Enthesitis detection by ultrasound: where are we now? M.-A. D’Agostino

Rheumatology Department, APHP, Hôpital ABSTRACT and the Group for Research and As- Ambroise Paré, INSERM U1173, Labex Over the last 25 years, ultrasound has sessment of Psoriasis and Psoriatic Ar- Inflamex, Université Versailles St-Quentin been used to evaluate involvement at thritis (GRAPPA) have recommended en Yvelines, Boulogne-Billancourt, France. the entheses in spondyloarthritis (SpA) enthesitis as one of the outcome do- Maria-Antonietta D’Agostino, MD, PhD and (PsA). Several mains for assessing disease activity and Please address correspondence to: studies have been reported indicating response in both axial and peripheral Prof. Maria-Antonietta D’Agostino, its value in detecting active inflamma- SpA and PsA (7, 8). The introduction Service de Rhumatologie tion at entheseal sites using both gray Université Versailles St-Quentin of new pharmacological therapies with en Yvelines, scale and Doppler findings. This review improved trial designs incorporating Hôpital Ambroise Paré, APHP, explores the recent literature and ap- entheseal outcomes, magnetic reso- 9 Avenue Charles de Gaulle, praises the current knowledge and the nance imaging (MRI) and ultrasound, 92100 Boulogne-Billancourt, France. unmet needs of enthesitis detection by as well as increased use of these sensi- E-mail: ultrasound in the management of both tive modalities in research and clinical [email protected] SpA and PsA. practice, also have contributed to rec- Received and accepted on September 10, ognition of a pivotal role of enthesitis in 2018. Introduction both diagnosis and management of SpA Clin Exp Rheumatol 2018; 36 (Suppl. 114): Enthesitis is usually defined as an in- (axial and peripheral) and PsA. S127-S130. flammation of the insertion of tendons, In this context, European League Against © Copyright Clinical and ligaments and capsules into the bone, (EULAR) and GRAPPA Experimental Rheumatology 2018. and it is considered a pathological hall- in their management recommendations mark of the spondyloarthritis (SpA) for PsA, have clearly highlighted the Key words: enthesitis, ultrasonography, group of conditions, including psoriatic importance of specific recommenda- ultrasound, power Doppler, arthritis (PsA) (1-3). Recent knowl- tions for predominant entheseal disease. OMERACT, scoring system, edge regarding the function, anatomy Somewhat different in their recommen- spondyloarthritis, psoriatic arthritis and pathophysiology of the enthesis dations, ultrasound evaluation is an ac- (4, 5) has improved our understanding cepted method for detecting enthesitis in of the involvement of this anatomical both sets (8-10). structure in the course of such diseases, The clinical assessment of enthesitis by and has confirmed initial observations physical examination may be challeng- concerning the relevance of enthesitis ing as the tenderness at the entheseal to the pathogenesis and clinical mani- site, is a non-specific finding: presence festations of SpA and PsA. Enthesitis of such tenderness does not always de- is characterised by pain and stiffness at note inflammation, nor does its absence tendon insertions, such as the Achilles exclude enthesitis. tendon, the or the com- Considering the value and importance mon extensor tendon insertion at the of imaging to detect this characteristic epicondyle of the elbow. Clinical as- lesion, the objective of this review is to sessment of enthesitis has been based summarise current knowledge and the traditionally by recognition of tender- unmet needs concerning the use of ul- ness elicited by the palpation of the en- trasound for the detection of enthesitis theseal site. Whereas the prevalence of in diagnosis and management of SpA clinically-detected enthesitis (i.e. pain and PsA. at specific sites) appears to be between 30% and 50% in patients with PsA and Ultrasound of enthesitis where SpA (6), the overall burden of enthesi- we are now? tis might be higher using more sensitive The comprehensive description of ul- tools such as imaging techniques. trasound involvement of entheses in Enthesitis is sometimes the primary SpA patients was made for the first time clinical manifestation of active SpA by Lehtinen and colleagues in 1994 (11, disease. The Assessment of Spondy- 12) and then by Balint and colleagues Competing interests: none declared. loarthritis International Society (ASAS) in 2002 (13). Both authors described,

Clinical and Experimental Rheumatology 2018 S-127 Enthesitis detection by ultrasound: where are we now? / M.-A. D’Agostino using grey scale (GS), ultrasound ab- been primarily focused on PsA and on trasound inflammatory activity at the normalities of lower limb entheses in the capacity of ultrasound to enhance Achilles, as well as none of the usual SpA patients, revealing a high frequen- early or differential diagnosis (23). biological parameters (C-reactive pro- cy of asymptomatic findings. Enthesi- Marchesoni and colleagues (24) in a tein and erythrocyte sedimentation tis in GS is characterised by the loss of recent report, expanded on a previous rate) used to evaluate PsA disease. normal fibrillar echogenicity of tendon observation (23) concerning the incre- However, ultrasound structural dam- insertion, especially in the acute inflam- mental value of using power Doppler age was statistically significantly as- matory phase, which appears as hypo- ultrasound to differentiate polyentheso- sociated with age, body mass index, echoic, with an increase in thickness pathic forms of PsA from fibromyalgia regular physical exercise and current and/or intralesional focal changes at the (FM). Sometimes the differential di- use of biological disease-modifying tendon insertion, such as calcific depos- agnosis between the two diseases may anti-rheumatic drugs, suggesting an in- its, fibrous scars, and periosteal changes be difficult, when the only symptom creased prevalence of structural dam- (erosions or new bone formation). The is pain. This is in part due to the fact age with increased duration of disease, latter are commonly seen during chron- that FM tender points may overlap with and increased age. These results, along ic inflammation or in longstanding fo- entheseal sites, particularly when there with those from previous studies, raise cal disease. Additionally, involvement is diffuse enthesitis involvement. In ad- a question of whether inflammatory of the body of tendon, distant from the dition, some PsA patients can present findings should be more weighted than enthesis, and of the adjacent bursae with concomitant FM symptoms to- structural damage in the development may also be observed. gether with active disease. In their first of an ultrasound enthesitis score. The Thus, GS ultrasound permits depiction cross-sectional study, they observed absence of correlation between clinical of both signs of acute and chronic in- that ultrasound findings of enthesitis in and ultrasound evaluation of enthesitis, flammation of the enthesis as well as GS were more frequent in PsA than in as well as the different ultrasound defi- structural damage. In 2002 and 2003, FM, and, furthermore, that power Dop- nitions of enthesitis used, have gener- for the first time, D’Agostino and col- pler findings were exclusively present ated discordant data about the capacity leagues described the capacity of in PsA-detected enthesitis (23). In their of the technique to clearly differentiate Doppler ultrasound, in addition to GS 2018 article they suggest a possible di- between enthesis involvement in SpA changes, to detect active inflammation agnostic algorithm which included the or PsA and in other conditions (28). at entheses as abnormal vascularisa- use of power Doppler ultrasound in This discordance is related to several tion at their bony insertion. They also case of difficulty in making the diag- factors, but in particular to the absence showed the discriminative capacity of nosis (24). Ultrasound of enthesitis also in some of these studies of a clear defi- adding Doppler information in differ- appears useful to detect SpA in ASAS- nition of ultrasound-detected enthesi- ential diagnosis and monitoring of treat- negative patients, as documented by a tis, including which components were ment response (14, 15). recent longitudinal study reported by evaluated for defining its presence Since then, several studies have been Poulain and colleagues (25). (29). Although GS scale components reported supporting the capacity of ul- The incremental value of ultrasound are important for detecting pathology trasound in GS combined with Doppler to detect enthesitis was explored in a at an entheseal site, they cannot be used (in particular, power Doppler) to evalu- study of psoriasis patients with mus- as the only information to differentiate ate enthesitis in SpA and PsA (16-22). culoskeletal complaints by van der between mechanical and inflammatory In a range of studies from those focused Ven and colleagues (26). The authors involvement. on the diagnostic value of the technique reported that adding ultrasound evalu- The absence of discriminant capac- to those exploring sensitivity to change, ation to the clinical assessment of en- ity of GS findings has already been re- all have shown that ultrasound can im- thesitis in these patients from a primary ported (15, 16) and recently confirmed prove the management of the SpA dis- care setting, demonstrated that 36% of by Wervers and colleagues and Lan- eases through accurate detection of the those with clinical enthesitis had active franchi and colleagues (30, 31). The presence of enthesitis. ultrasound inflammation, while struc- former group reported that the MASEI tural changes were seen in the vast ma- (MAdrid Sonographic Enthesitis In- Detection of enthesitis improves jority of patients, independent of clini- dex) (20), which includes GS struc- the diagnostic evaluation cal signs and symptoms. tural changes and Doppler signal at 5 The importance of ultrasound to en- A recent publication by Michelsen and entheseal insertions, could not be used hance the diagnostic evaluation have colleagues on PsA patients, confirmed to distinguish between PsA and young been noted previously, particularly on once again the discordance between healthy subjects, except when thickness the adding value of an earlier diag- clinical and ultrasound evaluation of of the patellar tendon was excluded, nosis of axial and peripheral SpA, or entheses, in particular for Achilles and the Doppler was weighted. They mixed SpA diseases including PsA (16, enthesitis (27). In this cross-sectional observed that increased thickness and 19, 20). Most of the published scoring study none of the clinical characteris- PD signal in knee entheses, as defined systems were developed for diagnos- tics of active enthesitis were statisti- by the score (in the body of the tendon tic purposes. More recent studies have cally significantly associated with ul- and perienthesis), were common for

S-128 Clinical and Experimental Rheumatology 2018 Enthesitis detection by ultrasound: where are we now? / M.-A. D’Agostino patients and healthy volunteers, while nition of ultrasound-detected enthesitis Ann Rheum Dis 2015; 74: 1327-39. changes at other locations occurred pre- for both SpA and PsA (34). 4. SHERLOCK JP, JOYCE-SHAIKH B, TURNER SP et al.: IL-23 induces by dominantly in patients only (and not in Recently, the group finalised this pro- acting on ROR-γt+ CD3+CD4-CD8- enthe- normal subjects). They therefore sug- cess by testing the intra and inter- seal resident T cells. Nat Med 2012; 18: 1069- gested excluding knee tendons from observer variability of this scoring 76. 5. SCHETT G, LORIES RJ, D’AGOSTINO MA et this index and to weight more heavily method (35). The definition of enthesi- al.: Enthesitis: from pathophysiology to treat- the Doppler findings. By contrast, Lan- tis validated by the OMERACT ultra- ment. Nat Rev Rheumatol 2017; 21; 13: 731- franchi and colleagues observed that the sound group is: “hypoechoic and/or 41. MASEI could be used to discriminate thickened insertion of the tendon close 6. POLACHEK A, LI S, CHANDRAN V et al.: Clinical enthesitis in a prospective longitudi- between SpA patients and athletes and to the bone (within 2 mm from the bony nal psoriatic arthritis cohort: Incidence, prev- healthy subjects. These reports confirm cortex), which exhibits Doppler signal alence, characteristics and outcome. Arthritis previous observations that structural if active and that may show erosions, Care Res (Hoboken) 2016; 69: 1685-91. changes may be too common in some /calcifications as a sign 7. van der HEIJDE D, van der LINDEN S, DOU- GADOS M et al.: : settings, to allow differentiation be- of structural damage”. The definition plenary discussion and results of voting on tween diseases or between healthy con- highlights the mandatory presence of selection of domains and some specific in- trols and diseased patients, especially in inflammatory findings for defining the struments. J Rheumatol 1999; 26: 1003-5. PsA. Nonetheless, a recent study from presence of SpA- or PsA-related en- 8. RITCHLIN CT, KAVANAUGH A, GLADMAN DD et al.: Group for Research and Assessment of Polachek and colleagues confirmed the thesitis, whereas the structural findings Psoriasis and Psoriatic Arthritis (GRAPPA). severity of enthesitis measured by the may not always be present. In this case, Treatment recommendations for psoriatic ar- MASEI is associated with radiographic the scoring of each lesion is made bina- thritis. Ann Rheum Dis 2009; 68: 1387-94. 9. GOSSEC L, SMOLEN JS, RAMIRO S et al.: damage in PsA (32). ry for facilitating detection, and some European League Against Rheumatism (EU- structural findings are scored together LAR) recommendations for the management Which ultrasound scoring system (as osteophytes and calcifications) in of psoriatic arthritis with pharmacological should be used? order not to increase, artificially the therapies: 2015 update. Ann Rheum Dis 2016; 75: 499-510. In recent years, several enthesitis scor- weight of these components in the final 10. GOSSEC L, COATES LC, de WIT M et al.: ing systems have been published (29, definition (and scoring). The sensitiv- Management of psoriatic arthritis in 2016: a 33), including the MASEI. However, ity to change of this proposed score is comparison of EULAR and GRAPPA recom- each system is different and incorpo- under evaluation in several multicentre mendations. Nat Rev Rheumatol 2016; 12: 743-50. rates different ultrasound elementary randomised and open label studies in 11. LEHTINEN A; TAAVITSAINEN M, LEIRISALO- lesions, and their validity, both discri- PsA. REPO M: Sonographic analysis of enthesopa- minant and diagnostic, may vary ac- thy in the lower extremities of patients with spondylarthropathy. Clin Exp Rheum 1994; cording to the elementary components Conclusions 12: 143-8. included in such scores. These differ- Since 1994, ultrasound has played an 12. LEHTINEN A, LEIRISALO-REPO M, TAAVIT- ences render comparisons across stud- important role to detect enthesitis in SpA SAINEN M: Persistence of enthesopathic ies difficult, and the use of ultrasound and PsA. Ultrasound has been incorpo- changes in patients with spondylarthropathy during a 6-month follow-up. Clin Exp Rheu- as outcome measurement instrument rated into the management of these pa- matol 1995; 13: 733-6. of enthesitis in multicentre studies re- tients in both clinical research and prac- 13. BALINT PV, KANE D, WILSON H et al.: mains problematic (33). tice. With the latest study, the OMER- Ultrasonography of entheseal insertions in Within the Outcome Measures in ACT group has finalised the process of the lower limb in spondyloarthropathy. Ann Rheum Dis 2002; 61: 905-10. Rheumatology (OMERACT) ultra- development of a reliable and unani- 14. D’AGOSTINO MA, BREBAN M, SAID-NAHAL sound Working Group, a sub-task force mously- defined definition of enthesitis R et al.: Refractory heel pain in spondylar- for enthesitis was created in order to by ultrasound, including each elemen- thropathy: a spectacular response to inflixi- produce a standardised, agreed defini- tary component. This is an important mab documented by ultrasound. Arthritis Rheum 2002; 46: 840-1. tion of enthesitis, and a reliable scor- step towards ensuring a higher degree of 15. D’AGOSTINO MA, SAID-NAHAL R, HAC- ing system. The group previously had homogeneity between studies and a fa- QUARD-BOUDER C et al.: Assessment of pe- published a systematic literature re- cilitation of the daily clinical work. ripheral enthesitis in the spondylarthropathies by ultrasonography combined with power view highlighting the great variability Doppler: a cross-sectional study. Arthritis in the definitions of enthesitis applied References Rheum 2003; 48: 523-33. in the ultrasound studies since 1994, 1. BALL J: of rheumatoid and an- 16. D’AGOSTINO MA, AEGERTER P, BECHARA in particular the great variability of the kylosing spondylitis. Ann Rheum Dis 1971; K et al.: How to diagnose spondyloarthritis 30: 213-23. early? Accuracy of peripheral enthesitis de- definition of its constituent elementary 2. 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Clinical and Experimental Rheumatology 2018 S-129 Enthesitis detection by ultrasound: where are we now? / M.-A. D’Agostino

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