title: Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) is characterized by gradual joint destruction. Tocilizumab (TCZ) significantly suppresses symptoms, however not all patients are protected from joint damage. We investigated whether early measurement of specific biomarkers could predict early joint protection response to tocilizumab.
  
  
  METHODS
  Serum biomarkers (CRPM, VICM, C1M, C2M, C3M (MMP-degraded CRP, vimentin type I, II and III collagen), CTX-I/OC (bone turnover), and CRP) were measured in 740 RA patients (the LITHE study) treated with Placebo, or 4 or 8 mg/kg TCZ. Early responders were those with ≥20 % improvement in SJC or TJC by week 16. The biomarkers' predictability of response was investigated by AUROC and classification regression tree analysis.
  
  
  RESULTS
  The best biomarker predictability for identification of TCZ responders were; baseline CTX-I/OC (AUC 0.66, p = 0.0005) and changes in C1M (AUC 0.67, p = 0.0072), C2M (AUC 0.72, p = 0.0002), C3M (AUC 0.63, p = 0.018) and the combination of biomarkers (AUC 0.81, p = 0.0025). Patients with high bone turnover (CTX-I/OC) and low C2M were 6.8-fold (p = 0.003) more likely to have an early response to TCZ.
  
  
  CONCLUSIONS
  This enhanced pharmacodynamic (PD) response enabled identification of early responders with a superior TCZ clinical benefit. This biomarker model may assist in the identification of TCZ responsive RA patients and thus potentially benefit individual patients.
  
  
  BACKGROUND
  Clinicaltrials.gov: NCT00106535 . JAN 2005.
authors.affiliation: Biomarkers and Research, Nordic Bioscience, Herlev Hovedgade 207, 2730, Herlev, Denmark. acbj@nordicbioscience.com.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Bay-Jensen
authors.affiliation: Roche Products Ltd., Welwyn Garden City, UK. adamplatt@btinternet.com.|Present Address: AstraZeneca UK Ltd., Cheshire, UK. adamplatt@btinternet.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
authors.affiliation: Biomarkers and Research, Nordic Bioscience, Herlev Hovedgade 207, 2730, Herlev, Denmark. aso@nordicbioscience.com.
authors.forename: Anne Sofie
authors.initials: AS
authors.lastname: Siebuhr
authors.affiliation: Clinical Development, Nordic Bioscience, Herlev, Denmark. cc@nordicbioscience.com.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Biomarkers and Research, Nordic Bioscience, Herlev Hovedgade 207, 2730, Herlev, Denmark. ib@nordicbioscience.com.|Clinical Development, Nordic Bioscience, Herlev, Denmark. ib@nordicbioscience.com.
authors.forename: Inger
authors.initials: I
authors.lastname: Byrjalsen
authors.affiliation: Biomarkers and Research, Nordic Bioscience, Herlev Hovedgade 207, 2730, Herlev, Denmark. mk@nordicbioscience.com.
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C502936:tocilizumab