Tumor‐Necrosis‐Factor Blockers: Differential Effects on Mycobacterial Immunity

Saliu, Oluwabunmi Y.; Sofer, Carolina; Stein, Dara; Schwander, Stephan; Wallis, Robert S.

doi:10.1086/505430

Cited by 170 publications

(129 citation statements)

References 39 publications

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“…For example, anti-TB-specific T cells show a clear difference in effector function. Two in vitro studies provided the same results: adjunctive infliximab or adalimumab treatment to specific human anti-TB T cells was much more efficient in decreasing proliferation and interferon-␥ secretion by these T cells than was adjunctive etanercept treatment (20,25). In addition, inhibition of interleukin-1 released by lipopolysaccharide-stimulated monocytes was greater with anti-TNF mAb treatment than with sTNFR treatment (26).…”

Section: Discussionmentioning

confidence: 90%

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

Tubach

Salmon

Ravaud

et al. 2009

Arthritis & Rheumatism

583

366

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Objective. Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence.Methods. We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects.Results. We collected 69 cases of TB in patients treated for rheumatoid arthritis (n ‫؍‬ 40), spondylarthritides (n ‫؍‬ 18), inflammatory colitis (n ‫؍‬ 9), psoriasis (n ‫؍‬ 1) and Behçet's disease (n ‫؍‬ 1) with infliximab (n ‫؍‬ 36), adalimumab (n ‫؍‬ 28), and etanercept (n ‫؍‬ 5). None of the patients had received correct chemoprophylactic treatment. The sex-and ageadjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (

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Section: Discussionmentioning

confidence: 90%

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

Tubach

Salmon

Ravaud

et al. 2009

Arthritis & Rheumatism

583

366

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“…However, cultures containing only memTNF still maintain control of LVS intracellular growth in vitro. In keeping with these observations, the highest incidences of infectious complications are associated with infliximab, which binds both soluble and membrane TNF (43). Although LVS-immune T cells expressing memTNF can control LVS growth in vitro and in vivo, the observed dysregulation of IFN-␥ and IL-12 production could lead to unexpected complications in vivo, even when memTNF is available.…”

Section: Discussionmentioning

confidence: 80%

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Cowley

Sedgwick

Elkins

2007

The Journal of Immunology

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During primary infection with intracellular bacteria, the membrane-associated form of TNF provides some TNF functions, but the relative contributions during memory responses are not well-characterized. In this study, we determined the role of T cell-derived secreted and membrane-bound TNF (memTNF) during adaptive immunity to Francisella tularensis live vaccine strain (LVS). Although transgenic mice expressing only the memTNF were more susceptible to primary LVS infection than wild-type (WT) mice, LVS-immune WT and memTNF mice both survived maximal lethal secondary Francisella challenge. Generation of CD44high memory T cells and clearance of bacteria were similar, although more IFN-γ and IL-12(p40) were produced by memTNF mice. To examine T cell function, we used an in vitro tissue coculture system that measures control of LVS intramacrophage growth by LVS-immune WT and memTNF-T cells. LVS-immune CD4+ and CD8+ T cells isolated from WT and memTNF mice exhibited comparable control of LVS growth in either normal or TNF-α knockout macrophages. Although the magnitude of CD4+ T cell-induced macrophage NO production clearly depended on TNF, control of LVS growth by both CD4+ and CD8+ T cells did not correlate with levels of nitrite. Importantly, intramacrophage LVS growth control by CD8+ T cells, but not CD4+ T cells, was almost entirely dependent on T cell-expressed TNF, and required stimulation through macrophage TNFRs. Collectively, these data demonstrate that T cell-expressed memTNF is necessary and sufficient for memory T cell responses to this intracellular pathogen, and is particularly important for intramacrophage control of bacterial growth by CD8+ T cells.

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“…The TNF antibodies infliximab and adalimumab, for example, are or appear to be effective in the treatment of granulomatous conditions such as Crohn's disease and sarcoidosis, whereas soluble type II TNF receptor (etanercept) is not (3)(4)(5)(6). In vitro, TNF antibodies inhibit the activation of T cells and the production of interferon-␥, whereas etanercept does not (7,8). Both TNF antibody and its soluble receptor are deleterious in acute murine M tuberculosis infection, but only the antibody exacerbates chronic murine TB (9), a condition thought to be a model of latent infection in humans.…”

Section: Objective Tumor Necrosis Factor (Tnf) Blockade Increases Thmentioning

confidence: 99%

Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade

Wallis

2008

Arthritis & Rheumatism

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Objective. Tumor necrosis factor (TNF) blockade increases the risk of tuberculosis (TB). The purpose of this study was to use Markov modeling to examine the contributions of reactivation of latent tuberculous infection (LTBI) and the progression of new infection withMycobacterium tuberculosis to active TB due to TNF blockade. These 2 pathogenic mechanisms cannot otherwise be readily distinguished.Methods. Monte Carlo simulation was used to represent the range of reported values for the incidence of TB associated with infliximab (TNF monoclonal antibody) and etanercept (soluble TNF receptor) therapy. Iterative methods were then used to identify for each pair of incidence rates the Markov model parameters that most accurately represented the distribution of time to onset of TB as reported to the Food and Drug Administration.Results. Modeling revealed an apparent median monthly rate of reactivation of LTBI by infliximab treatment of 20.8%, which was 12.1 times that with etanercept treatment (P < 0.001). In contrast, both drugs appeared to pose a high risk of progression of new M tuberculosis infection to active TB. Progression of new infection appeared to cause nearly half of the etanercept-associated cases; it became the predominant cause of infliximab-associated cases only after the first year.Conclusion. Despite sharing a common therapeutic target, infliximab and etanercept differ markedly in the rates at which they reactivate LTBI. Confirmation of these findings will require the application of molecular epidemiologic tools to studies of TB in future biologics registries. Hidden Markov modeling and Monte Carlo simulation are powerful tools for revealing otherwise hidden aspects of the pathogenesis of TB.

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Tumor‐Necrosis‐Factor Blockers: Differential Effects on Mycobacterial Immunity

Abstract: The tuberculosis risk posed by infliximab may reflect its combined effects on TNF and IFN- gamma .

Cited by 170 publications

References 39 publications

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

Risk of tuberculosis is higher with anti–tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three‐year prospective french research axed on tolerance of biotherapies registry

Differential Requirements by CD4+ and CD8+ T Cells for Soluble and Membrane TNF in Control of Francisella tularensis Live Vaccine Strain Intramacrophage Growth

Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade

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