- Email: [email protected]
Imaging for osteoarthritis
G Model
REHAB-947; No. of Pages 9 Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Review
Imaging for osteoarthritis D. Hayashi a, F.W. Roemer a,b, A. Guermazi a,* a b
Department of Radiology, Boston University School of Medicine, 820 Harrison Avenue, FGH Building 3rd Floor, Boston, MA 02118, United States Department of Radiology, University of Erlangen-Nuremberg, D-91012 Erlangen, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1st November 2015 Accepted 17 December 2015
Osteoarthritis (OA) is a widely prevalent disease worldwide and, with an increasing ageing society, is a challenge for the field of physical and rehabilitation medicine. Technologic advances and implementation of sophisticated post-processing instruments and analytic strategies have resulted in imaging playing a more and more important role in understanding the disease process of OA. Radiography is still the most commonly used imaging modality for establishing an imaging-based diagnosis of OA. The need for an effective non-surgical OA treatment is highly desired, but despite on-going research efforts no disease-modifying OA drugs have been discovered or approved to date. MR imaging-based studies have revealed some of the limitations of radiography. The ability of MR to image all relevant joint tissues within the knee and to visualize cartilage morphology and composition has resulted in MRI playing a key role in understanding the natural history of the disease and in the search for new therapies. Our review will focus on the roles and limitations of radiography and MRI with particular attention to knee OA. The use of other modalities (e.g. ultrasound, nuclear medicine, computed tomography (CT), and CT/MR arthrography) in clinical practice and OA research will also be briefly described. Ultrasound may be useful to evaluate synovial pathology in osteoarthritis, particularly in the hand. ß 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Osteoarthritis Imaging Radiography MR imaging Ultrasound CT PET
Knee osteoarthritis is a major public health problem that primarily affects the elderly. Almost 10% of the United States population suffers from symptomatic knee osteoarthritis by the age of 60 [S1]. In total, the health care expenditures of this condition have been estimated at US$ 186 billion annually [S2]. Despite this there are no approved interventions that ameliorate structural progression of this disorder. The increasing importance of imaging in osteoarthritis for diagnosis, prognostication and follow-up is well recognized by both clinicians and osteoarthritis researchers. While conventional radiography is the gold standard imaging technique for the evaluation of known or suspected osteoarthritis in clinical practice and research, it has limitations that have become apparent in the course of large magnetic resonance imaging (MRI)-based knee osteoarthritis studies [1,2]. Pathological changes may be evident in all structures of a joint with osteoarthritis although traditionally researchers have viewed articular cartilage as the central feature and as the primary target for intervention and measurement. Of the commonly employed imaging techniques, only MRI can assess all structures of the joint, including cartilage, meniscus, ligaments, * Corresponding author. Tel.: +16174143893. E-mail address: [email protected] (A. Guermazi).
muscle, subarticular bone marrow and synovium, and thus can show the knee as a whole organ three-dimensionally. In addition, it can directly help in the assessment of cartilage morphology and composition. The advantages and limitations of conventional radiography, MRI and other techniques such as ultrasound, nuclear medicine, computed tomography (CT) and CT arthrography in the imaging of osteoarthritis in both clinical practice and research are described in this review article. 1. Conventional radiography Radiography is the simplest, least expensive and most commonly deployed imaging modality for OA. It enables detection of OA-associated bony features such as osteophytes, subchondral sclerosis and cysts [3]. Radiography can also determine joint space width (JSW), which is a surrogate for cartilage thickness and meniscal integrity in knees, but direct visualization of these articular structures is not possible. Despite this limitation, slowing of radiographically detected joint space narrowing (JSN) remains the only structural end point currently approved by the U.S. Food and Drug Administration to demonstrate efficacy of diseasemodifying OA drugs in phase III clinical trials. OA is radiographically defined by the presence of marginal osteophytes
http://dx.doi.org/10.1016/j.rehab.2015.12.003 1877-0657/ß 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
2
Fig. 1. The Kellgren-Lawrence classification is a composite scale of OA severity taking into account primarily the radiographic OA features of marginal osteophytes and joint space narrowing in the AP radiograph. A. Kellgren-Lawrence grade 1. Minimal, equivocal osteophytes are observed at the medial joint margins (large arrows). Note that, socalled notch osteophytes at the centre of the joint (small arrow) are not considered in the Kellgren-Lawrence scale. B. Kellgren-Lawrence grade 2 is characterized by presence of at least one definite marginal osteophyte (arrow) without evidence of joint space narrowing. C. Kellgren-Lawrence grade 3 knees exhibit signs of definite joint space narrowing (black arrows) and marginal osteophytes (white arrows). The amount of joint space narrowing is not taken into account. D. Kellgren-Lawrence grade 4 is defined by bone-to-bone contact and complete obliteration of the joint space (black arrows). Note definite marginal osteophytes in addition (white arrows).
[S3]. Worsening of JSN is the most commonly used criterion for the assessment of structural OA progression and the total loss of JSW (‘‘bone-on-bone’’ appearance) is one of the indicators for joint replacement. We now know cartilage loss is not the only contributor to JSN but that changes in the meniscus such as meniscal extrusion and meniscal substance loss are also causative factors. The lack of sensitivity and specificity of radiography for the detection of OAassociated articular tissue damage, and its poor sensitivity to change longitudinally are other limitations of radiography. Changes in knee positioning can also be problematic in longitudinal studies and can affect the quantitative measurement of various radiographic parameters including JSW. Despite these limitations, radiography is still the gold standard for establishing an imaging-based diagnosis of OA and for assessment of structural modification in clinical trials of knee OA. 1.1. Semiquantitative assessments The severity of radiographic OA can be assessed with semiquantitative scoring systems. The Kellgren and Lawrence (KL) grading system [4] is a widely accepted scheme for defining radiographic OA based on the presence of a definite osteophyte (grade 2). However, KL grading has its limitations; in particular, KL grade 3 includes all degrees of JSN, regardless of the actual extent. Fig. 1 depicts representative examples of the different KL grades as shown on the AP radiograph. Recently, the so-called atrophic phenotype of knee OA that is characterized by definite joint space narrowing without concomitant osteophyte formation has gained increasing attention as a potential risk factor for more rapid progressive OA, which may be considered a potential adverse event in so-called anti-nerve growth factor (NGF) drug trials, a class of new promising antianalgesic compounds currently under investigation [5]. Although this phenotype is rare, it needs special attention in the research community as it potentially also is a reflection of more rapid disease progression [6]. Fig. 2 shows an example of the atrophic phenotype of radiographic OA. The Osteoarthritis Research Society International (OARSI) atlas [3] provides image examples for grades for specific features of OA rather than assigning global scores according to definitions like the KL grading system. The atlas grades tibiofemoral JSW and osteophytes separately for each compartment of the knee (medial
tibiofemoral, lateral tibiofemoral, and patellofemoral). A recent study using data from the OA Initiative and the OARSI atlas for semiquantitative grading of JSN demonstrated that centralized radiographic reading is important from the point of observer reliability, as even expert readers seem to apply different thresholds for JSN grading [7]. 1.2. Quantitative assessments JSW is the distance between the projected femoral and tibial margins on the anteroposterior radiographic image. Measurements may be performed manually or in a semi-automated fashion using computer software. Quantification using image processing software requires a digital image, whether digitized plain films or images acquired using fully digital modalities such as computed radiography and digital radiography. Minimum JSW is the standard metric, but the use of location-specific JSW has also been reported [S4]. Using software analysis of digital knee radiographic images, measures of location-specific JSW were shown to be comparable with MR imaging in detecting OA progression [8]. Various degrees of responsiveness have been
Fig. 2. Kellgren-Lawrence 3 knees with definite joint space narrowing (arrowheads) but only minimal osteophyte formation (arrow) are considered to represent the socalled atrophic phenotype of knee OA. This subtype of radiographic knee OA may be a reflection of more rapid disease progression.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
3
observed depending on the degree of OA severity, length of the follow-up period, and the knee positioning protocol [S4] [8]. Measurements of JSW obtained from knee radiographs have been found to be reliable, especially when the study lasted longer than two years and when the radiographs were obtained with the knee in a standardized flexed position [S5]. The role of malalignment in OA disease process has been described in the literature. A clinical trial showed that varus malalignment negated the slowing of structural progression of medial JSN by doxycycline [S6]. Valgus malalignment of the lower limb was shown to increase the risk of disease progression in knees with radiographic lateral knee OA [9]. Malalignment might be a target for prevention of radiographic knee OA as determined by JSN in overweight and obese women [10]. 2. Other radiography-based techniques Interestingly, two older methods – tomosynthesis and bone texture analysis – have experienced a revival recently. Tomosynthesis generates an arbitrary number of cross-sectional images from a single pass of the X-ray tube. A recent study showed that tomosynthesis is more sensitive in the detection of osteophytes and subchondral cysts than radiography, using 3T MRI as the reference [11]. Moreover, tomosynthesis was shown to offer excellent intrareader reliability regardless of the reader experience [12]. Quantification of JSW using tomosynthesis has also been reported [S7]. Bone texture analysis extracts from conventional radiographs information on two-dimensional trabecular bone texture that relates directly to three-dimensional bone structure. It has been shown that bone texture may be a predictor of progression of tibiofemoral OA [13]. 3. MRI Because of the high cost, MRI is not routinely used in clinical management of OA patients. However, MRI has become a keyimaging tool for OA research [14–16] thanks to its ability to assess pathology in structures not visualized by radiography i.e. articular cartilage, menisci, ligaments, synovium, capsular structures, fluid collections and bone marrow [2,17–21]. With MRI the joint can be evaluated as a whole organ and multiple tissue changes can be monitored simultaneously; pathologic changes of pre-radiographic OA can be detected; and biochemical changes within joint tissues such as cartilage can be assessed before morphologic changes become evident. An MRI-based definition of OA is available [22]. In addition, with MRI, OA can be classified into hypertrophic and atrophic phenotypes, according to the size of osteophytes and concomitant presence or absence of JSN [6]. Importantly, the use of MRI has led to significant findings about the association of pain with bone marrow lesions [23] and synovitis [24], with implications for future OA clinical trials. Fig. 3 shows an example of typical large bone marrow lesions that are commonly seen in conjunction with severe cartilage damage and may be responsible for pain in OA. 3.1. Technical considerations It should be emphasized that investigators need to select appropriate MR pulse sequences for the purpose of each study. For example, focal cartilage defects and bone marrow lesions are best assessed using fluid-sensitive fast spin echo sequences (e.g. T2weighted, proton density-weighted or intermediate-weighted) with fat suppression [14,17]. Moreover, MRI may sometimes be affected by artifacts that mimic pathological findings. For example, susceptibility artifacts can be misinterpreted as cartilage loss or meniscal tear. Gradient recalled-echo sequences are known to be
Fig. 3. Subchondral bone marrow lesions (BMLs) are commonly observed in knees with OA. These are a reflection of increased loading and particularly large BMLs may be responsible for pain and structural progression. BMLs are visualized as illdefined areas of hyperintensity in the subchondral bone (arrows).
particularly prone to this type of artifact [25]. To ascertain optimal assessment of MRI-derived data, trained musculoskeletal radiologists should be consulted when designing imaging-based OA studies or when interpreting data from the studies. 3.2. Semiquantitative MRI scoring systems for knee OA A detailed review of semiquantitative MRI assessment of OA has been published [15]. In addition to the three well-established scoring systems – the Whole Organ Magnetic Resonance Imaging Score (WORMS) [26], the Knee Osteoarthritis Scoring System (KOSS) [S8], and the Boston Leeds Osteoarthritis Knee Score (BLOKS) [S9] – a new scoring system called the MR Imaging Osteoarthritis Knee Score (MOAKS) [27] was most recently published. Of the three systems, WORMS and BLOKS have been widely disseminated and used, but these scoring systems both have strengths and weaknesses. MOAKS provides a refined scoring tool for cross-sectional and longitudinal semiquantitative MRI assessment of knee OA. It includes semiquantitative scoring of pathological features: bone marrow lesions; subchondral cysts; articular cartilage; osteophytes; Hoffa synovitis and synovitiseffusion; meniscus; tendons and ligaments; and periarticular features such as cysts and bursitides. The use of within-grade changes for longitudinal assessment is commonly applied in OA research using semiquantitative MRI approaches [28]. Within-grade scoring describes progression or improvement of a lesion that does not meet the criteria of a full grade change but does represent a definite visual change in comparison to the previous visit. A recent study demonstrated that within-grade changes in semiquantitative MRI assessment of cartilage and bone marrow lesions are valid and their use may increase the sensitivity of semiquantitative readings for detecting longitudinal changes in these structures [28]. Synovitis is an important feature of OA and is associated with pain [24]. Although synovitis can be evaluated with non-contrastenhanced MR imaging by using the presence of signal changes in the Hoffa fat pad or joint effusion as an indirect marker of synovitis,
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 4
D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
Fig. 4. Comparison of inflammatory manifestations of disease using non-enhanced and contrast-enhanced sequences. A. Axial intermediate-weighted fat-suppressed MRI shows homogeneous hyperintensity within the joint cavity consistent with grade 2 effusion-synovitis by MOAKS and WORMS (asterisk). Note: BML in the posterior lateral femoral condyle consistent with traction edema at the insertion of the anterior cruciate ligament (arrows). B. Corresponding T1-weighted fat-suppressed image after intravenous contrast administration clearly differentiates between intra-articular joint fluid depicted as hypointensity (asterisk) and true synovial thickening visualized as hyperintense contrast enhancement of the synovial membrane (arrows). Note that BMLs are similarly depicted on T2-weighted fat-suppressed and T1-weighted contrastenhanced fat-suppressed MRI (arrowheads).
only contrast-enhanced MR imaging can reveal the true extent of synovial inflammation [29]. Scoring systems of synovitis based on contrast-enhanced MR imaging have been published [24], and these could potentially be used in clinical trials of new OA drugs that target synovitis. Fig. 4 shows a direct comparison between non-enhanced and contrast-enhanced MRI for the visualization of synovitis and joint effusion. Other available semiquantitative MRI scoring systems related to knee OA include Cartilage Repair Osteoarthritis Knee Score (CROAKS) [30] and Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS) [31], which can be applied to research studies focusing on these structures. Specifically for imaging of cartilage repair tissue, MRI Observation Cartilage Repair Tissue (MOCART) scoring is available and has been applied to research studies involving cartilage repair surgery [32].
Scoring System (HOAMS) is available for use in observational studies and clinical trials of hip joints [35]. In HOAMS, fourteen articular features are assessed: cartilage morphology, subchondral bone marrow lesions, subchondral cysts, osteophytes, acetabular labrum, synovitis (scored only when contrast-enhanced sequences are available), joint effusion, loose bodies, attrition, dysplasia, trochanteric bursitis/insertional tendonitis of the greater trochanter, labral hypertrophy, paralabral cysts and herniation pits at the supero-lateral femoral neck. HOAMS demonstrated satisfactory reliability and good agreement concerning intra- and interobserver assessment. Recently another system was introduced that uses a similar approach [36]. Direct comparisons of HOAMS and SHOMRI in regard to responsiveness and validity are missing to date. 3.5. Quantitative analysis of articular cartilage and other tissues
3.3. Semiquantitative MRI scoring system for hand OA Radiography is still the modality of choice for assessment of hand OA in a clinical setting but the use of more sensitive imaging techniques such as ultrasound and MRI is becoming more common in OA research [S10]. A semiquantitative MRI scoring system for hand OA features called the OMERACT Hand Osteoarthritis Magnetic Resonance Scoring System (HOAMRIS) is available and offers high reliability and responsiveness [S11]. Scored pathological features include synovitis, erosions, cysts, osteophytes, JSN, malalignment and bone marrow lesions. Using these scoring systems, Haugen et al. showed that MRI could detect approximately twice as many joints with erosions and osteophytes as conventional radiography (P < 0.001) [33] and that moderate/ severe synovitis, bone marrow lesions, erosions, attrition and osteophytes were associated with joint tenderness independently of each other [34]. These studies demonstrated that some of the semiquantitatively assessed MRI features of hand OA may be potential targets for therapeutic interventions.
Quantitative measurement of cartilage morphology segments the cartilage image and exploits the three-dimensional nature of MRI data sets to evaluate tissue dimensions (such as thickness and volume) or signal as continuous variables. Examples of nomenclature for MRI-based cartilage measures and strategies for efficient analysis of longitudinal changes in subregional cartilage thickness were proposed by Eckstein et al. [37] [S12]. Quantitative cartilage morphometry has been widely applied in OA studies [S13] [38]. Quantitative measures of articular cartilage structure, such as cartilage thickness loss and denuded areas of subchondral bone have been shown to predict an important clinical outcome, i.e. knee replacement [S13]. Quantitative MRI analysis can also be applied to evaluate non-cartilage tissues in the joint including menisci [S14], bone marrow lesions [S15], synovitis [S16] and joint effusion [S17]. However, using segmentation approaches for illdefined lesions such as bone marrow lesions is more challenging than segmentation of clearly delineated structures such as cartilage, menisci and effusion. 3.6. Compositional MRI
3.4. Semiquantitative MRI scoring system for hip OA The hip joint has a spherical structure and its very thin covering of articular hyaline cartilage makes MRI assessment of the hip much more difficult than the knee. A whole organ semiquantitative multi-feature scoring system called the Hip Osteoarthritis MRI
Compositional MRI allows visualization of the biochemical properties of different joint tissues. It may be sensitive to early, pre-morphologic changes that cannot be visualized on conventional MRI. Compositional MRI has been mostly applied for ultrastructural assessment of catilage, although the technique can
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
also be used to assess other tissues such as the menisci or ligaments. Detailed reviews on this topic have been published recently [39,40]. Compositional MRI of cartilage matrix changes can be performed using advanced MRI techniques such as delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), T1 rho, and T2 mapping [S18]. Of these, the first two take advantage of the concentration of highly negatively charged glycosaminoglycans (GAGs) in healthy hyaline cartilage; loss of these GAGs in focal areas affected by possible early disease can be visualized. Both dGEMRIC and T1 rho focus on charge density in cartilage. In contrast, T2 concentrations are affected by a complex combination of collagen orientation and hydration of cartilage. Compositional MRI techniques are currently not routinely used in clinical practice and remain research tools that are available only at a limited number of institutions. Nevertheless, they have been applied in clinical trials and observational studies. A recent placebo-controlled double-blind pilot study of collagen hydrolysate for mild knee OA demonstrated that the dGEMRIC score increased (meaning higher GAG content and better cartilage status) in tibial cartilage regions of interest in patients receiving collagen hydrolysate, and decreased in the placebo group, with a significant difference being observed at 24 weeks [41]. Crema et al. showed that a decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment of the knee, suggesting that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration [42]. Souza et al. [43] demonstrated that acute loading of the knee joint resulted in a significant decrease in T1 rho and T2 relaxation times of the medial tibiofemoral compartment and especially in cartilage regions with small focal defects, suggesting that changes of T1 rho values under mechanical loading may be related to the biomechanical and structural properties of cartilage. Hovis et al. reported that light exercise was associated with low cartilage T2 values but moderate and strenuous exercise was associated with high T2 values in women, suggesting that activity levels can affect cartilage composition [44]. In an interventional study assessing the effect of weight loss on articular cartilage, Anandacoomarasamy et al. reported that improved articular cartilage quality was reflected as an increase in the dGEMRIC index over one year for the medial but not the lateral compartment [45], highlighting the role of weight loss in possible clinical and structural improvement. Fig. 5 shows an example of a knee with a prevalent meniscal tear and corresponding decrease in GAG
5
content in the central aspect of the cartilage of the central medial femoral condyle. Novel compositional techniques have been further explored, including in vivo diffusion tensor imaging [S19], T2* mapping [46], ultra-short echo time-enhanced (UTE) T2* mapping [47], and sodium imaging [48]. These techniques show promise, but are still at an early stage of research and development. 4. Ultrasound Ultrasound imaging enables real time, multiplanar imaging at relatively low cost. It offers reliable assessment of OA-associated features, including inflammatory and structural abnormalities, without contrast administration or exposure to radiation [49]. Limitations of ultrasound include that it is an operator-dependent technique and that the physical properties of sound limit its ability to assess deep articular structures and the subchondral bone. Ultrasound is useful for evaluation of cortical erosive changes and synovitis in inflammatory arthritis. In OA, the major advantage of ultrasound over conventional radiography is the ability to detect synovial pathology. Current generation ultrasound technology can detect synovial hypertrophy, increased vascularity and the presence of synovial fluid in joints affected by OA [49]. The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Ultrasonography Taskforce defined synovial hypertrophy on ultrasound as ‘‘abnormal hypoechoic (relative to subdermal fat, but sometimes may be isoechoic or hyperechoic) intra-articular tissue that is non-displaceable and poorly compressible and which may exhibit Doppler’’ [S20]. Although this definition was developed for use in rheumatoid arthritis, it may also be applied to OA because the difference in synovial inflammation between OA and rheumatoid arthritis is largely quantitative rather than qualitative [49]. A preliminary ultrasonographic scoring system for features of hand OA published in 2008 [50] included evaluation of grey-scale synovitis and power Doppler signal in 15 joints of the hand. These features were assessed for their presence/absence and if present were scored semiquantitatively using a 1–3 scale. Overall, the reliability exercise demonstrated moderately good intra- and inter-reader reliability. This study showed that an ultrasound outcome measure suitable for multicenter trials assessing hand OA is feasible and likely to be reliable, and has provided a foundation for further development.
Fig. 5. Compositional MRI. A. Sagittal fat-suppressed proton density-weighted image shows a horizontal meniscal tear at the posterior horn of the medial meniscus reaching the undersurface of the mensicus (arrow). B. Corresponding color-coded T1-weighted dGEMRIC image after intravenous contrast administration shows a decrease of the dGEMRIC index in the weight bearing part of the medial femoral condyle coded in red (arrows) representing early cartilage degeneration reflected as a decrease in glucosaminoglycan content compared to the posterior parts of the femoral cartilage that are coded in yellow and green.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
6
Fig. 6. Assessment of meniscal extrusion by ultrasound. A. Coronal ultrasound screenshot of the medial tibiofemoral compartment shows an extruded body of the medial meniscus under weight bearing conditions (arrows). B Corresponding coronal fat-suppressed proton density-weighted MRI shows extrusion to a lesser extent (arrows) due to the prone positioning for the MRI acquisition.
Ultrasound has been increasingly deployed for assessment of hand OA. Kortekaas et al. showed that ultrasound-detected osteophytes and JSN are associated with hand pain [51]. The same group of investigators also showed that ultrasound-detected signs of inflammation are associated with development of erosions in hand OA, implicating inflammation plays a role in its pathogenesis and could be a therapeutic target [S21]. Ultrasound can be used to evaluate the therapeutic efficacy. A decrease in pain correlated with a decrease in synovial thickening and power Doppler ultrasound score before and after weekly ultrasound-guided intra-articular injections of hyaluronic acid [52]. Real time fusion of ultrasound and MR imaging in hand and wrist OA have been attempted, and found a high concordance of the bony profile visualization at the level of osteophytes [S10]. Ultrasound has also been used to evaluate features of knee OA and hip OA. A cross-sectional, multicenter European study analyzed 600 patients with painful knee OA, and found ultrasound-detected synovitis correlated with advanced radiographic OA and clinical symptoms and signs suggestive of an inflammatory ‘‘flare’’ [53]. Ultrasound-detected inflammatory features were positively and linearly associated with knee pain in motion in patients with equal radiographic grades of knee OA in both knees [54], supporting the association between synovitis and knee pain, which has also been reported in MR imaging-based studies [24]. Fig. 6 shows an example of the utility of ultrasound for the visualization of meniscal extrusion. An advantage of ultrasound over MRI in regard to extrusion measurements is the possibility of weight bearing examinations [55]. 5. Nuclear medicine Nuclear medicine imaging with radiotracers enables imaging of active metabolism and visualization of bone turnover changes seen with osteophyte formation, subchondral sclerosis, subchondral cyst formation and bone marrow lesions as well as sites of synovitis [S22]. Scintigraphy with 99mTc-hydroxymethane diphosphonate (HDP) and positron emission tomography (PET) with 2-18F-fluoro-2-deoxy–D-glucose (18FDG) or 18F-fluoride (18F ) have been used to assess OA. Bone scintigraphy can provide a full-body survey that helps to discriminate between soft tissues and bone origin of pain, and to locate the site of pain in patients with complex symptoms [S23]. 18FDG-PET can demonstrate the
site of synovitis and bone marrow lesions associated with OA [56]. Additionally, there have been increasing research efforts to apply SPECT/CT for imaging of osteoarthritis [57]. A major limitation of radioisotope methods is poor anatomical resolution but there are ways to overcome it. Hybrid technologies such as PET-CT and PET-MR imaging combine functional imaging with high-resolution anatomical imaging. Fig. 7 shows an example of PET-CT in knee OA that combines the high resolution of the CT with the metabolic information of the PET. However, nuclear medicine imaging is not commonly applied to imaging of OA in a routine clinical setting. 6. CT CT is excellent for depicting cortical bone and soft tissue calcifications, and has an established role in assessing facet joint OA of the spine. Using a CT-based semiquantitative grading system of facet joint OA, studies have shown a high prevalence of facet joint OA which increases with age, and is most common at the L4– L5 spinal level [58] as well as associations between obesity with higher prevalence of facet joint OA and that between increasing age with higher prevalence of disc narrowing, facet joint OA, and degenerative spondylolisthesis [S24]. Ionizing radiation and limited ability of soft tissue evaluation limit the routine use of CT in clinical imaging of OA. 7. CT and MR arthrography With CT or MR arthrography, assessment of cartilage damage is possible with high anatomical resolution in a multiplanar fashion [S23] [59,60]. CT arthrography is currently the most accurate method for evaluating superficial and focal cartilage damage, offering high spatial resolution and high contrast between the lowattenuating cartilage and high-attenuating superficial (contrast material filling the joint space) and deep (subchondral bone) boundaries [S23]. Fig. 8 shows an example of CT arthrography that delineates superficial and full thickness cartilage damage in excellent fashion. CT can also depict subchondral bone sclerosis and osteophytes. For subchondral changes, MR arthrography allows delineation of subchondral bone marrow lesions on the fluid-sensitive sequences with fat suppression [S23]. Both techniques enable visualization of central osteophytes, which are
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
7
Fig. 7. PET-CT. A. Conventional coronal CT reformation shows definite OA on the left with marginal tibial and femoral osteophytes (thin arrows) and definite medial tibiofemoral joint space narrowing. Total knee arthroplasty of the right knee with the metal implants clearly depicted as markedly hyperdense structures (large arrows). Note beam-hardening artifacts due to the metal hardware particularly surrounding the distal femur. B. Color-coded fusion image of PET and CT shows marked tracer uptake in the perimensical region bilaterally representing active synovitis (large arrows). C. Corresponding axial fusion image shows synovitis also in the peripatellar recesses (small arrows). In addition, there is marked synovitis posteriorly adjacent to the posterior cruciate ligament, the most common location of synovitis in knee OA (large arrow). To date PET-CT does not play a relevant role for the assessment of knee OA structural changes in the clinical routine practice.
8. Conclusion
Fig. 8. CT arthrography is considered the imaging gold standard for the visualization of the articular surface integrity. After intra-articular injection of an iodine-based contrast agent the cartilage surface can be depicted as a hypodense structure. Image example shows a focal full thickness defect at the lateral tibia (arrow).
Imaging of OA has helped investigators to understand risk factors for disease onset and progression and the interactions between different joint tissues and peritarticular tissue changes. Despite those research advances the role of imaging in the routine clinical management of OA patients remains less well-defined in that imaging findings do not always correlate with clinical symptoms. Given such limitations, radiography is still most commonly used for semiquantitative and quantitative evaluation of structural OA features. MRI is currently the most important imaging modality for OA research, and available options include semiquantitative, quantitative and compositional analyses. Ultrasound is commonly used in hand OA studies and is particularly useful for evaluation of synovitis and for guidance of joint-related procedures. Nuclear medicine, CT and CT-MR arthrography have limited roles compared to radiography, MRI and ultrasound. Role of the funding source No funding received.
associated with more severe changes of OA than marginal osteophytes [S25]. Due to the high cost, invasive nature and potential risk, albeit low, associated with intra-articular injection, arthrographic examinations are rarely used in large scale clinical or epidemiological OA studies.
Disclosure of interests Dr. Guermazi has received consultancies, speaking fees, and/or honoraria from TissueGene, OrthoTrophix, and Merck Serono and is the President of Boston Imaging Core Lab (BICL), a company
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
8
providing image assessment services. Dr. Roemer is Chief Medical Officer and shareholder of BICL. Dr. Hayashi declares that he has no competing interest.
Appendix A. Supplementary data
[21]
[22]
[23]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.rehab.2015.12. 003.
[24]
References
[25]
[1] Guermazi A, Hayashi D, Roemer F, Felson DT, Wang K, Lynch J, et al. Severe radiographic knee osteoarthritis – does Kellgren and Lawrence grade 4 represent end stage disease? Osteoarthritis Cartilage 2015;23:1499–505. [2] Guermazi A, Niu J, Hayashi D, Roemer FW, Englund M, Neogi T, et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ 2012;345:e5339. [3] Altman RD, Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. Osteoarthritis Cartilage 2007;15(Suppl. A):A1–56. [4] Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. [5] Roemer FW, Hayes CW, Miller CG, Hoover K, Guermazi A. Imaging atlas for eligibility and on-study safety of potential knee adverse events in anti-NGF studies (Part 1). Osteoarthritis Cartilage 2015;23(Suppl. 1):S22–42. [6] Roemer FW, Guermazi A, Niu J, Zhang Y, Mohr A, Felson DT. Prevalence of magnetic resonance imaging-defined atrophic and hypertrophic phenotypes of knee osteoarthritis in a population-based cohort. Arthritis Rheum 2012;64:429–37. [7] Guermazi A, Hunter DJ, Li L, Benichou O, Eckstein F, Kwoh CK, et al. Different thresholds for detecting osteophytes and joint space narrowing exist between the site investigators and the centralized reader in a multicenter knee osteoarthritis study – data from the Osteoarthritis Initiative. Skeletal Radiol 2012;41:179–86. [8] Duryea J, Neumann G, Niu J, Totterman S, Tamez J, Dabrowski C, et al. Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: analysis of longitudinal data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2010;62:932–7. [9] Felson DT, Niu J, Gross KD, Englund M, Sharma L, Cooke TD, et al. Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: findings from MOST and the Osteoarthritis Initiative. Arthritis Rheum 2013;65:355–62. [10] Runhaar J, van Middelkoop M, Reijman M, Vroegindeweij D, Oei DH, BiermaZeinstra SM. Malalignment: a possible target for prevention of incident knee osteoarthritis in overweight and obese women. Rheumatology (Oxford) 2014;53:1618–24. [11] Hayashi D, Xu L, Roemer FW, Hunter DJ, Li L, Katur AM, et al. Detection of osteophytes and subchondral cysts in the knee with use of tomosynthesis. Radiology 2012;263:206–15. [12] Hayashi D, Xu L, Gusenburg J, Roemer FW, Hunter DJ, Li L, et al. Reliability of semiquantitative assessment of osteophytes and subchondral cysts on tomosynthesis images by radiologists with different levels of expertise. Diagn Interv Radiol 2014;20:353–9. [13] Woloszynski T, Podsiadlo P, Stachowiak GW, Kurzynski M, Lohmander LS, Englund M, et al. Prediction of progression of radiographic knee osteoarthritis using tibial trabecular bone texture. Arthritis Rheum 2012;64:688–95. [14] Hayashi D, Guermazi A, Roemer FW. MRI of osteoarthritis: the challenges of definition and quantification. Semin Musculoskelet Radiol 2012;16:419–30. [15] Guermazi A, Roemer FW, Haugen IK, Crema MD, Hayashi D. MRI-based semiquantitative scoring of joint pathology in osteoarthritis. Nat Rev Rheumatol 2013;9:236–51. [16] Alizai H, Roemer FW, Hayashi D, Crema MD, Felson DT, Guermazi A. An update on risk factors for cartilage loss in knee osteoarthritis assessed using MRIbased semiquantitative grading methods. Eur Radiol 2015;25:883–93. [17] Hayashi D, Guermazi A, Kwoh CK, Hannon MJ, Moore C, Jakicic JM, et al. Semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts of the knee at 3 T MRI: A comparison between intermediate-weighted fat-suppressed spin echo and Dual Echo Steady State sequences. BMC Musculoskelet Disord 2011;12:198. [18] Hayashi D, Englund M, Roemer FW, Niu J, Sharma L, Felson DT, et al. Knee malalignment is associated with an increased risk for incident and enlarging bone marrow lesions in the more loaded compartments: the MOST study. Osteoarthritis Cartilage 2012;20:1227–33. [19] Roemer FW, Felson DT, Wang K, Crema MD, Neogi T, Zhang Y, et al. Colocalisation of non-cartilaginous articular pathology increases risk of cartilage loss in the tibiofemoral joint – the MOST study. Ann Rheum Dis 2013;72: 942–8. [20] Roemer FW, Kwoh CK, Hannon MJ, Green SM, Jakicic JM, Boudreau R, et al. Risk factors for magnetic resonance imaging-detected patellofemoral and
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study. Arthritis Rheum 2012;64:1888–98. Roemer FW, Guermazi A, Felson DT, Niu J, Nevitt MC, Crema MD, et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann Rheum Dis 2011;70:1804–9. Hunter DJ, Arden N, Conaghan P, Eckstein F, Gold G, Grainger A, et al. Definition of osteoarthritis on MRI: results of a Delphi exercise. Osteoarthritis Cartilage 2011;19:963–9. Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum 2011;63:691–9. Guermazi A, Roemer FW, Hayashi D, Crema MD, Niu J, Zhang Y, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis 2011;70:805–11. Jarraya M, Hayashi D, Guermazi A, Kwoh CK, Hannon MJ, Moore CE, et al. Susceptibility artifacts detected on 3 T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study. Osteoarthritis Cartilage 2014;22:1499–503. Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. WholeOrgan Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage 2004;12:177–90. Hunter DJ, Guermazi A, Lo GH, Grainger AJ, Conaghan PG, Boudreau RM, et al. Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score). Osteoarthritis Cartilage 2011;19:990–1002. Roemer FW, Nevitt MC, Felson DT, Niu J, Lynch JA, Crema MD, et al. Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint – the MOST Study. Osteoarthritis Cartilage 2012;20:1391–8. Loeuille D, Sauliere N, Champigneulle J, Rat AC, Blum A, Chary-Valckenaere I. Comparing non-enhanced and enhanced sequences in the assessment of effusion and synovitis in knee OA: associations with clinical, macroscopic and microscopic features. Osteoarthritis Cartilage 2011;19:1433–9. Roemer FW, Guermazi A, Trattnig S, Apprich S, Marlovits S, Niu J, et al. Whole joint MRI assessment of surgical cartilage repair of the knee: cartilage repair osteoarthritis knee score (CROAKS). Osteoarthritis Cartilage 2014;22:779–99. Roemer FW, Frobel R, Lohmaner LS, Niu J, Guermazi A. Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS): longitudinal MRI-based whole joint assessment of anterior cruciate ligament injury. Osteoarthritis Cartilage 2014;22:668–82. Welsch GH, Zak L, Mamisch TC, Paul D, Lauer L, Mauerer A, et al. Advanced morphological 3D magnetic resonance observation of cartilage repair tissue (MOCART) scoring using a new isotropic 3D proton-density, turbo spin echo sequence with variable flip angle distribution (3D-SPACE) compared to an isotropic 3D steady-state free precession sequence (True-FISP) and standard 2D sequences. J Magn Reson Imaging 2011;33:180–8. Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, Bijsterbosch J, van der Heijde D, et al. Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis. Ann Rheum Dis 2012;71:345–50. Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, van der Heijde D, Kvien TK. Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis. Ann Rheum Dis 2012;71:899–904. Roemer FW, Hunter DJ, Winterstein A, Li L, Kim YJ, Cibere J, et al. Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings. Osteoarthritis Cartilage 2011;19:946–62. Lee S, Nardo L, Kumar D, Wyatt CR, Souza RB, Lynch J, et al. Scoring hip osteoarthritis with MRI (SHOMRI): a whole joint osteoarthritis evaluation system. J Magn Reson Imaging 2015;41:1549–57. Eckstein F, Ateshian G, Burgkart R, Burstein D, Cicuttini F, Dardzinski B, et al. Proposal for a nomenclature for magnetic resonance imaging-based measures of articular cartilage in osteoarthritis. Osteoarthritis Cartilage 2006;14:974–83. Eckstein F, Collins JE, Nevitt MC, Lynch JA, Kraus V, Katz JN, et al. Cartilage thickness change as an imaging biomarker of knee osteoarthritis progression– data from the fnih OA biomarkers consortium. Arthritis Rheumatol 2015. http://dx.doi.org/10.1002/art.39324 [Epub ahead of print]. Guermazi A, Roemer FW, Alizai H, Winalski CS, Welsch G, Brittberg M, et al. State of the art: MR imaging after knee cartilage repair surgery. Radiology 2015;277:23–43. Guermazi A, Alizai H, Crema MD, Trattnig S, Regatte RR, Roemer FW. Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis. Osteoarthritis Cartilage 2015;23:1639–53. McAlindon TE, Nuite M, Krishnan N, Ruthazer R, Price LL, Burstein D, et al. Change in knee osteoarthritis cartilage detected by delayed gadoliniumenhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis Cartilage 2011;19:399–405. Crema MD, Hunter DJ, Burstein D, Roemer FW, Li L, Eckstein F. Association of changes in delayed gadoliun-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2 year follow-up study using 3.0T MRI. Ann Rheum Dis 2014;73:1935–41. Souza RB, Stehling C, Wyman BT, Hellio Le Graverand MO, Li X, Link TM, et al. The effects of acute loading on T1rho and T2 relaxation times of tibiofemoral articular cartilage. Osteoarthritis Cartilage 2010;18:1557–63.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx [44] Hovis KK, Stehling C, Souza RB, Haughom BD, Baum T, Nevitt M, et al. Physical activity is associated with magnetic resonance imaging-based knee cartilage T2 measurements in asymptomatic subjects with and those without osteoarthritis risk factors. Arthritis Rheum 2011;63:2248–56. [45] Anandacoomarasamy A, Leibman S, Smith G, Caterson I, Giuffre B, Fransen M, et al. Weight loss in obese people has structure-modifying effects on medial but not on lateral knee articular cartilage. Ann Rheum Dis 2012;71: 26–32. [46] Newbould RD, Miller SR, Toms LD, Swann P, Tielbeek JA, Gold GE, et al. T2* measurement of the knee articular cartilage in osteoarthritis at 3T. J Magn Reson Imaging 2012;35:1422–9. [47] Wiliams A, Qian Y, Golla S, Chu CR. UTE-T2* mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear. Osteoarthritis Cartilage 2012;20:486–94. [48] Madelin G, Babb J, Xia D, Chang G, Krasnokutsky S, Abramson SB, et al. Articular cartilage: evaluation with fluid-suppressed 7.0T sodium MR imaging in subjects with and subjects without osteoarthritis. Radiology 2013;268:481–91. [49] Keen HI, Conaghan PG. Ultrasonography in osteoarthritis. Radiol Clin N Am 2009;47:581–94. [50] Keen HI, Lavie F, Wakefield RJ, D’Agostino MA, Hammer HB, Hensor E, et al. The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis. Ann Rheum Dis 2008;67:651–5. [51] Kortekaas MC, Kwok WY, Reijnierse M, Huizinga TW, Kloppenburg M. Osteophytes and joint space narrowing are independently associated with pain in finger joints in hand osteoarthritis. Ann Rheum Dis 2011;70:1835–7. [52] Klauser AS, Faschingbauer R, Kupferthaler K, Feuchnter G, Wick MC, Jaschke WR, et al. Sonographic criteria for therapy follow-up in the course of ultrasound-guided intra-articular injections of hyaluronic acid in hand osteoarthritis. Eur J Radiol 2012;81:1607–11.
9
[53] Conaghan PG, D’Agostino MA, Le Bars M, Baron G, Schmidely N, Wakefield R, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study. Ann Rheum Dis 2010;69:644–7. [54] Wu PT, Shao CJ, Wu KC, Wu TT, Chern TC, Kuo LC, et al. Pain in patients with equal radiographic grades of osteoarthritis in both knees: the value of gray scale ultrasound. Osteoarthritis Cartilage 2012;20:1507–13. [55] Nogueira-Barbosa MH, Gregio-Junior E, Lorenzato MM, Guermazi A, Roemer FW, Chagas-Neto FA, et al. Ultrasound assessment of medial meniscal extrusion: a validation study using MRI as reference standard. AJR Am J Roentgenol 2015;204:584–8. [56] Nakamura H, Masuko K, Yudoh K, Kato T, Nishioka K, Sugihara T, et al. Positron emission tomography with 18F-FDG in osteoarthritic knee. Osteoarthritis Cartilage 2007;15:673–81. [57] Maas O, Joseph GB, Sommer G, Wild D, Kretzschmar M. Association between cartilage degeneration and subchondral bone remodeling in patients with knee osteoarthritis comparing MRI and (99 m)Tc-DPD-SPECT/CT. Osteoarthritis Cartilage 2015;23:1713–20. [58] Kalichman L, Li L, Kim DH, Guermazi A, Berkin V, O’Donnell CJ, et al. Facet joint osteoarthritis and low back pain in the community-based population. Spine 2008;33:2560–5. [59] Omoumi P, Michoux N, Thienpont E, Roemer FW, Vande Berg BC. Anatomical distribution of areas of preserved cartilage in advanced femorotibial osteoarthritis using CT arthrography (Part 1). Osteoarthritis Cartilage 2015;23(1): 83–7. [60] Omoumi P, Michoux N, Roemer FW, Thienpont E, Vande Berg BC. Cartilage thickness at the posterior medial femoral condyle is increased in femorotibial knee osteoarthritis: a cross-sectional CT arthrography study (Part 2). Osteoarthritis Cartilage 2015;23(2):224–31.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
REHAB-947; No. of Pages 9 Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Review
Imaging for osteoarthritis D. Hayashi a, F.W. Roemer a,b, A. Guermazi a,* a b
Department of Radiology, Boston University School of Medicine, 820 Harrison Avenue, FGH Building 3rd Floor, Boston, MA 02118, United States Department of Radiology, University of Erlangen-Nuremberg, D-91012 Erlangen, Germany
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1st November 2015 Accepted 17 December 2015
Osteoarthritis (OA) is a widely prevalent disease worldwide and, with an increasing ageing society, is a challenge for the field of physical and rehabilitation medicine. Technologic advances and implementation of sophisticated post-processing instruments and analytic strategies have resulted in imaging playing a more and more important role in understanding the disease process of OA. Radiography is still the most commonly used imaging modality for establishing an imaging-based diagnosis of OA. The need for an effective non-surgical OA treatment is highly desired, but despite on-going research efforts no disease-modifying OA drugs have been discovered or approved to date. MR imaging-based studies have revealed some of the limitations of radiography. The ability of MR to image all relevant joint tissues within the knee and to visualize cartilage morphology and composition has resulted in MRI playing a key role in understanding the natural history of the disease and in the search for new therapies. Our review will focus on the roles and limitations of radiography and MRI with particular attention to knee OA. The use of other modalities (e.g. ultrasound, nuclear medicine, computed tomography (CT), and CT/MR arthrography) in clinical practice and OA research will also be briefly described. Ultrasound may be useful to evaluate synovial pathology in osteoarthritis, particularly in the hand. ß 2015 Elsevier Masson SAS. All rights reserved.
Keywords: Osteoarthritis Imaging Radiography MR imaging Ultrasound CT PET
Knee osteoarthritis is a major public health problem that primarily affects the elderly. Almost 10% of the United States population suffers from symptomatic knee osteoarthritis by the age of 60 [S1]. In total, the health care expenditures of this condition have been estimated at US$ 186 billion annually [S2]. Despite this there are no approved interventions that ameliorate structural progression of this disorder. The increasing importance of imaging in osteoarthritis for diagnosis, prognostication and follow-up is well recognized by both clinicians and osteoarthritis researchers. While conventional radiography is the gold standard imaging technique for the evaluation of known or suspected osteoarthritis in clinical practice and research, it has limitations that have become apparent in the course of large magnetic resonance imaging (MRI)-based knee osteoarthritis studies [1,2]. Pathological changes may be evident in all structures of a joint with osteoarthritis although traditionally researchers have viewed articular cartilage as the central feature and as the primary target for intervention and measurement. Of the commonly employed imaging techniques, only MRI can assess all structures of the joint, including cartilage, meniscus, ligaments, * Corresponding author. Tel.: +16174143893. E-mail address: [email protected] (A. Guermazi).
muscle, subarticular bone marrow and synovium, and thus can show the knee as a whole organ three-dimensionally. In addition, it can directly help in the assessment of cartilage morphology and composition. The advantages and limitations of conventional radiography, MRI and other techniques such as ultrasound, nuclear medicine, computed tomography (CT) and CT arthrography in the imaging of osteoarthritis in both clinical practice and research are described in this review article. 1. Conventional radiography Radiography is the simplest, least expensive and most commonly deployed imaging modality for OA. It enables detection of OA-associated bony features such as osteophytes, subchondral sclerosis and cysts [3]. Radiography can also determine joint space width (JSW), which is a surrogate for cartilage thickness and meniscal integrity in knees, but direct visualization of these articular structures is not possible. Despite this limitation, slowing of radiographically detected joint space narrowing (JSN) remains the only structural end point currently approved by the U.S. Food and Drug Administration to demonstrate efficacy of diseasemodifying OA drugs in phase III clinical trials. OA is radiographically defined by the presence of marginal osteophytes
http://dx.doi.org/10.1016/j.rehab.2015.12.003 1877-0657/ß 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
2
Fig. 1. The Kellgren-Lawrence classification is a composite scale of OA severity taking into account primarily the radiographic OA features of marginal osteophytes and joint space narrowing in the AP radiograph. A. Kellgren-Lawrence grade 1. Minimal, equivocal osteophytes are observed at the medial joint margins (large arrows). Note that, socalled notch osteophytes at the centre of the joint (small arrow) are not considered in the Kellgren-Lawrence scale. B. Kellgren-Lawrence grade 2 is characterized by presence of at least one definite marginal osteophyte (arrow) without evidence of joint space narrowing. C. Kellgren-Lawrence grade 3 knees exhibit signs of definite joint space narrowing (black arrows) and marginal osteophytes (white arrows). The amount of joint space narrowing is not taken into account. D. Kellgren-Lawrence grade 4 is defined by bone-to-bone contact and complete obliteration of the joint space (black arrows). Note definite marginal osteophytes in addition (white arrows).
[S3]. Worsening of JSN is the most commonly used criterion for the assessment of structural OA progression and the total loss of JSW (‘‘bone-on-bone’’ appearance) is one of the indicators for joint replacement. We now know cartilage loss is not the only contributor to JSN but that changes in the meniscus such as meniscal extrusion and meniscal substance loss are also causative factors. The lack of sensitivity and specificity of radiography for the detection of OAassociated articular tissue damage, and its poor sensitivity to change longitudinally are other limitations of radiography. Changes in knee positioning can also be problematic in longitudinal studies and can affect the quantitative measurement of various radiographic parameters including JSW. Despite these limitations, radiography is still the gold standard for establishing an imaging-based diagnosis of OA and for assessment of structural modification in clinical trials of knee OA. 1.1. Semiquantitative assessments The severity of radiographic OA can be assessed with semiquantitative scoring systems. The Kellgren and Lawrence (KL) grading system [4] is a widely accepted scheme for defining radiographic OA based on the presence of a definite osteophyte (grade 2). However, KL grading has its limitations; in particular, KL grade 3 includes all degrees of JSN, regardless of the actual extent. Fig. 1 depicts representative examples of the different KL grades as shown on the AP radiograph. Recently, the so-called atrophic phenotype of knee OA that is characterized by definite joint space narrowing without concomitant osteophyte formation has gained increasing attention as a potential risk factor for more rapid progressive OA, which may be considered a potential adverse event in so-called anti-nerve growth factor (NGF) drug trials, a class of new promising antianalgesic compounds currently under investigation [5]. Although this phenotype is rare, it needs special attention in the research community as it potentially also is a reflection of more rapid disease progression [6]. Fig. 2 shows an example of the atrophic phenotype of radiographic OA. The Osteoarthritis Research Society International (OARSI) atlas [3] provides image examples for grades for specific features of OA rather than assigning global scores according to definitions like the KL grading system. The atlas grades tibiofemoral JSW and osteophytes separately for each compartment of the knee (medial
tibiofemoral, lateral tibiofemoral, and patellofemoral). A recent study using data from the OA Initiative and the OARSI atlas for semiquantitative grading of JSN demonstrated that centralized radiographic reading is important from the point of observer reliability, as even expert readers seem to apply different thresholds for JSN grading [7]. 1.2. Quantitative assessments JSW is the distance between the projected femoral and tibial margins on the anteroposterior radiographic image. Measurements may be performed manually or in a semi-automated fashion using computer software. Quantification using image processing software requires a digital image, whether digitized plain films or images acquired using fully digital modalities such as computed radiography and digital radiography. Minimum JSW is the standard metric, but the use of location-specific JSW has also been reported [S4]. Using software analysis of digital knee radiographic images, measures of location-specific JSW were shown to be comparable with MR imaging in detecting OA progression [8]. Various degrees of responsiveness have been
Fig. 2. Kellgren-Lawrence 3 knees with definite joint space narrowing (arrowheads) but only minimal osteophyte formation (arrow) are considered to represent the socalled atrophic phenotype of knee OA. This subtype of radiographic knee OA may be a reflection of more rapid disease progression.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
3
observed depending on the degree of OA severity, length of the follow-up period, and the knee positioning protocol [S4] [8]. Measurements of JSW obtained from knee radiographs have been found to be reliable, especially when the study lasted longer than two years and when the radiographs were obtained with the knee in a standardized flexed position [S5]. The role of malalignment in OA disease process has been described in the literature. A clinical trial showed that varus malalignment negated the slowing of structural progression of medial JSN by doxycycline [S6]. Valgus malalignment of the lower limb was shown to increase the risk of disease progression in knees with radiographic lateral knee OA [9]. Malalignment might be a target for prevention of radiographic knee OA as determined by JSN in overweight and obese women [10]. 2. Other radiography-based techniques Interestingly, two older methods – tomosynthesis and bone texture analysis – have experienced a revival recently. Tomosynthesis generates an arbitrary number of cross-sectional images from a single pass of the X-ray tube. A recent study showed that tomosynthesis is more sensitive in the detection of osteophytes and subchondral cysts than radiography, using 3T MRI as the reference [11]. Moreover, tomosynthesis was shown to offer excellent intrareader reliability regardless of the reader experience [12]. Quantification of JSW using tomosynthesis has also been reported [S7]. Bone texture analysis extracts from conventional radiographs information on two-dimensional trabecular bone texture that relates directly to three-dimensional bone structure. It has been shown that bone texture may be a predictor of progression of tibiofemoral OA [13]. 3. MRI Because of the high cost, MRI is not routinely used in clinical management of OA patients. However, MRI has become a keyimaging tool for OA research [14–16] thanks to its ability to assess pathology in structures not visualized by radiography i.e. articular cartilage, menisci, ligaments, synovium, capsular structures, fluid collections and bone marrow [2,17–21]. With MRI the joint can be evaluated as a whole organ and multiple tissue changes can be monitored simultaneously; pathologic changes of pre-radiographic OA can be detected; and biochemical changes within joint tissues such as cartilage can be assessed before morphologic changes become evident. An MRI-based definition of OA is available [22]. In addition, with MRI, OA can be classified into hypertrophic and atrophic phenotypes, according to the size of osteophytes and concomitant presence or absence of JSN [6]. Importantly, the use of MRI has led to significant findings about the association of pain with bone marrow lesions [23] and synovitis [24], with implications for future OA clinical trials. Fig. 3 shows an example of typical large bone marrow lesions that are commonly seen in conjunction with severe cartilage damage and may be responsible for pain in OA. 3.1. Technical considerations It should be emphasized that investigators need to select appropriate MR pulse sequences for the purpose of each study. For example, focal cartilage defects and bone marrow lesions are best assessed using fluid-sensitive fast spin echo sequences (e.g. T2weighted, proton density-weighted or intermediate-weighted) with fat suppression [14,17]. Moreover, MRI may sometimes be affected by artifacts that mimic pathological findings. For example, susceptibility artifacts can be misinterpreted as cartilage loss or meniscal tear. Gradient recalled-echo sequences are known to be
Fig. 3. Subchondral bone marrow lesions (BMLs) are commonly observed in knees with OA. These are a reflection of increased loading and particularly large BMLs may be responsible for pain and structural progression. BMLs are visualized as illdefined areas of hyperintensity in the subchondral bone (arrows).
particularly prone to this type of artifact [25]. To ascertain optimal assessment of MRI-derived data, trained musculoskeletal radiologists should be consulted when designing imaging-based OA studies or when interpreting data from the studies. 3.2. Semiquantitative MRI scoring systems for knee OA A detailed review of semiquantitative MRI assessment of OA has been published [15]. In addition to the three well-established scoring systems – the Whole Organ Magnetic Resonance Imaging Score (WORMS) [26], the Knee Osteoarthritis Scoring System (KOSS) [S8], and the Boston Leeds Osteoarthritis Knee Score (BLOKS) [S9] – a new scoring system called the MR Imaging Osteoarthritis Knee Score (MOAKS) [27] was most recently published. Of the three systems, WORMS and BLOKS have been widely disseminated and used, but these scoring systems both have strengths and weaknesses. MOAKS provides a refined scoring tool for cross-sectional and longitudinal semiquantitative MRI assessment of knee OA. It includes semiquantitative scoring of pathological features: bone marrow lesions; subchondral cysts; articular cartilage; osteophytes; Hoffa synovitis and synovitiseffusion; meniscus; tendons and ligaments; and periarticular features such as cysts and bursitides. The use of within-grade changes for longitudinal assessment is commonly applied in OA research using semiquantitative MRI approaches [28]. Within-grade scoring describes progression or improvement of a lesion that does not meet the criteria of a full grade change but does represent a definite visual change in comparison to the previous visit. A recent study demonstrated that within-grade changes in semiquantitative MRI assessment of cartilage and bone marrow lesions are valid and their use may increase the sensitivity of semiquantitative readings for detecting longitudinal changes in these structures [28]. Synovitis is an important feature of OA and is associated with pain [24]. Although synovitis can be evaluated with non-contrastenhanced MR imaging by using the presence of signal changes in the Hoffa fat pad or joint effusion as an indirect marker of synovitis,
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 4
D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
Fig. 4. Comparison of inflammatory manifestations of disease using non-enhanced and contrast-enhanced sequences. A. Axial intermediate-weighted fat-suppressed MRI shows homogeneous hyperintensity within the joint cavity consistent with grade 2 effusion-synovitis by MOAKS and WORMS (asterisk). Note: BML in the posterior lateral femoral condyle consistent with traction edema at the insertion of the anterior cruciate ligament (arrows). B. Corresponding T1-weighted fat-suppressed image after intravenous contrast administration clearly differentiates between intra-articular joint fluid depicted as hypointensity (asterisk) and true synovial thickening visualized as hyperintense contrast enhancement of the synovial membrane (arrows). Note that BMLs are similarly depicted on T2-weighted fat-suppressed and T1-weighted contrastenhanced fat-suppressed MRI (arrowheads).
only contrast-enhanced MR imaging can reveal the true extent of synovial inflammation [29]. Scoring systems of synovitis based on contrast-enhanced MR imaging have been published [24], and these could potentially be used in clinical trials of new OA drugs that target synovitis. Fig. 4 shows a direct comparison between non-enhanced and contrast-enhanced MRI for the visualization of synovitis and joint effusion. Other available semiquantitative MRI scoring systems related to knee OA include Cartilage Repair Osteoarthritis Knee Score (CROAKS) [30] and Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS) [31], which can be applied to research studies focusing on these structures. Specifically for imaging of cartilage repair tissue, MRI Observation Cartilage Repair Tissue (MOCART) scoring is available and has been applied to research studies involving cartilage repair surgery [32].
Scoring System (HOAMS) is available for use in observational studies and clinical trials of hip joints [35]. In HOAMS, fourteen articular features are assessed: cartilage morphology, subchondral bone marrow lesions, subchondral cysts, osteophytes, acetabular labrum, synovitis (scored only when contrast-enhanced sequences are available), joint effusion, loose bodies, attrition, dysplasia, trochanteric bursitis/insertional tendonitis of the greater trochanter, labral hypertrophy, paralabral cysts and herniation pits at the supero-lateral femoral neck. HOAMS demonstrated satisfactory reliability and good agreement concerning intra- and interobserver assessment. Recently another system was introduced that uses a similar approach [36]. Direct comparisons of HOAMS and SHOMRI in regard to responsiveness and validity are missing to date. 3.5. Quantitative analysis of articular cartilage and other tissues
3.3. Semiquantitative MRI scoring system for hand OA Radiography is still the modality of choice for assessment of hand OA in a clinical setting but the use of more sensitive imaging techniques such as ultrasound and MRI is becoming more common in OA research [S10]. A semiquantitative MRI scoring system for hand OA features called the OMERACT Hand Osteoarthritis Magnetic Resonance Scoring System (HOAMRIS) is available and offers high reliability and responsiveness [S11]. Scored pathological features include synovitis, erosions, cysts, osteophytes, JSN, malalignment and bone marrow lesions. Using these scoring systems, Haugen et al. showed that MRI could detect approximately twice as many joints with erosions and osteophytes as conventional radiography (P < 0.001) [33] and that moderate/ severe synovitis, bone marrow lesions, erosions, attrition and osteophytes were associated with joint tenderness independently of each other [34]. These studies demonstrated that some of the semiquantitatively assessed MRI features of hand OA may be potential targets for therapeutic interventions.
Quantitative measurement of cartilage morphology segments the cartilage image and exploits the three-dimensional nature of MRI data sets to evaluate tissue dimensions (such as thickness and volume) or signal as continuous variables. Examples of nomenclature for MRI-based cartilage measures and strategies for efficient analysis of longitudinal changes in subregional cartilage thickness were proposed by Eckstein et al. [37] [S12]. Quantitative cartilage morphometry has been widely applied in OA studies [S13] [38]. Quantitative measures of articular cartilage structure, such as cartilage thickness loss and denuded areas of subchondral bone have been shown to predict an important clinical outcome, i.e. knee replacement [S13]. Quantitative MRI analysis can also be applied to evaluate non-cartilage tissues in the joint including menisci [S14], bone marrow lesions [S15], synovitis [S16] and joint effusion [S17]. However, using segmentation approaches for illdefined lesions such as bone marrow lesions is more challenging than segmentation of clearly delineated structures such as cartilage, menisci and effusion. 3.6. Compositional MRI
3.4. Semiquantitative MRI scoring system for hip OA The hip joint has a spherical structure and its very thin covering of articular hyaline cartilage makes MRI assessment of the hip much more difficult than the knee. A whole organ semiquantitative multi-feature scoring system called the Hip Osteoarthritis MRI
Compositional MRI allows visualization of the biochemical properties of different joint tissues. It may be sensitive to early, pre-morphologic changes that cannot be visualized on conventional MRI. Compositional MRI has been mostly applied for ultrastructural assessment of catilage, although the technique can
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
also be used to assess other tissues such as the menisci or ligaments. Detailed reviews on this topic have been published recently [39,40]. Compositional MRI of cartilage matrix changes can be performed using advanced MRI techniques such as delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), T1 rho, and T2 mapping [S18]. Of these, the first two take advantage of the concentration of highly negatively charged glycosaminoglycans (GAGs) in healthy hyaline cartilage; loss of these GAGs in focal areas affected by possible early disease can be visualized. Both dGEMRIC and T1 rho focus on charge density in cartilage. In contrast, T2 concentrations are affected by a complex combination of collagen orientation and hydration of cartilage. Compositional MRI techniques are currently not routinely used in clinical practice and remain research tools that are available only at a limited number of institutions. Nevertheless, they have been applied in clinical trials and observational studies. A recent placebo-controlled double-blind pilot study of collagen hydrolysate for mild knee OA demonstrated that the dGEMRIC score increased (meaning higher GAG content and better cartilage status) in tibial cartilage regions of interest in patients receiving collagen hydrolysate, and decreased in the placebo group, with a significant difference being observed at 24 weeks [41]. Crema et al. showed that a decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment of the knee, suggesting that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration [42]. Souza et al. [43] demonstrated that acute loading of the knee joint resulted in a significant decrease in T1 rho and T2 relaxation times of the medial tibiofemoral compartment and especially in cartilage regions with small focal defects, suggesting that changes of T1 rho values under mechanical loading may be related to the biomechanical and structural properties of cartilage. Hovis et al. reported that light exercise was associated with low cartilage T2 values but moderate and strenuous exercise was associated with high T2 values in women, suggesting that activity levels can affect cartilage composition [44]. In an interventional study assessing the effect of weight loss on articular cartilage, Anandacoomarasamy et al. reported that improved articular cartilage quality was reflected as an increase in the dGEMRIC index over one year for the medial but not the lateral compartment [45], highlighting the role of weight loss in possible clinical and structural improvement. Fig. 5 shows an example of a knee with a prevalent meniscal tear and corresponding decrease in GAG
5
content in the central aspect of the cartilage of the central medial femoral condyle. Novel compositional techniques have been further explored, including in vivo diffusion tensor imaging [S19], T2* mapping [46], ultra-short echo time-enhanced (UTE) T2* mapping [47], and sodium imaging [48]. These techniques show promise, but are still at an early stage of research and development. 4. Ultrasound Ultrasound imaging enables real time, multiplanar imaging at relatively low cost. It offers reliable assessment of OA-associated features, including inflammatory and structural abnormalities, without contrast administration or exposure to radiation [49]. Limitations of ultrasound include that it is an operator-dependent technique and that the physical properties of sound limit its ability to assess deep articular structures and the subchondral bone. Ultrasound is useful for evaluation of cortical erosive changes and synovitis in inflammatory arthritis. In OA, the major advantage of ultrasound over conventional radiography is the ability to detect synovial pathology. Current generation ultrasound technology can detect synovial hypertrophy, increased vascularity and the presence of synovial fluid in joints affected by OA [49]. The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Ultrasonography Taskforce defined synovial hypertrophy on ultrasound as ‘‘abnormal hypoechoic (relative to subdermal fat, but sometimes may be isoechoic or hyperechoic) intra-articular tissue that is non-displaceable and poorly compressible and which may exhibit Doppler’’ [S20]. Although this definition was developed for use in rheumatoid arthritis, it may also be applied to OA because the difference in synovial inflammation between OA and rheumatoid arthritis is largely quantitative rather than qualitative [49]. A preliminary ultrasonographic scoring system for features of hand OA published in 2008 [50] included evaluation of grey-scale synovitis and power Doppler signal in 15 joints of the hand. These features were assessed for their presence/absence and if present were scored semiquantitatively using a 1–3 scale. Overall, the reliability exercise demonstrated moderately good intra- and inter-reader reliability. This study showed that an ultrasound outcome measure suitable for multicenter trials assessing hand OA is feasible and likely to be reliable, and has provided a foundation for further development.
Fig. 5. Compositional MRI. A. Sagittal fat-suppressed proton density-weighted image shows a horizontal meniscal tear at the posterior horn of the medial meniscus reaching the undersurface of the mensicus (arrow). B. Corresponding color-coded T1-weighted dGEMRIC image after intravenous contrast administration shows a decrease of the dGEMRIC index in the weight bearing part of the medial femoral condyle coded in red (arrows) representing early cartilage degeneration reflected as a decrease in glucosaminoglycan content compared to the posterior parts of the femoral cartilage that are coded in yellow and green.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
6
Fig. 6. Assessment of meniscal extrusion by ultrasound. A. Coronal ultrasound screenshot of the medial tibiofemoral compartment shows an extruded body of the medial meniscus under weight bearing conditions (arrows). B Corresponding coronal fat-suppressed proton density-weighted MRI shows extrusion to a lesser extent (arrows) due to the prone positioning for the MRI acquisition.
Ultrasound has been increasingly deployed for assessment of hand OA. Kortekaas et al. showed that ultrasound-detected osteophytes and JSN are associated with hand pain [51]. The same group of investigators also showed that ultrasound-detected signs of inflammation are associated with development of erosions in hand OA, implicating inflammation plays a role in its pathogenesis and could be a therapeutic target [S21]. Ultrasound can be used to evaluate the therapeutic efficacy. A decrease in pain correlated with a decrease in synovial thickening and power Doppler ultrasound score before and after weekly ultrasound-guided intra-articular injections of hyaluronic acid [52]. Real time fusion of ultrasound and MR imaging in hand and wrist OA have been attempted, and found a high concordance of the bony profile visualization at the level of osteophytes [S10]. Ultrasound has also been used to evaluate features of knee OA and hip OA. A cross-sectional, multicenter European study analyzed 600 patients with painful knee OA, and found ultrasound-detected synovitis correlated with advanced radiographic OA and clinical symptoms and signs suggestive of an inflammatory ‘‘flare’’ [53]. Ultrasound-detected inflammatory features were positively and linearly associated with knee pain in motion in patients with equal radiographic grades of knee OA in both knees [54], supporting the association between synovitis and knee pain, which has also been reported in MR imaging-based studies [24]. Fig. 6 shows an example of the utility of ultrasound for the visualization of meniscal extrusion. An advantage of ultrasound over MRI in regard to extrusion measurements is the possibility of weight bearing examinations [55]. 5. Nuclear medicine Nuclear medicine imaging with radiotracers enables imaging of active metabolism and visualization of bone turnover changes seen with osteophyte formation, subchondral sclerosis, subchondral cyst formation and bone marrow lesions as well as sites of synovitis [S22]. Scintigraphy with 99mTc-hydroxymethane diphosphonate (HDP) and positron emission tomography (PET) with 2-18F-fluoro-2-deoxy–D-glucose (18FDG) or 18F-fluoride (18F ) have been used to assess OA. Bone scintigraphy can provide a full-body survey that helps to discriminate between soft tissues and bone origin of pain, and to locate the site of pain in patients with complex symptoms [S23]. 18FDG-PET can demonstrate the
site of synovitis and bone marrow lesions associated with OA [56]. Additionally, there have been increasing research efforts to apply SPECT/CT for imaging of osteoarthritis [57]. A major limitation of radioisotope methods is poor anatomical resolution but there are ways to overcome it. Hybrid technologies such as PET-CT and PET-MR imaging combine functional imaging with high-resolution anatomical imaging. Fig. 7 shows an example of PET-CT in knee OA that combines the high resolution of the CT with the metabolic information of the PET. However, nuclear medicine imaging is not commonly applied to imaging of OA in a routine clinical setting. 6. CT CT is excellent for depicting cortical bone and soft tissue calcifications, and has an established role in assessing facet joint OA of the spine. Using a CT-based semiquantitative grading system of facet joint OA, studies have shown a high prevalence of facet joint OA which increases with age, and is most common at the L4– L5 spinal level [58] as well as associations between obesity with higher prevalence of facet joint OA and that between increasing age with higher prevalence of disc narrowing, facet joint OA, and degenerative spondylolisthesis [S24]. Ionizing radiation and limited ability of soft tissue evaluation limit the routine use of CT in clinical imaging of OA. 7. CT and MR arthrography With CT or MR arthrography, assessment of cartilage damage is possible with high anatomical resolution in a multiplanar fashion [S23] [59,60]. CT arthrography is currently the most accurate method for evaluating superficial and focal cartilage damage, offering high spatial resolution and high contrast between the lowattenuating cartilage and high-attenuating superficial (contrast material filling the joint space) and deep (subchondral bone) boundaries [S23]. Fig. 8 shows an example of CT arthrography that delineates superficial and full thickness cartilage damage in excellent fashion. CT can also depict subchondral bone sclerosis and osteophytes. For subchondral changes, MR arthrography allows delineation of subchondral bone marrow lesions on the fluid-sensitive sequences with fat suppression [S23]. Both techniques enable visualization of central osteophytes, which are
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
7
Fig. 7. PET-CT. A. Conventional coronal CT reformation shows definite OA on the left with marginal tibial and femoral osteophytes (thin arrows) and definite medial tibiofemoral joint space narrowing. Total knee arthroplasty of the right knee with the metal implants clearly depicted as markedly hyperdense structures (large arrows). Note beam-hardening artifacts due to the metal hardware particularly surrounding the distal femur. B. Color-coded fusion image of PET and CT shows marked tracer uptake in the perimensical region bilaterally representing active synovitis (large arrows). C. Corresponding axial fusion image shows synovitis also in the peripatellar recesses (small arrows). In addition, there is marked synovitis posteriorly adjacent to the posterior cruciate ligament, the most common location of synovitis in knee OA (large arrow). To date PET-CT does not play a relevant role for the assessment of knee OA structural changes in the clinical routine practice.
8. Conclusion
Fig. 8. CT arthrography is considered the imaging gold standard for the visualization of the articular surface integrity. After intra-articular injection of an iodine-based contrast agent the cartilage surface can be depicted as a hypodense structure. Image example shows a focal full thickness defect at the lateral tibia (arrow).
Imaging of OA has helped investigators to understand risk factors for disease onset and progression and the interactions between different joint tissues and peritarticular tissue changes. Despite those research advances the role of imaging in the routine clinical management of OA patients remains less well-defined in that imaging findings do not always correlate with clinical symptoms. Given such limitations, radiography is still most commonly used for semiquantitative and quantitative evaluation of structural OA features. MRI is currently the most important imaging modality for OA research, and available options include semiquantitative, quantitative and compositional analyses. Ultrasound is commonly used in hand OA studies and is particularly useful for evaluation of synovitis and for guidance of joint-related procedures. Nuclear medicine, CT and CT-MR arthrography have limited roles compared to radiography, MRI and ultrasound. Role of the funding source No funding received.
associated with more severe changes of OA than marginal osteophytes [S25]. Due to the high cost, invasive nature and potential risk, albeit low, associated with intra-articular injection, arthrographic examinations are rarely used in large scale clinical or epidemiological OA studies.
Disclosure of interests Dr. Guermazi has received consultancies, speaking fees, and/or honoraria from TissueGene, OrthoTrophix, and Merck Serono and is the President of Boston Imaging Core Lab (BICL), a company
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx
8
providing image assessment services. Dr. Roemer is Chief Medical Officer and shareholder of BICL. Dr. Hayashi declares that he has no competing interest.
Appendix A. Supplementary data
[21]
[22]
[23]
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.rehab.2015.12. 003.
[24]
References
[25]
[1] Guermazi A, Hayashi D, Roemer F, Felson DT, Wang K, Lynch J, et al. Severe radiographic knee osteoarthritis – does Kellgren and Lawrence grade 4 represent end stage disease? Osteoarthritis Cartilage 2015;23:1499–505. [2] Guermazi A, Niu J, Hayashi D, Roemer FW, Englund M, Neogi T, et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study). BMJ 2012;345:e5339. [3] Altman RD, Gold GE. Atlas of individual radiographic features in osteoarthritis, revised. Osteoarthritis Cartilage 2007;15(Suppl. A):A1–56. [4] Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. [5] Roemer FW, Hayes CW, Miller CG, Hoover K, Guermazi A. Imaging atlas for eligibility and on-study safety of potential knee adverse events in anti-NGF studies (Part 1). Osteoarthritis Cartilage 2015;23(Suppl. 1):S22–42. [6] Roemer FW, Guermazi A, Niu J, Zhang Y, Mohr A, Felson DT. Prevalence of magnetic resonance imaging-defined atrophic and hypertrophic phenotypes of knee osteoarthritis in a population-based cohort. Arthritis Rheum 2012;64:429–37. [7] Guermazi A, Hunter DJ, Li L, Benichou O, Eckstein F, Kwoh CK, et al. Different thresholds for detecting osteophytes and joint space narrowing exist between the site investigators and the centralized reader in a multicenter knee osteoarthritis study – data from the Osteoarthritis Initiative. Skeletal Radiol 2012;41:179–86. [8] Duryea J, Neumann G, Niu J, Totterman S, Tamez J, Dabrowski C, et al. Comparison of radiographic joint space width with magnetic resonance imaging cartilage morphometry: analysis of longitudinal data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2010;62:932–7. [9] Felson DT, Niu J, Gross KD, Englund M, Sharma L, Cooke TD, et al. Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: findings from MOST and the Osteoarthritis Initiative. Arthritis Rheum 2013;65:355–62. [10] Runhaar J, van Middelkoop M, Reijman M, Vroegindeweij D, Oei DH, BiermaZeinstra SM. Malalignment: a possible target for prevention of incident knee osteoarthritis in overweight and obese women. Rheumatology (Oxford) 2014;53:1618–24. [11] Hayashi D, Xu L, Roemer FW, Hunter DJ, Li L, Katur AM, et al. Detection of osteophytes and subchondral cysts in the knee with use of tomosynthesis. Radiology 2012;263:206–15. [12] Hayashi D, Xu L, Gusenburg J, Roemer FW, Hunter DJ, Li L, et al. Reliability of semiquantitative assessment of osteophytes and subchondral cysts on tomosynthesis images by radiologists with different levels of expertise. Diagn Interv Radiol 2014;20:353–9. [13] Woloszynski T, Podsiadlo P, Stachowiak GW, Kurzynski M, Lohmander LS, Englund M, et al. Prediction of progression of radiographic knee osteoarthritis using tibial trabecular bone texture. Arthritis Rheum 2012;64:688–95. [14] Hayashi D, Guermazi A, Roemer FW. MRI of osteoarthritis: the challenges of definition and quantification. Semin Musculoskelet Radiol 2012;16:419–30. [15] Guermazi A, Roemer FW, Haugen IK, Crema MD, Hayashi D. MRI-based semiquantitative scoring of joint pathology in osteoarthritis. Nat Rev Rheumatol 2013;9:236–51. [16] Alizai H, Roemer FW, Hayashi D, Crema MD, Felson DT, Guermazi A. An update on risk factors for cartilage loss in knee osteoarthritis assessed using MRIbased semiquantitative grading methods. Eur Radiol 2015;25:883–93. [17] Hayashi D, Guermazi A, Kwoh CK, Hannon MJ, Moore C, Jakicic JM, et al. Semiquantitative assessment of subchondral bone marrow edema-like lesions and subchondral cysts of the knee at 3 T MRI: A comparison between intermediate-weighted fat-suppressed spin echo and Dual Echo Steady State sequences. BMC Musculoskelet Disord 2011;12:198. [18] Hayashi D, Englund M, Roemer FW, Niu J, Sharma L, Felson DT, et al. Knee malalignment is associated with an increased risk for incident and enlarging bone marrow lesions in the more loaded compartments: the MOST study. Osteoarthritis Cartilage 2012;20:1227–33. [19] Roemer FW, Felson DT, Wang K, Crema MD, Neogi T, Zhang Y, et al. Colocalisation of non-cartilaginous articular pathology increases risk of cartilage loss in the tibiofemoral joint – the MOST study. Ann Rheum Dis 2013;72: 942–8. [20] Roemer FW, Kwoh CK, Hannon MJ, Green SM, Jakicic JM, Boudreau R, et al. Risk factors for magnetic resonance imaging-detected patellofemoral and
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
tibiofemoral cartilage loss during a six-month period: the joints on glucosamine study. Arthritis Rheum 2012;64:1888–98. Roemer FW, Guermazi A, Felson DT, Niu J, Nevitt MC, Crema MD, et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann Rheum Dis 2011;70:1804–9. Hunter DJ, Arden N, Conaghan P, Eckstein F, Gold G, Grainger A, et al. Definition of osteoarthritis on MRI: results of a Delphi exercise. Osteoarthritis Cartilage 2011;19:963–9. Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum 2011;63:691–9. Guermazi A, Roemer FW, Hayashi D, Crema MD, Niu J, Zhang Y, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis 2011;70:805–11. Jarraya M, Hayashi D, Guermazi A, Kwoh CK, Hannon MJ, Moore CE, et al. Susceptibility artifacts detected on 3 T MRI of the knee: frequency, change over time and associations with radiographic findings: data from the joints on glucosamine study. Osteoarthritis Cartilage 2014;22:1499–503. Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. WholeOrgan Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage 2004;12:177–90. Hunter DJ, Guermazi A, Lo GH, Grainger AJ, Conaghan PG, Boudreau RM, et al. Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score). Osteoarthritis Cartilage 2011;19:990–1002. Roemer FW, Nevitt MC, Felson DT, Niu J, Lynch JA, Crema MD, et al. Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint – the MOST Study. Osteoarthritis Cartilage 2012;20:1391–8. Loeuille D, Sauliere N, Champigneulle J, Rat AC, Blum A, Chary-Valckenaere I. Comparing non-enhanced and enhanced sequences in the assessment of effusion and synovitis in knee OA: associations with clinical, macroscopic and microscopic features. Osteoarthritis Cartilage 2011;19:1433–9. Roemer FW, Guermazi A, Trattnig S, Apprich S, Marlovits S, Niu J, et al. Whole joint MRI assessment of surgical cartilage repair of the knee: cartilage repair osteoarthritis knee score (CROAKS). Osteoarthritis Cartilage 2014;22:779–99. Roemer FW, Frobel R, Lohmaner LS, Niu J, Guermazi A. Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS): longitudinal MRI-based whole joint assessment of anterior cruciate ligament injury. Osteoarthritis Cartilage 2014;22:668–82. Welsch GH, Zak L, Mamisch TC, Paul D, Lauer L, Mauerer A, et al. Advanced morphological 3D magnetic resonance observation of cartilage repair tissue (MOCART) scoring using a new isotropic 3D proton-density, turbo spin echo sequence with variable flip angle distribution (3D-SPACE) compared to an isotropic 3D steady-state free precession sequence (True-FISP) and standard 2D sequences. J Magn Reson Imaging 2011;33:180–8. Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, Bijsterbosch J, van der Heijde D, et al. Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis. Ann Rheum Dis 2012;71:345–50. Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, van der Heijde D, Kvien TK. Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis. Ann Rheum Dis 2012;71:899–904. Roemer FW, Hunter DJ, Winterstein A, Li L, Kim YJ, Cibere J, et al. Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings. Osteoarthritis Cartilage 2011;19:946–62. Lee S, Nardo L, Kumar D, Wyatt CR, Souza RB, Lynch J, et al. Scoring hip osteoarthritis with MRI (SHOMRI): a whole joint osteoarthritis evaluation system. J Magn Reson Imaging 2015;41:1549–57. Eckstein F, Ateshian G, Burgkart R, Burstein D, Cicuttini F, Dardzinski B, et al. Proposal for a nomenclature for magnetic resonance imaging-based measures of articular cartilage in osteoarthritis. Osteoarthritis Cartilage 2006;14:974–83. Eckstein F, Collins JE, Nevitt MC, Lynch JA, Kraus V, Katz JN, et al. Cartilage thickness change as an imaging biomarker of knee osteoarthritis progression– data from the fnih OA biomarkers consortium. Arthritis Rheumatol 2015. http://dx.doi.org/10.1002/art.39324 [Epub ahead of print]. Guermazi A, Roemer FW, Alizai H, Winalski CS, Welsch G, Brittberg M, et al. State of the art: MR imaging after knee cartilage repair surgery. Radiology 2015;277:23–43. Guermazi A, Alizai H, Crema MD, Trattnig S, Regatte RR, Roemer FW. Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis. Osteoarthritis Cartilage 2015;23:1639–53. McAlindon TE, Nuite M, Krishnan N, Ruthazer R, Price LL, Burstein D, et al. Change in knee osteoarthritis cartilage detected by delayed gadoliniumenhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. Osteoarthritis Cartilage 2011;19:399–405. Crema MD, Hunter DJ, Burstein D, Roemer FW, Li L, Eckstein F. Association of changes in delayed gadoliun-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2 year follow-up study using 3.0T MRI. Ann Rheum Dis 2014;73:1935–41. Souza RB, Stehling C, Wyman BT, Hellio Le Graverand MO, Li X, Link TM, et al. The effects of acute loading on T1rho and T2 relaxation times of tibiofemoral articular cartilage. Osteoarthritis Cartilage 2010;18:1557–63.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003
G Model
REHAB-947; No. of Pages 9 D. Hayashi et al. / Annals of Physical and Rehabilitation Medicine xxx (2015) xxx–xxx [44] Hovis KK, Stehling C, Souza RB, Haughom BD, Baum T, Nevitt M, et al. Physical activity is associated with magnetic resonance imaging-based knee cartilage T2 measurements in asymptomatic subjects with and those without osteoarthritis risk factors. Arthritis Rheum 2011;63:2248–56. [45] Anandacoomarasamy A, Leibman S, Smith G, Caterson I, Giuffre B, Fransen M, et al. Weight loss in obese people has structure-modifying effects on medial but not on lateral knee articular cartilage. Ann Rheum Dis 2012;71: 26–32. [46] Newbould RD, Miller SR, Toms LD, Swann P, Tielbeek JA, Gold GE, et al. T2* measurement of the knee articular cartilage in osteoarthritis at 3T. J Magn Reson Imaging 2012;35:1422–9. [47] Wiliams A, Qian Y, Golla S, Chu CR. UTE-T2* mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear. Osteoarthritis Cartilage 2012;20:486–94. [48] Madelin G, Babb J, Xia D, Chang G, Krasnokutsky S, Abramson SB, et al. Articular cartilage: evaluation with fluid-suppressed 7.0T sodium MR imaging in subjects with and subjects without osteoarthritis. Radiology 2013;268:481–91. [49] Keen HI, Conaghan PG. Ultrasonography in osteoarthritis. Radiol Clin N Am 2009;47:581–94. [50] Keen HI, Lavie F, Wakefield RJ, D’Agostino MA, Hammer HB, Hensor E, et al. The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis. Ann Rheum Dis 2008;67:651–5. [51] Kortekaas MC, Kwok WY, Reijnierse M, Huizinga TW, Kloppenburg M. Osteophytes and joint space narrowing are independently associated with pain in finger joints in hand osteoarthritis. Ann Rheum Dis 2011;70:1835–7. [52] Klauser AS, Faschingbauer R, Kupferthaler K, Feuchnter G, Wick MC, Jaschke WR, et al. Sonographic criteria for therapy follow-up in the course of ultrasound-guided intra-articular injections of hyaluronic acid in hand osteoarthritis. Eur J Radiol 2012;81:1607–11.
9
[53] Conaghan PG, D’Agostino MA, Le Bars M, Baron G, Schmidely N, Wakefield R, et al. Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study. Ann Rheum Dis 2010;69:644–7. [54] Wu PT, Shao CJ, Wu KC, Wu TT, Chern TC, Kuo LC, et al. Pain in patients with equal radiographic grades of osteoarthritis in both knees: the value of gray scale ultrasound. Osteoarthritis Cartilage 2012;20:1507–13. [55] Nogueira-Barbosa MH, Gregio-Junior E, Lorenzato MM, Guermazi A, Roemer FW, Chagas-Neto FA, et al. Ultrasound assessment of medial meniscal extrusion: a validation study using MRI as reference standard. AJR Am J Roentgenol 2015;204:584–8. [56] Nakamura H, Masuko K, Yudoh K, Kato T, Nishioka K, Sugihara T, et al. Positron emission tomography with 18F-FDG in osteoarthritic knee. Osteoarthritis Cartilage 2007;15:673–81. [57] Maas O, Joseph GB, Sommer G, Wild D, Kretzschmar M. Association between cartilage degeneration and subchondral bone remodeling in patients with knee osteoarthritis comparing MRI and (99 m)Tc-DPD-SPECT/CT. Osteoarthritis Cartilage 2015;23:1713–20. [58] Kalichman L, Li L, Kim DH, Guermazi A, Berkin V, O’Donnell CJ, et al. Facet joint osteoarthritis and low back pain in the community-based population. Spine 2008;33:2560–5. [59] Omoumi P, Michoux N, Thienpont E, Roemer FW, Vande Berg BC. Anatomical distribution of areas of preserved cartilage in advanced femorotibial osteoarthritis using CT arthrography (Part 1). Osteoarthritis Cartilage 2015;23(1): 83–7. [60] Omoumi P, Michoux N, Roemer FW, Thienpont E, Vande Berg BC. Cartilage thickness at the posterior medial femoral condyle is increased in femorotibial knee osteoarthritis: a cross-sectional CT arthrography study (Part 2). Osteoarthritis Cartilage 2015;23(2):224–31.
Please cite this article in press as: Hayashi D, et al. Imaging for osteoarthritis. Ann Phys Rehabil Med (2016), http://dx.doi.org/10.1016/ j.rehab.2015.12.003