Synovitis is the usual presenting sign of inflammatory arthritis and has a central role in the progression of joint damage in rheumatoid arthritis (RA) (1). Synovitis is also frequently present in osteoarthritis (OA), especially with advanced structural damage (2), and has recently been associated with the degree of pain (3) and predicted progression of cartilage loss (4) in the knee. Clinical assessment of the knee for synovitis has poor sensitivity and reproducibility (5–7), and a more reliable method of detecting and quantifying synovitis is therefore desirable.
Arthroscopy allows direct visualization of the synovial membrane and structures within the joint compartment. It is frequently used as a method of quantifying synovitis of the knee, and has been validated against histologic findings in both OA and inflammatory arthritis (8, 9). In addition, recent evidence suggests that synovitis visible on arthroscopy is a predictor of progression of OA (4). Magnetic resonance imaging (MRI) has been shown to be a sensitive tool for detecting synovitis when compared with arthroscopy (10), but issues relating to cost may affect patient access.
The use of ultrasonography (US) is increasing because it is relatively inexpensive, noninvasive, does not involve exposure to ionizing radiation, and as a result can be used repeatedly on the same patient in multiple anatomic areas. It therefore has the potential for use in assessing the extent of synovitis and changes in the synovial volume over time. However, there are few validation studies of US and its ability to detect synovitis in large joints. A relatively small number of studies have compared synovitis detected by gray-scale US with MRI (11) and with arthroscopy (12–14), although the latter studies assessed only patients with inflammatory arthritis with persistent knee synovitis who were referred for synovectomy (a group who may be expected to have a greater degree of synovitis). A recent study assessed the relatively new technique of power Doppler US in the knee, comparing its results with histopathologic findings of synovial membrane vascularity in 23 patients with RA or OA who were undergoing arthroplasty; the findings suggested good correlation (15).
Whereas US has demonstrated good reproducibility for detecting erosions in the metacarpophalangeal joint (16) and assessing cartilage thickness in the knee (17), there are no published data on its reproducibility in the assessment of knee synovitis. In this study, US and clinical examination were compared with arthroscopy for the detection of synovitis in a large group of patients with knee pain. We also assessed the inter- and intrareader reproducibility of US, as well as intrareader reproducibility of arthroscopy, in a subset of patients.
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- PATIENTS AND METHODS
This is the largest study undertaken to date to validate US-detected knee synovitis in patients with a spectrum of disease and synovitis severity. We used arthroscopy as the gold standard, while also assessing its reproducibility and comparing US with clinical examination. The results suggest that US can detect and accurately localize synovitis in the knee, and is more sensitive than clinical examination. This is the first study to document the reproducibility of US-detected synovitis in the knee, and the results suggest that US is a technique with high inter- and intraobserver reproducibility.
Compared with arthroscopy, US of the knee has the advantage of being noninvasive and enabling visualization of extracapsular features such as the collateral ligaments, Baker's cysts, and quadriceps and patellar tendons. We have demonstrated a high positive predictive value for detection of synovitis by US, suggesting that a US examination of the knee may well eliminate the need for further, often more expensive and invasive, investigations. However, arthroscopy still has an important role, particularly in differentiating between the inflammatory arthritides, performing tissue sampling under direct visualization, and assessing the retropatellar space or the cruciate ligaments. The fact that only 1 knee had isolated retropatellar granular hypertrophy (with a VAS for overall synovitis of 13 mm) suggests that in this group of patients there was little additional information regarding synovitis in the retropatellar space. That this space cannot be fully visualized with US may be less important for the detection of synovitis.
With US, synovitis was detected in 7 of the 8 patients (88%) in whom clinical assessment failed to detect synovitis that was seen arthroscopically. The 1 patient with a false-negative US result had a very low arthroscopy synovitis score (VAS 7 mm), compared with an average VAS score of 21 mm for the patients with false-negative results on clinical examination. This is consistent with previous reports suggesting that low-grade synovitis cannot be detected by clinical examination (5). The clinical relevance of this lower-grade synovitis may be particularly important in OA, where the degree of synovitis may be less, but still an important cause of symptoms (3) and predictor of damage (4). The findings of this study also suggest that US is more sensitive at detecting villous hypertrophy than simple granularity of the synovial membrane, which is to be expected given that granularity represents an early, more subtle process with less synovial thickening compared with villous hypertrophy.
A small amount of synovial fluid may be seen in the normal knee joint with US and was present in all patients with arthroscopically evident synovitis, including the 1 patient with a false-negative US result and the other patient with isolated retropatellar synovitis, suggesting that increased vigilance for synovitis is warranted if synovial fluid is detected. Synovial fluid was also detected by US in 3 patients without synovitis on arthroscopy, but in only 1 of these 3 was synovitis incorrectly diagnosed with US and clinical examination, suggesting that synovial fluid has no major impact on the false-positive diagnosis of synovitis using these techniques.
This study demonstrated very good inter- and intraobserver reproducibility of US in the detection of the presence or absence of synovitis in the knee, and intraobserver reproducibility for grading synovitis. This suggests that US can be used with confidence in longitudinal studies by either individual or multiple readers for determining the presence or absence of synovitis, and by an individual reader for determining the grade of synovitis. The level of interobserver agreement using the semiquantitative grading scale, although good, suggests that in studies involving multiple readers, other methods, such as measurement of synovial thickness, may need to be considered.
There are some limitations to this study. The use of macroscopic findings on arthroscopy as the gold standard could be questioned due to the dearth of studies comparing this evaluation with histologic changes (8, 9, 18, 19). Earlier studies (18, 19) had contrasting outcomes, with one demonstrating poor (18) and the other demonstrating good (19) correlation, although neither took into account the variation of histologic findings that can be seen within a single joint (8, 9, 20–22). Studies addressing this variation, using an assessment technique similar to that in the present study, demonstrated good correlation between site-specific macroscopic findings and histologic analysis (8, 9). Our group has also demonstrated good correlation between global arthroscopy VAS for synovitis and immunohistologic results (CD4 levels) (23), as well as synovial fluid matrix metalloproteinase 1 (MMP-1), MMP-3, and CD3 levels (24). Furthermore, the current study also confirms the excellent intraobserver reproducibility with arthroscopy.
Finally, the clinical applicability of any gold standard is related to its pathogenic relevance, without which its prognostic capacity is diminished (25). Currently, there is no firm evidence that correlates histologic findings with clinical outcomes, in particular, joint damage. Also there appears to be only poor correlation between histologic findings and levels of C-reactive protein (26), an often-used surrogate for disease activity that cumulatively correlates well with disease progression (27, 28). In contrast, there is a growing body of evidence that synovial volume correlates with subsequent development of joint erosions (29, 30). Arthroscopy allows direct visualization of the synovium, and current scoring methods offer a semiquantitative assessment of severity, and therefore, disease amount. Although there is a paucity of studies demonstrating a correlation between arthroscopically evident synovitis and damage (4), it appears that one can conclude this by association.
Due to the difficulty in the anatomic delineation of the 3 compartments, there may well be some overlap of compartments between those visualized by US and those visualized by arthroscopy. For example, if a patient had synovitis extending medially and laterally from the SPP, the arthroscopist may have identified this as being in the SPP only, whereas the ultrasonographer may have judged this as extending into both the medial and lateral compartments, hence scoring 2 false-positives. The better results for patients as a whole compared with individual compartments (Table 1) may reflect this.
There was a selection bias in the present study in that all patients were referred for arthroscopy because of knee pain, and it is therefore more likely that they would have been thought to have synovitis on clinical examination. Furthermore, the relatively low number of joints without arthroscopically evident synovitis (n = 8) makes it difficult to extrapolate the specificity of US, although it is clear that, even in this group in which the majority of patients had synovitis, clinical examination is relatively inaccurate.
Clinical examination assessed the knee as a whole and did not differentiate between the retropatellar space and the other compartments, but only 1 patient had isolated retropatellar disease, and US remained more sensitive than clinical examination when compared with arthroscopy VAS for overall synovitis, which would have included this space. In this study the definition of clinical synovitis deliberately did not include joint tenderness (periarticular tenderness in the knee is common, especially in degenerative and entheseal disease). Any increase in sensitivity as a result of including tenderness may have also been accompanied by an increase in false-positive diagnosis, resulting in an even lower specificity and negative predictive value. Newer techniques such as power Doppler or contrast-enhanced Doppler may improve the accuracy of US by differentiating between hypervascular (active) and fibrotic (inactive) synovial thickening or pannus.
This study demonstrates that US is a valid and reproducible tool for the detection of synovitis in the knee joint and confirms previous reports that it is superior to clinical examination. Improved rates of detection of synovitis with US, and the role of synovitis in the symptoms and progression of knee arthritis, suggest that this technique should be used increasingly in order to improve disease diagnosis and management (1, 4). This has important implications with regard to the future practice and training of rheumatologists. Further studies are needed to validate more recent US techniques, the ability of US to detect changes following therapy, and the cost-effectiveness of US compared with other assessment techniques.