Formosan Journal of Rheumatology 2009;23:1-7 Review Article Ultrasound in rheumatoid arthritis Ying-Chou Chen 1, Tien-Tsai Cheng 1, Shih-Wei Hsu 2 1 Department of Rheumatology, Allergy and Immunology, 2 Department of Radiology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan Ultrasound is a promising tool for assessment of rheumatoid arthritis patients. While acceptable ultrasound assessment was previously confined to large joints, high-frequency linear array transducers now allow high-resolution imaging of superficially located structures such as the joints of the hands and feet. Ultrasound has a particular advantage over magnetic resonance imaging in that an experienced observer can rapidly screen several joints for erosions in a relatively short time. Further data regarding important methodological and measurement issues must be obtained before ultrasound gains wider acceptance. Key words: Ultrasound, rheumatoid arthritis Introduction Rheumatoid arthritis (RA) is a systemic inflammatory condition that primarily involves the diarthrodial joints. However, mild degrees of synovial inflammation might not be detected by physical examination alone, and radiographic findings to support the diagnosis of RA might not be apparent for several months. Although magnetic resonance imaging (MRI) has been the diagnostic modality for the musculoskeletal system, ultrasound has also been steadily gaining popularity in the evaluation of joints and soft tissues. The features of ultrasound, including low cost, portability, real-time dynamic imaging, and highresolution images of bone surfaces and soft tissues, are some of the reasons for this growth. Additionally, technological advances in color Doppler have increased our ability to better evaluate inflammatory processes involving soft tissues, including the synovial lining of joints. These techniques allow us to identify early inflammatory changes involving the synovial tissues and joint spaces, including periarticular erosions, cystic Corresponding author: Ying-Chou Chen, M.D. Department of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital-Kaohsiung Medical Center. No. 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien 833, Taiwan Tel: +886-7-7317123, Fax: +886-7-7322402 E-mail: r820713@ms13.hinet.net Received: June 30, 2008 changes, tendon sheath thickening, and various degrees of active synovial inflammation. It has been previously shown that sonographic imaging of the hand and wrist in RA can detect abnormalities associated with this disease. Ultrasound has also been recommended as the first line of investigation in the assessment of soft tissue involvement in patients with RA. Below, we review the sonographic findings of changes in RA, including fluid in joints, bursae and tendon sheaths [1,2]. Tendons, ligaments and inflammation at their insertions (enthesitis) are also evaluated. Synovitis We can assess synovitis by detecting thickening in the synovial membrane of inflamed joints (Fig. 1), bursae or tendon sheaths using grey-scale ultrasound [3,4] and Doppler techniques [5-8]. Doppler ultrasound can detect and quantify the increased synovial blood flow occurring in joint inflammation (Fig. 2). In knee and hip joints, the power Doppler signal has been found to correlate well with the histological assessment of synovial membrane microvascular density [9,10]. The high concordance between Doppler ultrasound and contrast enhanced MRI for the detection of synovitis in RA wrist and finger joints indicates that both examinations reflect similar physiological phenomena [11], and that ultrasound has a high level of agreement with MRI assessments [12,13].
Ultrasound in RA Figure 3. Improvement of the effusion score after etanercept therapy in our clinic. Figure 1. Sonography showed synovial effusion and thickening of the synovial membrane of the knee joint in a 40-year-old man. Ultrasound contrast agents may increase the sensitivity of Doppler ultrasound, but also imply considerable additional costs, time and invasiveness [14,15]. The future role of ultrasound contrast media in early RA is not yet clear, particularly as both new contrast agents and novel ultrasound equipment with improved flow sensitivities even without contrast use, and improved B-mode imaging are being developed [16]. A recent study visualized a Doppler signal in healthy joints, illustrating that physiological joint flow can be displayed with high-end units [17]. Follow-up data have revealed that ultrasound measures of synovitis (Doppler signal and B-mode), synovial membrane thickness, or tumor necrosis factor-α (TNF-α) antagonists [18-20] are administered in parallel with similar changes in synovial inflammation exposed to effective anti-inflammatory drugs (Fig. 3). Only one ultrasound study of RA wrist, finger or toe joints includes both reproducibility and longitudinal data. Infliximab therapy changed the synovial thickness more than the coefficient of variance in the majority of joints, suggesting that this measure is sensitive to change in clinically relevant situations. Thus, ultrasound may be a valid method for monitoring synovitis, but data on sensitivity to change are needed. Angiogenesis Figure 2. Sonography showed increasing blood flow and the decreasing resistance index (RI = 0.53) of the wrist joint in a 30-year-old woman. Angiogenesis, as well as synovial proliferations and the development of tenosynovitis, bursitis and erosions, are the pathomechanisms of RA. The pathogenesis of RA synovial hyperemia is the first step of the inflammatory process that can be identified by imaging procedures (Fig. 4). The immune response mediated by cytokines with infiltration by inflammatory cells leads to edema and swelling of the synovium. This causes widening of the joint space [21]. 2
Chen et al Figure 5. Sonography of the wrist showed pannus with increasing Doppler activity. Figure 4. Sonography of the knee joint showed hyperemia of the synovial membrane. Synovial proliferation The inflammatory response leads to hypertrophy of the synovial membrane by invasive granulation tissue with a proliferation of synoviocytes, macrophages, lymphocytes, plasma cells and mast cells. As synovial hypertrophy continues, the hypertrophied synovium, usually referred to as pannus (the Latin word for cloth ) undergoes villous transformation and expands concentrically into the joint space, leading to damage of the central portion of the articular cartilage and the subchondrale bone (formation of subchondral cysts and erosions) (Fig. 5). The destructive action of the pannus, a tumor-like focal proliferation of inflammatory tissue, is responsible for progressive joint surface damage, ligament and capsule tearing, and finally, joint instability and deformities. The degree of hyperemia is an indicator for synovial proliferation and disease activity, and therefore may be helpful in the prognosis of disease. occur within the first months of disease if the patient is left untreated or inadequately treated (Fig. 6). Within the first year after the onset of RA, up to 47% of patients develop erosive disease. Four months after the onset of symptoms, carpal erosions were found in 45% of patients using MRI, while only 15% of patients had erosions on plain radiographs [22,23]. Several other studies have confirmed the superiority of MRI and ultrasound over conventional radiography to assess synovial activity as a predictor for erosions and joint destruction [3, 24-26]. Contrast agents may be of value in the presence of erosive lesions, because vascularized erosions are a sign Erosive destruction Erosive destruction, a sign of disease progress, can Figure 6. Arrow head showed erosion of the wrist bone. 3
Ultrasound in RA of progressive active disease, and contrast administration may help to exclude active vascularized erosions. Tendons Ultrasound also facilitates better characterization of the synovitis around tendons and in enthesopathies. In the tendinopathy of early RA, MRI has been used to quantify synovitis at the wrist. High scores were predictive of tendon rupture in a small group of patients. Therefore, sensitive assessment of peritendinous synovitis might be of clinical relevance in predicting the course of tendon involvement and the risk of tendon rupture in later disease [27]. In one study, the presence of vacularization of the heel enthesis after contrast administration was interpreted as a sign of early enthesitis [28]. Ultrasound permits excellent assessment of tendon structure and tendon gliding during active and passive motion. Detection of persistent peritendinous vascularized synovitis with vessels entering the tendon might be consistent with aggressive disease and possible tendon rupture. Bursae In bursitis or in the suprapatellar recess, ultrasound may show peripheral enhancement of the synovitis and thus help to distinguish between fluid, fibrous and hypervascular synovial thickening [29]. Furthermore, the administration of a contrast medium may help in detecting hypervascularization in patients with only mild synovial proliferation and this can be proven by contrast administration on a very sensitive level [30]. Advantages and limitations Since early changes are nonosseous in nature, ultrasound and MRI are superior to conventional radiography and computed tomography. The variability of joint involvement and disease activity in the examined areas, the occasionally low correlation of clinical symptoms with radiological results, and the fact that different sites may respond differently to RA therapy, call for imaging modalities allowing examination of several joints within a relatively short period of time, or at least during a single patient visit. All of the potentially affected regions can be investigated well by ultrasound within a single examination session [31]. Some authors described bone marrow edema, which is identified by MRI alone, as possessing a high negative predictive value for the development of erosions. However, bone marrow edema is not specific for RA [32]. Another issue which is currently discussed critically is the periarticular osteoporosis in RA diagnosed by radiography as an early sign of joint involvement. Diagnostic value No studies have truly investigated the diagnostic value of ultrasound in RA, as the ability of ultrasound to distinguish between early RA patients and other relevant differential diagnoses has not been tested. Two studies by Frediani et al. [33-34] suggested that, in agreement with comparable MRI studies, ultrasound signs of inflammation are more frequent in the joint than at the tendon insertions; other studies have reported that ultrasound signs of peripheral enthesitis are frequent in seronegative spondyloarthropathies [20,35] but not in RA. It would be expected that the ability of ultrasound to visualize intra-articular, as well extra-articular changes would translate such that ultrasound could assist in the clinical process of diagnosing. Current knowledge strongly encourages testing this hypothesis, particularly in patients with early unclassified arthritis. Prognostic value In a recent randomized controlled trial of anti-tnfα therapy in early RA, baseline ultrasound determined synovial thickening and the degree of vascularity in the metacarpophalangeal joints correlated with the in the placebo group, but not in the group receiving biological therapy [36]. Apart from this study, we are not aware of any data on the importance of ultrasound findings with respect to later radiographic or functional status, i.e. the prognostic value of ultrasound in RA is unknown. Some indirect support of the predictive value of ultrasound is provided by the high level of agreement with MRI findings, because MRI findings (synovitis, bone edema and MRI bone erosions) have been shown to possess predictive value with respect to subsequent destructive bone damage [37]. In several studies, however, the strongest MRI predictor of future erosive damage was the presence of bone marrow edema [38,39], and this cannot be visualized by ultrasound. Consequently, a prognostic value of MRI is not directly transferable to ultrasound. 4
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