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Why does tumor necrosis factor targeted therapy reactivate tuberculosis?
1Molecular Infection Biology Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany. sehlers@fz-borstel.de
The Journal of Rheumatology. Supplement
|March 3, 2005
Summary
Tumor necrosis factor (TNF) biologics for inflammatory diseases increase infection risk, particularly tuberculosis (TB). Monoclonal antibodies like infliximab pose a higher TB reactivation risk than etanercept, suggesting differential mechanisms of action.
Area of Science:
- Immunology
- Pharmacology
- Infectious Diseases
Background:
- Biologic therapies targeting tumor necrosis factor (TNF) are effective for chronic inflammatory conditions like rheumatoid arthritis and Crohn's disease.
- These TNF-targeted biologics are associated with an elevated risk of infectious complications, notably tuberculosis (TB).
- Clinical observations indicate a higher incidence of TB reactivation with monoclonal anti-TNF antibodies (e.g., infliximab) compared to TNF receptor fusion constructs (e.g., etanercept).
Purpose of the Study:
- To explore potential explanations for the observed differential risk of TB reactivation between different classes of TNF-targeted biologics.
- To review existing experimental and clinical data regarding TNF's role in host defense against tuberculosis.
- To propose and discuss hypotheses addressing the unpredicted differences in infectious complication risks associated with infliximab and etanercept.
Main Methods:
- Review of clinical studies comparing TB reactivation rates for infliximab and etanercept.
- Analysis of experimental studies investigating the role of TNF in granuloma formation and host defense.
- Examination of the pharmacological properties and mechanisms of action of prototype TNF-targeted biologics.
Main Results:
- TNF is crucial for protective granuloma formation, a key component in controlling tuberculosis.
- Monoclonal anti-TNF antibodies (infliximab) appear to carry a greater risk of TB reactivation than TNF receptor fusion constructs (etanercept).
- The differential risk is not fully explained by current understanding, necessitating further investigation.
Conclusions:
- The differential risk of TB reactivation associated with TNF-targeted biologics may stem from distinct effects on target cells, receptor signaling, or overall TNF bioavailability.
- Hypotheses include differential induction of target cell death, differential TNF receptor signaling pathways, and differential net inhibition of TNF bioavailability.
- Further research is needed to elucidate these mechanisms and optimize the safe use of TNF-targeted therapies in patients at risk for tuberculosis.