title: Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis.
abstract: OBJECTIVE
  To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA).
  
  
  METHODS
  Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan™ assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12weeks after treatment with methotrexate (MTX) for MTX-naïve RA patients (n=28) or with the biologics tocilizumab (TCZ) (n=7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method.
  
  
  RESULTS
  Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (ρ=0.51, p<0.01) and were significantly increased in patients with untreated active RA compared to HCs (p<0.01) or those with pSS (p<0.01). IL-16 levels decreased following treatment in both the MTX-naïve and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (ρ=0.89, p<0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups.
  
  
  CONCLUSIONS
  IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: atsukomurota@a3.keio.jp.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Murota
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: katsuyas@z5.keio.jp.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yoshiaki.kassai@takeda.com.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kassai
authors.affiliation: Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takahiro.miyazaki@takeda.com.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: rimpeim@a7.keio.jp.
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: yasutonko@yahoo.co.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: takeshita02@hotmail.com.
authors.forename: Masaru
authors.initials: M
authors.lastname: Takeshita
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: y-niki@keio.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Niki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: yoshimura@a6.keio.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8552, Japan. Electronic address: tsutake@z5.keio.jp.
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*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis* / Q000276:immunology; D001799:Blood Sedimentation; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use; D019410:Interleukin-16 / Q000097:blood*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D040901:Proteomics; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D001798:Blood Proteins; D019410:Interleukin-16; D000069594:Abatacept; D000069285:Infliximab; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C502936:tocilizumab; D008727:Methotrexate
keywords: Biomarker; Interleukin-16; Proteomics; Rheumatoid arthritis; Serum protein