Numerous papers have been published on the advantage to use ultrasonography and MRI for detecting enthesitis for diagnosing and managing patients with spondyloarthritis. This paper describes the latest advances in the imaging of enthesitis. A research agenda has also been defined for answering unmet clinical needs.
Key points
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Power Doppler ultrasonography (PDUS) and MRI have changed the management of spondyloarthritis (SpA).
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MRI and PDUS are key imaging modalities for evaluating disease activity at entheseal level.
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Recent advancement in MRI, as whole body MRI, may have potential in early diagnosis and better understanding of SpA; further testing and validation are warranted.
Introduction
Over the last 40 years, the concept of spondylarthritis (SpA) has evolved thanks to the introduction of new drugs and an earlier detection of the disease, owing to the introduction of new imaging techniques such as MRI and ultrasound imaging (US; Fig. 1 ). The latter have permitted to visualize what is considered the landmark lesion: the enthesitis. Understanding of the imaging findings of enthesitis hinges on the knowledge of the relevant joint anatomy.
Introduction
Over the last 40 years, the concept of spondylarthritis (SpA) has evolved thanks to the introduction of new drugs and an earlier detection of the disease, owing to the introduction of new imaging techniques such as MRI and ultrasound imaging (US; Fig. 1 ). The latter have permitted to visualize what is considered the landmark lesion: the enthesitis. Understanding of the imaging findings of enthesitis hinges on the knowledge of the relevant joint anatomy.
Enthesis, enthesopathy, and enthesitis
The term enthesis refers to the anatomic interface, or bony attachment, of tendons, ligaments, fascia, muscles, and joint capsules. The involvement of the entheses in any pathologic process, whatever the origin (ie, metabolic, inflammatory, traumatic or degenerative), is usually defined as “enthesopathy,” whereas “enthesitis” defines the “inflammatory” involvement. In this context, Niepel and associates were the first to use the term “enthesitis” for describing the inflammatory symptoms commonly observed at the calcaneal insertion of the Achilles tendon in patients with ankylosing spondylitis. The pivotal role of enthesitis as common characteristic lesion of the SpA complex was suggested for the first time by John Ball. In his famous “Heberden Horation,” Ball pointed out that the persistent inflammation of the entheses (ie, “enthesitis”) is the distinctive pathologic feature of ankylosing spondylitis, whereas the characteristic feature of rheumatoid arthritis (RA) is the persistent inflammation of the synovial membrane (ie, “synovitis”). Recent knowledge regarding the function, anatomy, and physiology of the enthesis in human and animal models led to improvements in our understanding of the entheseal pathology in the course of many rheumatic diseases, especially SpA.
Anatomy, function, and histopathology of enthesitis
Although anatomic studies are difficult to perform, because the entheses represent areas where hard and soft tissues meet, 2 types of enthesis are usually described: fibrous and fibrocartilageous. In the fibrous entheses the collagen fibers of the tendons or ligaments attach directly to the bone, whereas in fibrocartilaginous entheses 4 transitional zones are observed : (1) collagen zone, directly derived from the tendon (or ligament, capsule, tendon, aponeurosis, or annulus) structure, (2) noncalcified fibrocartilaginous zone, (3) tidemark-calcified fibrocartilaginous zone, and (4) subchondral bone zone. The entheses are vascularized primarily by the vessels coming from the bone marrow, and partially by the vessels of the peritenon (eg, in the fibrocartilaginous entheses). Blood vessels are present predominantly at the junction between the uncalcified and calcified fibrocartilaginous zones. Few histopathologic studies have been performed on the entheses of ankylosing spondylitis patients, and most of them were performed on material obtained during joint replacement; some of them (especially in late 1960s) using biopsies from painful entheseal sites. The histologic hallmark of the “enthesitis” seems to be the coexistence of lesions of different durations at the same site, with erosions, microscopic inflammatory foci at the tendon/ligament insertion, and areas of bone repair.
The enthesis was primarily viewed as a site of metabolic activity, notably during growth. In a second time the role of the enthesis as biomechanical site has played a major role. In contrast with other skeletal locations, the enthesis is a site of repetitive biomechanical forces. Clinical observations, supported by animal model experiences, suggest that mechanical stress may trigger the development of an enthesitis, by stimulating an inflammatory cascade with cytokine production, which affects not only the bony attachment interface and the enthesis itself, but also the surrounding tissues, such as the bursa, fat pad, and synovium. In the early phases of this process, the predominant pattern seems to be the destruction of the fibrocartilage, with neovascularization and infiltration of inflammatory cell predominantly at the sites where synovium, subchondral bone, and bone marrow are close. This results in an articular inflammatory response in the adjacent synovial tissue, driving the concept of the synovio–entheseal complex. Secondarily, the adjacent bone reacts with formation of enthesophytes and spurs.
Imaging and enthesitis
Historically, the radiographic features of enthesitis have played a pivotal role in defining the enthesitis lesions in SpA. Enthesitis was defined mainly by the abnormalities observed at the bone insertion such as osteopenia, bone cortex irregularity, erosions, entheseal soft tissue calcifications, and new bone formation ( Fig. 2 ).
However, entheseal bone changes appear late and are also common in mechanical disorders and in crystal related pathology. Aging is also associated with an increased prevalence of asymptomatic radiographic changes. In the past, before the extensive use of MRI and US, the only technique able to study inflammatory changes of articular and periarticular structures was bone scintigraphy, revealing diffuse increase in bone and articular uptake in active SpA patients. However, the poor spatial resolution of this technique, the lack of specificity, and the relative radiation hampered its extensive use.
MRI and enthesitis
MRI is currently considered the best imaging modality to identify early axial involvement (spine and sacroiliac joints) in patients with SpA, when conventional radiography is still normal. Although MRI methods have faced a rapid evolution over the past years, the imaging technique itself has not completely changed. Conventional T1-weighted sequences and short T1 inversion recovery images are regarded as the methods of choice to depict structural and inflammatory lesions, respectively. The use of MRI for evaluating peripheral entheses has permitted to demonstrate elegantly the link between enthesitis and synovitis. The use of fat-suppressed, fat-saturated, and water-sensitive MRI sequences has shown that the extraarticular inflammation quite often observed represents enthesitis. In fact, the typical appearance of peripheral enthesitis on MRI includes soft tissue inflammatory changes and perientheseal bone marrow edema ( Fig. 3 ). However, with the actual MRI equipment, the depiction of enthesitis is limited in case of absence of concomitant bone edema. In structures with low water accumulation, such as at the bone attachment, the visualization of lesions is quite difficult owing to the low signal on conventional MRI. To improve the visualization of early inflammatory changes several techniques and sequences used in other fields (such as neuroimaging) are now being tested for potential use in SpA.
Whole body MRI
Another limitation of the conventional MRI is the fact that only 1 site at time can be examined. To permit the simultaneous assessment of the entire spine (including the sacroiliac joints) and of peripheral structures (including the peripheral entheses) Whole body MRI has now been applied ( Fig. 4 ). The simultaneous evaluation is possible by the concurrent use of several coils scanning the entire body within 30 to 40 minutes without patient repositioning. The visualization of inflammatory changes in the spine has a spatial resolution similar to the standard MR examinations ; however, the quality and reproducibility of the detection of the peripheral involvement, especially of peripheral enthesitis and of synovitis of small joints, is not completely adequate. Whole body MRI may be useful in the initial evaluation of disease activity as well as for follow-up evaluation and in clinical trials.
High-resolution MRI
High-resolution MRI using gradient echo sequences with fat saturation produce images with hyperintense depiction of cartilage whereas surrounding bone is depicted hypointense, thus allowing detailed analysis of erosions and, when applied, to small joints a greater visualization of the entheses insertion.
Diffusion-weighted MRI
Diffusion-weighted MRI is based on the tissue-dependent signal attenuation caused by incoherent thermal motion of water molecules. Mobility of water molecules is driven by thermal agitation and depends greatly on its cellular environment. This technique might potentially permit to detect early inflammatory changes especially in the bone.
MRI and ultrasonography in the evaluation of peripheral enthesitis: which modalities?
Table 1 delineates the advantages and limitations of US and MRI. Although MRI should be consider the reference choice for the assessment of the axial involvement, the use of MRI for the evaluation of peripheral enthesitis is actually limited by its cost, availability, and accuracy. Moreover, there are not available scoring systems at the moment. Therefore, US should be considered the method of choice both in clinical practice and in the research setting.
| Ultrasound | MRI | ||
|---|---|---|---|
| Strengths | Weaknesses | Strengths | Weaknesses |
| Real-time and dynamic imaging | Unable to image within bone | Ability to image bone | Limited to 1 body region |
| Immediately accessible; complements the physical examination | Specialist training not always available | More complete assessment of whole joint (all articular surfaces) | Potential for motion artifact and contraindications (eg, pacemaker) |
| Relatively easy to examine multiple body regions | Limited accessibility of some structures (acoustic window) | Quantitative measurement of synovium | Time and patient tolerance |
| Portability | Interobserver variability and training needs | Better reproducibility | Cost |
Ultrasound and Enthesitis
The extensive description of US involvement of entheses in SpA patients was made for the first time by Lehtinen and colleagues in 1994 and then by Balint and colleagues in 2002. These authors described in grey scale the US abnormalities of lower limb enthesitis of SpA, revealing the high frequency of asymptomatic findings. Grey scale enthesitis is characterized by the loss of normal fibrillar echogenicity of tendon insertion with an increase of the thickness insertion, or by intralesional focal changes of tendon insertion, such as calcific deposits, fibrous scares aspect, and periosteal changes (erosions or new bone formation). Additionally, a clear involvement of the body of tendon, far from the enthesis, and of the adjacent bursae can be observed. Thus grey scale US permits to depict both signs of acute and chronic inflammation of enthesis as well as structural damage.
Since then, discordant data have been published about the capability of grey scale US alone to differentiate between enthesis involvement in SpA and in other pathologies. This discordance is related to several factors: the absence in some of these studies of a clear definition of enthesis involvement (most of these data regarded also the tendon and bursa involvement) ; the difficulty to clearly define inflammatory changes by using only grey scale. The main appearance of inflammation in grey scale is edema, which is characterized by the loss of normal echostructure (ie, hypoechogenicity), associated or not to the increase of the thickness of tendon insertion, which is very difficult to quantify. The use of power Doppler for visualizing abnormal vascularization and hyperemia has made possible to overcome this lack of specificity. The landmark of an enthesitis detected on US in SpA patients when compared with controls (RA patients and mechanical spinal disease patients) is the presence of abnormal vascularization at enthesis insertion, allowing the differentiation between SpA involvement and other mechanical or metabolic involvements. US has indeed proven to be a highly useful and sensitive tool in the evaluation of enthesitis by improving the ability of the clinical examination to detect enthesitis. Several studies have also demonstrated the prognostic value of the detection of enthesitis for an early diagnosis of SpA. In particular, the most recent prospective cohort study conducted in patients with symptoms suggestive of SpA has shown that vascularization at cortical bone detected by PDUS was the only independent contributor to a diagnosis of SpA made 2 years later, and that PDUS vascularized enthesis combined with Amor’s criteria was highly effective in making an early diagnosis of SpA in the absence of other clinical, imaging and biological findings. US is also useful for evaluating disease activity and to monitor response to treatment, although this aspect has been explored in few studies until now.
Despite promising results, the use of power Doppler US for the management of SpA has remained less often evaluated than in RA. This discrepancy is probably owing to the perception that US, especially for detecting enthesitis, remains an operator-dependent technique owing to the greater difficulty of assessing vascular blood flow with Doppler in the entheses than in the synovium. The latter difference can be explained by a greater abundance of vessels in the inflamed synovium, than in enthesitis. In addition, Doppler artifacts are frequently produced at the enthesis attachment owing the close proximity of the cortical bone, which is a highly reflecting surface, and only few studies are available comparing histology evidence of inflammation and signs of enthesitis assessed by US. A study comparing the grey scale US signs of enthesitis and the histologic sample taken in the same place, showed that the hypoechoic area detected by US corresponds with macrophage infiltration, increased vascularity, and edema.
Three competences are critically needed to optimize the evaluation of enthesitis by grey scale and Doppler US: (i) a specific knowledge of the anatomy of each enthesis (in particular the localization of normal nutrition vessels), (ii) the capacity to distinguish very slow vascular flow (which is the hallmark of the inflammatory process in the enthesis) from artifacts, on power Doppler, and (iii) the US machine used as the characteristics of the Doppler modality vary according to the US device used.
Normal Ultrasound Aspect of Peripheral Enthesis
Under normal conditions, the 4 zones of fibrocartilageous enthesis are not visible or are only just visible owing to the small thickness of the fibrocartilage and to the quality and resolution of US equipment ( Fig. 5 ). Thus, the normal US aspect of the enthesis is difficult to distinguish from the US aspect of the body of tendon or ligament and it appears as a normal continuity of the tendon/ligament into the bone.
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