Early diagnosis of inflammatory arthritis is important because early, aggressive treatment may reduce long-term disability (21
). For early detection of synovial inflammatory changes on conventional radiography (22
), clinical examination and laboratory tests are limited in their usefulness (28
). Recently, MRI and US have improved the sensitivity for early detection of RA (11
). Hyperplastic and locally invasive synovia, inflammatory infiltrates, fibroblast proliferation, and intense neovascularization are common histological findings of RA. MRI provides useful information on soft tissue changes, bone destruction (erosion), bone marrow edema, and joint effusion; it also contributes to the evaluation of prognosis for RA (5
). Although MRI is a powerful tool for the evaluation of synovitis with easy detection of synovial hypertrophy with contrast administration, the high costs, long examination times, and limited evaluation of only one anatomic lesion at a time may restrict the use of MRI for the evaluation of RA, especially in follow-up examinations (5
US is also considered a promising tool for detecting morphological changes in RA. It can detect synovial changes earlier, even in asymptomatic arthritis (1
), and it can reveal bone erosion, although the sound can not penetrate the cortex (12
). US may be superior to conventional radiography or MRI in certain situations, for instance, detection of small bone erosions (34
). So, US has been often used as a complementary tool in the clinic to evaluate high-risk patients with inflammatory arthritis who do not have abnormalities on radiography (34
Vascularization and angiogenesis develop in the pannus of RA because blood vessels are needed to recruit leukocytes or to provide nutrients and oxygen to starved tissue (35
). Weber and De Bandt suggested that endothelial cell proliferation might be the inciting factor, and that persistent angiogenesis was a major factor in the chronicity of rheumatoid synovitis (36
). With advances in MRI and US, much concern has been given to assessing angiogenesis and vascularity of RA.
With PD US, in particular, it is possible to assess the vascularity of synovitis (7
). PD US correlates with histological findings in RA, proving its validity for qualitative evaluation of RA (37
). However, PD is limited in its ability to detect slowly flowing vessels and small vessels. To improve the signal from weak tumor vascularity, the use of an US contrast agent was introduced. In a few recent studies, US contrast agent has been used for synovitis and proved to be useful for evaluating synovial vascularity (38
). The US contrast agent improved the echo enhancement from synovial vessels, which correlated with MRI data (38
) and clinical grouping (39
). However, these studies were designed for qualitative assessment. In contrast to previous studies, our study quantitatively measured the synovial vessels through computer-aided color-pixel counting. The use of an US contrast agent significantly increased the vascular signal areas in both arthritic and control knees. Moreover, it also increased the vascular yield in arthritic knees more than in control knees. When compared with control knees and correlated with MRI and MVD data, quantitative evaluation of PD US using a contrast agent allowed for the evaluation of synovial vascularity in cases of synovitis. Szkudlarek et al. (40
) reported that contrast-enhanced PD US at the metacarpophalangeal joints did not increase the sensitivity for detecting rheumatoid arthritis; all six patients who did not have pre-contrast PD signal also did not show PD signal after US contrast agent administration. However, Klauser et al. (39
) demonstrated that contrast agent administration significantly improved the detection of color flow signals in the finger joints of patients with RA. Fiocco et al. (41
) reported that contrast-enhanced PD US in knee joints was more useful than the unenhanced PD US, showing higher sensitivity and more reproducible PD signal scores. In our study, all arthritic knees had PD signals. Even in control knees, the three that did not have pre-contrast power Doppler signal manifested post-contrast PD signal. Szkudlarek et al. (40
) did not correlate their data with histologic findings, whereas Fiocco et al. (41
) performed arthroscopic correlation, and histological correlation was done in our study. MVDs of the joint only correlated with post-enhancement PD US images in arthritic knee. Thus, post-contrast enhancement PD US images are important for evaluating angiogenesis.
The variable results of studies using US contrast agent are thought to be due to differences in joint size, numbers of examinations, selection criteria, Doppler techniques, and joint diseases (42
). The depth of the target area in Doppler examination is also important because the sensitivity is affected by penetration depth of lowest detectable velocity (43
). Human knee joint is deeper than superficial joints, so the detection of PD or color Doppler signals in the knee joint will be lower than that in hand and finger joints. And the curved or linear transducers used in many US scanners had different Doppler performance (43
). Variation of vascularity in each joint might also affect the results. Thus, further controlled evaluations will be required to assess the usefulness of the contrast-enhanced PD US.
In our study, contrast-enhanced US is superior to MR for the evaluation of synovial vascularity as an indicator of synovitis. Many studies have evaluated MR and color Doppler or PD US in rheumatoid arthritis; some reveal comparable results with MR and US (38
), whereas some are superior at US (46
) or at MR evaluation (47
). Magarelli et al. (38
), Backhaus et al. (46
), and Wamser et al. (47
) studied contrast-enhanced PD US and MRI for the evaluation of synovitis, but reported different results. Backhaus et al. (46
) reported that contrast-enhanced US was more sensitive than MRI in the detection of synovitis and tenosynovitis. In contrast, contrast-enhanced US was not as sensitive as MR in the study by Wamser et al. (47
), where they evaluated four anatomic locations of the shoulder joint with a single bolus injection. However, the time of evaluation in contrast-enhanced PD US with Levovist is limited because of rapid destruction of microbubbles at high mechanical index, which decreases signal intensity with time (48
). As a result, evaluation of multiple anatomic locations with a single contrast injection might decrease the sensitivity for microbubble detection. To overcome this problem, repeated injection of US contrast agent can be applied, as in our study, and continuous or slow infusion of US contrast agent (9
) and application of third generation of US contrast agents (50
) can also help.
US contrast agent has the potential to act as a macromolecular agent that could evaluate the perfusion and hemodynamics of soft tissues or tumors. The mean molecular diameter of Levovist is large, approximately 3 µm (50
), and no extravasation into the surrounding tissue was demonstrated (52
), which indicates that Levovist acts as a true intravascular contrast agent. Contrast-enhanced MR imaging may also provide information on vascular perfusion and permeability (53
). However, the MR contrast agent Gd-DTPA is easily extravasated and is not a true intravascular agent (55
MR evaluation of synovial vascularity in our arthritic model was based on assessing the enhancement region. Enhancement grading is not a quantitative method, but a semi-quantitative method. This could be the reason why MR evaluation correlated less with PD US and histological evaluation. Dynamic evaluation of synovitis would better correlate with histologic evaluation, as shown in inflammatory arthritis (30
). Thus, more elaborate MRI techniques are required for the evaluation of synovitis.
The use of a sonic contrast agent has some limitations, i.e., the blooming artifact after injection, signal changes due to patient movement, restricted scanning time because PD US detects the destroyed microbubbles, increase in systolic peak velocity, and high-intensity transient signals (38
). Recently, new US contrast agents have been introduced for low mechanical index imaging and for relatively longer examination times (50
In summary, contrast-enhanced PD US helps quantify and detect synovial inflammation in the arthritic knee model of the rabbit by showing increased PD signal compared to the pre-contrast imaging of the arthritic knee and the post-contrast imaging of the control knee.