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Received：December 16, 2015, Revised：January 21, 2016, Accepted：January 22, 2016

Corresponding to：Taeyoung Kang, Department of Rheumatology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea. E-mail：taeyoung@yonsei.ac.kr

pISSN: 2093-940X, eISSN: 2233-4718Copyright ⓒ 2016 by The Korean College of Rheumatology. All rights reserved.This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Review ArticleJournal of Rheumatic Diseases Vol. 23, No. 1, February, 2016http://dx.doi.org/10.4078/jrd.2016.23.1.11

Recent Trends of Ultrasound in Rheumatology

Taeyoung Kang1, Richard J. Wakefield2,3, Paul Emery2,3

1Department of Rheumatology, Yonsei University Wonju College of Medicine, Wonju, Korea, 2Leeds Institute of Rheumatic and Musculoskeletal Medicine, Chapel Allerton Hospital, University of Leeds, and 3NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

Owing to the ability of musculoskeletal ultrasound (US) to depict cross sectional images of synovial joint and related structures, US has become the most reliable tool for evaluation of arthritic activity of rheumatoid arthritis (RA). US can detect early synovi-tis, assess disease activity, and determine true remission in patients with RA. US also can detect early enthesitis in patients with spondyloarthropathies. In addition, US can provide a reliable tool for measuring skin thickness in patients with systemic sclerosis. With guidance of injection or aspiration, US can result in a better clinical outcome. Thus, educational needs and re-search networks are increasing. We present a review of rheumatology US, focusing on recent trends and advances. (J Rheum Dis 2016;23:11-18)

Key Words. Doppler ultrasonography, Rheumatoid arthritis, Scleroderma systemic, Spondylitis ankylosing

INTRODUCTION

Of the many advances achieved in the past decade in rheumatology, ultrasound (US) is the most highlighted owing to the fact that US is able to depict inside the joint and surrounding structures as images. US in rheumatol-ogy has concreted its unique position as a fully validated tool in the evaluation of arthritic activity, assessment of therapeutic responses and prediction of recurrence. The aim of this review is to provide recent trends and ad-vances achieved in the application of US in rheumatology.

MAIN SUBJECTS

Rheumatoid arthritisRheumatoid arthritis (RA) is a chronic inflammatory

autoimmune disorder which primarily affect the syno-vium of synovial joints of human body. RA is the major disease primarily studied with US in rheumatology. The joint that synovitis was first demonstration was the knee joint in 1978 by Cooperberg et al. [1]. To evaluate the re-

sult of yttrium-90 injection as therapy of RA in the knee joint, gray scale US was used. They demonstrated that de-gree of supra-patellar effusion and synovial thickening of the knee joint can be evaluated with US. Since then, stud-ies have shown that US have superiority in detecting syn-ovitis compared with clinical examination through its in-born ability to see proliferated synovium and abnor-mally increased micro-vascularity [2-4]. US can evaluate the joint and its surrounding structures

with two aspects: gray scale and Doppler (Figure 1). With gray scale US, cross sectional anatomy and its abnormal-ities can be assessed. In contrast, with Doppler the abnor-mally increased micro-vascularity which represent ar-thritic or disease activity can be assessed. US studies in RA have explored how to assess synovitis with gray scale and Doppler using scoring system. Although there is no single gold standard for quantifying activity of RA, differ-ent at present, different scoring systems for both gray scale and Doppler scoring have been proposed [5-7]. Based on these previous establishment, studies in RA have been focusing earlier diagnosis of RA in patients

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Figure 1. Gray scale and power Doppler ultrasound (US) mode. (A) Gray scale US of the right 3rd metacarpophalangeal joint shows anatomical abnormalities of joint effusion and synovial proliferation. (B) In contrast, power Doppler shows the presence of Doppler signal. The positive Doppler signal detected inside the joint cavity always represents active ongoing inflammation. Active synovitis is seen in the right wrist joint.

with preclinical stage as well as quantification of sy-novitis.Other than synovial joint, tendon sheath is also com-

posed of synovial sheath where thin layer of synovial membrane exists around the tendon. The tendon sheath is often involved in the disease course of RA. Inflamed tendon sheath, which is called as tenosynovitis, is ob-served as hypoechoic or anechoic fluid inside the tendon sheath with or without Doppler signal (Figure 2). Doppler signal can be detected where active ongoing synovial pro-liferation exists anywhere in the tendon sheath. Also ten-don itself can be affected by various inflammatory or non-inflammatory conditions. Tendons can be visualized with US along their course up to distal insertion site. Loss of their unique fibrillar pattern of echotexture is an early sensitive marker of tendon damage. More affected tendon become swollen with internal hypoechogenicity [8]. In a certain condition, US is more sensitive compared with magnetic resonance imaging (MRI) in the detection of te-nosynovial swelling and tendon tearing because US can allow a dynamic examination of tendon in the real time. US is also useful to differentiate inflammatory causes of

joint pain from numerous non-inflammatory causes in various musculoskeletal diseases in rheumatology. For instance, rotator cuff tendinopathies which is the most common but mechanical cause of shoulder pain can be easily differentiated from the involvement of RA using gray scale and Doppler mode. In the same manner, medial and lateral epicondylitis of the elbow can be exactly differ-entiated from elbow joint effusion or synovitis, both of which are sometimes difficult to distinguish using clinical examination only. In the foot, US can help differentiating

plantar fasciitis caused by mechanical repetitive irritation from that of enthesitis in spondyloarthropathies (SpA) [9,10].

1) Clinical assessment of rheumatoid arthritis activity Due to new application of biologic disease modify an-

ti-rheumatic drug (DMARD) in RA treatment, the pre-cise measurement of RA activity in clinical practice has become supreme important than ever. The concept of re-mission as a therapeutic target of RA treatment has be-come notably highlighted in accordance with treat to tar-get strategies [11]. True remission can be defined as com-plete absence of symptoms and signs of synovitis. Traditionally, remission is defined according to the modi-fied American College of Rheumatology (ACR) criteria. In time, several composite score were developed such as disease activity score (DAS) [12], disease activity score counting 28 joints (DAS 28) [13], Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). However, clinical remission defined by all of these criteria is likely to unable to reflect true remission because counting tender and swollen joint is always de-pendent on the clinician’s experience and judgement. Moreover, a deformed joint in which if only fibrous tissue exists without inflammatory activity cannot be differ-entiated from true swollen joint with clinical examination only. Naturally, this results in insensitivity of clinical as-sessment of true arthritic activity. Furthermore, modified pain tolerability of patients and lack of elevation of in-flammatory parameters also can lead to inaccuracy as-sessment of clinical remission. Thus, there has been a general agreement that these criteria can reflect low dis-

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Figure 2. Tenosynovitis in a patient with rheumatoid arthritis. (A) Proliferation of synovium (arrow) of tendon sheath with effusionis observed in transverse scan of left 2nd finger flexor tendon. (B) In longitudinal scan of the same lesion, thickened tendon (arrow)with surrounding proliferated synovium is also seen. (C) Confluent power Doppler signals (arrow) are observed near the insertion site of tibialis posterior tendon in left ankle joint, which represents active tenosynovitis at the corresponding site. (D) In transverse view of the same lesion, power Doppler hyperemia (arrow) is also seen within the proliferated tenosynovium.

ease activity rather than true remission [14]. With these background, clinical remission criteria was redefined in 2011 by the ACR and European League against Rheuma-tism (EULAR) collaboration initiative [15]. However, still this criteria is also based on tender and swollen joints count, which starts from an assumption that the clinical assessment of joint is an accurate reflection of determi-nation of presence of synovitis.

2) Doppler signal as a reflection of joint inflammationMRI has a capability to visualize synovial inflammation.

Enhanced synovium seen on gadolinium enhanced MRI is believed to represent the inflamed synovium with in-creased synovial vascularity, therefore it can be used as the unique marker of synovial inflammation. Studies have shown that power or colour Doppler signals detected in-side the synovial joint is correlated with enhanced syno-vial membrane seen on MRI or degree of vascularity seen

in histopathology. Szkudlarek et al. [16] showed the pres-ence of power Doppler signal correlated with the rate of early synovial enhancement in gadolinium enhanced MRI in patients with RA. Terslev et al. [17] compared the quantitative and qualitative colour Doppler signals with gadolinium enhanced MRI in larger number of joints (29 wrists and 167 finger joints) in patients with RA. Doppler colour fraction which is the number of color pixels ex-pressed in relation to the total number of pixels in the marked region of interest and resistance index showed correlation with the thickness of enhanced synovium in postcontrast MRI scores. Walther et al. [18] compared power Doppler findings with histopathologic findings of synovial membrane vascularity. The power Doppler sig-nal of the synovial membrane was graded qualitatively on a scale of 1 to 4, and analyzed quantitatively using the manufacturer’s power Doppler distribution function algorithm. Both qualitative and quantitative measure-

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ment of power Doppler vascularization correlated with histopathologic findings. Compared with MRI, US has its superiority in terms of

repeatability, dynamic examination, multiple joint exami-nation at one sitting and portability. Furthermore, MRI requires contrast injection to reliably distinguish active synovial inflammation which is identified by synovial enhancement. On the contrary, US cannot visualize bone edema and it is inherently operator dependent. Because both US and MRI can detect synovitis sensitively and im-portant in the diagnosis and management of RA, they do complementary role each other in most of rheumatologic evaluation as well as RA [19].

3) Power Doppler remission Both power and colour Doppler can be used in rheuma-

tology US. Colour Doppler represents blood flow by en-coding an estimate of the mean “Doppler shift”. Thus, colour Doppler is mainly used when flow velocity and di-rection is essential information to be obtained, e.g., tem-poral arteritis or carotid artery stenosis evaluation. In contrast, power Doppler do not use “Doppler shift”. Instead of it, power Doppler uses back scattered power or energy, which is reflected echo signals from per unit of tis-sue [20]. The integrated total power is approximately proportional to the number of moving red blood cells pro-ducing Doppler shift. The power Doppler does not aliase inherently, less incidence angle dependent and more sen-sitive to microvascular flow. Thus, in rheumatology US examination, power Doppler is preferred to colour Doppler.As mentioned earlier, disease remission is the major

goal of treatment for patients with RA [21] and clinical measure only do not reflect a true absence of synovitis. Thus imaging remission which is defined as complete ab-sence of synovial inflammation seen on MRI or US has emerged as an alternative criteria that should be con-sidered. It was first suggested in 2006 by Brown et al. [22] that the term of true remission should be confined for pa-tient who are not only in a state of clinical remission, but also show an absence of synovitis on imaging studies. Further studies have demonstrated that US observed syn-ovitis which is evaluated with gray scale and Doppler is associated with worse clinical and radiographic outcomes in patients with RA. Peluso et al. [23] aimed to define how many patients reached power Doppler remission in a cohort of patients with early RA compared with long-standing RA. Power Doppler remission occurred in half of patients (43.7%) with early RA and only in a minority of

patients (17.4%) with longstanding RA in clinical re-mission. The US findings in DAS 28 remission (DAS 28 ＜2.6) patients treated with a combination therapy (a tumor necrosis factor [TNF] blocker and methotrexate [MTX]) as initial therapy was compared with patients who received delayed therapy (after failing at least two DMARDs including MTX or previous TNF blocker) in a study by Saleem et al. [24]. The initial treatment group had significantly lower gray scale synovial hypertrophy score compared delayed treatment group, but no differ-ence in power Doppler activity (35% and 45% respec-tively) was noted. These studies support the fact that the presence of

Doppler signal inside the synovial joint always indicate the presence of synovial inflammation at any given situation. In contrast, the level of gray scale synovitis which is represented by synovial proliferation can corre-late with disease duration and subsequent fibrotic changes [24]. Therefore, power Doppler remission could be a new therapeutic target in the treatment of RA. To es-tablish this new concept, there should be a consensus re-garding new definition of US imaging remission [14]: which joint and how many joints should be scanned, what cut-off value should be applied to Doppler signals and is it achievable goal? The researchers have already started to work on these questions.

SpondyloarthropathiesEnthesopathy is the hallmark of the SpA. Affected en-

theseal tendons show typical tendinopathies charac-terized by loss of normal fibrillar structures. The US defi-nition of enthesopathy proposed by the OMERACT ultra-sound group was as “abnormally hypoechoic (loss of nor-mal fibrillar architecture) and/or thickened tendon or lig-ament at its bony attachment (may occasionally contain hyperechoic foci consistent with calcification), seen in 2 perpendicular planes that may exhibit Doppler signal and/or bony changes including enthesophytes, erosions, or irregularity” [25]. In contrast, the term “enthesitis” is restricted to inflammatory entheosopathy, which also characteristic feature of SpA (Figure 3). Mechanical caus-es such as degenerative or traumatic stress also cause en-thesopathies, but it usually does not show Doppler signals. US showed greater sensitivity for the detection of en-

thesitis in patients with SpA over clinical examination [26]. The usefulness of US in SpA was also demonstrated in a large scale study by D’Agostino et al. [27]. They dem-

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Figure 3. Achilles tendon enthesitis in a patient with ankylosing spondylitis. (A) Longitudinal scan shows Doppler signals detectedaround the insertion site of left Achilles tendon (arrows), which means that there is active enthesitis. (B) Transverse scan of the samelesion also shows power Doppler signals (arrows) at the entheseal site.

onstrated that B-mode US with power Doppler can in-crease detection of peripheral enthesitis in patients with SpA, but not in mechanical back pain. Like the attempt to quantify US synovitis, in order to quantify entheseal in-volvement, different scoring systems have been sug-gested by different study groups including Glasgow Ultrasound Enthesitis Scoring System (GUESS) [28], Sonographic Enthesitis Index (SEI) [29] and Madrid Sonographic Enthesis Index (MASEI) [30]. However, there is a lack of well-reported methodology on the num-ber and choice of enthesis to examine [31]. Nevertheless, due to its greater sensitivity for the detection of entheseal abnormality, US is regarded as a key imaging modality for early diagnosis and assessment of SpA [32,33].

1) Systemic sclerosisSystemic sclerosis (SSc) is a connective tissue disease

characterized by obliterative microvasculopathies and progressive cutaneous and internal organ fibrosis. The differentiation of interfaces between epidermis and der-mis with US was first introduced in 1979 by American or-thopedic surgeons Alexander and Miller [34]. Using an A-mode 15 MHz transducer, they compared the accuracy of this new US technique with a radiographic method of proven accuracy. They suggested that what they called an “ultrasonic biometric ruler” could be an accurate, simple, and non-invasive method for measuring thickness. Further results showed that US is a reliable tool to meas-ure skin thickness. Myers et al. [35] measured skin thick-ness over the volar surface of the forearm using a 25 MHz transducer and reported high degree of correlation be-

tween US and radiography. Systematic scoring system was also proposed. Moore and colleagues [36] proposed 17-point US scoring method in 2003. They showed that US measured dermal thickness at 17 sites, corresponding to those assesses in the modified Rodnan skin score re-sulted in good reliability. Akesson et al. [37] also meas-ured skin thickness and echogenicity represented on an arbitrary scale of 0 to 255 pixels at five skin site. They showed that repeated measurement of skin thickness and echogenicity at 2 to 4 years with US can be an objective tool for the assessment of skin involvement. The overall dermal thickness varies from 0.5 to 3 mm. The epidermal thickness is less than 0.1 mm thick [38]. The epi-dermal/dermal/subcutaneous tissue interfaces are not linear, thus clear identification of each layer may be difficult. Nevertheless, studies have shown overall good inter and intra-observer variability for the measurement of skin thickness with US. Scheja and Akesson [39] re-ported interobserver variability of 1.0% for the proximal phalanx, 4.2% for the hand, and 0.0016% for the forearm by comparing the results obtained by two independent in-vestigators. The precision of measurements at 17 sites by identifying the surface/epidermis, dermis/epidermis, and dermis/subcutis interfaces was also good at most sites [36]. Kaloudi et al. [40] also assessed variability by 2 ob-servers at 2 different sites on the second digit of the hand. They reported low intra- and interobserver variability, showing US is a reliable tool that can give reproducible re-sults to detect skin thickness. At present, it is quite obvious that US can provide a vali-

dated outcome measurement tool, aiding better under-

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Figure 4. Measurement of skin thickness (the distance between the upper and lower arrow in each image) in (A) a patient with sys-temic sclerosis (SSc) patient and (B) normal subject. High resolution ultrasound (US) machine can visualize the interface betweenskin and subcutaneous tissue (lower arrow), as well as the interface between US gel and epidermis (upper arrow). Using measure-ment function of US system, the thickness of skin can be assessed. The thickness of skin in a patient with SSc was measured higherthan the normal subjects as shown in this image.

standing of disease process (Figure 4). However, there are much more needs regarding the standardization in terms of image acquisition, regions of interest and skin thick-ness to be measured (e.g., dermal thickness only or epi-dermis and dermal thickness) to expand its utility [41,42].

2) Interventional ultrasoundUS guided intervention is based on the ability of US to

identity the region to be aspirated or injected through real time visualization of needle. The transducer can be pro-tected with prove cover and any generic 75% propanol containing or other disinfectant can be used to clean the needle insertion site. If more stringent sterility is in-dicated such as hip joint injection, sterile probe cover, sterile gel, drapes, gloves and povidone-iodine solution can also be used. Most of all US guided procedures in rheumatology are performed with free-hand technique, which allows direct and indirect visualization of needle and its tip [43]. Owing to these advantages, US guidance has clearly demonstrated superior accuracy and better clinical outcomes compared conventional blind injection [44,45]. Compared to conventional palpation guided method, US guidance resulted in more reduction in pro-cedural pain, absolute pain scores and increase in the re-sponse rate [44]. Especially, small joint space injection in ankle/foot and wrist/hand, US guidance demonstrated a greater accuracy contrasted to larger joint injections in which showed a similar accuracy [46]. Tarsal and carpal joints are also involved in inflam-

matory arthritis. With blind method, these joints are to-

tally difficult to place a needle into the joint space because the outline of articular carpal or tarsal bone cannot be palpated. US can provide guidance for precise location of needle for any interventional procedures in carpal and tar-sal joints. US also can guide needle tip to be located in a very small space between tendon sheath and tendon, pre-venting injection of steroid into the tendon substance. Apparently, this guidance makes clinical outcome better in any given inflammatory or non-inflammatory conditions.

3) Educational and research network: EULAR and tar-geted ultrasound initiative

To address learning needs of US, EULAR Working Group for Musculoskeletal US was formed in 1998 by European expert rheumatologist and subsequently the first EULAR US training course was held in Netherlands. Since then, EULAR has been holding US courses annually in order to provide systematic learning and hands-on experience. Expansion of learning needs among rheuma-tologist have made EULAR courses more dedicated. In 2007, EULAR educational model which is composed of three levels of basic, intermediate and advanced course and corresponding contents were proposed [47]. Fur-thermore, EULAR started to provide a training program for “ultrasound trainers in rheumatology” in 2012. EULAR also launched the competency assessment in US in 2015, which provides two levels of competency: Level 1 and level 2. Each level represents the ability to perform full US examination without supervision and to teach US examination in rheumatology. US is no longer be considered as an optional tool in

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rheumatology. Rheumatologist must learn and know how to apply and how it can be used in the evaluation of various rheumatic diseases. US in rheumatology has been expanding its research fields to various agenda. Ongoing research agenda is focusing on validation of US in RA ero-sion, pediatric arthritis, and outcome measure of other in-flammatory arthritis such as gout, psoriatic arthritis [48]. Recently formed an international collaboration US net-work named as targeted ultrasound initiative (TUI) has been raising awareness of a targeted ultrasound approach in the management of inflammatory arthritis. TUI pro-vides educational and training tools to aid more rheuma-tologists to develop US skills and knowledge in collabo-ration with Asian countries [49].

CONCLUSION

Nowadays, US has become essential tool for rheumatol-ogists to do clinical practice rightly. Accumulated evi-dences have established the reliability, validity and feasi-bility of US use in rheumatology. RA disease activity can be assessed more exactly with US and the recurrence in patients in remission can be predicted with Doppler. In patient with SpA, enthesitis can be detected earlier with US. In patient with SSc, US measurement of skin thick-ness can provide an alternative way to assess disease process. Through exact guidance of needle tip to at any point that rheumatologist wants, the best clinical out-come can be assured. Importantly, systematic educational program and competency assessment have been being provided by EULAR and international collaboration for research network are expanding.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

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