title: Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.
abstract: OBJECTIVE
  To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant Ktrans, in a multicentre trial setting.
  
  
  METHODS
  DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated.
  
  
  RESULTS
  At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. Ktransintra-subject coefficient of variation (N = 14) was 30%. Ktranschange demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks.
  
  
  CONCLUSIONS
  This demonstrated repeatability of Ktransand its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials.
  
  
  CONCLUSIONS
  • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI Ktransshowed fostamatinib inferior to adalimumab after 6 weeks. • Ktransrepeatability coefficient of variation was 30% multicentre.
authors.affiliation: Manchester Academic Health Sciences Centre, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. john.waterton@manchester.ac.uk.|Personalised Healthcare & Biomarkers, AstraZeneca, Macclesfield, UK. john.waterton@manchester.ac.uk.
authors.forename: John C
authors.initials: JC
authors.lastname: Waterton
authors.affiliation: Global Medicines Development, AstraZeneca, Macclesfield, UK.
authors.forename: Meilien
authors.initials: M
authors.lastname: Ho
authors.affiliation: Global Medicines Development, AstraZeneca, Mölndal, Sweden.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Nordenmark
authors.affiliation: Global Medicines Development, AstraZeneca, Cambridge, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Jenkins
authors.affiliation: Spire Sciences Inc, Boca Raton, FL, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: DiCarlo
authors.affiliation: Imorphics, Manchester, UK.
authors.forename: Gwenael
authors.initials: G
authors.lastname: Guillard
authors.affiliation: Bioxydyn, Manchester, UK.
authors.forename: Caleb
authors.initials: C
authors.lastname: Roberts
authors.affiliation: Bioxydyn, Manchester, UK.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Buonaccorsi
authors.affiliation: Manchester Academic Health Sciences Centre, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.|Bioxydyn, Manchester, UK.
authors.forename: Geoffrey J M
authors.initials: GJM
authors.lastname: Parker
authors.affiliation: Imorphics, Manchester, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bowes
authors.affiliation: Spire Sciences Inc, Boca Raton, FL, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Peterfy
authors.affiliation: Private Practice and Division of Rheumatology KHI Neuwittelsbach, München, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Kellner
authors.affiliation: Kennedy Institute, University of Oxford, Oxford, UK.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000631:Aminopyridines; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D005260:Female; D006225:Hand / Q000000981:diagnostic imaging; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines; D015203:Reproducibility of Results; D014955:Wrist Joint / Q000000981:diagnostic imaging
chemical_list: D000631:Aminopyridines; D015415:Biomarkers; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D000068879:Adalimumab; C523665:fostamatinib
keywords: Adalimumab; Arthritis, rheumatoid; Biological markers; Fostamatinib; Magnetic resonance imaging