Longitudinal Changes in Knee Joint Synovial Vascularity in a Rabbit Model of Rheumatoid Arthritis: Quantification Using Power Doppler Ultrasound and Contrast-Enhanced Ultrasound

Abstract

We studied a rabbit model of rheumatoid arthritis (RA) to examine the time course of changes in synovial neovascularization based on quantitative power Doppler ultrasound and contrast-enhanced ultrasound (CEUS). Twenty-five male New Zealand rabbits were in the ovalbumin-induced arthritis (OIA) group, and 5 were in the control group. Both rear knee joints of all rabbits were examined using conventional US and CEUS over 16 weeks. The knee synoviums of OIA rabbits were sampled by US-guided biopsy, and expression of CD31 and vascular endothelial growth factor (VEGF) was determined by immunohistochemistry. The correlation of joint damage based on multimodal US with microvessel density (CD31 positivity) and VEGF expression at different times was analyzed. OIA rabbits had increased synovial expression of CD31 and VEGF from weeks 6 to 12 (p < 0.01). During the early stage of CEUS enhancement, "dot enhancement" was more common at weeks 6 and 8, and "stripe enhancement" was more common at weeks 12 and 16 (p < 0.05). There were significant positive correlations of synovial CD31 and VEGF expression with power Doppler image grade, CEUS grade and peak intensity (p < 0.05 for all). Thus, OIA rabbits mimicked early-stage RA at 6 to 8 weeks, middle-stage RA at 8 to 12 weeks and late-stage RA at 12 to 16 weeks. Power Doppler image grade, CEUS grade and peak intensity, especially when combined with CD31 expression data, accurately characterized the extent of synovial vascularization in a rabbit model of RA. Increased vascularity based on CEUS may have value for the early diagnosis of RA.

Keywords: Angiogenesis; Contrast-enhanced ultrasound; Ovalbumin-induced arthritis; Power Doppler ultrasound; Rheumatoid arthritis.