RHEUMATOLOGY Rheumatology 2012;51:vii13–vii17 doi:10.1093/rheumatology/kes342

Spondyloarthritis: a journey within and around the joint

Peter V. Balint1 and Maria Antonietta D’Agostino2 Downloaded from https://academic.oup.com/rheumatology/article/51/suppl_7/vii13/1787041 by guest on 30 September 2021

Abstract Imaging has always been an integral part of the assessment of SpA. This group of diseases involving the axial skeleton and peripheral joints is a particularly intriguing area for sonographers, because it requires the evaluation of both articular and extra-articular regions. Among extra-articular features enthesitis has recently emerged as an area of special interest for both basic science and clinical researchers as well as for those working in the field of musculoskeletal imaging. This review provides information about research in this area focusing on the current concept and definition of enthesitis by US. Key words: spondyloarthritis, enthesitis, ultrasound, power Doppler.

Introduction Enthesitis or enthesopathy?

US in the past decade was often used for assessing In the literature, the term enthesitis (i.e. inflammatory peripheral involvement of SpA for clinical, educational involvement of the enthesis) and enthesopathy (i.e. patho- and research purposes rather than for the assessment logical involvement of the enthesis whatever the cause) of the more frequent axial manifestations of the disease are often used as synonyms; however, we prefer to use such as sacroiliitis. US can visualize most of the relevant enthesitis only for inflammatory involvement related to musculoskeletal pathologies associated with SpA, includ- SpA. Clinicians and researchers investigated enthesitis ing enthesitis, bone erosions, synovitis, bursitis and as the probable fundamental lesion responsible not only tenosynovitis. The exception is osteitis, since the US for entheseal involvement in itself, but also as an initial beam is not capable of penetrating the bony cortex. and/or additional process of synovitis, dactylitis and While conventional radiography allows a clear docu- sacroiliitis [1]. mentation of the later stages of the inflammatory changes In addition to peripheral arthritis and dactylitis, enthesi- of joint involvement, US (both grey-scale and Doppler) tis is included in several available classification criteria for are sensitive enough to also detect early inflammatory SpA, including the most recent criteria [2]. lesions. Examining the morphology and function of entheses is US features of synovitis, erosion and tenosynovitis in essential to understanding the process and phenomenon SpA patients generally do not differ from those observed of enthesitis. in other inflammatory arthritides including RA or PsA. The We can distinguish two types of enthesis according to main difference is related to the US appearance of enthe- their anatomical properties: fibrocartilaginous and fibrous. sitis, i.e. inflammation at the insertion of tendons, liga- The two types have different histological features. The ments and capsules into the bone. fibrocartilaginous enthesis consists of the tendon, non- calcified fibrocartilage, calcified fibrocartilage and adja- cent bone. The two layers of fibrocartilage are virtually separated by the tidemark. Defining fibrocartilage remains 1Third Department of Rheumatology, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary and 2Service a challenge since it is considered by many as a sort of de Rhumatologie, Hoˆ pital Ambroise Pare´ , APHP, Universite´ Paris half-way structure between cartilage and dense collage- Ouest-Versailles Saint Quentin en Yvelines, Boulogne-Billancourt, nous connective tissue, but is actually closer in its con- France. formation to connective tissue than to cartilage [3]. Most Submitted 28 February 2012; revised version accepted 16 October 2012. of the histological studies describing this tissue are based Correspondence to: Maria Antonietta D’Agostino, Service de on the analysis of lower limb entheses. Rhumatologie, Hoˆ pital Ambroise Pare´ , APHP, Universite´ Paris Fibrocartilage was described as being within the Ouest-Versailles Saint Quentin en Yvelines, UPRES EA 2506, 9 Avenue Achilles enthesis itself (entheseal fibrocartilage); however, Charles de Gaulle, 92100 Boulogne-Billancourt, France. E-mail: [email protected] analogous tissue may also be found on the surface of the

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calcaneus facing the enthesis (periosteal fibrocartilage) Despite considerable developments in US technique, and also in the inner surface of the Achilles tendon the past 10 years have seen the emergence of more re- which faces the calcaneus (sesamoid fibrocartilage) [3]. search questions that need to be answered. In the near This seems to denote that the retrocalcaneal bursa is future, high-end US machines will be capable of depicting only partly covered by a synovial lining, while the rest is fibrocartilage. At this moment ultrasonographic scans of covered by fibrocartilage. The same phenomenon may fibrocartilage have only been published using bovine spe- also be observed at other entheses, including the tibial cimens [4]. Differentiating between normal and patho- tuberosity enthesis and the deep infrapatellar bursa. logical fibrocartilage by US remains a challenge. This observation, associated with the clinical symptoms One explanation that may provide a link between the reported by patients, who frequently describe articular two concepts can be related to the duration of disease pain far from the anatomical entheseal attachment, has at the attachment site. If the disease is long-standing or Downloaded from https://academic.oup.com/rheumatology/article/51/suppl_7/vii13/1787041 by guest on 30 September 2021 led a group of researchers to distinguish between two very active, the inflammation transcends the limits of the concepts of entheseal involvement: one strictly localized anatomical insertion to involve the adjacent structures as to the bony interface in which the involved structures in- well. clude fibrocartilage, subchondral bone and related bone Demonstrating the presence of local inflammation at the marrow and its respective neural and vascular network; entheseal insertion establishes the enthesitis as a land- and the other more related to clinical symptoms in which mark feature of SpA. Examination of the pathological adjacent structures are also included, such as adjacent enthesis in SpA has demonstrated local inflammation bursae or synovial membrane-lined fat pads [3]. In this with CD4+ and CD8+ T lymphocyte cell infiltration, sense, this group has suggested that the enthesis oedema, angiogenesis, fibrosis, osteitis, erosion and should be considered as an organ or unit in which all con- new bone formation [5]. Inflammation may occur at any tinuous collagenous connective tissue fibres running over enthesis in SpA, but clinically detected symptoms of and along a fibrocartilage structure are considered as part enthesitis are more frequently detected in the entheses of the enthesis, even without the presence of an actual of the lower limbs, probably for mechanical reasons. The tendon or ligament insertion. Figure 1a shows knee and US examination of these entheses confirms the frequency Fig. 1b shows heel anatomy, including the superior pole, of their involvement [6]. However, we cannot exclude that inferior pole of the patella and tibial tuberosity enthesis the frequency of enthesitis may be artificially increased and the Achilles and plantar aponeurosis enthesis. and explained by the accessibility of those entheses to

FIG.1Continuous fibres run along the length of the tendon or aponeurosis and may even connect two or three entheses (arrows).

Images from P. V. Balint’s Doctor of Philosophy thesis (US imaging in joint and soft tissue inflammation), University of Glasgow, 2002. Courtesy of Miklo´ sTo´ th, Szabolcs Benis and Lajos Patonay.

vii14 www.rheumatology.oxfordjournals.org US visualization of enthesitis in SpA

US. In fact, when the entheses of the upper arms are consensus definitions of the most frequently detected examined, the entheses of the elbow, in particular the in- pathologies [10]. The group at that time decided to sertion of the common extensor tendon, appears to be define enthesopathy (general involvement of the enthesis frequently involved [6]. irrespective of the origin) instead of enthesitis: abnormally hypoechoic (loss of normal fibrillar architecture) and/or US appearance of enthesitis thickened tendon or ligament at its bony attachment (may occasionally contain hyperechoic foci consistent Extensive description of entheseal involvement in SpA pa- with calcification), seen in two perpendicular planes that tients by US was initially provided by Lehtinen et al.in may exhibit a Doppler signal and/or bony changes includ- 1994 [7] followed by the study of Balint et al. in 2002 [8] ing enthesophytes, erosions or irregularity. and that of D’Agostino et al. in 2003 [6]. The first two au- Taking into account other aspects such as age and Downloaded from https://academic.oup.com/rheumatology/article/51/suppl_7/vii13/1787041 by guest on 30 September 2021 thors described the grey-scale US abnormalities of lower gender may cause considerable problems when attempting limb enthesitis of SpA, revealing a high frequency of to formulate a uniform definition of enthesitis. At age 18, asymptomatic findings, while the third described for the an enthesophyte in grey scale may be accepted as a first time corresponding power Doppler findings. pathological sign of enthesopathy due to inflammation or Grey-scale US permits us to depict the signs of both to mechanical impact, in view of the frequency of this find- acute and chronic inflammation of enthesis as well as ing in the general population and its association with patho- structural damage. logical conditions. The same phenomenon, however, Grey-scale scans of enthesitis are characterized by the occurs much more frequently at age 80, probably due loss of the normal fibrillar echogenicity of the tendon in- only to the ageing process, and should not be considered sertion with or without an increase in tendon thickness or as a pathological sign in this population. by intralesional focal changes at the tendon insertion, Moreover, US technique has undergone fundamental such as calcium deposits, fibrotic scars and periosteal changes in the last decade, and Doppler technique has changes (erosions or new bone formation). Additionally, become a fundamental part of the assessment of synovitis involvement of the body of the tendon far from the and enthesitis and is likely to be included in the new cri- enthesis and of adjacent bursae may be observed; how- teria for the US assessment of enthesitis, despite being ever, these two processes can also be observed in the underrepresented in the studies of the last 10 years as absence of enthesitis in other inflammatory and compared with grey-scale features of enthesitis. Before non-inflammatory diseases. a consensus definition of enthesitis can be reached and The anatomical borders of the enthesis should also be subsequently validated, the elementary grey-scale and taken into account within the framework of new definitions power/colour Doppler US lesions and their relationship and recommendations. It is still unclear as to what extent with enthesitis and other forms of enthesopathy, as sug- the soft tissue part of tendons and ligaments needs to be gested in Fig. 2, must be evaluated. This review also included in the examination. The principal focus of atten- demonstrated that in addition to the robust variability of tion should be directed to the part adjacent to the bone accepted US signs of enthesitis, face and content validity surface; however, we know from clinical experience that were found to be generally acceptable; however, criterion thickening of the tendon or ligament is more commonly and construct validity results are still missing and need to detected somewhat removed from the bony attachment. be evaluated. Only a few studies have compared US and It should be noted, however, that moving too far away MRI of enthesitis and have led to controversial results from the actual entheseal insertion also has its dangers. [11, 12]. In one study, US demonstrated better sensitivity In our view, mid-portion (fusiform) tendinopathy of the in detecting enthesitis than MRI; however, other studies Achilles tendon represents a totally different pathological have shown opposite results [12]. This is probably due to and imaging entity, wholly distinct from enthesitis. the fact that the two techniques examine different aspects The elementary US features of enthesitis were listed in a of the enthesitis and that the definition and border of the recent systematic review that analysed 48 research enthesis were not defined, leading the authors to put papers [9]. Enthesitis was mainly characterized by together tendon, bursa and enthesis in the definition of increased thickness (94% of studies) and hypoechogeni- enthesitis involvement. Finally, the review showed the city (83% of studies) of different soft tissue structures. capability of the technique to reliably assess the presence Signs of structural damage, including enthesophytes, ero- of enthesitis [13, 14]. sions, calcifications and cortical irregularity were less rep- resentative. Interestingly, 46% of studies included associated bursitis as a characteristic sign among the cri- How to score activity and severity of teria of enthesitis. Although all recent studies included a peripheral enthesitis by US pathological Doppler signal among the criteria, altogether only 46% of studies included Doppler US assessment. Following the development of the Glasgow University This systematic review also highlighted the lack of con- Enthesitis Scoring System (GUESS) [8], new scoring sys- sensus definition for enthesitis. This was also observed for tems have also been formulated. The Madrid and French other US studies and defined pathological lesions such as scores [6, 15, 16] were each evaluated recently; however, synovitis, tenosynovitis, etc. For this reason the large international, multicentre studies assessing validity OMERACT task force produced the first preliminary US for sensitivity to change instead for diagnostic purposes

www.rheumatology.oxfordjournals.org vii15 Peter V. Balint and Maria Antonietta D’Agostino

FIG.2Relationship between the possible physiopathological process of enthesitis and the US findings.

Process Pathological US signs

Inflammation Thickened enthesis

(enthesitis) Hypoechogenicity of enthesis

Loss of fibrillar structure of enthesis Failure of enthesis Mechanical injury Erosion at enthesis

or Downloaded from https://academic.oup.com/rheumatology/article/51/suppl_7/vii13/1787041 by guest on 30 September 2021 Enthesophyte development of Metabolic changes enthesopathy Bone irregularity at enthesis Calcification at enthesis

Endocrine influence Bursitis related to enthesis (all pathological processes)

Increased power/color Doppler signal at enthesis (only for enthesitis= inflammation) are still lacking, hindering the routine use of such instru- References ments in both clinical practice and clinical trials. Only a few studies have evaluated the sensitivity to change of US 1 Ball J. Enthesopathy of rheumatoid and ankylosing spon- in SpA patients following anti-TNF-a treatment [17]. dylitis. Ann Rheum Dis 1971;30:213–23. 2 Rudwaleit M, van der Heijde D, Landewe´ R et al. The de- What is the diagnostic value of the velopment of Assessment of SpondyloArthritis interna- tional Society classification criteria for axial technique? spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. Several studies have recently shown the impact of US in the early diagnosis of SpA [15, 16, 18]. However, the dif- 3 Benjamin M, Moriggl B, Brenner E et al. The ‘enthesis ferential diagnostic capabilities of US should continue to organ’ concept: why enthesopathies may not present as focal insertional disorders. Arthritis Rheum 2004;50: be tested to determine to what extent US can differentiate 3306–13. between enthesitis and local non-inflammatory condi- tions, e.g. Sinding–Larsen–Johansson disease (patella), 4 Aydin SZ, Bas E, Basci O et al. Validation of ultrasound Osgood–Schlatter disease (tibial tuberosity) or Sever’s imaging for Achilles entheseal fibrocartilage in bovines and description of changes in humans with spondyloarthritis. disease (calcaneus). Ann Rheum Dis 2010;69:2165–8. New US techniques such as elastography, contrast ultrasonography and 4D ultrasonography are currently 5 Laloux L, Voisin MC, Allain J et al. Immunohistological under evaluation for their use for both adult and paediatric study of entheses in spondyloarthropathies: comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis enthesitis. In conclusion, US is an important tool for the 2001;60:316–21. evaluation of peripheral involvement of SpA, especially in the diagnosis and follow-up enthesitis. 6 D’Agostino MA, Said-Nahal R, Hacquard-Bouder C et al. Assessment of peripheral enthesitis in the spondylarthro- pathies by ultrasonography combined with power Rheumatology key messages Doppler: a cross-sectional study. Arthritis Rheum 2003;48: 523–33. . Power Doppler US permits a complete evaluation of SpA enthesitis. 7 Lehtinen A, Taavitsainen M, Leirisalo-Repo M. Sonographic analysis of enthesopathy in the lower extre- . Inflammation and structural damage should be dif- ferentiated for quantifying enthesitis. mities of patients with spondylarthropathy. Clin Exp – . Further validation is needed as US is an evolving Rheumatol 1994;12:143 8. technique. 8 Balint PV, Kane D, Wilson H, McInnes IB, Sturrock RD. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61: Supplement: This paper forms part of the supplement 905–10. ‘Ultrasound in rheumatology: the future is now’. This sup- 9 Gandjbakhch F, Terslev L, Joshua F et al. Ultrasound in plement was supported by an unrestricted educational the evaluation of enthesitis: status and perspectives. grant by the Fundacio´ n Espan˜ ola de Reumatologı´a. Arthritis Res Ther 2011;13:R188. Disclosure statement: The authors have declared no con- 10 Wakefield RJ, Balint PV, Szkudlarek M et al. flicts of interest. Musculoskeletal ultrasound including definitions for

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