Review
Tumour necrosis factor antagonists: structure, function, and tuberculosis risks

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Summary

Our understanding of the infection risks presented by tumour necrosis factor (TNF) antagonists has continued to evolve in the 10 years since these drugs were first introduced. Several recent studies have confirmed the increased risk of tuberculosis posed by TNF antibodies compared with soluble TNF receptor, particularly with regard to reactivation of latent infection. Structural and functional differences seem to account for this finding. This Review examines the potential relations between target specificity, stoichiometry, and binding kinetics of TNF blockers and their associated risk of infection. Clinical strategies for prevention and management of tuberculosis in patients treated with TNF blockers may be improved based on our evolving understanding of these differences.

Introduction

This year marks the tenth anniversary of the approvals of the first tumour necrosis factor (TNF)-alpha antagonists for the treatment of chronic inflammatory conditions. Two classes of antagonists, monoclonal antibody and soluble receptor, have proven to be highly effective treatments for rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. However, as clinical experience with these drugs has grown, differences between them, regarding efficacy in granulomatous inflammatory conditions and risk of granulomatous infections—especially tuberculosis—have become apparent. Our understanding of this subject has continued to evolve since it was reviewed in 2003.1 This Review focuses on recent publications that elucidate the structure–function relation of the TNF blockers in the context of tuberculosis, and that inform tuberculosis prevention and management in this susceptible patient population.

Section snippets

TNF biology

Members of the TNF and TNF receptor (TNFR) superfamily are important regulators of immune cell proliferation, survival, differentiation, and apoptosis.2, 3, 4 TNF is first produced as a transmembrane protein (tmTNF), which then is cleaved by a metalloproteinase to a soluble form (sTNF).5, 6, 7 Biological activity results from the association of three monomers to form trimeric TNF, which then binds to cell-surface TNFR1 or TNFR2, leading to receptor oligomerisation.8, 9, 10

TNFR1 and TNFR2 have

TNF antagonists

There are currently three approved TNF monoclonal antibodies: infliximab, adalimumab, and certolizumab pegol (figure 1). Infliximab is a chimeric monoclonal antibody composed of a human IgG1 constant region and a murine variable region. Adalimumab is a humanised monoclonal antibody, with both human IgG1 constant and variable regions. Certolizumab pegol is a pegylated, humanised monoclonal anti-TNF Fab' (fragment, antigen binding) fragment. Infliximab and adalimumab are approved for the

TNF antagonists and granulomatous infections

Clinical studies of the effect of TNF antagonists on granulomatous infections face several distinct challenges. The rarity of these infections in North America or Europe has prevented their analysis as an endpoint in prospective randomised controlled clinical trials. A meta-analysis of pooled randomised placebo-controlled trials and extension studies of etanercept, for example, did not detect any effect of this treatment on tuberculosis compared with expected rates in these regions.46 This

Structural and functional insights into differential infection risks

Several structural and functional differences among the TNF antagonists could account for the differences in granulomatous infection risk.

Diagnosis and treatment of latent tuberculosis infection

Our understanding of the human tuberculosis risks of the TNF blockers largely reflects experience garnered in regions of low tuberculosis transmission. In the USA, for example, both the prevalence of latent tuberculosis infection and the annual risk of acquiring infection in the general population are low.96, 97 As a result, most tuberculosis cases are thought to arise from reactivation of latent infection acquired in high prevalence regions. Current strategies to minimise tuberculosis risks in

Management of incident tuberculosis cases

Many questions remain regarding optimum management of patients who develop tuberculosis as a consequence of TNF blockade. Most authorities recommend that anti-TNF therapy be halted in such cases until a response to antituberculosis therapy is evident, but clinical trials in this regard have not yet been done. A single case report describes the successful resumption of infliximab therapy after 2 months of tuberculosis treatment in a patient with peritoneal tuberculosis.118 A small clinical trial

Conclusions

The introduction of TNF antagonists into clinical medicine has greatly advanced the treatment of several chronic inflammatory diseases, but has also resulted in a greater clinical awareness of the risks these therapies pose for granulomatous infections. Several studies have confirmed the increased risk of granulomatous infections of TNF antibodies compared with soluble receptor, particularly with regard to reactivation of latent M tuberculosis infection, which for infliximab occurs at a monthly

Search strategy and selection criteria

Articles cited in this Review were obtained through searches of Medline, meeting abstract databases, and reference lists from key reviews. Search terms included the names of TNF antagonists with one or more of the following: “mechanism”, “monocyte”, “macrophage”, “T cell”, “cytokine”, “lysis”, “apoptosis”, “granuloma”, “granulomatous”, “tuberculosis”, “histoplasmosis”, “coccidioidomycosis”, or “aspergillosis”. Priority was given to primary research publications. No date restrictions were

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