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.

Kenzie D Macisaac,Chan Beals,Andrey Loboda,Charles Peterfy,Jonathan Riek,Julie Dicarlo,Richard Baumgartner,Jia Kang,Arvind Chopra

doi:10.1371/journal.pone.0113937

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. Trial Registration: ClinicalTrials.gov NCT01313520

Highlights

Anti-TNF biologics are an important class of therapeutics in the treatment of rheumatoid arthritis, but approximately 30% of patients achieve inadequate response
Given the gradual reduction of Ktrans of wrist with infliximab over time, we examined the association of the signature score with 4 week change in Ktrans, and found that the gene signature was statistically associated with 4-week change in Ktrans data (p56.1e-3 signature main effect, p54.7e-3 signature by treatment interaction term)
In the infliximab treatment arm we examined the distribution of signature scores across EULAR response categories [18]

Summary

Introduction

Anti-TNF biologics are an important class of therapeutics in the treatment of rheumatoid arthritis, but approximately 30% of patients achieve inadequate response. Hypothesizing that inadequate responders constitute a distinct molecular subtype, several blood gene expression studies have been undertaken to identify gene expression-based biomarkers predicting response to anti-TNF [2,3,4,5,6,7,8,9]. The generally poor validation of published signatures is perhaps not surprising since the signatures tested were not derived from consistent patient populations or blood cell fractions In these studies response was assessed using composite disease activity scores like the DAS28 or American College of Rheumatology (ACR) response criteria. Since these endpoints are known to be subject to large placebo effects [11], inclusion of appropriate placebo controls may be crucial for successful biomarker discovery. None of these studies included a placebo control, confounding true responders and patients with flaring disease that subsequently subsides in a treatment-independent manner

Methods

Results

Discussion

Conclusion