TB Reactivation During Immunosuppressive Therapy
TB Reactivation During Immunosuppressive Therapy
Purpose of Review: Biological agents used to treat rheumatologic conditions have made a significant impact on these difficult to treat autoimmune diseases. The tradeoff has been an increase in infections, and particularly tuberculosis with tumor necrosis factor blocker use. Because reactivation of latent tuberculosis infection is preventable, new data have demonstrated that these agents can be made safer when the clinician addresses latent tuberculosis infection.
Recent Findings: Research that supports the screening and treatment of rheumatology patients with latent tuberculosis infection is reviewed, and the emerging consensus on how best to do this is discussed. The limitations of testing to rule out latent tuberculosis infection in this group is emphasized, as this often prevents the tumor necrosis factor blocker prescriber from offering the patient complete reassurance with regard to tuberculosis risk.
Summary: Findings to date support the close screening and treatment for tumor necrosis factor in this uniquely vulnerable group. Such vigilance should probably be applied to future drugs that interfere with cytokines known to play a role in tuberculosis immunity.
Patients with rheumatoid arthritis (RA) are reported to have an increased susceptibility to infection. The precise cause of the increased susceptibility is unclear but it has been attributed to immunological disturbances associated with disease, to immunosuppressive effects of disease-modifying antirheumatic drug (DMARD) therapies and to associated comorbidities. However, a review of available data provides little evidence to support a direct association between individual rheumatic diseases per se, or the use of conventional DMARDs, and an inherent or induced susceptibility to infection.
Studies of a specific susceptibility to tuberculosis (TB) in patients with RA have produced contrasting results. For example in the USA, an increased incidence of TB in patients with RA was not observed. In contrast, a substantial increase in the risk of acquiring TB in RA has been reported in Europe and Asia. The risk of acquiring TB in RA may be increased in patients receiving oral glucocorticoid therapy.
The advent of targeted anticytokine therapies, especially tumor necrosis factor (TNF) blockers, has been associated with an increased prevalence of TB and, rarely, a range of opportunistic infections, such as nontuberculous mycobacteria, Histoplasma capsulatum, Aspergillus fumigatus, Cryptococcus neoformans and Listeria monocytogenes. TNFα is essential for host defenses against mycobacterial infection. TNFα regulates macrophage activation, cell recruitment to the sites of infection, granuloma formation and maintenance of granuloma integrity. In patients with latent tuberculosis infection (LTBI), inhibition of TNFα by monoclonal antibodies may result in dissolution of well formed granulomas and the release of viable mycobacteria causing reactivation of disease. Clinical studies of TB occurring in patients receiving a monoclonal antibody, infliximab, reported a relatively short median time to onset of TB (12-21 weeks), consistent with reactivation of LTBI. In contrast, studies of TB occurring in patients receiving a soluble TNFα receptor, etanercept, reported a median time to onset that was 3-5 times longer. This observation could be consistent with progression to disease following new exposure to M. tuberculosis infection or a longer time to reactivation compared with infliximab. The frequency of TB reported in patients receiving etanercept has been less than in patients receiving either of the two available monoclonal antibody therapies, infliximab and adalimumab. There have been no reports of a clear association of TB reactivation with the use of rituximab, abatacept or anakinra.
Purpose of Review: Biological agents used to treat rheumatologic conditions have made a significant impact on these difficult to treat autoimmune diseases. The tradeoff has been an increase in infections, and particularly tuberculosis with tumor necrosis factor blocker use. Because reactivation of latent tuberculosis infection is preventable, new data have demonstrated that these agents can be made safer when the clinician addresses latent tuberculosis infection.
Recent Findings: Research that supports the screening and treatment of rheumatology patients with latent tuberculosis infection is reviewed, and the emerging consensus on how best to do this is discussed. The limitations of testing to rule out latent tuberculosis infection in this group is emphasized, as this often prevents the tumor necrosis factor blocker prescriber from offering the patient complete reassurance with regard to tuberculosis risk.
Summary: Findings to date support the close screening and treatment for tumor necrosis factor in this uniquely vulnerable group. Such vigilance should probably be applied to future drugs that interfere with cytokines known to play a role in tuberculosis immunity.
Patients with rheumatoid arthritis (RA) are reported to have an increased susceptibility to infection. The precise cause of the increased susceptibility is unclear but it has been attributed to immunological disturbances associated with disease, to immunosuppressive effects of disease-modifying antirheumatic drug (DMARD) therapies and to associated comorbidities. However, a review of available data provides little evidence to support a direct association between individual rheumatic diseases per se, or the use of conventional DMARDs, and an inherent or induced susceptibility to infection.
Studies of a specific susceptibility to tuberculosis (TB) in patients with RA have produced contrasting results. For example in the USA, an increased incidence of TB in patients with RA was not observed. In contrast, a substantial increase in the risk of acquiring TB in RA has been reported in Europe and Asia. The risk of acquiring TB in RA may be increased in patients receiving oral glucocorticoid therapy.
The advent of targeted anticytokine therapies, especially tumor necrosis factor (TNF) blockers, has been associated with an increased prevalence of TB and, rarely, a range of opportunistic infections, such as nontuberculous mycobacteria, Histoplasma capsulatum, Aspergillus fumigatus, Cryptococcus neoformans and Listeria monocytogenes. TNFα is essential for host defenses against mycobacterial infection. TNFα regulates macrophage activation, cell recruitment to the sites of infection, granuloma formation and maintenance of granuloma integrity. In patients with latent tuberculosis infection (LTBI), inhibition of TNFα by monoclonal antibodies may result in dissolution of well formed granulomas and the release of viable mycobacteria causing reactivation of disease. Clinical studies of TB occurring in patients receiving a monoclonal antibody, infliximab, reported a relatively short median time to onset of TB (12-21 weeks), consistent with reactivation of LTBI. In contrast, studies of TB occurring in patients receiving a soluble TNFα receptor, etanercept, reported a median time to onset that was 3-5 times longer. This observation could be consistent with progression to disease following new exposure to M. tuberculosis infection or a longer time to reactivation compared with infliximab. The frequency of TB reported in patients receiving etanercept has been less than in patients receiving either of the two available monoclonal antibody therapies, infliximab and adalimumab. There have been no reports of a clear association of TB reactivation with the use of rituximab, abatacept or anakinra.
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