Imaging in the crystal arthropathies has undergone great advances in the past decade, with newer techniques having additional benefits for assisting diagnosis, predicting prognosis, and monitoring the treatment of these conditions. Three-dimensional digitized modalities such as computed tomography, dual-energy computed tomography, and magnetic resonance imaging (MRI) offer a multislice view of any anatomic region. Both ultrasonography and MRI reveal features of inflammation and joint damage in all crystal arthropathies, and can be used to monitor the inflammatory response to therapy. The type of imaging used needs to be adapted to the clinical question of relevance.
Key points
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Advanced imaging in gout using computed tomography (CT) scanning, dual-energy CT (DECT), and magnetic resonance imaging (MRI) has revealed the close association between erosions and tophi suggesting a mechanistic link.
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The ultrasound double-contour sign in gout is likely to represent monosodium urate crystals deposited over hyaline cartilage, and often appears adjacent to tophi.
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Some imaging techniques, especially ultrasonography, CT, and DECT, may be useful to reveal tophus resolution during trials of urate-lowering therapy in gout.
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Plain radiography remains the imaging investigation of choice for the diagnosis of calcium pyrophosphate dihydrate (CPPD) arthropathy, as it reveals the typical pattern and distribution of crystal deposits.
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CT is important in the investigation of neck pain, as it can reveal CPPD deposition adjacent to C1/C2 that leads to the crowned dens syndrome, or retropharyngeal tendinitis, resulting from deposition of calcium hydroxyapatite crystals within fibers of the longus colli muscle.
Introduction
Over the last decade there have been important advances in imaging of the crystal arthropathies. Although plain radiography remains the cornerstone modality in this setting and is most familiar to rheumatologists and radiologists, it is now possible with advanced techniques to visualize not only joint damage but also soft-tissue inflammation, including synovitis and tenosynovitis, crystal deposition, and cartilage change. Three-dimensional (3D) multislice imaging via computed tomography (CT), dual-energy computed tomography (DECT), and magnetic resonance imaging (MRI) provide an opportunity to identify abnormalities in complex regions such as the midfoot, a common site of gouty involvement, and the upper cervical spine, where calcium pyrophosphate dihydrate (CPPD) and hydroxyapatite (HA) arthropathies may contribute to significant pathologic features. Ultrasonography (US) is also contributing to the understanding of these conditions, in particular by revealing crystal deposition within cartilage with variable patterns that have diagnostic implications. The opportunity provided by CT and DECT scanning to visualize tophi in extraordinary detail has helped to elucidate the pathologic links between deposition of monosodium urate (MSU) crystals and the development of bone erosion in gout. Advanced imaging is also increasingly being used in the setting of clinical trials, as digitized formats allow comparison of data, such as tophus volume, over time. In the clinical arena diagnostic applications are expanding, especially regarding gout, whereby imaging now sometimes offers the opportunity to identify MSU crystals without invasive joint aspiration. This article reviews the use of imaging techniques in the crystal arthropathies, with an emphasis on recent advances in this field and evolving clinical applications.
Introduction
Over the last decade there have been important advances in imaging of the crystal arthropathies. Although plain radiography remains the cornerstone modality in this setting and is most familiar to rheumatologists and radiologists, it is now possible with advanced techniques to visualize not only joint damage but also soft-tissue inflammation, including synovitis and tenosynovitis, crystal deposition, and cartilage change. Three-dimensional (3D) multislice imaging via computed tomography (CT), dual-energy computed tomography (DECT), and magnetic resonance imaging (MRI) provide an opportunity to identify abnormalities in complex regions such as the midfoot, a common site of gouty involvement, and the upper cervical spine, where calcium pyrophosphate dihydrate (CPPD) and hydroxyapatite (HA) arthropathies may contribute to significant pathologic features. Ultrasonography (US) is also contributing to the understanding of these conditions, in particular by revealing crystal deposition within cartilage with variable patterns that have diagnostic implications. The opportunity provided by CT and DECT scanning to visualize tophi in extraordinary detail has helped to elucidate the pathologic links between deposition of monosodium urate (MSU) crystals and the development of bone erosion in gout. Advanced imaging is also increasingly being used in the setting of clinical trials, as digitized formats allow comparison of data, such as tophus volume, over time. In the clinical arena diagnostic applications are expanding, especially regarding gout, whereby imaging now sometimes offers the opportunity to identify MSU crystals without invasive joint aspiration. This article reviews the use of imaging techniques in the crystal arthropathies, with an emphasis on recent advances in this field and evolving clinical applications.
Gout
Radiography
Most often the radiographic appearance of acute gout, especially at the time of the first attack, is nonspecific. Plain radiographs (XRs) are frequently normal apart from soft-tissue swelling in the affected region, and typical gouty erosions can take up to 10 years to develop as timed from the first attack. However, plain radiography is part of the workup of acute gout not only to look for erosions but also to help exclude other differential diagnoses and investigate for possible complicating factors such as septic arthritis or osteomyelitis (typically associated with the rapid development of erosion and bone lysis on both sides of the joint). In addition, an XR will give some information about other forms of arthropathy such as osteoarthritis, which frequently coexists with gout.
The typical radiographic appearance of chronic gout is of an asymmetric erosive arthropathy, most prominent at the feet (especially involving the first metatarsophalangeal [MTP] joint), but potentially affecting any joint in the peripheral skeleton including the hands, as shown in Fig. 1 . Axial involvement may also occur but is rare. Tophi appear as soft-tissue opacities, which often (but not invariably) overlie erosions. Erosions have a characteristic well-corticated appearance, often with overhanging margins, and they may be sited away from the margins of the joint (extramarginal) or within the joint, and/or sometimes be fully enclosed within periarticular bone without a breach of the cortex (intraosseous). In contrast to the XR appearances of rheumatoid arthritis (RA), there is typically no periarticular osteopenia in gout and, indeed, adjacent bone tends to be sclerotic. The bone beneath the joint margin may appear cystic or be subject to subchondral collapse. Hence the 2006 European League Against Rheumatism (EULAR) task force included the finding of “asymmetric joint swelling” and “subcortical cysts without erosion” in their list of 10 key diagnostic features of gout, consistent with the 1977 American Rheumatism Association preliminary gout classification criteria. However, the EULAR guidelines development group acknowledged that plain radiography usually plays only a minor role in diagnosis, especially when gout is early or acute, when XRs are frequently normal. Rettenbacher and colleagues formally examined the sensitivity and specificity of plain radiography for a gout diagnosis, in comparison with a clinical gold standard, and found a sensitivity of 31% and specificity of 93%. An XR scoring system for evaluating damage in gouty arthropathy has been developed, based on a modified Sharp/van der Heijde scoring method with inclusion of the distal interphalangeal joints. This aspect is of particular importance now that potent disease-modifying urate-lowering therapies (ULTs) have become available that may actually modify structural damage. A recent pilot study revealed that use of pegloticase over a 12-month period in patients with erosive tophaceous gout could actually lead to a reduction in erosion scores, with regression of soft-tissue masses and increased sclerosis at the time of the follow-up plain radiographic assessment.
In addition to bone erosion in gout, there has been recent interest in new bone formation (NBF). A study of paired XRs and CT scans found that NBF in gout can appear in the form of bone sclerosis, osteophytes, bony spurs and, rarely, periosteal deposition and ankylosis. NBF was more likely to occur when erosions were present, and there was also a strong association with tophi, as determined from CT scans. Results suggested a link between tophus, bone erosion, and NBF during joint remodeling in gout; interestingly, a somewhat similar association has been observed in some patients with the mutilans form of psoriatic arthritis.
Advanced Imaging in Gout
CT scanning
Multislice helical CT scanning is useful for imaging bone and tophi in gout, as the very thin slices (0.5 mm) and potential for 3D reconstruction allow excellent resolution to be achieved. Fig. 2 shows a CT 3D reconstruction of the wrist in a patient with long-standing tophaceous gout, revealing multiple tophi (typically with a density of density of 160–170 Hounsfield units) adjacent to erosions and also extending into soft tissues. 3D imaging with CT is particularly successful for revealing bone erosions and their relationship with tophi, as shown in Fig. 3 . This relationship was also illustrated in the study by Dalbeth and colleagues, where CT scans from 20 patients with gout were assessed for tophi and erosions. Of those joints where CT erosions were detected, 82% were separately scored as positive for the presence of tophi. When CT erosions of greater than 5 mm diameter were considered, this figure increased to 95%. These data suggest that erosions are likely to represent regions of bone that have been mined by tophus deposition, via several mechanisms including cytokine-mediated osteoclast activation. The Auckland group also used CT to examine surface tophi and compared results with those of a physical examination. Of those tophi identified clinically, 89% were scored on CT scanning, and there was a very strong correlation between the 2 methods in terms of measured size of lesions. Thus, CT has potential both as a diagnostic tool in gout and as an instrument with which to measure progressive erosive damage and, indeed, tophus growth or resolution. Its metrics demonstrate excellent reader reliability, and a scoring system for use in the feet has recently been developed.
DECT
DECT is a recent arrival on the imaging scene in rheumatology, but has been used in other medical settings for some years. In urology, DECT has been used to determine the composition of renal calculi and has been used in cardiology for imaging coronary anatomy, characterizing atherosclerotic plaque, and, more recently, evaluating myocardial perfusion. This technique uses 2 x-ray tubes with different voltages, aligned at 90° to each other. Data are acquired simultaneously at 2 different energy levels (80 kV and 140 kV), creating 2 different data sets, which are then processed by specialized software and analyzed using an image-based 2-material decomposition algorithm to separate calcium from monosodium urate, using soft tissue as a baseline. Calcium, which has a high atomic number, causes a greater change in attenuation of X-rays than MSU, which has low atomic number components. These materials are then given different color coding, which allows them to be differentiated on the resultant CT scan ( Fig. 4 ). The detection of MSU does depend on the computer software settings and in particular the parameter ratio, which dictates the slope of the line that is used to help differentiate MSU from calcium. Although this work by Nicolaou and colleagues suggests using a parameter ratio of 1.28, a recent comparative study with 3T MRI indicated that a ratio of 1.55 had greater sensitivity. However, higher ratios frequently lead to nonspecific artifact. Further investigation into the operating characteristics of DECT in gout may be necessary to optimize the scanning procedure and minimize the potential for false positives or negatives.
There is an unmet clinical need for an imaging procedure that will detect MSU deposits and help diagnose gout in those patients for whom joint aspiration is not possible. The idea that this could be achieved using DECT is very attractive to patients and physicians alike. Choi and colleagues reported the first study of DECT in gout in 2009, and described its ability to reveal multiple intra-articular and extra-articular urate deposits, many of which were undetectable clinically. Sensitivity and specificity were both 100% for a diagnosis of tophaceous gout, as all 20 patients studied were DECT-positive and the regions where deposits were detected were aspirate-positive for MSU crystals, whereas all 10 controls were DECT-negative. Another retrospective DECT study examining a larger group used 2 separate readers and found interreader agreement to be very high for scoring DECT deposits (κ value 0.87). In their hands DECT scans were positive for urate deposits in all 12 patients with clinically suspected gout, where the same joints were MSU-aspirate–positive (100% sensitivity). Specificity was 89% for reader 1 (false-positive DECT scans in 2 of 19 patients) and 79% for reader 2 (false positives in 4 of 19 patients if joint-aspiration negative). To clarify these issues, a larger prospective study was performed by Choi and colleagues. Forty crystal-proven gout patients and 40 patients with other arthritic conditions acting as controls underwent DECT scanning of all peripheral joints. The specificity and sensitivity of DECT in this setting were 93% and 78%, indicating that both were very high, but diagnostic accuracy was not 100%. Glazebrook and colleagues have provided further evidence of this recently with their report of a false-negative DECT scan in a patient with acute aspirate-proven gout affecting the third metacarpophalangeal (MCP) joint. Thus, DECT may be a useful diagnostic tool but is not infallible, and more information is needed about its sensitivity and specificity in acute or nontophaceous gout for which the clinical diagnosis remains in doubt.
DECT has also provided new insights into gout pathology, including the finding that urate very commonly deposits around tendons and bursae as well as joints. In a prospective DECT study of 92 patients with tophaceous gout where scans of the feet were obtained, 39% of all Achilles tendons imaged showed MSU deposition, followed in terms of frequency by 18% of peroneal tendons and 10% of extensor hallucis longus tendons. Much of this tophus was observed in the region of the enthesis, raising the possibility that biomechanical strain may influence patterns of urate deposition. Thus, gout is definitely more than a joint disease, and the deposition of tophaceous material in soft tissues has clinical implications ranging from nerve compression syndromes to tendon rupture.
DECT also has the potential to be useful in a randomized clinical trial (RCT) setting to follow the reduction in urate burden achieved with effective ULT, because DECT can quantify urate using automated, computerized volume assessment software, providing reproducible data that may be stored digitally and compared with subsequent measurements over time. It also enables measurement of the crystal component of tophi, which is most likely to change with ULT, as opposed to the soft-tissue granulomatous response that makes up the bulk of the tophus. Only one longitudinal study has been published to date reporting the relationship between DECT urate volumes and serum urate (SU) measurements in 73 patients observed over 12 months. Although higher SU levels were observed in patients with increased DECT urate volumes, there was no consistent relationship between these parameters in terms of change over time, and it is possible that DECT may not be as useful as hoped in this context. Clearly, however, further studies are warranted.
Ultrasonography
US has an emerging role in gout, to both facilitate joint aspiration for confirmation of the presence of MSU crystals and assist in making a diagnosis in its own right because of certain US-specific imaging features. US can detect joint inflammation in terms of synovitis and tenosynovitis by revealing synovial thickening using gray-scale US, often with additional vascular signal detected using power Doppler US. There may be an associated signal-free region, representing a synovial effusion. These features are nonspecific and common to all inflammatory arthropathies. A recent systematic review by Chowalloor and Keen examined the literature related to US-detected pathologic features in gout, and found that tophi have been well studied using this technique. It should be recalled that not all sites of possible tophus deposition are accessible to US (including regions of the tarsus and carpus), and also that intraosseous tophi cannot be detected by this modality. Where tophi are accessible to US, they are typically ovoid in shape, with a hypoechoic border and an internal stippled signal, as shown in Fig. 5 . Validation of US tophi has been performed against MRI and histology as gold standards. Perez-Ruiz and colleagues reported that MSU crystals could be aspirated from 83% of US-defined tophi. In some cases, floating hyperechoic foci have been described within synovial fluid, likely representing microtophi, resulting in a snowstorm appearance. A longitudinal study has shown that the US measurement of tophi is reliable and responsive to change, suggesting a possible role for RCTs to monitor the efficacy of ULT. Of note, patients with asymptomatic hyperuricemia have also been found to have evidence of US tophi within joints, tendons, and soft tissues. However, different studies have designated tophi in different ways, and more standardized definitions are required. Estimation of reliability also needs further work, as most US studies in gout have assessed this by rereading stored images. Given the potential variability in technique used when performing a US scan, future studies need to incorporate a true test of interreader reliability by reimaging patients on 2 consecutive occasions and employing 2 separate readers.
US erosions have also been well studied and compared with radiographic and MRI erosions. Wright and colleagues compared high-resolution US (HRUS) with XR at the first MTP joints of 39 male gout patients and 22 matched controls. Poor agreement was found between HRUS and XR for erosion detection (κ = 0.2), and the investigators concluded that there were a large number of false-negative XRs. Ten erosions were detected by HRUS, compared with 3 using XR, in 22 MTP joints that had never been clinically affected by gout, and it was concluded that US is a much more sensitive modality than XR for erosion detection. Rettenbacher and colleagues compared US with XR in a larger prospective study of 105 patients with a clinical suspicion of gout. XR findings suggested gout with sensitivity of 31% and specificity of 93% (compared with the final clinical diagnosis), whereas US had sensitivity of 96% and specificity of 73%. It is instructive to balance these very positive reports with that of Carter and colleagues, who studied an “index joint,” which had been affected by clinical gout but remained free of XR erosions, using US and MRI. Of 27 subjects, 15 (56%) had erosions on MRI of their index joint, whereas only 1 (4%) had erosions identified by US. Therefore US would seem to be much less sensitive than MRI, but further comparative studies are needed.
The double-contour sign was described by Thiele and Schlesinger in 2010. One hyperechoic line is due to a US signal bouncing off cortical bone, for example at the head of an MCP or MTP joint, while a second outer line is thought to represent the deposition of MSU crystals in a fine layer over hyaline cartilage, forming a new reflective barrier. Sandwiched between these lines is the articular hyaline cartilage, which is not echogenic (see Fig. 5 ). This sign has been described as being relatively common in gout, detected in symptomatic and asymptomatic joints, and also in asymptomatic hyperuricemia. It has also been detected (uncommonly) in controls. Naredo and colleagues recently reported an ultrasound-guided aspiration study of intra-articular hyperechoic aggregates from joints or tendons from 49 gout patients and 8 control patients. Aspirated material was positive for MSU crystals in 78% of gout patients and none of the controls, and negative for crystals in 20% of gout patients. Calcium pyrophosphate crystals were found in 1 gout patient and 1 control. This study is the closest approximation to comparative imaging/histologic verification that is available. A cadaveric study of gout cartilage from the 1950s described cartilage surfaces as being “diffusely dusted with white crystal deposits” in 11 gout patients. A more recent arthroscopic study of the wrist described “diffuse synovitis and crystalline deposits throughout the radiocarpal joint with focal crystalline precipitates on the scapholunate and lunotriquetral ligaments,” but there was no imaging comparator. The sensitivity and specificity of the double-contour sign in diagnosing gout have been estimated by one group as 44% and 99%, respectively. Ottaviani and colleagues found in their MSU-aspirate–positive gout patients that all those with urate levels greater than 600 μM (10 mg/dL) had a double-contour sign in at least 1 assessed joint. Disappearance of this sign has been observed in response to ULT. However, pitfalls certainly exist in interpreting this feature, particularly when echogenicity at the interface between synovial fluid and cartilage can be variable. Therefore it cannot yet be recommended as a reliable diagnostic feature that might replace the necessity for joint aspiration.
MRI
MRI has not been as widely studied in gout as the other imaging modalities already mentioned, but is quite frequently used clinically for diagnostic reasons. Like US, it allows joint inflammation to be assessed as well as joint damage, and has some advantages over the latter in terms of greater accessibility for certain joint regions and less operator dependence. Tophi have particular characteristics when imaged using MRI. Tophi are visible as discrete masses or nodules with low signal on T1-weighted (T1w) images, whereas T2-weighted (T2w) signal intensity ranges from low to high, and there may be variable contrast enhancement related to vascularity ( Fig. 6 ). Comparative US and MRI studies are few, but Perez-Ruiz and colleagues validated the measurement of tophi by US against MRI as a gold standard, and found a good correlation between the 2 methods for tophus detection but only moderate agreement for measurement of tophus dimensions. Digitized MRI data have the potential to be useful for longitudinal review, and Schumacher and colleagues suggested MRI tophus volume could be a useful outcome measure in clinical trials of ULT. However, this would involve a time-consuming manual outlining procedure for computation of volume, and thus far there are no reports of this application. A recent study comparing MRI with DECT for detection of tophi at the wrist found a good correlation between the 2 modalities, with MRI having a specificity of 0.98 and a sensitivity of 0.63 for detecting tophi, using DECT as a gold standard. Thus MRI could have a place in assisting in gout diagnosis, especially in situations where DECT scanning is not available.
Related posts:
Gout and Crystal Arthropathies
Diagnosis and Clinical Manifestations of Calcium Pyrophosphate and Basic Calcium Phosphate Crystal Deposition Diseases
Comorbidities in Patients with Crystal Diseases and Hyperuricemia
Nonpharmacologic and Pharmacologic Management of CPP Crystal Arthritis and BCP Arthropathy and Periarticular Syndromes
Long-Term Management of Gout
Emerging Therapies for Gout
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