Noninvasive Quantitative Assessment of Synovial Pannus Angiogenesis by Contrast-enhanced Gray-scale Sonography in Antigen-induced Arthritis in Rabbits

Rationale and Objectives

The aim of this study was to evaluate the value of contrast-enhanced gray-scale sonography in quantitative assessment of synovial pannus angiogenesis in antigen-induced arthritis in rabbits.

Materials and Methods

Twenty-four adult New Zealand White rabbits were divided into two groups. Inflammatory arthritis was induced by intra-articular injection of ovalbumin into right knee joints with 4 mg in low-dose group (LD, n = 12) and 8 mg in high-dose group (HD, n = 12). The left side of the knee on each rabbit was used as normal control. Contrast-enhanced gray-scale sonography with time intensity curve (TIC) was performed on the synovia of suprapatellar bursa and posterior capsules 4 weeks after the injection. Immunohistochemical examinations of synovia were applied to assess the microvessel density and the expression of vascular endothelial growth factor. Correlation analysis between sonographic and immunohistochemical findings was performed.

Results

Contrast-enhanced gray-scale sonography of all right knees demonstrated intra-articular hypoechoic lesions with enhanced blood flow and no abnormal findings on all left knees. Parameters of TIC, including ascending curve (A), derived peak intensity (DPI), and area under curve (AUC) on arthritis joints were significantly higher in HD group compared to LD group ( P < .05). Positive correlation was found between immunohistochemical findings and parameters of A, DPI, and AUC ( P < .05). However, no correlation was found between other parameters (slope of descending rate, time to peak, time to rise, and initial intensity) and immunohistochemical findings.

Conclusions

Contrast-enhanced gray-scale sonography with TIC measurement could provide reliable method for noninvasive quantitative assessment of synovial pannus angiogenesis of arthritis in clinical settings.

Rheumatoid arthritis (RA) is a chronic systematic autoimmune disorder that principally attacks synovial joints, especially small joints of the hands and feet. It is mainly characterized by massive synovial proliferation and changes in synovial architecture resulting in interdigitating folds of tissue, termed pannus . Recurrent inflammation leads to the destruction of the cartilage, bones, and ligaments, causing deformity and loss of function. The formation of active inflamed pannus is central to this erosive disease. Synovial vascularity is correlated with disease activity and response to therapy . Studies showed that angiogenesis was regulated by a complex set of inducers and inhibitors. Of these, vascular endothelial growth factor (VEGF) is a potent endothelial cell–specific growth factor involved in inflammatory activities. However, histologic measurement of microvessel density (MVD) and VEGF of synovial tissue is invasive and impractical in clinical settings . Therefore, the introduction of a noninvasive and efficient alternative is of great important and necessary.

The development of color and power Doppler sonography was a complement of the conventional gray-scale sonography. However, sensitivity and quantification cannot be perfectly achieved by these imaging techniques. The introduction of contrast-enhanced gray-scale sonography has made imaging of synovial microvessels possible. This imaging technique exploits the nonlinear oscillations of microbubbles that produce harmonic overtones of the original sound wave . It allows dynamic measurement of region of interest (ROI) to achieve quantitative assessment of blood flow in synovial pannus at the microvascular level . However, there were deficient studies using quantification parameters of time-intensity curve (TIC) for assessing the degree of RA. The following questions have to be addressed before its clinical application. Can the TIC parameters achieved from contrast-enhanced gray-scale sonography quantitatively evaluate the activity and the treatment effectiveness of RA? Is it possible, hence, with the new method to display the microperfusion of synovial pannus, to determine the valuable parameters to assess the activity of RA?

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Materials and methods

Antigen-induced Arthritis Model in the Rabbit Joint

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Contrast-enhanced Sonographic Technique

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Immunohistochemical Studies of Synovial Pannus

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Statistical Analysis

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Results

Comparison of Contrast-enhanced Sonography between Two Groups

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Comparison of Immunohistochemical Findings between Two Groups

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Correlation between Contrast-enhanced Sonography and Immunohistochemical Findings

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Discussion

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