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. Trial Registration: ClinicalTrials.gov NCT01313520

Synovial volume vs synovial measurements from dynamic contrast enhanced MRI as measures of response in osteoarthritis

“…The histological features correlated with contrast enhancement include infiltration of inflammatory cells into the sub-synovial layer and especially vascular proliferation. DCE-MRI has also demonstrated a response to various different treatments in RA 11 , 12 , 13 , 14 . It has also been used to investigate OA in the hand 15 where it has shown a response to treatment in erosive OA of the interphalangeal joints 16 .…”

Magnetic resonance imaging of Hoffa's fat pad and relevance for osteoarthritis research: a narrative review

“…DCE-MRI has been used to evaluate tissue perfusion and has mainly been applied in oncology. In musculoskeletal research, DCE-MRI has been used as an alternative method for the quantification of synovitis in order to assess therapeutic response and disease progression in inflammatory diseases such as rheumatoid arthritis 47,48 . DCE-MRI is based on a sequential acquisition of rapid T1-weighted MR sequences before and during the intravenous administration of a gadolinium-based contrast agent.…”

Molecular profiling of rheumatoid arthritis patients reveals an association between innate and adaptive cell populations and response to anti-tumor necrosis factor

“…Some of the differences among their results might be attributed to the diversity of the gene arrays [14, 15] and definitions of response to the treatment [14, 16, 17]. Findings from more recent investigations of the relationship between baseline gene expression profiles of blood samples from RA patients and their response to treatment with TNF inhibitors are also mixed, with one study reporting associations between non-response and increased plasma and B cell markers [19], whereas another finds a lack of consistent differences between co-expression patterns for good and poor responders across multiple patient cohorts [12].…”