title: Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study.
abstract: According to EULAR recommendations, biologic DMARDs (bDMARDs) such as tumor necrosis factor inhibitor, tocilizumab (TCZ), and abatacept (ABT) are in parallel when prescribing to rheumatoid arthritis (RA) patients who have shown insufficient response to conventional synthetic DMARDs. However, most prediction studies of therapeutic response to bDMARDs using gene expression profiles were focused on a single bDMARD, and consideration of the results from the perspective of RA pathophysiology was insufficient. The aim of this study was to identify the specific molecular biological features predicting the therapeutic outcomes of three bDMARDs (infliximab [IFX], TCZ, and ABT) by studying blood gene expression signatures of patients before biologic treatment in a unified test platform.
  
  
  
  RA patients who responded inadequately to methotrexate and were later commenced on any one of IFX (n = 140), TCZ (n = 38), or ABT (n = 31) as their first biologic between May 2007 and November 2011 were enrolled. Whole-blood gene expression data were obtained before biologic administration. Patients were categorized into remission (REM) and nonremission (NON-REM) groups according to CDAI at 6 months of biologic therapy. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets differentially expressed between these two groups for each biologic. Then, we compiled "signature scores" for these gene sets, and the prediction performances were assessed.
  
  
  
  GSEA showed that inflammasome genes were significantly upregulated with IFX in the NON-REM group compared with the REM group. With TCZ in the REM group, B-cell-specifically expressed genes were upregulated. RNA elongation, apoptosis-related, and NK-cell-specifically expressed genes were upregulated with ABT in the NON-REM group. Logistic regression analyses showed that "signature scores" of inflammasomes, B-cell-specifically expressed, and NK-cell-specifically expressed genes were significant, independently predictive factors for treatment outcome with IFX, TCZ, and ABT, respectively. The AUCs of ROC curves of these signature scores were 0.637, 0.796, and 0.768 for IFX, TCZ, and ABT, respectively.
  
  
  
  We have identified original gene expression predictive signatures uniquely underlying the therapeutic effects of IFX, TCZ, and ABT. This is, to our knowledge, the first attempt to predict therapeutic effects of three drugs concomitantly using a unified gene expression test platform.
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan. nakamura@dna-chip.co.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iijima
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hata
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Chun Ren
authors.initials: CR
authors.lastname: Lim
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ishizawa
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Muguro-ku, Tokyo, 153-8515, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kameda
authors.affiliation: Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, 1981 Tsujido-machi Kamoda, Kawagoe-shi, Saitama, 350-8550, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Amano
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: DNA Chip Research Inc., 1-15-1 Kaigan, Suzuebaydium 5F, Minato-ku, Tokyo, 105-0022, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Matoba
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012372:ROC Curve; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D000069594:Abatacept; D000069285:Infliximab; C502936:tocilizumab
keywords: Gene expression; Prediction; Rheumatoid arthritis; bDMARDs (biologic agents)