title: Pretreatment Prediction of Individual Rheumatoid Arthritis Patients' Response to Anti-Cytokine Therapy Using Serum Cytokine/Chemokine/Soluble Receptor Biomarkers.
abstract: The inability to match rheumatoid arthritis (RA) patients with the anti-cytokine agent most efficacious for them is a major hindrance to patients’ speedy recovery and to the clinical use of anti-cytokine therapy. Identifying predictive biomarkers that can assist in matching RA patients with more suitable anti-cytokine treatment was our aim in this report. The sample consisted of 138 RA patients (naïve and non-naïve) who were administered tocilizumab or etanercept for a minimum of 16 weeks as a prescribed RA treatment. Pretreatment serum samples were obtained from patients and clinical measures of their disease activity were evaluated at baseline and 16 weeks after treatment commenced. Using patients’ pretreatment serum, we measured 31 cytokines/chemokines/soluble receptors and used multiple linear regression analysis to identify biomarkers that correlated with patients’ symptom levels (DAS28-CRP score) at week 16 and multiple logistic analyses for biomarkers that correlated with patients’ final outcome. The results revealed that sgp130, logIL-6, logIL-8, logEotaxin, logIP-10, logVEGF, logsTNFR-I and logsTNFR-II pretreatment serum levels were predictive of the week 16 DAS28-CRP score in naïve tocilizumab patients while sgp130, logGM-CSF and logIP-10 were predictive in non-naïve patients. Additionally, we found logIL-9, logVEGF and logTNF-α to be less reliable at predicting the week 16 DAS28-CRP score in naïve etanercept patients. Multiple linear regression and multiple logistic regression analyses identified biomarkers that were predictive of remission/non-remission in tocilizumab and etanercept therapy. Although less reliable than those for tocilizumab, we identified a few possible biomarkers for etanercept therapy. The biomarkers for these two therapies differ suggesting that their efficacy will vary for individual patients. We discovered biomarkers in RA pretreatment serum that predicted their week 16 DAS28-CRP score and clinical outcome to tocilizumab therapy. Most of these biomarkers, especially sgp130, are involved in RA pathogenesis and IL-6 signal transduction, which further suggests that they are highly reliable.
  
  
  BACKGROUND
  UMIN-CTR Clinical Trial UMIN000016298.
authors.affiliation: Department of Organic Fine Chemicals, Division of Biological and Molecular Sciences, The Institute of Scientific and Industrial Research, Osaka University, Suita, Osaka, Japan; Louis Pasteur Center for Medical Research, Kyoto, Kyoto, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Uno
authors.affiliation: Department of Organic Fine Chemicals, Division of Biological and Molecular Sciences, The Institute of Scientific and Industrial Research, Osaka University, Suita, Osaka, Japan; Tokushukai Medical Corporation, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshizaki
authors.affiliation: Higashi Hiroshima Memorial Hospital, Higashi Hiroshima, Hiroshima, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Iwahashi
authors.affiliation: Higashi Hiroshima Memorial Hospital, Higashi Hiroshima, Hiroshima, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Yamana
authors.affiliation: Higashi Hiroshima Memorial Hospital, Higashi Hiroshima, Hiroshima, Japan.
authors.forename: Seizo
authors.initials: S
authors.lastname: Yamana
authors.affiliation: Department of Organic Fine Chemicals, Division of Biological and Molecular Sciences, The Institute of Scientific and Industrial Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tanigawa
authors.affiliation: Louis Pasteur Center for Medical Research, Kyoto, Kyoto, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yagi
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood*; D018925:Chemokines / Q000097:blood*; D050822:Cytokine Receptor gp130 / Q000097:blood; D000068800:Etanercept / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D019707:Receptors, Chemokine / Q000097:blood*; D012044:Regression Analysis; D012074:Remission Induction; D012995:Solubility; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D018925:Chemokines; D019707:Receptors, Chemokine; D050822:Cytokine Receptor gp130; C502936:tocilizumab; D000068800:Etanercept