title: Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab-treated rheumatoid arthritis patients.
abstract: Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response. Sixty-one patients with active RA despite methotrexate treatment, and with MRI-documented synovitis, were randomized to receive infliximab or placebo. Blood was collected at baseline and genome-wide transcription in whole blood was measured using microarrays. The primary endpoint in this study was determined by measuring the transfer rate constant (Ktrans) of a gadolinium-based contrast agent from plasma to synovium using MRI. Secondary endpoints included repeated clinical assessments with DAS28(CRP), and assessments of osteitis and synovitis by the RAMRIS method. Infliximab showed greater decrease from baseline in DCE-MRI Ktrans of wrist and MCP at all visits compared with placebo (P<0.001). Statistical analysis was performed to identify genes associated with treatment-specific 14-week change in Ktrans. The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient. The resulting score correlated with improvement of Ktrans in infliximab-treated patients and with deterioration of Ktrans in placebo-treated subjects. Poor responders showed high expression of activated B-cell genes whereas good responders exhibited a gene expression pattern consistent with mobilization of neutrophils and monocytes and high levels of reticulated platelets. This gene signature was significantly associated with clinical response in two previously published whole blood gene expression studies using anti-TNF therapies. These data provide support for the hypothesis that anti-TNF inadequate responders comprise a distinct molecular subtype of RA characterized by differences in pre-treatment blood mRNA expression. They also highlight the importance of placebo controls and robust, objective endpoints in biomarker discovery.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01313520.
authors.affiliation: Merck & Co. Inc., Department of Genetics and Pharmacogenomics, Boston, Massachusetts, United States of America.
authors.forename: Kenzie D
authors.initials: KD
authors.lastname: MacIsaac
authors.affiliation: Merck & Co. Inc., Department of Biometrics Research, Whitehouse Station, New Jersey, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Merck & Co. Inc., Department of Biometrics Research, Whitehouse Station, New Jersey, United States of America.
authors.forename: Jia
authors.initials: J
authors.lastname: Kang
authors.affiliation: Merck & Co. Inc., Department of Genetics and Pharmacogenomics, Boston, Massachusetts, United States of America.
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.affiliation: Spire Sciences Inc., Boca Raton, Florida, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Peterfy
authors.affiliation: Spire Sciences Inc., Boca Raton, Florida, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: DiCarlo
authors.affiliation: Virtual Scopics, Rochester, New York, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Riek
authors.affiliation: Merck & Co. Inc., Clinical Research, Whitehouse Station, New Jersey, United States of America.
authors.forename: Chan
authors.initials: C
authors.lastname: Beals
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000069285:Infliximab; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D017423:Sequence Analysis, RNA; D016896:Treatment Outcome; D014953:Wrist / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab