Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability

• Published in: The Journal of immunology (1950) Vol. 188; no. 7; pp. 3169 - 3178
• Main Authors: Fallahi-Sichani, Mohammad, Flynn, JoAnne L, Linderman, Jennifer J, Kirschner, Denise E
• Format: Journal Article
• Language: English
• Published: England 01.04.2012
• Subjects: Adalimumab; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - blood; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antirheumatic Agents - adverse effects; Antirheumatic Agents - blood; Antirheumatic Agents - classification; Antirheumatic Agents - pharmacokinetics; Apoptosis - drug effects; Certolizumab Pegol; Computer Simulation; Cytotoxicity, Immunologic; Etanercept; Humans; Immunoglobulin Fab Fragments - adverse effects; Immunoglobulin Fab Fragments - blood; Immunoglobulin G - adverse effects; Immunoglobulin G - blood; Infliximab; Latent Tuberculosis - immunology; Latent Tuberculosis - physiopathology; Models, Biological; Mycobacterium; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - immunology; Permeability; Polyethylene Glycols - adverse effects; Polyethylene Glycols - pharmacokinetics; Protein Binding; Receptors, Tumor Necrosis Factor - blood; Receptors, Tumor Necrosis Factor - drug effects; Receptors, Tumor Necrosis Factor - physiology; Risk; Tuberculoma - immunology; Tuberculoma - microbiology; Tuberculoma - physiopathology; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - physiopathology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1103298

Increased rates of tuberculosis (TB) reactivation have been reported in humans treated with TNF-α (TNF)-neutralizing drugs, and higher rates are observed with anti-TNF Abs (e.g., infliximab) as compared with TNF receptor fusion protein (etanercept). Mechanisms driving differential reactivation rates and differences in drug action are not known. We use a computational model of a TB granuloma formation that includes TNF/TNF receptor dynamics to elucidate these mechanisms. Our analyses yield three important insights. First, drug binding to membrane-bound TNF critically impairs granuloma function. Second, a higher risk of reactivation induced from Ab-type treatments is primarily due to differences in TNF/drug binding kinetics and permeability. Apoptotic and cytolytic activities of Abs and pharmacokinetic fluctuations in blood concentration of drug are not essential to inducing TB reactivation. Third, we predict specific host factors that, if augmented, would improve granuloma function during anti-TNF therapy. Our findings have implications for the development of safer anti-TNF drugs to treat inflammatory diseases.