PMID- 29556418
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220316
IS  - 2056-5933 (Print)
IS  - 2056-5933 (Electronic)
IS  - 2056-5933 (Linking)
VI  - 4
IP  - 1
DP  - 2018
TI  - Identification of sarilumab pharmacodynamic and predictive markers in patients 
      with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 
      TARGET study.
PG  - e000607
LID - 10.1136/rmdopen-2017-000607 [doi]
LID - e000607
AB  - INTRODUCTION: Interleukin-6 (IL-6) orchestrates formation of an inflammatory 
      pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a 
      human monoclonal antibody blocking the IL-6Ralpha. In TARGET (NCT01709578), a phase 3 
      study in adults with moderate-to-severe RA and inadequate response or intolerance 
      to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg 
      every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic 
      drugs (csDMARDs) significantly reduced disease activity versus placebo plus 
      csDMARDs. METHODS: Circulating levels of biomarkers associated with synovial 
      inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved 
      fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble 
      intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid 
      activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating 
      factor) and bone remodelling (receptor activator of nuclear factor-kappaB ligand 
      (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a 
      TARGET substudy. RESULTS: Sarilumab significantly decreased C1M, C3M, CXCL13, 
      MMP-3 and total RANKL levels at week 24 versus placebo; some markers were 
      significantly suppressed at week 2 and normalised to levels in healthy controls. 
      Levels of sICAM-1 were predictive of disease activity score by C-reactive protein 
      and clinical disease activity index low disease activity (LDA) response in the 
      sarilumab 200 mg q2w group at week 12. A trend was observed in which patients 
      with lower sICAM-1 levels at baseline had better response compared with patients 
      with higher sICAM-1. CONCLUSIONS: Sarilumab plus csDMARDs decreased circulating 
      biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive 
      of achieving LDA with sarilumab. TRIAL REGISTRATION NUMBER: NCT01709578; 
      Post-results.
FAU - Gabay, Cem
AU  - Gabay C
AD  - University Hospitals of Geneva, Geneva, Switzerland.
FAU - Msihid, Jerome
AU  - Msihid J
AD  - Sanofi R&D, Chilly-Mazarin, France.
FAU - Zilberstein, Moshe
AU  - Zilberstein M
AD  - Sanofi R&D, Bridgewater, New Jersey, USA.
FAU - Paccard, Caroline
AU  - Paccard C
AD  - Sanofi R&D, Chilly-Mazarin, France.
FAU - Lin, Yong
AU  - Lin Y
AD  - Sanofi Genzyme, Bridgewater, New Jersey, USA.
FAU - Graham, Neil M H
AU  - Graham NMH
AD  - Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
FAU - Boyapati, Anita
AU  - Boyapati A
AD  - Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01709578
PT  - Journal Article
DEP - 20180314
PL  - England
TA  - RMD Open
JT  - RMD open
JID - 101662038
PMC - PMC5856917
OTO - NOTNLM
OT  - *dmards (biologic)
OT  - *rheumatoid arthritis
OT  - *treatment
COIS- Competing interests: CG has received consulting fees from Roche, Merck, AbbVie, 
      Pfizer, Bristol-Myers Squibb, Sanofi and AB2 Bio. JM, MZ and CP are employees of 
      Sanofi R&D and may hold stock and/or stock options in the company. YL is an 
      employee of Sanofi Genzyme and may hold stock and/or stock options in the 
      company. NMHG and AB are employees of Regeneron Pharmaceuticals, Inc, and may 
      hold stock and/or stock options in the company.
EDAT- 2018/03/21 06:00
MHDA- 2018/03/21 06:01
PMCR- 2018/03/14
CRDT- 2018/03/21 06:00
PHST- 2017/10/26 00:00 [received]
PHST- 2018/01/23 00:00 [revised]
PHST- 2018/02/15 00:00 [accepted]
PHST- 2018/03/21 06:00 [entrez]
PHST- 2018/03/21 06:00 [pubmed]
PHST- 2018/03/21 06:01 [medline]
PHST- 2018/03/14 00:00 [pmc-release]
AID - rmdopen-2017-000607 [pii]
AID - 10.1136/rmdopen-2017-000607 [doi]
PST - epublish
SO  - RMD Open. 2018 Mar 14;4(1):e000607. doi: 10.1136/rmdopen-2017-000607. eCollection 
      2018.