AbstractUltrasonography is a useful technique to detect soft tissue changes of rheumatoid arthritisnot only synovitis, but also tenosynovitis, bursitis, and enthesitis-even at a subclinical stage. However, radiologists tend to focus on synovitis in daily practice, and unusual peri- or extra-articular manifestations of rheumatoid arthritis are difficult to detect at the initial presentation. This pictorial essay describes a broad spectrum of ultrasonographic findings in tendons, bursae, ligaments, subcutaneous tissues, bones, and nerves to assist in the accurate diagnosis of rheumatoid arthritis.
IntroductionRheumatoid arthritis (RA) is a systemic, chronic inflammatory disorder of unknown etiology. RA mainly affects the joints; however, it can also have multiple peri- and extra-articular manifestations. The fundamental target area of RA is the synovium, which causes synovitis when antigens present in the synovial membrane elicit a cellular immune response. In addition, RA affects the synovium-lined tendon sheaths, bursae, and entheses where ligaments and tendons attach to bone. Ultrasonography (US) is a non-invasive, cost-effective diagnostic tool for evaluating synovitis that can easily be applied in outpatient clinics. When a patient with RA undergoes a US examination, radiologists tend to focus on synovitis. Furthermore, peri- or extra-articular manifestations are difficult to detect at initial presentation without specific medical history or clinical information. Therefore, radiologists should be knowledgeable of the various imaging characteristics of the broad disease spectrum to enable a correct and early diagnosis of RA. Furthermore, these various and unusual imaging findings could assist rheumatologists in making appropriate therapeutic decisions for patients with RA.
Herein, we describe the broad spectrum of ultrasonographic characteristics of peri- and extra-articular involvement to assist in the accurate diagnosis of RA.
Peri-articular ManifestationsTendonRA affects the synovial lining of the tendon sheath, which causes tenosynovitis. Tenosynovitis is an early phenomenon occurring in patients at risk of RA, and is a predictive factor of RA development [1]. The reported prevalence of tendon involvement in patients with RA is considerably high, ranging from 12.2% to 50.0% for hand and ankle tendons [2]. The histopathological mechanism of RA tenosynovitis is similar to that of joint synovitis, including hyperplasia of the synovial lining and infiltration of inflammatory cells and mediators. On US, tenosynovitis presents as hypoechoic or anechoic thickening of the tendon sheath, often accompanied by surrounding tenosynovial fluid within the sheath [3-6]. Color Doppler US can be used to examine hyperemia associated with active inflammation or chronic disease exacerbation [3-6].
Although any tendon may be affected, extensor tendon sheaths at the level of the wrist, from compartments I to VI, are more frequently affected than those of the flexors (Fig. 1) [4,6]. The extensor carpi ulnaris tendon is a common site affected by RA (Fig. 2) [3,6]. At the level of the ankle, the tibialis posterior (Fig. 3), flexor digitorum longus, flexor hallucis longus, and peroneal tendons are more frequently involved than are the extensors [4]. Moreover, isolated tenosynovitis without joint involvement can occur.
In the chronic stage, partial or complete tendon rupture may result from the weakening of the tendon sheath caused by infiltrative synovitis or from friction caused by tendon movement across the irregularly eroded bone surface (Fig. 4) [7,8]. Caput ulnae syndrome is characterized by end-stage destruction of the distal radioulnar joint caused by RA. It results in dorsal dislocation of the distal ulna, supination of the carpus, and volar subluxation of the extensor carpi ulnaris tendon. Eventually, the ulnar-side extensor tendons directly overlie the ulna prominence, which leads to tendon rupture, particularly on the ulnar side (Fig. 5).
In the wrist, the differential diagnoses of RA tenosynovitis include other infectious or inflammatory conditions such as tuberculosis (TB), psoriatic arthritis, and overuse tendon injury. RA is difficult to distinguish because other diseases can have similar features on US; however, a few points can be helpful for the differential diagnosis. TB tenosynovitis may be included in the differential diagnosis due to the chronic course of disease with similar clinical characteristics to RA. Similar findings, such as tendon sheath fluid with synovial proliferation and tendon sheath thickening, can be seen on US. However, TB tenosynovitis selectively targets the wrist and the volar aspect of the flexor tendon [9]. A lack of other rheumatoid features would make TB tenosynovitis more likely. In addition to TB infection, seronegative spondyloarthropathy may have similar imaging findings to RA. Spondyloarthropathy is mainly differentiated from RA by the involvement of non-synovial articular and peri-articular structures. Psoriatic tenosynovitis more commonly involves the flexor tendon of finger in the distal interphalangeal joints rather than the wrist, and entheseal involvement of the fingers, psoriasis, nail changes, and sausage digit may help distinguish it from rheumatoid tenosynovitis [4]. It is difficult to differentiate the early inflammatory features of RA from overuse tenosynovitis, but RA coexists with synovitis in most cases. Additionally, RA tenosynovitis accompanies other RA-related findings such as bone erosion or joint subluxation in the chronic stage [4,6].
BursaRA involves the synovial membrane in the bursae. It can occur in any bursa in the body, particularly the subacromial-subdeltoid, olecranon, trochanteric, forefoot, and retrocalcaneal bursae.
On US, inflamed bursae appear as thickened hypertrophied synovium with exudate [4]. The presence of US-detected subacromial-subdeltoid bursitis has been reported in 18%-69% of cases of rheumatoid shoulders [5]. Subacromial-subdeltoid bursitis is associated with glenohumeral joint synovitis, rotator cuff tear, bone erosion, and effusion in the long head of the biceps tendon (Fig. 6) [10]. In the hip, the greater trochanteric bursae are frequently distended by anechoic or hypoechoic fluid through synovial proliferation in patients with RA (Fig. 7).
Forefoot bursae can be classified as either intermetatarsal or adventitial. Intermetatarsal bursae are anatomic bursae with a synovial lining that show close cohesion with the intermetatarsal neurovascular bundle. Conversely, the adventitial bursae are characterized by fluid-filled sacs lacking synovial lining. Adventitial bursae are located in the submetatarsal pad, and are considered to be mechanically derived, where the friction or weight-bearing forces result in collagen degradation and concomitant localized fluid [11]. On US, hypertrophied intermetatarsal bursae manifest as well-defined fluid collections with a hypoechoic zone usually bulging >1 mm under the metatarsal heads (Fig. 8). In contrast, adventitial bursae present as anechoic or heterogeneous fluid collections within the submetatarsal fat pad (Fig. 9) [11]. Forefoot bursae may reduce the mobility of the foot by causing foot pain and dysfunction. Therefore, it is crucial to look not only for synovitis and tenosynovitis, but also for bursitis, in patients with RA to make an accurate diagnosis and to optimize patient care.
LigamentAn enthesis is the insertion site of a tendon, ligament, or articular capsule into the bone. Entheseal inflammation is often asymptomatic and may be overlooked during a clinical examination. Extra-articular enthesitis is common in spondyloarthropathy; however, it can also occur in RA. On US, enthesitis appears as hypoechoic (loss of normal fibrillar architecture) and/or thickened tendons or ligaments at their bony attachment site, which may present peri-entheseal hyperemia upon a Doppler examination during the acute phase. It may be associated with bone erosion, bursitis, and enthesophytes. During the inactive or chronic stage, US shows tendon or ligament thickening, prominent enthesophytes, intratendinous calcification, and bone erosion. McGonagle et al. [12] proposed the concept of the synovio-entheseal complex, where primary entheseal damage may occur from inflammatory reactions at adjacent synovial tissues. The Achilles tendon is among the enthesis structures and lacks a neighboring synovial joint line along with the articular cartilage; however, because a synovial membrane covers the tip of the protruding fat pad, the Achilles tendon is closely associated with the synovium [12]. Although Achilles tendon enthesitis is more frequent in spondyloarthropathy than in RA, it still occurs in the symptomatic ankles of 22% of patients with early RA (Fig. 10) [13]. Suzuki et al. [14] recently reported that retrocalcaneal bursitis could be preceded or accompanied by Achilles tendon enthesitis and suggested that synovio-entheseal complex inflammation in RA arises from synovial tissues, supporting the concept proposed by McGonagle et al. [12].
Extra-articular ManifestationsSubcutaneous TissueRheumatoid nodules are the most common extra-articular manifestations of RA and are frequent in longstanding RA, with an approximate occurrence of 20%-30% in patients with seropositive RA [8]. However, the pathogenesis of rheumatoid nodules remains unclear. Rheumatoid nodules are common at sites with mechanical irritation and pressure, including the olecranon region often associated with the olecranon bursa (Fig. 11), forearm, finger joints, and, rarely, foot joints (Fig. 12). Nodules are usually asymptomatic, palpable, firm, and easily movable subcutaneous lesions that can become painful when irritated. Mature rheumatoid nodules are composed of inner central necrosis, middle palisading fibroblasts, and an outer collagenous capsule with perivascular infiltration of chronic inflammatory cells [8]. On US, nodules usually appear as lobulated heterogeneous hypoechoic, and non-erosive compressible masses close to the bone surface. Some nodules present as central demarcated hypoechoic areas, which correspond to the central necrotic portion [15].
A common differential includes tophi in gout. Gout nodules mostly appear as heterogeneous masses, and occasionally have calcifications that appear as hyperechoic lesions with acoustic shadowing. Cortical bone erosion can be seen adjacent to the bone surface [15]. Rheumatoid nodules rarely calcify, which is a diagnostic feature that distinguishes them from gout tophi. Additionally, rheumatoid nodules rarely cause subjacent bone erosion [1].
BoneThe inflammatory nature of RA increases the risk of bone loss and fracture. Moreover, corticosteroid and methotrexate usage renders the bone more vulnerable to fracture. Thus, the prevalence of insufficiency fracture is higher in patients with RA (0.8%), and it can cause significant morbidity [17]. Diagnosing insufficiency fracture is challenging because it frequently masquerades as an inflammatory disease exacerbation. Moreover, the diagnosis of insufficiency fracture may be delayed by the late appearance of a callus; radiographs are normal until periosteal reactions appear or until cortical thickening at 2-4 weeks after symptom onset. Therefore, radiologists should suspect the presence of an insufficiency fracture if there is a mismatch between clinical symptoms and the radiologic findings of other structures associated with RA, particularly in high-risk patients.
Magnetic resonance imaging and bone scintigraphy are gold standards for the early diagnosis of insufficiency fractures. Although it is generally not the method of choice, US also can be useful for the early detection of insufficiency fracture with good sensitivity and specificity [18]. The following US findings are highly suggestive of insufficiency fracture: hypoechoic periosteal elevation above the cortical bone, increased posterior shadowing, fluid collection surrounding an injured bone, and increased vascularity on color Doppler (Fig. 14) [19].
NerveRA is a systemic inflammatory disease with potential neurologic manifestations. The clinical presentations of peripheral neuropathy include entrapment neuropathy (carpal, cubital, and tarsal tunnel syndrome, and peroneal neuropathy), distal sensory neuropathy, combined sensorimotor polyneuropathy, and mononeuritis multiplex. Entrapment neuropathies are the most common cause of neurologic impairment [8] and may occur at sites where nerves pass. Joint deformities, as well as inflamed synovium, ligaments, and tendon sheaths, may compress the peripheral nerves close to the joints or bursae. US can distinguish entrapment neuropathies by detecting the anatomical site and structures compressing the nerve. For instance, the inflammatory conditions of RA with tendon swelling, synovitis, effusion, or extra-articular ganglion displacing the tibial nerve can be visualized on US for tarsal tunnel syndrome (Fig. 15) [20]. Carpal tunnel syndrome is the most common entrapment neuropathy, and RA is the most commonly associated rheumatologic disorder [21]. Smerilli et al. [21] reported that the sonographic spectrum of carpal tunnel syndrome in patients with RA is characterized by an inflammatory pattern, which is defined by finger flexor tendon tenosynovitis and/or radio-carpal joint synovitis, with marked median nerve swelling being the dominant feature of idiopathic carpal tunnel syndrome (Fig. 16).
ConclusionA better understanding of the broad spectrum of RA, including its peri- and extra-articular manifestations, could improve the accuracy of RA diagnoses and assist rheumatologists in making more appropriate therapeutic decisions. US is a useful, relatively inexpensive, and non-invasive modality to detect various RA manifestations.
NotesAuthor Contributions Conceptualization: Suh JY, Park SY, Koh SH. Data acquisition: Park SY, Koh SH. Data analysis or interpretation: Suh JY, Park SY, Koh SH. Drafting of the manuscript: Suh JY, Park SY. Critical revision of the manuscript: Koh SH, Lee IJ, Lee K. Approval of the final version of the manuscript: all authors. References1. Resnick DL, Kransdorf MJ. Bone and joint imaging. Philadelphia, PA: Elsevier Health Sciences, 2004.
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