There are currently five approved “biologic” drug therapies that target tumor necrosis factor (TNF) in rheumatoid arthritis. A cytokine, TNF, promotes the normal inflammatory response to pathogen or injury. In people with rheumatoid arthritis, scientists postulate that a surfeit of TNF leads to synovial inflammation due to increased white cells in and around the joints. The central role of TNF in rheumatoid arthritis has been confirmed by the efficacy of TNF antagonists adalimumab, infliximab, and etanercept. Adalimumab and infliximab are monoclonal antibodies that block TNF receptors on cell surfaces to render TNF ineffective. Etanercept is a fusion protein comprising a human lgG1 Fe fragment linked to two extracellular portions of the human p75 TNF receptor (TNF-R) 2. Etanercept binds with circulating TNF to render it inactive before it even gets to receptors.1
Although all these compounds target TNF, some differences in their clinical effectiveness have been observed. For example, etanercept, while effective in rheumatoid arthritis, is not effective in inflammatory bowel disease, while both inflixamab and adalimumab are effective. This observation suggests that TNF neutralization may not be the only mechanism of action of these agents and has led to questions regarding differences in the pharmacology of these biologic approaches to TNF inhibition.2
This would help to explain why approximately one-third of patients with rheumatoid arthritis do not respond to one or another of these compounds but generally will respond given the “right one” for them. Currently, clinicians have no scientific way to select one biologic treatment over another and proceed via trial and error — using patient response as a means to judge which compound to prescribe. This process is inefficient, inflates system costs, and can reduce valuable time to treatment for patients, leading to permanent joint damage. A diagnostic that would predict response — administered in advance of drug selection — would be beneficial.
One recent study used quantitative proteomic methods to find protein biomarkers predictive of outcome in rheumatoid arthritis patients treated with infliximab. The study combined depletion of the most abundant serum proteins, two-dimensional liquid crystal fractionation, protein identification, and relative quantification with a hybrid Orbitrap mass spectrometer (Thermo Scientific). This approach allowed them to identify 315 proteins, 237 of which were confidently quantified with two or more peptides. The team identified a set of 14 potential biomarker proteins significantly more abundant in patients who did not respond to infliximab treatment. These proteins were more abundant in apolipoproteins, components of the complement system and acute phase reactants, providing a set of candidates for a diagnostic that might classify rheumatoid arthritis patients before treatment so that anticipated nonresponders are prescribed an alternate to infliximab.4 Companion testing for efficacy for all TNF-blocker drugs would bring rheumatoid arthritis treatment into the realm of personalized medicine.
1. Taylor, P.C. (2010) ‘Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases‘, Current Opinion in Pharmacology, 10 (3), (pp. 308-315)
2. Tracey, D., et al. (2007) ‘Tumor necrosis factor antagonist mechanisms of action: A comprehensive review‘, Pharmacology & Therapeutic, 117 (2), (pp. 44-279)
3. Kaymakcalan, Z., et al. (2009) ‘Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor‘, Clinical Immunology, 131 (2), (pp. 308—316)
4. Ortea, I., et al. (2012) ‘Discovery of serum proteomic biomarkers for prediction of response to infliximab (a monoclonal anti-TNF antibody) treatment in rheumatoid arthritis‘, Journal of Proteomics, 77, (pp. 372-382)