Ultrasound in the evaluation of enthesitis: status and perspectives

Enthesitis, that is, the inflammation of insertions of tendons, ligaments and capsules into the bone, is the characteristic sign of ankylosing spondylitis and related pathologies, which are commonly regrouped as spondyloarthritis (SPA). The functioning enthesis dissipates stress over a wide area, including the insertion, immediately adjacent tendon and adjacent bone. The soft tissue components of an enthesis have traditionally been evaluated by clinical examination based on the presence of tenderness and/or swelling while X-rays have been used to assess associated bony changes. The accuracy of these methods, however, is uncertain, which is why new imaging techniques such as ultrasound and magnetic resonance imaging (MRI) have been sought. The role of MRI for assessing the spectrum of pathology in SPA has recently been reported [1, 2]. This technique has been most commonly used to assess axial disease. The MRI pattern of SPA enthesitis has been described as a diffuse bone edema adjacent to enthesis, associated with surrounding soft tissue edema [3]. However, MRI lacks sensitivity and specificity for peripheral enthesitis [4]. This can be explained because changes in the fibrous part of the enthesis, where fibroblasts are tightly cross-linked with little scope for accumulation of water, cannot easily be detected with MRI [4, 5]. Additionally, MRI cannot easily assess multiple sites or be used to assess the contralateral joints.

Most of the available data on the potential application of ultrasound for rheumatology is currently about the assessment of its role in rheumatoid arthritis with limited data or studies in other rheumatic diseases, among which SPA is themost frequently studied [6‐53]. For routine use in daily practice and clinical trials, the assessment of ultrasound performance in terms of metric qualities is recommended [54]. Though several studies have highlighted the value of ultrasound in assessing inflammation of enthesis in SPA, there is no clear agreement on which structures to examine. Even though a clear distinction between the meaning of the word enthesitis and enthesopathy exists in the rheumatologic literature, no clear definition of an enthesitis lesion has been reported in the ultrasound literature. Thus, technical and anatomical issues, combined with a lack of standardization, may have hampered the development and validation of the ultrasound technique applied to clinical practice, or to multicenter studies, in SPA. Consensus definitions for ultrasound-related pathologies were published by the OMERACT (Outcome Measure in Rheumatology in Clinical Trials) ultrasound group in 2005, including enthesopathy [52]. However, no data are available about the implementation of this definition in clinical and research practice.

The objective of this study was to first determine the level of homogeneity in the ultrasound definitions for the principal lesions of enthesitis in the published literature, and second, to evaluate the metric properties of ultrasound for the detection of enthesitis according to the OMERACT filter through a systematic literature review. We focused our review on the anatomical definition of enthesitis, that is, attachment of ligaments or tendons or capsules on bones, which does not imply body tendon nor surrounding tissue, such as bursae.

Figure 1 illustrates the flow chart of the selection of the articles. Of the 3,852 references obtained from databases, 237 abstracts were selected after reading titles, 94 articles were selected after reading abstracts and, finally, 48 articles were analyzed to determine the ultrasonographic enthesitis definition and characteristics. These articles included 22 case-control studies, 5 case-report studies, 17 case-series studies, 2 cohorts, 1 expert consensus and 1 randomized control trial (Table 1). Most of them (n = 37) focused on inflammatory pathologies: spondylarthropathy or ankylosing spondylitis (n = 24), spondylartropathy or other inflammatory rheumatism (n = 3), and psoriatic arthritis (n = 10). Only six studies focused on degenerative involvement of enthesis. Two studies did not report the patients' diagnoses.

Entheses of lower limbs were the most common studied, especially Achilles tendon (80% of articles) followed by the entheses of upper limbs. No consensus concerning either the location or the number of enthesis to be examined was observed.

The present review has demonstrated that ultrasound is considered a valuable tool for assessing enthesitis. Since 1985, when the first description was made by Lehtinen and colleagues, an increasing interest for using this technique in the evaluation of SpA enthesitis has been observed, especially within the last 10 years. This is probably due to the tremendous technological progression of ultrasound equipment. However, standardization of enthesitis assessment by ultrasound would facilitate the dissemination of this technique in daily practice, and also allow adequately trained sonographers to participate in multicenter research studies. A wide variability was observed among studies in the definition of ultrasound enthesitis, associated with a broad heterogeneity of definitions of its elementary components, and the absence of a consensus on technical parameters and methods of examination probably led to the observed heterogeneity in metric properties of the studies according to the OMERACT filter. No consensus concerning either the location or the number of enthesitis to be examined was observed.

Those discrepancies can be explained by the inclusion of studies from 1985 until the present, assuming that ultrasound equipment has improved considerably since that time, and the differences in the quality of equipment may have hampered the detection of those lesions. However, the quality and the attention in the description of enthesitis features have improved in the studies published after 2005, which may be explained by the publication from our group on the preliminary OMERACT definition of enthesopathy [52]. Indeed, previous studies have shown that grey-scale elementary lesions may be observed in both mechanical and inflammatory enthesopathy [11, 30]. Yet, in order to help diagnosis, a more specific feature is the detection of inflammatory signs, especially the vascularization.

Since the first observation on the utility of power Doppler for visualizing vascularization of the enthesis as a sign of inflammation made in 2003 [22], an increasing number of studies have included Doppler evaluation. Some authors have well demonstrated the presence of vascularization of the enthesis/bone junction in SPA patients [13, 20, 23, 37]. Even if Doppler use seems to be important, a wide heterogeneity in its use was recorded. Most of the studies referred to the presence of Doppler signal in different locations: tendon, enthesis, bursa. The lack of consensus with regards to the site of examination of abnormal vascularization may contribute to explaining discrepancies among studies. Some authors may call "inflammatory enthesitis" what would be called "tendonitis" by others. Moreover, this review has shown a large difference in the Doppler parameters used among studies. Doppler sensitivity to inflammatory flow (low-velocity flow) depends partly on the settings and partly on the type of equipment.

The differences found in the articles may, therefore, be explained by the lack of consensus on the optimal Doppler settings for enthesitis. Since no information concerning inter-equipment reliability for enthesitis evaluation is available, the different types of ultrasound equipment used may also explain part of the discrepancies observed. Indeed, Doppler sensitivity could have been affected by the type of equipment used; better sensitivity may have been reported with new generation equipment with the highest quality of Doppler parameters.

Only 73% of the studies clearly described acquisition technique. For example, the method for measuring enthesis thickness, which appears as one of the most important features recorded by authors for characterizing enthesitis of the Achilles tendon, was only described in 31% of the studies despite the fact that the necessity of measuring the thickness for defining the presence of enthesitis was reported by 94% of the authors. Measurement methods and site of measurement varied consistently and none of the proposed methods have been extensively tested and validated yet.

The quantification of enthesitis by ultrasound was predominantly performed by using semi-quantitative scoring methods. However, some differences were observed in the evaluation of involvement as all of the proposed scoring systems combined both evaluation of inflammatory activity, mostly by taking into account echogenicity and increased thickness and structural damage, mostly enthesophytes and erosions. As these are all grey-scale changes, this could explain the discrepancy observed in the sensitivity to change. In recent years, there has been more focus on enthesitis vascularization, probably the most interesting and specific feature to differentiate inflammatory enthesitis from mechanical enthesitis [22]. Consequently, enthesitis scoring systems taking Doppler signal into account have been proposed. These scoring systems, taking more into account the inflammatory activity may better present sensitivity to change. Hatemi et al. proposed to add a semi-quantitative scoring concerning vascularization to the GUESS score [7].

The proposal of a scoring system validated at the patient level, taking into account inflammatory activity and structural damage is one of the challenges for future studies regardless of ultrasound enthesitis. This implicates to determine which enthesis are the most relevant to include in the scoring system. Moreover, different scoring systems probably would have to be proposed and validated for diagnostic purposes and for monitoring treatment.

Are the analyzed studies correctly designed for applying one or all parameters of validity of the OMERACT filter?

Concerning face validity, most of the authors agreed on the ability of ultrasound to detect enthesitis and related abnormalities. Thus, ultrasound measures of enthesis involvement (both inflammation and structural damage) must be considered to have face and content validity according to the filter. Concerning construct and criterion aspects, validity results are mitigated, probably because of the lack of a good comparator (or reference standard) for evaluating ultrasound enthesitis. In fact, we cannot consider any other imaging techniques, such as X-rays, MRI or clinical evaluation as a true gold standard because they do not measure the same phenomenon. X-rays can only detect structural damage and do not give information concerning soft tissue evaluation, and, therefore, do not give information on inflammatory activity as ultrasounds do. Clinical evaluation underestimates enthesitis involvement due to the difficulty to clearly appreciate the enthesis by physical examination; and a conventional MRI, due to technical limitations, is unable to visualize isolated enthesitis [57]. MRI findings, particularly the measures suggestive of inflammatory activity, need further comparison with ultrasound to evaluate the differences in the imaging techniques and to determine which are the common areas of involvement in order to help further clarification of construct validity. The only real reference which can correctly evaluate ultrasound capabilities is histology, which cannot be currently used because of ethical reasons.

Concerning the discrimination aspect of the filter, published studies have demonstrated that ultrasound can be a reliable and sensitive tool, even if some of the aspects of reliability need to be improved. This applies to the detection of grey-scale abnormalities which were less reliable than the detection of a Doppler signal in the two studies evaluating both the reading and acquisition phases.

Responsiveness was not always evaluated and frequently only a merely description of changes was reported. Among the nine studies in which sensitivity to change was reported, responsiveness was not demonstrated in three which used grey-scale evaluation alone, while all the studies including Doppler evaluation showed responsiveness. Doppler evaluation appeared to be an important feature to take into account in order to evaluate responsiveness to treatment and it should be included in enthesis examination for this purpose. Further evaluation of the responsiveness of enthesitis evaluation should be performed on scoring systems with evidence of statistical difference.

In conclusion, ultrasound enthesitis may be useful for diagnosis or monitoring of SPA patients, but has still to be validated. It appears as a valid (especially for face and content validity) and reliable tool for enthesitis evaluation. A consensus on enthesitis definition is required in order to improve the quality of studies and to improve the value of ultrasound in SPA management. This article is part of the series Advances in the imaging of rheumatic diseases, edited by Mikkel Ostergaard. Other articles in this series can be found at http://arthritis-research.com/series/imaging