Prediction of Therapeutic Responses to Tocilizumab in Patients With Rheumatoid Arthritis: Biomarkers Identified by Analysis of Gene Expression in Peripheral Blood Mononuclear Cells Using Genome‐Wide DNA Microarray

Abstract

Objective. The aim of this prospective multicenter study was to identify biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with rheumatoid arthritis (RA).Methods. We recruited patients with RA who were treated with tocilizumab for the first time, and determined therapeutic responses at 6 months. In the training cohort (n ‫؍‬ 40), gene expression in peripheral blood mononuclear cells (PBMCs) at baseline was analyzed using genome-wide DNA microarray, with 41,000 probes derived from 19,416 genes. In the validation cohort (n ‫؍‬ 20), expression levels of the candidate genes in PBMCs at baseline were determined using real-time quantitative polymerase chain reaction (qPCR) analysis.Results. We identified 68 DNA microarray probes that showed significant differences in signal intensity between nonresponders and responders in the training cohort. Nineteen putative genes were selected, and a significant correlation between the DNA microarray signal intensity and the qPCR relative expression was confirmed in 15 genes. In the validation cohort, a significant difference in relative expression between nonresponders and responders was reproduced for 3 type I interferon response genes (IFI6, MX2, and OASL) and MT1G. Receiver operating characteristic curve analysis of models incorporating these genes showed that the maximum area under the curve was 0.947 in predicting a moderate or good response to tocilizumab in the validation cohort.Conclusion. Using genome-wide DNA microarray analyses, we identified candidate biomarkers that can be used to predict therapeutic responses to tocilizumab in patients with RA. These findings suggest that type I interferon signaling and metallothioneins are involved in the pathophysiology of RA.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, which

Assessment of immune status using blood transcriptomics and potential implications for global health

“…This trend accelerated for Rheumatoid Arthritis and Multiple Sclerosis with counts nearing 40 in 2014, but on the other hand stagnated for Lupus with only 3 new studies added between 2010 and 2014, with a count of 23 studies to date. These differences can largely be attributed to the fact that investigations of Rheumatoid Arthritis and Multiple Sclerosis shifted from examining changes associated with disease processes to the investigation of mechanism of action of recently introduced biological drugs and especially the identification of markers predicting response to therapy [24][25][26][27]. No such treatment modalities are available to date for the treatment of patients with Lupus and the few recent studies have for the most part focused instead on patient stratification [28][29][30].…”

Pathogenetic insights from the treatment of rheumatoid arthritis

“…Thereafter, a series of elegant studies using either arthroscopic or ultrasound guided synovial [21]. Synovial studies are more limited but demonstrate that IL-6R blockade leads to reduction in T cell activation markers and chemokine expression but also induced pro-repair gene sets [22].…”

SPECT imaging of interleukin-6 receptor in ovarian tumor xenografts with a novel radiotracer of 99mTc-HYNIC-Aca-LSLITRL

“…However, almost none of parameters provide an objective and early analysis of a therapeutic effect for above IL-6/IL-6R pathway targeting drugs. Recently, Nishina N suggested that baseline levels of soluble interleukin-6 receptor could be considered as one of the predictors when using molecular targeted therapy (Sanayama et al 2014). However, previous reports have showed that baseline levels of sIL-6R predicted clinical remission in RA patients treated with tocilizumab without showing associations with disease activity.…”