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- PATIENTS AND METHODS
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is associated with different rheumatologic and neoplastic diseases, typically in elderly men. An abrupt onset of pitting edema of the dorsum of the hands associated with synovitis of the wrist carpus, small joints, and tendon sheaths are described clinical features (1–3). A laboratory test for diagnosing RS3PE is not yet available. Magnetic resonance imaging (MRI) is the only imaging technique that has been previously used for the diagnostic evaluation and followup of RS3PE (4). MRI has shown to be helpful and provides useful information; however, availability and costs may limit its use.
Gray-scale ultrasound (US) has proven to be a useful imaging method for evaluation of joints and superficial structures (5). In addition, color Doppler ultrasound (CDUS) enables characterization of inflammatory activity in synovial proliferation and depicts soft-tissue hyperemia in musculoskeletal inflammatory disease by assessing blood flow in vessels at specific sites (6, 7). However, this technique is limited in the detection of slow flow and flow in small vessels. The addition of recently developed microbubble-based US contrast agents improve the detection of low-volume blood flow by increasing the signal-to-noise ratio (8, 9).
To the best of our knowledge, there are no published data about the use of US, CDUS, and contrast-enhanced CDUS in RS3PE. The purpose of this study was to assess the value of US, CDUS, contrast enhanced CDUS, and MRI in the diagnostic evaluation of hands in patients with RS3PE.
- Top of page
- PATIENTS AND METHODS
Although clinical examination usually allows for diagnosis of RS3PE, Schaeverbeke et al (15) reported that RS3PE was diagnosed retrospectively in 9 of 24 patients. The diagnostic gap between determination of RS3PE and clinical findings requires imaging to establish the final diagnosis. MRI has been utilized for the diagnostic evaluation of RS3PE and has shown to be useful (3). Cantini et al (4) described improved detection of joint synovitis by MRI in comparison with clinical examination, which was limited due to extensive swelling. However, MRI has its well-known limitations.
A readily available and less-expensive imaging method might assist in early diagnosis and treatment of patients with a false-negative clinical examination result. US can detect pannus and joint vascularization, which are associated with disease activity in rheumatoid arthritis (RA) (16). However, gray-scale US is limited in the differentiation between hypoechoic thickening of the joint caused by increased fluid or synovial proliferation, because low-level echoes are often present in joint fluid (7). In this study, US, CDUS, and contrast-enhanced CDUS findings in RS3PE were compared with MRI findings to determine whether contrast-enhanced CDUS might improve the differentiation of synovial proliferation and joint fluid. Hypoechoic joint thickening was noted on gray-scale US in 37 of 96 joints (38.5%), and CDUS showed vascularization in 9 of 37 joints (24.3%) (grade 1), and contrast-enhanced CDUS demonstrated vascularization in 22 of 37 joints (59.5%) (grade 1–2). MRI demonstrated vascularization in the same 22 of 37 joints (59.5%). No intraarticular vascularization was evident in the hypoechoic thickening found sonographically in 15 of 37 joints (40.5%), whereas MRI diagnosed joint effusion in 21 of 96 joints (21.9%) (not outlined in Table 3). Thus, MRI seems to be more sensitive in the characterization of small amounts of joint effusion, even when US shows no thickening. Our results clearly demonstrate that contrast-enhanced CDUS is superior to unenhanced CDUS in the delineation of articular fluid from inflammatory activity, and correlated well with MRI. There is no overestimation of perfusion in contrast-enhanced CDUS compared with the gold standard MRI. As demonstrated in Table 4, even with the use of high-resolution US, MRI has shown to be better in the detection of joint thickening in 3 joints. This relies on the excellent detection of fluid on MRI. Our findings are in line with previously published data (4), which reported that joint synovitis is less frequent and less dominant than inflammation in tendon sheaths in patients with RS3PE. Joint synovitis was less frequent and less dominant than inflammation in tendon sheaths in patients with RS3PE. We could confirm this aspect because both MRI and contrast-enhanced CDUS found only ∼50% of hypoechoic articular thickening to be synovitis, contrary to the extensive presence of tenosynovitis.
Synovial proliferation in tendon sheaths could be depicted with both contrast-enhanced CDUS and MRI in 23 extensor tendons and 12 flexor tendons, whereas CDUS was positive in 10 extensor and 5 flexor tendons only. Thickening of flexor tendons was observed by both US and MRI in 1 case only, with hypervascularization of the tendon itself caused by extensive tenosynovitis.
During dynamic US examination, which is performed by active and passive finger motion, no impaired gliding ability of the tendons was detected. The clinical finding of impairment of finger motion may be explained by synovial tissue proliferation in the tendon sheaths, which was a predominant finding in our study, as well as by effusions in the PIP joints and extensive subcutaneous thickening.
Subcutaneous thickening in RS3PE is characterized by the presence of pitting edema. RS3PE edema is smoother in comparison with other causes of lymphatic edema and rapidly improves with antiinflammatory treatment. The underlying pathogentic mechanism of pitting edema is still not completely clear, but lymphatic involvement with a decreased lymphatic clearance has been described in a few cases associated with RA. In RA, an increased capillary permeability as a result of local inflammation with increased filtration of tissue fluid has been reported. Increased tissue pressure may cause “small vessel congestion” due to edema and synovial proliferation and may explain the poor sensitivity of unenhanced CDUS for subcutaneous vascularization (17).
Because of the improved sensitivity for slow flow with microbubble contrast agents, contrast-enhanced CDUS found hypervascularity (grade 2–3) in the subcutaneous tissue in all patients. In fact, contrast-enhanced CDUS findings correlated better with contrast-enhanced MRI findings than with unenhanced CDUS.
The identification of lymphatics in RS3PE is an important issue, which can be well delineated by high-frequency US as hypoechoic tubular structures (13). CDUS enables the differentiation between vessels and dilated lymphatics, as both can appear as tubular structures. Based on the pharmacologic kinetics of the microbubbles, it is unlikely that contrast-enhanced CDUS is able to enhance dilated lymphatics because the microbubbles are blood pool agents that remain in the blood pool until they dissolve and therefore further allows a better differentiation of small vessels and dilated lymphatics.
Interestingly, in 2 of our patients, subcutaneous thickening was detected without delineation of extensive lymphatic vessel dilatation, but with extensive vascularity in the unenhanced CDUS examination. We hypothesize that this could represent a very early presentation. It is possible that increased vascularity may be an early finding on CDUS. Later in the course of the disease, vessel compression due to edema might reduce blood flow. Longitudinal studies may be necessary to characterize the sonographic findings of pitting edema during different stages of RS3PE.
In a study by Cantini et al (4), wrist synovitis (which is difficult to detect clinically) was detected in 83% by MRI. This seems to be in line with our findings. Our data give results for US, and we found that only contrast-enhanced US enables an accurate differentiation of synovitis and fluid. However MRI seems to be more sensitive. Cantini et al described a limited dorsal and palmar flexion of both hands and feet, mainly due to tenosynovitis. In our study using dynamic US examination with active and passive finger motion, we could not detect an impaired gliding mobility of the tendon itself. However, the impaired motion was caused by the extensive joint and tendon sheath fluid/synovitis, which is in line with the suggestions of Cantini et al (4).
We note several limitations of our study. First, a single investigator performed the US examinations. Although the investigator was blinded to clinical and MRI findings, we do not have data on intra- and interobserver variability. Second, the grading of the vascularity was subjective. Although a study by Walther et al (18) found a good correlation between subjective grading of vascularity in the pannus of the knee and digital image evaluation, objective assessment by computer-assisted quantification might further improve the value of contrast-enhanced CDUS. The assessment of vascularity using 2 different imaging modalities with different contrast agents (microbubbles are blood pool agents whereas MRI gadolinium leaks into the tissue) is a further limitation. Terslev et al (19) compared power Doppler US with contrast-enhanced MRI using terms like color fraction, color Doppler pixels, and measurements of the resistive index, and they found an association between US and MRI enhancement. Recently, the term color pixel has shown to be helpful for the assessment of vascularity by CDUS in healthy joints (20). Finally, we evaluated a limited small number of patients to establish the value of US, CDUS, contrast-enhanced CDUS, and MRI. Our results for differentiation of effusion and synovial proliferation might be of clinical importance even in other rheumatic conditions and should therefore be evaluated further. As a final point, we note that an advantage of contrast-enhanced CDUS, compared with MRI, is the availability, the lower costs, even using microbubble contrast agents, and its effectiveness as a bedside modality.
US, CDUS, contrast-enhanced CDUS, and MRI have been shown to add detailed information to the clinical examination of involved anatomic structures in patients with RS3PE. Our series demonstrated predominant extraarticular synovial structures involved in the inflammatory process with tenosynovitis of extensor and flexor tendons, and only mild articular synovitis. Increased vascularity could be less detected by CDUS, whereas contrast-enhanced CDUS showed an improved detection with comparable results with MRI. Articular synovial proliferation, which is difficult to assess by clinical examination due to extensive swelling and edema, showed hypoechoic changes on US and increased vascularity on contrast-enhanced CDUS. Contrast-enhanced CDUS was superior to unenhanced CDUS in the detection of hypervascularity in tendons and joints, thus enabling the differentiation of synovial proliferation or effusion, and MRI was the best method for detection of small amounts of effusion.
In conclusion, our study shows that US, CDUS, contrast-enhanced CDUS, and MRI are valuable tools, which may be helpful adjuncts to clinical examination in diagnosing RS3PE.