Biomarkers for prediction of TNFα blockers response in rheumatoid arthritis

Abstract

Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that plays pivotal roles in regulating the inflammatory response in rheumatoid arthritis (RA). Intensive studies on TNFα-driven inflammation processes have led to the development of TNFα blockers for RA treatment. However, response to these therapies is heterogeneous with roughly two-thirds of patient response and one-third non-response. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for TNFα blocker therapy, there is a strong need to identify predictors of response prior to start the TNFα blocker therapy. Here we review several studies focused on predicting the response to TNFα blockers. Demographic, clinical, radiological, blood, genetic or synovial tissue biomarkers were studied to find some predictive biomarkers of TNFα blocker response. Unfortunately, results from these studies are heterogeneous. Discrepancy between these studies can be explained in part to the heterogeneity between the studies. As difference in the response criteria used, the delay of efficacy for the primary endpoint, and the genetic background of each population were all observed. Nevertheless, a high local and systemic level of TNFα prior to TNFα blocker therapy seems to be associated with a good clinical response. However, to validate these results, additional studies using independent and large cohorts are needed.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which predominantly involves synovial tissues and affects roughly 0.5% of the French population. The last 10 years have led us to recognize tumor necrosis factor alpha (TNFα) as one of the key cytokines involved in the pathogenesis of RA. Such results have provided the basis for the development of TNFα blockers for treating RA when methotrexate fails. Currently, three TNFα blockers are available in clinical practice: infliximab (a chimeric monoclonal antibody), adalimumab (a human monoclonal antibody), and etanercept (a fusion protein consisting of a dimer of the extracellular portion of p75 TNFα receptor linked to the Fc portion of human IgG1). Etanercept is also able to bind to lymphotoxin α (LTA). Roughly all TNFα blockers are efficient in two-thirds of patients, but this means that one-third of patients fail to respond to TNFα blocker therapy. In addition to the clinical effect, it was observed that TNFα blockers prevent joint [1] and bone destruction [2]. Despite their efficiency, the use of TNFα blockers exposes patients to some risks (infectious, neoplastic, allergic, etc.) that seem disproportional, especially if the patient might not respond to the therapy. Therefore, identifying biomarkers that predict responses to TNFα blockers are crucial for optimizing patient selection and increasing the balance between benefit and risk. This personalized form of medicine will also become increasingly advantageous as the number of available drugs grows. In addition, this prediction is also an economic issue at this time where costs need to be reduced.

As the prediction of response to TNFα blockers is a key issue, extensive biomarker analysis was performed using several complex methods to identify one or more biomarkers, which should be then easy to assess in the daily practice. Here we will review these studies performed to predict the response to TNFα blockers in RA. We will order this review according the following markers: demographic, clinical and radiological parameters; blood biomarkers; genetic markers and synovial markers.