Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up






Ali GUERMAZI,aMD, PhD
Frank W. ROEMER,bMD
a,bQuantitative Imaging Center Department of Radiology Boston University School of Medicine, Boston, USA
bDepartment of Radiology Klinikum Augsburg
Augsburg, GERMANY



Harry K. GENANT,MD
Department of Radiology
University of California
San Francisco, USA

Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up


by A. Guermazi, F. W. Roemer,
and H. K. Genant,
USA and Germany



Osteoarthritis is a highly prevalent joint disorder primarily affecting elderly people worldwide. The importance of imaging for assessment of all the structures of the joint such as cartilage, meniscus, subarticular bone marrow, and synovium for diagnosis, prognostication, and follow up has been well recognized over the past decade. Conventional radiography is still the most commonly used imaging technique for evaluation of a patient with a known or suspected diagnosis of osteoarthritis. However, recent MRI based knee osteoarthritis studies have begun to reveal the limitations of radiography. The ability of MRI to image the knee as a whole organ and to directly and three-dimensionally assess cartilage morphology and composition plays a crucial role in understanding the natural history of the disease and in the search for new therapies. Use of the appropriate MRI pulse sequences is crucial to assess the various features of osteoarthritis, and support from experienced musculoskeletal radiologists is necessary for study design, image acquisition, and interpretation. This article describes the roles and limitations of conventional radiography and MRI in osteoarthritis imaging, and also provides some insight into the use of other modalities such as ultrasound, nuclear medicine, computed tomography, and computed tomography arthrography in clinical practice and research in osteoarthritis, with a particular emphasis on the assessment of knee osteoarthritis in the tibiofemoral joint

Medicographia. 2013;35:164-171 (see French abstract on page 171)



Osteoarthritis (OA) is a highly prevalent joint disorder and is becoming increasingly common, posing major health and economic challenges for aging industrialized societies. Despite various surgical and symptom-oriented approaches, there is still no definitive disease-modifying therapy, other than total joint replacement, for this complex and heterogeneous disease.

Most research studies of knee OA involve acquisition of conventional radiographs and magnetic resonance images, including the Osteoarthritis Initiative (OAI, http://www.oai.ucsf.edu/datarelease/), one of the largest epidemiological OA studies.1 The OAI is an ongoing 4-year observational study of approximately 4800 participants, sponsored by the National Institutes of Health, and targeted at identifying the most reliable and sensitive biomarkers for evaluating the development and progression of symptomatic knee OA. Data from baseline through the 48-month follow-up visit for the entire cohort were made publically available in 2011. This article aims to describe the current role of radiography and magnetic resonance im- aging (MRI) in OA imaging, and also to give some insight into the use of other modalities: ultrasound, nuclear medicine, and computed tomography (CT). Current research tends to focus on the knee due to the high prevalence of knee OA and the relative ease of use of MRI compared with other central appendicular joints. This nonsystematic review article will focus primarily on the assessment of OA in the tibiofemoral joint of the knee.

Conventional radiography

Radiography is the simplest and least expensive imaging technique. It can detect OA-associated bony features including marginal osteophytes, subchondral sclerosis, and subchondral cysts.2 Radiography can also determine joint space width (JSW), an indirect surrogate of cartilage thickness and meniscal integrity, but precise measurement of each of these articular structures is not possible by x-ray.3 Despite this, slowing of radiographically detected joint space narrowing (JSN) is the only structural end point currently recommended by the regulatory bodies in the United States (US Food and Drug Administration [FDA]) and in Europe (European Medicines Agency [EMA]) to prove the efficacy of disease-modifying OA drugs in phase-3 clinical trials. OA is defined radiographically by the presence of osteophytes.4 Progression of JSN is the most commonly used criterion for the assessment of OA progression and the complete loss of JSW characterized by bone on- bone contact is one of the indicators for joint replacement. The severity of OA can be estimated using semiquantitative scoring systems. Published atlases provide images that represent specific grades.2 The most widely used system, the Kellgren and Lawrence (K&L) classification,5 has limitations, especially as K&L grade 3 includes all degrees of JSN, regardless of the actual extent. In contrast, the Osteoarthritis Research Society International (OARSI) atlas2 classification grades tibiofemoral JSW and osteophytes separately for each compartment of the knee. Compartmental scoring appears to be more sensitive to longitudinal radiographic changes than K&Lgrading.





Figure 1
Figure 1. Multitissue contribution to joint space narrowing.

(A) Baseline anterior-posterior radiograph showing doubtful joint space narrowing in the medial tibiofemoral compartment
(arrowheads). (B) Follow-up image at 24 months showing a definite increase in joint space loss medially
(arrows).(C) Corresponding baseline intermediate-weighted magnetic resonance imaging (MRI) showing normal
cartilaginous tibiofemoral surface and no relevant meniscal extrusion. (D) MRI at 24 months showing definite meniscal
extrusion (arrows) likely to be responsible for the joint space narrowing on the radiograph.



Methods of JSW measurement can be manual or semiautomated using computer software. However, previously held beliefs that JSN and its changes are the only visible evidence of cartilage damage have been shown to be incorrect. Recent studies have demonstrated that alterations in the meniscus, such as meniscal extrusion or subluxation, also contribute to JSN (Figure 1).3 The lack of sensitivity and specificity of radiography for the detection of the pathologic features associated with OA, and the poor sensitivity to change at follow-up imaging, are inherent limitations of radiography.

Interestingly, an older method—digital tomosynthesis—has lately experienced a revival. Tomosynthesis generates an arbitrary number of section images from a single pass of the xray tube. Using 3T MRI as a reference, Hayashi et al found that tomosynthesis depicted more osteophytes and subchondral cysts than radiography.6 The clinical availability of these systems is currently limited, but the potential of this technique for OA research may be worth exploring.

Magnetic resonance imaging

MRI offers a number of advantages for OA imaging. First, MRI has a tomographic viewing perspective and thus provides cross-sectional images of the anatomy free of the projectional limitations of radiography. Second, MRI is uniquely able to directly depict all the components of the joint and their pathologies, including the articular cartilage, menisci, intraarticular ligaments, synovium, effusion, bone attrition, bone marrow lesions (BMLs), subchondral cysts, and intra- and periarticular cystic lesions (Figure 2). The joint can be evaluated as a whole organ, providing a much more detailed picture of the changes associated with OA than is possible with other techniques.7 Third, MRI can detect the pathology of preradiographic OA and possible complications of the disease at a much earlier stage than radiography.8

_ Technical considerations
Several MRI systems are commercially available but 1.5T systems are the most widely used in clinical and research settings. Examination times vary depending on the purpose of the exam, but usually last between 20 and 40 minutes, including patient positioning. High-field 3T MRI was introduced for clinical application several years ago. A higher signal-to-noise ratio is a definitive advantage, but disadvantages include increased susceptibility artifacts, high costs, and the limited commercial availability of coils. Most OA studies that include MRI use 1.5T MRI systems because of their wide availability and reliable image quality. The OAI is one of the few large studies to have used a 3T system (Figure 3).

So far, 7T MRI in humans has only been applied in research.9 In the future, 7T systems may be able to produce higher-resolution images with a shorter scan time than 3T systems. So far, however, the available 7T protocols have not been any better than 3T for knee cartilage evaluation.10


Figure 2
Figure 2. Osteoarthritis is a whole-joint disease process that can only be completely visualized by magnetic resonance imaging.

This sagittal intermediate-weighted fatsaturated image shows diffuse cartilage loss in the medial tibio-femoral joint.
A horizontal-oblique tear extending to the superior surface is seen in the posterior horn of the medial meniscus (arrowhead) and a small subchondral cyst appears in the medial weight bearing part of the femoral condyle (arrow).
There is also joint effusion and a popliteal cyst (asterisk) and a small osteophyte at the posterior medial femoral condyle (no arrow).



The role of contrast-enhanced MRI (CE-MRI) in the clinical and research environment remains to be fully established. Visualization of synovitis in OA is superior on contrast-enhanced scans using the intravenous paramagnetic agent gadolinium with histological correlation,11 and recent studies have shown that CE-MRI-detected synovitis is associated with knee pain (Figure 4).12

Since different tissues are involved in OA and both morphologic and quantitative analyses are needed, a variety of different sequences have been developed for “whole-organ” assessment of OA. Selecting the appropriate MR pulse sequences to study specific features of OA is essential for success. In general, fluid-sensitive fat-suppressed sequences (eg, T2-weighted, proton-density-weighted, or intermediate weighted fast spin-echo sequences) are useful for evaluation of cartilage, bone marrow, ligaments, menisci, and tendons.13 It is particularly important to use these sequences to assess focal cartilage defects and BMLs. Gradient-recalled echo (GRE)- type sequences (eg, 3D-spoiled gradient echo at steady state [SPGR], double-echo steady state [DESS], and fast low-angle shot [FLASH]) are not suitable for marrow or focal defect assessment. They are prone to susceptibility artifacts, which hinder accurate interpretation of images.14 GRE-type sequences also usually require long imaging times, and motion artifacts can degrade image quality.15 A recent study demonstrated that focal cartilage lesions were more conspicuous and larger on the intermediate-weighted fast spin-echo sequence with fat suppression compared with the DESS sequence.16 It was also shown that GREtype sequences have limited sensitivity to BMLs compared with fast spin-echo sequences (Figure 5).17 For synovitis, CE-MRI is preferable to non–CE-MRI, but if only non–CE-MRI is available, gradient- echo type sequences should again be avoided because they are prone to chemical shift artifacts, making accurate assessment difficult.18


Figure 3
Figure 3. Development of a focal cartilage defect over two years as visualized with 3T magnetic resonance imaging (MRI).

(A) Coronal intermediate-weighted image showing a small superficial cartilage defect in the weight-bearing part of the medial femoral condyle (arrow). (B) Follow-up MRI at 12 months reveals extension of defect to the subchondral bone, now representing a full-thickness focal lesion (arrow). (C) MRI image at 24 months showing a slight increase in the size of the focal full thickness defect.



Figure 4
Figure 4. Visualization of synovitis on contrast-enhanced magnetic resonance imaging (MRI).

Sagittal T1-weighted fatsaturated image showing severe synovitis in the suprapatellar recess (arrowheads), at the Hoffa fat pad (small arrow) and especially posterior to the posterior cruciate ligament, the most common location of synovitis in osteoarthritic knees (large arrow). Synovitis cannot be visualized with nonenhanced MRI.



On the other hand,GRE-type sequences do provide high spatial resolution and excellent contrast of cartilage to subchondral bone, and are well suited for quantitative measurement of volume and thickness.15 MRI is a powerful tool for OA research, but it is also complex and how it is used is largely determined by the goal of the research. Clinicians planning clinical OA research using MRI derived data should seek expert advice from trained and experienced musculoskeletal radiologists on which pulse sequences are best suited to their purpose.

_ Semiquantitative MRI whole-organ scoring
Semiquantitative whole-organ scoring has been applied to a multitude of OA studies.7,19 Analyses based on semiquantitative scoring have added greatly to our understanding of the pathophysiology and natural history of OA as well as to the clinical implications of structural changes. A short list of semiquantitative scoring systems includes the Whole-ORgan Magnetic resonance imaging Score (WORMS),7 the Knee Osteoarthritis Scoring System (KOSS),20 the Boston Leeds Osteoarthritis Knee Score (BLOKS),21 and the MRI OsteoArthritis Knee Score (MOAKS).22 MOAKS is a recent effort to combine the strengths of existing systems, but little information on its use has been published to date. In addition to these scoring systems based on non-enhanced MRI, semiquantitative scoring systems for synovitis using contrast-enhanced MRI have been proposed.12,23 In particular, the system proposed by Guermazi et al enables comprehensive assessment of synovitis in the whole knee joint,12 rather than being restricted to the peripatellar regions.23 These contrast-enhanced MRI–based scoring systems will enable longitudinal assessment of synovitis in future clinical trials.12

Recently, MRI-based semiquantitative scoring systems for hand OA (Oslo Hand OA MRI score [OHOA-MRI]) and hip OA (Hip OA MRI Scoring system [HOAMS]) have been proposed.24,25 However, further validation, evaluation of responsiveness, and iterative refinement of these new systems are needed to assess their utility in clinical trials and epidemiological studies. To the authors’ knowledge, no semiquantitative scoring systems enabling evaluation of other joints, such as the shoulder, elbow, and ankle, as a “whole joint” have been published. A limited number of small studies have been published recently involving cartilage repair techniques or novel imaging methodologies for these joints.26


Figure 5
Figure 5. Sequence selection for visualizing specific osteoarthritis features.

(A) Coronal proton-density-weighted fat-saturated image showing a large bone marrow lesion (BML) in the central part of the medial femur (ill-defined area of hyperintensity indicated by arrows). A large BML is also depicted in the medial tibial plateau (asterisk). (B) Fast low-angle shot (FLASH) image. Although commonly used for cartilage segmentation due to the excellent contrast between cartilage and subchondral bone and high resolution acquisition, the FLASH image depicts the femoral BML poorly compared with the protondensity-weighted image (arrow). The large tibial BML can barely be distinguished on the FLASH image.



_ Compositional imaging of cartilage
Compositional MRI can assess the biochemical properties of different joint tissues and is thus very sensitive to early premorphologic changes. The vast majority of studies applying compositional MRI have focused on cartilage, although the technique can also be used to assess other tissues such as the meniscus or ligaments.27 T2 mapping has been used to describe the molecular composition of hyaline cartilage in the knee on the basis of collagen structure and hydration.

In healthy cartilage, T2 values increase from deep to superficial cartilage layers.28 It has been shown that T2 values are related to age and activity levels and that they are associated with OA severity.29,30 T2* relaxation measures have also been tested for their ability to depict the collagen matrix. T2* mapping was shown to be a reproducible process that can differentiate between OA and non-OA subjects.31

T1rho is also sensitive to the interactions of water with macromolecules. It has been shown to correlate with the proteoglycan concentration in cartilage,32 and is also sensitive to collagen.33 Although T1rho has been shown to have a larger dynamic range than T2,34 it is more complex to implement, and is limited by radiofrequency power deposition. It has been reported that T1rho and T2 values show different spatial distributions and may provide complementary information on cartilage degeneration.35

Sodium MRI and the delayed gadolinium-enhanced MRI of cartilage technique (dGEMRIC) are designed to measure fixed charge densities in cartilage and, by implication, its proteoglycan content (Figure 6).36 These techniques are based on the premise that mobile ions will distribute themselves in cartilage in relation to the concentration of the charged proteoglycan molecules; in MRI, the mobile ions are the naturally abundant sodium, or the negatively charged MRI contrast agent Gd(DTPA)2– (Magnevist, Berlex, NJ, USA).

In the dGEMRIC technique, Gd(DTPA)2– is injected intravenously, and images are acquired typically around 90 minutes after injection. The negative charge on the Gd(DTPA)2– molecule causes it to disperse into the cartilage in inverse relation to the negatively charged glycosaminoglycan molecular concentration.37 A recent interventional study evaluating the effect of weight loss on articular cartilage showed an improvement in cartilage quality reflected by an increase in the dGEMRIC index over 12 months in the medial but not in the lateral tibiofemoral compartment. This finding supports the notion that body weight affects disease progression and emphasizes the role of weight loss in clinical and structural improvement.38


Figure 6
Figure 6. Biochemical magnetic resonance imaging.

(A) Sagittal intermediate-weighted fat-saturated image depicts a horizontal-oblique tear of the posterior horn of the medial meniscus (arrow). (B) Corresponding baseline color-coded T1-weighted image showing normal delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) map of femoro-tibial cartilage. (C) At 24 months there is a marked decrease in the dGEMRIC index in the medial femoral cartilage (coded in red – arrowheads). An incidental partial meniscal maceration is also seen (arrow).



Novel compositional techniques have been reported. Raya et al studied the feasibility of in vivo diffusion tensor imaging at 7T MRI and demonstrated better discrimination of OA versus non-OA knees than with T2mapping.39 Although this technique shows promise, it will have to be more practical and widely available for use with standard MRI systems before it can be applied in broader clinical research settings.

_ Quantitative cartilage morphometry
Quantitative analysis of knee OA features has been applied mainly to cartilage morphology, where the three-dimensional nature of MRI data can be exploited to assess tissue parameters such as volume, thickness, or other continuous variables. The real strength of quantitative measurements is that they are more objective and less observer-dependent than semiquantitative scoring methods and that relatively small changes in cartilage thickness or volume can be detected over time.40 Correctly segmenting the cartilage requires well-trained users, working either manually or with segmentation software. Most investigations have focused on measuring cartilage volume, but volume has its limitations. Discrimination of patients with OA from healthy subjects is limited because men in general, and anybody with large bones, will have larger joint surfaces and more cartilage volume, so there is a wide overlap between groups.41 While this problem can be mostly overcome by adjusting the analysis for the bone surface area in each subject, a new analytic strategy called “extended ordered values” has been proposed.42 The extended ordered values approach sorts changes in subregional thickness in the medial and lateral tibial and femoral cartilage plates in ascending order. This analytic method enables more efficient measurement of changes in cartilage thickness, independently of theiranatomical locations, and shows better sensitivity for detecting differences in longitudinal rates of cartilage loss than anatomical subregions and radiography.42

Ultrasound

Ultrasound is a technique that enables multiplanar and realtime imaging at a relatively low cost, without radiation exposure. It has the ability to image soft tissue and to detect synovial pathology without the need for contrast administration. Limitations of ultrasound are primarily that it is an operator-dependent technique and that the physical properties of sound hinder its application to deeper articular structures and the subchondral bone. The ability to detect synovial pathology is perhaps the major advantage of ultrasound over radiography. Ultrasound-detected grey-scale synovitis has been validated against arthroscopy, MRI, and histology in large-joint OA, and ultrasound has been demonstrated to be more sensitive than clinical examination in detecting synovial hypertrophy and joint effusion.43 Additionally, color-coded Doppler signal has been validated as an indirect measure of histological synovial vascularity in large-joint OA.44 Tissues other than synovium have also been studied using ultrasound. Saarakkala et al compared knee ultrasonography to arthroscopic grading for detecting degenerative changes in articular cartilage.45,46 The authors concluded that positive findings on ultrasound are strong indicators of degenerative changes in cartilage, but also stated that negative findings do not rule out degenerative cartilage alterations. A study by Kawaguchi et al used ultrasound to look at medial radial displacement of the meniscus in the supine and weight-bearing positions and showed that the medial meniscus was significantly displaced radially by weight bearing in control knees and in knees with K&L grades 1-3.46 Its use with dynamic and weight-bearing conditions is one of the inherent strengths of ultrasound and warrants further exploration.

Computed tomography

CT is a valuable tool for the characterization of OA, particularly when imaging of osseous changes or detailed presurgical planning is required. Helical multidetector (MD) CT systems enable acquisition of isotropic voxels and multiplanar reconstructions in any given plane with quality equal to the original plane. Cortical bone and soft tissue calcifications are better depicted than on MRI. CT has an established clinical role in assessing facet joint OA of the spine.47 Drawbacks are its low soft-tissue contrast and the relatively high dose of radiation it delivers. CT arthrography is an alternative method for indirect visualization of cartilage and other intrinsic joint structures, especially in the knee joint. CT arthrography may be relevant especially where access to MRI facilities is limited or when MRI is contraindicated. Spiral CT arthrography of the knee and shoulder enables excellent imaging of the articular surface.48 Penetration of contrast medium into the deeper layers of the cartilage surface indicates an articular-side defect of the chondral surface. The high spatial resolution and the high attenuation difference between the cartilage and the contrast medium within the joint make focal morphologic changes conspicuous. Limitations of the technique are its insensitivity to changes of the deep layers of cartilage without surface alterations and its invasive nature.

Nuclear medicine

Scintigraphy uses radiopharmaceuticals to visualize skeletal metabolism, to contribute to the localization of disease, and to assess the severity of pathologic changes in OA. 99mTC-hydroxymethane diphosphate scintigraphy shows increased activity during the bone phase in the subchondral region in nodal hand OA.49 This finding can be observed before the typical radiographic changes and reflects the osteoblastic activity of early cartilage loss. A study comparing MRI with scintigraphy in patients with chronic knee pain demonstrated good agreement between MRI-detected subchondral BMLs and radionuclide uptake, but generally poor agreement between increased bone uptake and cartilage defects or osteophytes.50 A prospective study showed that a normal bone scan at baseline was highly predictive of a lack of progression of knee OA over a 5-year period.51 Two other recent studies showed that scintigraphy may predict JSN, but no better than baseline radiographic or pain status.52,53

Positron emission tomography (PET) demonstrates metabolic changes in target tissues and can detect foci of inflammation, infection, and tumors. PET utilizes 2-18F-fluoro-2-deoxy– D-glucose (FDG) and reflects glucose metabolism. A recent pilot study in knees with medial OA showed increased uptake in periarticular regions, the intercondylar notch, and also in areas of subchondral bone marrow corresponding to MRI-detected BMLs.54 A recent animal study showed increased uptake of FDG after experimentally induced knee OA in rats, suggesting that PET could be useful for early detection of OA changes.55 However, whether FDG-PET will have a role in the assessment of OA in a clinical and research setting remains to be seen. Limitations of PET include its limited availability, high radiation exposure, and costs.

Conclusion

Conventional radiography is still the first and most widely used imaging technique for evaluation of a patient with a known or suspected diagnosis of OA. In research and clinical trials it is the only EMA- and FDA-recommended imaging modality for defining the inclusion criteria and efficacy end points of a clinical trial. However, radiography has its limitations and well-defined MRI-based diagnostic criteria of OA are needed. MRI plays a crucial role in understanding the natural history of the disease and in guiding future therapies due to its ability to image the knee as a whole organ and to directly and threedimensionally assess cartilage morphology and composition. Ultrasound and contrast-enhanced MRI play important subsidiary roles in the diagnosis and follow-up of treatment of OArelated synovitis. _


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Keywords: magnetic resonance imaging, osteoarthritis, radiography, ultrasound