title: Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab.
abstract: BACKGROUND
  Treat-to-target strategies to achieve low disease activity or clinical remission are key in the treatment of rheumatoid arthritis (RA). 14-3-3η is a joint-derived biomarker that is expressed at significantly higher levels in patients with RA than in healthy subjects, other autoimmune diseases, or viral and bacterial arthritides. In this study, we sought to investigate the utility of pretreatment levels of 14-3-3η and serial measurement of 14-3-3η to inform therapeutic outcomes.
  
  
  METHODS
  Serum 14-3-3η levels were measured in 149 Japanese patients with RA before the initiation of therapy and at 1-year follow-up. Patients were treated with either methotrexate (MTX), adalimumab (ADA), tocilizumab (TCZ), or tofacitinib (TOF). 14-3-3η positivity was defined as ≥0.19 ng/ml and at two times and four times this cutoff. In contingency analysis, we determined the association of 14-3-3η with disease severity. Wilcoxon matched-pairs test was used to evaluate the significance of pre- to post-treatment changes. Mann-Whitney U test was performed for differences between treatment response groups. Fisher's exact test was used to assess associations of 14-3-3η with a good response defined by European League Against Rheumatism criteria as well as remission defined by the Disease activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) and the Clinical Disease Activity Index score.
  
  
  RESULTS
  14-3-3η-positive patients had more severe disease before the initiation of treatment. When combined with C-reactive protein (CRP), 14-3-3η positivity added significantly and incrementally to the identification of patients with high disease activity. 14-3-3η levels were significantly decreased at 1 year and were modifiable across all classes of therapeutics. Patients who reverted to negative 14-3-3η levels had better clinical response than patients who remained positive at 1 year or became positive. Pretreatment 14-3-3η levels informed 1-year DAS28-ESR remission in the TCZ-treated group, in contrast to the ADA, MTX, or TOF groups, while no differences in pretreatment 14-3-3η expression based on clinical response.
  
  
  CONCLUSIONS
  14-3-3η is a modifiable marker in identifying patients with RA in a high disease state. Patients who achieve a negative 14-3-3η status following 1-year of treatment do better clinically with pretreatment 14-3-3η informing response to TCZ.
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan. s-hirata@med.uoeh-u.ac.jp.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hirata
authors.affiliation: Augurex Life Sciences Corporation, Vancouver, BC, Canada. amarotta@augurex.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marotta
authors.affiliation: Augurex Life Sciences Corporation, Vancouver, BC, Canada. ygui@augurex.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gui
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan. hanami@med.uoeh-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hanami
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu, 807-8555, Japan. tanaka@med.uoeh-u.ac.jp.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D048948:14-3-3 Proteins / Q000097:blood*; 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*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D048948:14-3-3 Proteins; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; C502936:tocilizumab