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.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01313520.