In this chapter we focus on the application of ultrasound imaging for the assessment of rheumatoid arthritis (RA), both as a means of identifying structural joint changes (e.g., joint erosions, subluxations, loss of cartilage, osteophytes) and of evaluating the degree of inflammatory activity (e.g., synovial proliferation, joint fluid, and hyperemia) within a joint. In this way, ultrasonography can serve as both a structural and functional imaging tool. Ultrasound evaluation has a number of specific attributes that make it an especially desirable imaging tool for patients with RA. First, it is able to scan multiple joints in a relatively short period of time. This is of value because RA is a polyarticular disease. Second, it is relatively inexpensive and very widely available (as compared with MRI). Third, it is able to simultaneously image bone and soft tissue. Finally, ultrasound imaging uniquely allows dynamic, real-time examination.
The aims of this chapter are to (1) review key pathologic and clinical features of RA and especially those that lend themselves to imaging assessment and therapeutic intervention and (2) discuss the role of ultrasonography in relation to other imaging modalities in the management of RA.
Rheumatoid arthritis is a severe, progressive, and debilitating multisystem autoimmune disease with an overall prevalence of approximately 1% worldwide. Thus, it affects tens of millions of people, with approximately a 3 : 1 female-to-male incidence ratio. Manifestations of the disease, which may begin at any age (peak 30-50 years), are highly variable between affected persons and tend to follow a relapsing and remitting course; if untreated, the disease will progress to irreversible joint damage and, potentially, premature death. The primary site of pathology in RA is the synovium. In normal joints, the synovium is a thin membrane that lines the joint capsule and does not encroach on the articular cartilage. At arthroscopy it appears almost translucent with a few blood vessels barely visible. In RA, however, there is expansion of the synovial tissue as the superficial layers become hyperplastic, while the deeper layers are infiltrated by abundant inflammatory cells and new blood vessels. This thickened synovium, known as pannus (L., “cloth” or “covering”), begins to migrate in a tumor-like fashion toward the center of the joint, resulting in initial cartilage loss and then subsequent bone loss (erosions). The first bony erosions occur in the periarticular region of a joint where the cartilage is at its thinnest—the so-called bare area. Subsequent invasion by the pannus leads to central erosions and, ultimately, to joint failure. Persistent inflammation within the joint also results in permanent capsule and collateral ligament damage that contributes to the many deformities seen in RA.
Clinical Presentation and Diagnosis
RA usually manifests as a polyarthritis (of six or more involved joints) with pain, stiffness, and swelling in the wrists and small joints of the hands (the metacarpophalangeal [MCP] and proximal interphalangeal [PIP] joints) and the feet (metatarsophalangeal [MTP] joints) in over 90% of patients. It subsequently progresses to involve most of the other synovial joints, including the knees, shoulders, hindfeet, and neck. It is relatively rare for RA to manifest as a monoarthritis (single joint) or oligoarthritis (five or fewer joints). Systemic symptoms such as fatigue, night sweats, and/or weight loss are common at disease presentation or during a flare. The clinical diagnosis of RA is based on criteria devised by the American College of Rheumatology. These criteria, which were most recently revised in 1987, require a minimum of four specific indices to be fulfilled out of a possible seven to permit the diagnosis of RA. These include early morning stiffness lasting more than an hour, hand involvement, swelling of more than three joints, joint symmetry of three or more joint groups, presence of rheumatoid nodules, positive rheumatoid factor, and presence of radiographic bone erosions on radiographs of the hands and feet. The symptoms and signs need to be present for at least 6 weeks to exclude self-limited diseases, such as postinfectious arthritis (viral or streptococcal), which generally resolve within this period. The early physical signs of RA may be difficult to identify because the joints may only appear puffy; however, if left untreated or if inadequately treated, irreversible deformities may occur ( Fig. 5-1 ). This progression may take only 2 to 5 years.
Although RA is a multisystem disease and potentially affects many organs, these manifestations are now fortunately rare, because in current practice patients are much more aggressively treated with immunosuppressive agents. However, situations do arise when a knowledge of these extra-articular manifestations is important, especially in the minority of patients who appear resistant to drug treatments. The most frequent extra-articular manifestation is that of soft tissue nodules, which classically occur at the elbows but also are evident on the hands; occasionally, they involve the sclera and lungs, where they may cavitate, resembling lung cancer. The kidneys are relatively spared in RA, although renal impairment may result from the use of drugs such as nonsteroidal anti-inflammatory agents. Renal amyloidosis is now fortunately very rare owing to earlier and more effective medical control of inflammation. In children, an RA pattern of disease may be seen with juvenile inflammatory arthritis that appears to have a different cluster of systemic and characteristic joint manifestations from that of adults and may be treated less aggressively.
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful markers of inflammation. They increase, however, in the presence of any inflammation in the body and are therefore nonspecific. Rheumatoid factor (RF) is an antibody found in the blood of approximately 75% of patients with RA. Not all people with the condition, therefore, will have the antibody in their serum. Approximately 1 in 20 normal volunteers (5%) will have RF in their serum, and other inflammatory conditions may also cause a positive result. For this reason, results of the blood test must be interpreted with the clinical findings. Anti–cyclic citrullinated peptide antibody (anti-CCP Ab) is a newer laboratory test for RA. It is as sensitive as RF but much more specific and therefore can distinguish RA from other conditions. Furthermore, the anti-CCP antibody may predict who will develop the condition and identify who will be affected more severely.
RA appears to be a uniquely human disease, although limited animal models exist and have been used in research. RA synovitis has characteristic patterns of joint involvement but can potentially affect all of the synovial joints. It is triggered by unknown factors in an individual who is probably genetically susceptible and results in a complex interplay of inflammatory cells and chemical mediators. A significant body of research has demonstrated key roles for both cellular and humoral factors, most notably macrophages, fibroblasts, lymphocytes, tumor necrosis factor-alpha (TNF-α), interleukins 1 and 2 (IL-1 and IL-2), prostaglandins (PG), amines, vascular endothelial growth factor (VEGF), neuropeptides, various chemoattractant molecules, and nitric oxide, although other inflammatory cell lines and cytokines are also known to play perhaps significant roles in the pathophysiologic process. Many of these cellular and humoral disease mediators provide avenues both for imaging and laboratory evaluation of patients with RA, as well as for the pharmacologic intervention. The role of autoantibodies such as RF and anti-CCP Ab is still unknown; they may have a pathogenic role or merely represent an epiphenomenon due to the prolonged inflammation in RA.
Angioneogenesis, a feature more commonly associated with the growth and proliferation of malignancy, is seen within affected joints at the earliest stages of the disease. This includes pathologic small vessel proliferation within the synovium, a process that significantly increases overall blood flow in proportion to the severity and “activity” of the disease process. Small vessel permeability is also increased. There is, in fact, a close coupling between the disease state or “clinical disease activity” and the degree of abnormally increased synovial vascularity, with more severe symptoms and joint damage associated with higher degrees of abnormally increased vascularization, essentially one occurring in proportion to the other. Furthermore, it has been demonstrated that, with effective treatment, the angioneogenesis ceases and resultant synovial vascularization rapidly diminishes. For example, treatment with corticosteroids and anti–TNF-α agents (e.g., etanercept [Enbrel]) are known to antagonize factors that promote angioneogenesis, and thus the benefit of steroids and biologic response modifying agents may be largely due to inhibition of the neovascularization.
Over the past decade it has been unequivocally proven that if inflammation in RA is identified and suppressed as soon as possible, then joint damage can be minimized and function maintained. The place of modern imaging, therefore, has been to optimize inflammation assessment over what is already currently available (e.g., clinical examination, blood tests, and radiography). The general aim of RA management is to treat patients with immunosuppressive agents from the outset. Conventionally, this will include treatments such as corticosteroids, methotrexate, or sulfasalazine. Recently, as noted earlier, more targeted antibody therapies (the so-called biologics, or biologic response modifiers) that inhibit different parts of the inflammatory pathway have been developed as a direct result of our improved basic understanding of the pathophysiology of the disease. The most noticeable success has been with the anti–TNF-α agents, such as etanercept, but more recently agents that inhibit the B-cell production of autoantibodies, such as rituximab, or the co-stimulation of B and T cells (anti-CLTA4Ig) have been used successfully. The timing of initiation of biologic response modifiers is controversial because they are very expensive and pose other risks to patients, such as a heightened risk of infection. However, there is a compelling and growing body of evidence that in early disease their effect may be sustained after withdrawal after only 1 year of treatment. This raises the possibility that the drugs may not be required over the long term for all patients.
ULTRASOUND IMAGING FOR RHEUMATOID ARTHRITIS
Ultrasonography is an imaging technique that evolved from World War II submarine SONAR technology and was first introduced to the radiologic community for the purpose of medical diagnostic imaging in the 1960s. Images are generated by analyzing the echo reflections of high-frequency sound waves that are both generated and received by an electronic probe, or transducer, that is applied directly to the skin, usually along with a small amount of acoustic coupling gel. Since its introduction, ultrasonography has benefited from continuous technological improvements occurring over the past decade, most especially improvements in transducer (probe) design and computerized image processing. Currently, ultrasonography is the second most commonly utilized imaging method overall, after plain film radiography, and has also become the predominant imaging modality in obstetrics. As a direct result of these relatively recent technological advances, musculoskeletal ultrasonography in general and the sonographic imaging of small joints in particular have become viable clinical tools. Evaluation with ultrasound was perhaps first applied to patients with RA in 1988, and now a significant body of literature supports the use of ultrasound for a variety of musculoskeletal applications, including evaluating injuries and internal derangements of joints, guiding interventional procedures, and so on. These topics are the subjects of their own comprehensive textbooks. As regards the care of patients with RA, ultrasound imaging technology is also a powerful and versatile asset for rheumatologists and radiologists; it is valuable indeed for the evaluation of all types of inflammatory arthritis but relatively few clinicians currently avail themselves of its benefits in clinical practice.
Since the first report by De Flaviis and associates, ultrasound imaging has been evaluated as applied to all human arthritides and enthesopathies, including both degenerative and erosive joint diseases; however, its use has been best studied in RA. Like MRI, ultrasonography is a cross-sectional imaging modality and one that utilizes no ionizing radiation. It has shown greater utility in the detection of erosions than plain radiography, but it is less sensitive in this regard than MRI. Because ultrasound imaging requires physical placement and manipulation of a transducer, or probe, that is placed directly onto or close to the region of anatomic interest, stearic hindrance can interfere. As such, several authors have noted the presence of relative “blind spots” for the sonographic detection of joint erosions in RA, most notably including significant portions of the third and fourth MCP joints of the hand, which are situated such that the probe cannot be placed in close enough proximity. MRI, which is a tomographic tool, does not have this disadvantage.
There is incomplete consensus regarding standard examination techniques or technical parameters, but guidelines for ultrasound techniques for the evaluation of RA have been offered. Patients are scanned by direct application of a transducer optimized for musculoskeletal imaging, typically a high-frequency broadband (usually ranging from 18-5 MHz) electronically steered, linear small-footprint transducer with good near-field focus, such as the “hockey stick” or Entos probe transducer type illustrated in Figure 5-2 . A standoff pad is thus obviated, but a small amount of acoustic coupling gel is used. It is important, particularly when using Doppler imaging, to examine joints in a relaxed position without too much joint flexion or overlying transducer pressure, because the findings of abnormally increased blood flow to the joint may be obliterated.
Ultrasonography vs. Radiography in Rheumatoid Arthritis: Diagnosis vs. Evaluation
The plain radiograph in RA remains the primary radiologic means for the establishment of the initial diagnosis of RA. It is the cornerstone of the diagnostic classification of all of the arthritides and is still a superb tool for the detection and characterization of erosive disease. Although ultrasonography is a more sensitive diagnostic tool, it lacks the specificity of plain radiographs for recognition of the specific manifestations and disease patterns that allow the radiologist and rheumatologist to readily discriminate RA from other prevalent inflammatory arthropathies. Many studies, however, have demonstrated that plain films are relatively insensitive in the earliest stages of the disease and have only very limited utility in evaluating response to treatment. For example, Backhaus and associates showed that both MRI and ultrasonography can detect evidence of RA in patients with completely normal radiographs.
Dr. Robert Lopez-Ben and colleagues at the University of Alabama at Birmingham studied 168 joints in 21 patients with RA and found that ultrasonography detected 15-fold more erosions than plain films at baseline and more than 6-fold more erosions on follow-up than did radiography. In their series, the use of power Doppler imaging also allowed the detection of synovitis in 100% of affected patients at baseline and in most patients on follow-up. Interobserver reliability for erosions was excellent, with Cohen’s κ value for inter-reader agreement equal to 0.98 and that for the severity of synovitis on power Doppler imaging of 0.96. Surprisingly, in their series, the interobserver agreement for the detection of erosions on radiographs, which is something the readers had much more experience doing, was not as good (κ = 0.86)! Wakefield and associates compared radiography and ultrasonography for the detection of erosions in the MCP joints of 100 patients with RA ( Figs. 5-3, 5-4, and 5-5 ). They found that ultrasonography was able to detect smaller erosions than radiography, particularly if the erosions were en face, that is, lost in a 2D radiographic image. It was also noted that “blind spots” existed where the probe did not have acoustic access, which meant the ultrasonography failed to detect some abnormalities, most notably between the third and fourth MCP joints. In clinical practice, serial radiographs are used somewhat sparingly in the long-term management of RA patients. In the short term, radiographic changes can be quite subtle, although over longer time periods very significant differences are readily apparent on radiographs.
For the radiologist, characteristic bone erosions on the plain films of the hands and feet have been the sine qua non of diagnosis in RA, and for many research studies the identification of characteristic erosions is essential to allow the classification of a joint process in a particular patient as being erosive. Indeed, studies examining RA by MRI and ultrasound have often used the radiographic erosion as their gold standard.
For research purposes, plain film–based rating scales of varying degrees of complexity have been developed to assess the progression of RA findings and to infer the response to treatment. In recent years, simplified or modified versions of the Sharp and/or Larsen scoring systems have been most commonly used, although their true predictive value has been questioned. Each of the several published methods relies on the recognition and scoring of a large number of the radiographic manifestations of RA, including counting the erosions in target joints. A relatively large number of discrete radiographic observations contribute to the final score, which provides an index for comparison and grading the progress of the disease over time. The natural history of RA is for the manifestations to worsen, and thus for the score to inexorably rise. A favorable response to treatment is inferred when the scores stabilize over time or if the scores progress more slowly than expected. The problem with radiography is simply as it relates to the assessment of the effects of ongoing therapy, in that the plain film response is significantly delayed and is relatively sluggish as an indicator of treatment response. Indeed, the radiograph itself can be thought of as a relatively static record of the cumulative effects of joint damage; there is only limited depiction of the salutary effects of treatment, or lack thereof. In essence, changes that are visible on plain radiographs evolve too slowly to be of good clinical use in the management of RA patients.
There are indeed reliable radiographic manifestations of treatment success, such as partial healing of RA erosions, as shown in Figure 5-6 . The regrowth of cortical bone margins within erosions, and increased mineralization of the periarticular bone, however, are examples of changes seen only late in the treatment process; and at least initially their absence does not indicate treatment failure. In the early stages of treatment these findings will not yet be present to reassure the clinician and patient that the current treatment plan is an adequate one. Often these radiographic changes are both very subtle and significantly delayed with respect to the onset of effective therapies.
Tenosynovitis in Rheumatoid Arthritis
Tenosynovitis in RA is a complex pathophysiologic processes involving various cytokines (IL-1, TNF-α, VEGF, and other chemical and cellular mediators, with a significant role played by macrophages. Ultrasound and MRI studies have both independently confirmed that tenosynovitis has an extremely high prevalence in RA but relatively little data exist in early disease. Tendon pathology is readily demonstrated by ultrasound, and its contribution to the morbidity of RA has previously been underestimated. Fuchs and Pincus and their colleagues at the Vanderbilt University Medical Center have shown that joint destruction in RA follows a first-order kinetics model, and several studies have shown that, in early RA, synovitis is the primary abnormality and bone damage is subsequent and occurs in proportion to the level of synovitis and never in its absence.
Normal tendons have a characteristic “fibrillary” appearance on ultrasound evaluation, as shown in Figures 5-2 and 5-7 , owing to their composition of highly organized linear collagen bundles; as a result of this high level of linear orientation, tendons demonstrate isotropic echogenicity with respect to the angle of insonation by the ultrasound beam.
In early inflammatory change, one of the first manifestations is edema within the tendon, which alters the echogenicity (usually reducing it). This is because interstitial fluid intercalates between the collagen bundles, effectively reducing the density of their sonographic interfaces, and their degree of regularity, dampening their overall echogenicity and the isotropic effect. Widening or thickening of the tendon is also a frequent early finding, and fluid or debris in the tendon sheath is commonly seen ( Fig. 5-8 ). In early ultrasound publications describing the ultrasound characteristics of RA, this fluid layer was erroneously offered as a pathognomonic finding in RA. It is not, however, the frequency of its observation in patients with RA that underscores the extremely high prevalence of tenosynovitis as a manifestation of the disease in its early phases.
Either MRI, as is illustrated in Chapter 6 , or ultrasonography can be used to measure imaging findings of tenosynovitis in RA. As with joint pannus, both synovial volume and vascularity can be assessed. Wakefield and colleagues compared gray-scale ultrasonography with gadolinium-enhanced MRI for the detection of finger tenosynovitis in 50 patients with early RA and 20 normal controls. Flexor tenosynovitis was found in 57 (28.5%) of 200 joints in 24 (48%) of 50 patients on ultrasonography compared with 128 (64%) of 200 joints in 41 (82%) of 50 patients on MRI. Peri-extensor tenosynovitis was found in 14 (7%) joints in 9 (18%) patients on ultrasonography compared with 80 (40%) joints in 36 (72%) patients on MRI. No controls had imaging tenosynovitis. By using MRI as the gold standard, the sensitivity, specificity, and negative and positive predictive values for ultrasonography were 0.44, 0.99, 0.49, and 0.98, respectively, for flexor tenosynovitis and 0.15, 0.98, 0.63, and 0.86 for extensor tenosynovitis, respectively. The inter-reader reliability κ values were good: 0.85 and 0.8 for ultrasonography and MRI, respectively. The most frequently involved joints on ultrasonography and MRI were the second and third MCP joints. The authors concluded that a negative gray-scale ultrasound scan does not exclude inflammation and that, if clinically suspected, an MRI study should be considered. Further work is recommended to standardize definitions and image acquisition for both ultrasound and MR images. It was considered that Doppler imaging would have increased the specificity of the sonographic findings but decreased the sensitivity further, because abnormal Doppler signal rarely occurred in joint areas with gray-scale abnormalities.
Ultrasonography vs. MRI in Rheumatoid Arthritis: Structure vs. Function
In comparison of the modalities of ultrasonography and MRI, it has become clear that MRI allows earlier detection of joint erosions than is possible by either ultrasonography or plain radiographs. Ultrasonography does detect most joint erosions in RA, although not as many as can be visualized by MRI on a site-by-site basis. As noted earlier, in the hands of patients with RA, erosions are well visualized sonographically in some locations but not as well in others owing to limitations in probe positioning and placement, whereas all joint erosions are equally well depicted by MRI. Conversely, where ultrasonography has good visualization, it corresponds very accurately with MRI. For this reason, ultrasonography performs less well for detecting erosions in deeper joints (e.g., the hip, where only the anterior part can be seen) and complex joints (e.g., the intercarpal region of the wrist). In addition, in some joints where there many be concomitant degenerative changes, distinguishing an erosion from a depression between two adjacent osteophytes may be difficult. This problem is commonly encountered in the wrist, proximal interphalangeal joints, and mid foot.
As functional imaging methods, both ultrasonography and MRI have the ability to depict active synovitis; however, with MRI, detection of synovitis is accomplished indirectly, by injecting an intravenous contrast agent and inferring the degree of inflammatory activity on the basis of T1 contrast enhancement of the joint tissues on fat-saturation images (see Chapter 6 ). In the case of Doppler ultrasonography, the relationship between measurable abnormal blood flow and synovitis is more direct and the effect is quite robust ( Figs. 5-9 and 5-10 ). In our own work, we have observed as much as a 10-fold difference between a normal degree of synovial blood flow and pathologic synovial hyperemia in RA, a finding that has subsequently been confirmed by several others using varying techniques for quantification, including Hau and associates, who demonstrated a very high degree of statistical significance in their series ( P < .001) and Teh and colleagues, who had similar results from different methods. Studies comparing ultrasonography and MRI in RA of the hands have shown a high level of agreement for synovitis; a study by Backhaus and coworkers in 60 patients showed that ultrasonography was more sensitive than MRI in detecting synovitis, whereas MRI was more sensitive for detection of erosions (see Fig. 5-9 ). Szkudlarek and associates published similar results, in which they found that power Doppler imaging has a sensitivity of 89% and a specificity of 98% for RA in the MCP joints, significantly outperforming the clinical examination.