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Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

ABSTRACT: OBJECTIVES: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 K trans , 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. K trans intra-subject coefficient of variation (N?=?14) was 30%. K trans change 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. CONCLUSION:This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS:• DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

SUBMITTER: Waterton JC

PROVIDER: S-EPMC5544811 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

Waterton John C JC Ho Meilien M Nordenmark Lars H LH Jenkins Martin M DiCarlo Julie J Guillard Gwenael G Roberts Caleb C Buonaccorsi Giovanni G Parker Geoffrey J M GJM Bowes Michael A MA Peterfy Charles C Kellner Herbert H Taylor Peter C PC

European radiology 20170123 9

<h4>Objectives</h4>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 K <sup>trans</sup> , in a multicentre trial setting.<h4>Methods</h4>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 synovit ...[more]

PMID: 28116513

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Project description:UnlabelledApproximately 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 registrationClinicalTrials.gov NCT01313520.

Dataset Information

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

Publications

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

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