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.

• Authors: Yoshie Sanayama, Kei Ikeda, Yukari Saito, Shin-Ichiro Kagami, Mieko Yamagata, Shunsuke Furuta, Daisuke Kashiwakuma, Itsuo Iwamoto, Takeshi Umibe, Yasushi Nawata, Ryutaro Matsumura, Takao Sugiyama, Makoto Sueishi, Masaki Hiraguri, Ken Nonaka, Osamu Ohara, Hiroshi Nakajima
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 66 Issue 6 Pg. 1421-31 (Jun 2014) ISSN: 2326-5205 [Electronic] United States
• PMID: 24591094 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American College of Rheumatology.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Biomarkers
• Interferon Type I
• Metallothionein
• tocilizumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Arthritis, Rheumatoid (blood, drug therapy, physiopathology)
• Biomarkers (metabolism)
• Case-Control Studies
• Female
• Gene Expression Regulation (genetics)
• Humans
• Interferon Type I (blood, genetics, physiology)
• Leukocytes, Mononuclear (metabolism)
• Male
• Metallothionein (blood, genetics, physiology)
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Predictive Value of Tests
• Prospective Studies
• Reproducibility of Results
• Treatment Outcome