title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Chiba University Hospital, Chiba, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Sanayama
authors.forename: Kei
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yukari
authors.initials: Y
authors.lastname: Saito
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kagami
authors.forename: Mieko
authors.initials: M
authors.lastname: Yamagata
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Furuta
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kashiwakuma
authors.forename: Itsuo
authors.initials: I
authors.lastname: Iwamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Umibe
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nawata
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Matsumura
authors.forename: Takao
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Sueishi
authors.forename: Masaki
authors.initials: M
authors.lastname: Hiraguri
authors.forename: Ken
authors.initials: K
authors.lastname: Nonaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakajima
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000097:blood* / Q000235:genetics / Q000502:physiology; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000097:blood* / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D007370:Interferon Type I; D008668:Metallothionein; C502936:tocilizumab