial
Lancet
Consensus statement: WHO Global Surveillance and Monitoring Project. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country
JAMA
In situ production of gamma interferon, interleukin-4, and tumor necrosis factor alpha mRNA in human lung tuberculous granulomas
Infect Immun
Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent
N Engl J Med
Tuberculosis and etanercept
Proceedings of American College of Rheumatology Conference
Infection of human macrophages and dendritic cells with Mycobacterium tuberculosis induces a differential cytokine gene expression that modulates T cell response
J Immunol
Cytokine pathways and joint inflammation in rheumatoid arthritis
N Engl J Med
Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin
J Immunol
Tumor necrosis factor receptor 2 plays a minor role for mycobacterial immunity
Pathobiology
Evidence that tumor necrosis factor has an important role in antibacterial resistance
J Immunol
Tumor necrosis factor and granulocyte macrophage-colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill avirulent M avium: killing effector mechanism depends on the generation of reactive nitrogen intermediates
J Leukoc Biol
TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection
J Immunol
Fatal granuloma necrosis without exacerbated mycobacterial growth in tumor necrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium
Infect Immun
Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology
Infect Immun
Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology
Immunology
Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis
Infect Immun
Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha
J Immunol
Restraining mycobacteria: role of granulomas in mycobacterial infections
Immunol Cell Biol
Local role for tumor necrosis factor alpha in the pulmonary inflammatory response to Mycobacterium tuberculosis infection
Infect Immun
Expression of chemokines and induction of rapid cell death in human blood neutrophils by Mycobacterium tuberculosis
J Infect Dis
Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation
J Exp Med
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