title: IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis.
abstract: OBJECTIVE
  To determine whether heterogeneity in interleukin-6 (IL-6), IL-6 receptor and other components of the IL-6 signalling pathway/network, at the gene, transcript and protein levels, correlate with disease activity in patients with rheumatoid arthritis (RA) and with clinical response to tocilizumab.
  
  
  METHODS
  Biomarker samples and clinical data for five phase 3 trials of tocilizumab were analysed using serum (3751 samples), genotype (927 samples) and transcript (217 samples) analyses. Linear regression was then used to assess the association between these markers and either baseline disease activity or treatment response.
  
  
  RESULTS
  Higher baseline serum IL-6 levels were significantly associated (p<0.0001) with higher baseline DAS28, erythrocyte sedimentation rate, C reactive protein and Health Assessment Questionnaire in patients whose responses to disease-modifying antirheumatic drugs (DMARD-IR) and to antitumour necrosis factor (aTNF-IR) were inadequate and patients who were naive/responders to methotrexate (MTX). Higher baseline serum IL-6 levels were also significantly associated with better clinical response to tocilizumab (versus placebo) measured by cDAS28 in the pooled DMARD-IR (p<0.0001) and MTX-naive populations (p=0.04). However, the association with treatment response was weak. A threefold difference in baseline IL-6 level corresponded to only a 0.17-unit difference in DAS28 at week 16. IL-6 pathway single nucleotide polymorphisms and RNA levels also were not strongly associated with treatment response.
  
  
  CONCLUSIONS
  Our analyses illustrate that the biological activity of a disease-associated molecular pathway may impact the benefit of a therapy targeting that pathway. However, the variation in pathway activity, as measured in blood, may not be a strong predictor. These data suggest that the major contribution to variability in clinical responsiveness to therapeutics in RA remains unknown.
authors: Roche Products Ltd, Welwyn Garden City, UK.
authors: Jianmei
authors: J
authors: Wang
authors: Adam
authors: A
authors: Platt
authors: Ruchi
authors: R
authors: Upmanyu
authors: Søren
authors: S
authors: Germer
authors: Guiyuan
authors: G
authors: Lei
authors: Christina
authors: C
authors: Rabe
authors: Ryma
authors: R
authors: Benayed
authors: Andrew
authors: A
authors: Kenwright
authors: Andrew
authors: A
authors: Hemmings
authors: Mitchell
authors: M
authors: Martin
authors: Olivier
authors: O
authors: Harari
keywords: Immunology; Rheumatology
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