Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring

Abstract

The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI. In addition to clinical assessments with DAS28(CRP), the severity of inflammation was measured as synovial leak of gadolinium based contrast agent (GBCA) using DCE-MRI (Ktrans, primary endpoint) at weeks 0, 2, 4, and 14. Two radiologists independently scored synovitis, osteitis and erosion using RA MRI Score (RAMRIS) and cartilage loss using a 9-point MRI scale (CARLOS). Infliximab showed greater decrease from baseline in DAS28(CRP), DCE-MRI Ktrans of wrist and MCP synovium, and RAMRIS synovitis and osteitis at all visits compared with placebo (p<0.001). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08; 90% CI (0.63-1.53)) and MRI inflammation endpoints: wrist Ktrans (1.00 (0.55-1.45)), RAMRIS synovitis (0.85 (0.38-1.28)) and RAMRIS osteitis (0.99 (0.52-1.43)). Damage measures of bone erosion (RAMRIS) and cartilage loss (CARLOS) were reduced with infliximab compared to with placebo at 14 weeks (p≤0.025). DCE-MRI and RAMRIS were equally sensitive and responsive to the anti-inflammatory effects of infliximab. RAMRIS and CARLOS showed suppression of erosion and cartilage loss, respectively, at 14 weeks. (ClinicalTrials.gov registration: NCT01313520).

Conflict of interest statement

Competing Interests: C. Beals, R. Baumgartner, A. Cheng, D. Feng, M.-H. Vallee, and B. Dardzinski are currently (or were at the time the study was conducted) employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, who may own stock and/or hold stock options in Merck. C. Peterfy and J. DiCarlo are employees of Spire Sciences, Inc., employed by the study sponsor Merck to analyze study results; E. Ashton is an employee of VirtualScopics, employed by Merck to analyze study results; A. Balanescu, G. Mirea, A. Harabagiu, and S. Popa claim no conflicts of interest. There are no additional declarations from the authors relevant to this research relating to employment, consultancy, products in development, patents, or revenues from marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials, with the following exception: To protect the privacy and confidentiality of research participants, there are restrictions on the availability of data from this study (see Merck’s data sharing policy at http://engagezone.msd.com/ds_documentation.php). Requests for data access can be submitted to: dataaccess@merck.com.

Figures

Fig 1. Study diagram.

Fig 2. Mean changes from baseline (SE) in DAS28(CRP) and Dynamic Contrast Enhanced assessments of the wrist and metacarpophalengeal joint (MCP) in subjects with rheumatoid arthritis treated with infliximab 3 mg/kg (N = 30) or placebo (N = 31).

Fig 3. Baseline vs Week 14 DCE-MRI.

Enhancing Synovium (green regions of interest) decreased dramatically from baseline to Week 14 in a clinical responder treated with infliximab (left), but was largely unchanged in a non-responder treated with placebo (right). Responder was defined as change from baseline in DAS28(CRP) >1.2 and non-responder as

Fig 4. Mean changes from baseline (SE) in Rheumatoid Arthritis MRI Score (RAMRIS) of synovitis at the wrist and metacarpophalengeal joint (MCP) in subjects with rheumatoid arthritis treated with infliximab 3 mg/kg (N = 30) or placebo (N = 31).

Fig 5. Cumulative probability of change from baseline in RAMRIS synovitis.

The change in RAMRIS synovitis, osteitis and erosions between baseline and 14 weeks is shown by the percent of subjects less than the threshold of change for Placebo and Infliximab.

Fig 6. Effect sizes of treatment responses for various measures of rheumatoid arthritis for infliximab 3 mg/kg vs placebo.

See statistical methods.