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

Charles Peterfy,Julie DiCarlo,Lars H. Nordenmark,John C. Waterton,Herbert Kellner,Martin Jenkins,Caleb Roberts,Michael A. Bowes,Geoffrey J. M. Parker,Meilien Ho,Giovanni Buonaccorsi,Peter C. Taylor,Gwenael Guillard

doi:10.1007/s00330-017-4736-9

Abstract

ObjectivesTo 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 Ktrans, in a multicentre trial setting.MethodsDCE-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.ResultsAt early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. Ktrans intra-subject coefficient of variation (N = 14) was 30%. Ktrans 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.ConclusionThis demonstrated repeatability of Ktrans 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 Ktransshowed fostamatinib inferior to adalimumab after 6 weeks.• Ktransrepeatability coefficient of variation was 30% multicentre.

Highlights

magnetic resonance imaging (MRI) with gadolinium-based contrast agents (Gd-CAs) provides biomarkers dependent on perfusion, vascular volume, capillary endothelial permeability and interstitial volume, all of which increase in inflammation
Dynamic contrast enhanced (DCE)-MRI Ktrans showed fostamatinib inferior to adalimumab after 6 weeks
MRI with gadolinium-based contrast agents (Gd-CAs) provides biomarkers dependent on perfusion, vascular volume, capillary endothelial permeability and interstitial volume, all of which increase in inflammation

Summary

Introduction

MRI with gadolinium-based contrast agents (Gd-CAs) provides biomarkers dependent on perfusion, vascular volume, capillary endothelial permeability and interstitial volume, all of which increase in inflammation. Dynamic contrast enhanced (DCE) MRI [5] characterises regional uptake and washout of Gd-CA. It has been extensively used in oncology [6] and other diseases, and in RA provides biomarkers of synovial inflammation [7]. A likely reason for failure to exploit DCE-MRI in multicentre RA studies is that the heuristic variables commonly used to characterise synovial Gd-CA uptake curves are inherently scanner-dependent, and unlikely to provide biomarker values comparable between centres and studies. As with any intensive variable, DCE-MRI biomarkers depend on how their region-of-interest (ROI) is defined, and because of variations in patient positioning and other technical factors, it is difficult to ensure that ROIs correspond between time points and subjects

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