Ex vivo cell-based assay for assessment of response to TNF inhibitors in patients with rheumatic diseases.

Abstract

There are five TNF inhibitors (TNFis), whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of patients with rheumatic diseases may respond inadequately to TNFis. The downstream signalling of the various TNFis may determine their clinical efficacy. Several reports have shown that the different TNFis exhibited differential effects on Th17 cells. We analysed the effects of the various TNFis on IL-17A expression in peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases, in order to evaluate the possibility of predicting responses in an ex vivo setting. PBMCs were co-cultured with the various TNFis or medium (control), and IL-17A mRNA levels were analysed by quantitative PCR. IL-17A expression levels in response to four TNFis (not including certolizumab pegol) were compared with that of the control. The IL-17A expression level as determined by the assay was correlated with the clinical response. The assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. The results of the assay for a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the various TNFis with 89.5% accuracy. Our results indicated that the assay predicted the responses of a prospective cohort (n = 54) to specific TNFis with 79% accuracy. This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.