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Home , Enthesis, Enthesitis

The enthesis in D. McGonagle1,2, A.L. Tan1,2

1NIHR Leeds Musculoskeletal Biomedical ABSTRACT entheses, but there many hundreds of Research Unit, Chapel Allerton Hospital, In recent years the argument that en- insertions around the skeleton when 2 Leeds, UK; Leeds Institute of Rheumatic thesitis is the primary lesion in many all the capsules, , and and Musculoskeletal Medicine, University or most patients with psoriatic arthri- fascial attachments are counted, the of Leeds, Leeds, United Kingdom. tis and spondyloarthritis has gained idea arose that maybe enthesitis was Dennis McGonagle, PhD FRCPI further credence from animal models the primary lesion, or pointed towards Ai Lyn Tan, MD MRCP including IL23/IL17 axis and TNF de- a primary mechanism for disease (4, 5). Please address correspondence to: pendent models. The role of bio- Prof. Dennis McGonagle, Wright further described 5 groups of Leeds Institute of Rheumatic and mechanics at entheses and other sites PsA, namely distal interphalangeal joint Musculoskeletal Medicine, of high physical stressing as a unifying involvement, , sym- Chapel Allerton Hospital, underlying basis has also been strongly metrical polyarthritis, oligoarthritis and Chapeltown Road, supported by animal models. Mirroring spondylitis (2). The polyarthritis group Leeds LS7 4SA, United Kingdom. the animal model data, it has been em- had been suggested to be ‘indistinguish- E-mail: [email protected] pirically shown that therapies that work able’ from RA; it would be reasonable Received and accepted on September 1, for entheseal-related inflammation in to question if the primary pathology for 2015. man including IL23/17 axis or TNF cy- this group of patients is indeed enthe- Clin Exp Rheumatol 2015; 33 (Suppl. 93): tokine antagonism are effective for en- seal. However, one could argue that this S36-S39. theseal pathology. The biological basis group could very well be seronegative © Copyright Clinical and for the effectiveness of other therapies RA with skin psoriasis; even then, it is Experimental Rheumatology 2015. including PDE4 inhibitors on enthesitis likely that enthesitis is a feature, as will is poorly understood due to the relative be described later in this review, where Key words: psoriatic, arthritis, difficultly in procurement of entheseal enthesitis is evident even in patients enthesis, , ligaments, psoriasis tissue. This absence of a histological with skin psoriasis alone. gold standard renders it difficult to de- cipher how effective various therapies Clinical enthesitis in PsA are in treatment of enthesitis. Despite Following the enthesitis theory of dis- advances in understanding enthesitis in ease being put forward, it is of note that animal models, there is a dearth of data the clinical prevalence of enthesitis as thus far on the immunology of human assessed by clinical means appears to entheses that likely will be key to further be higher in clinical trials now than it refinements in therapy development. was historically. The clinical assessment of enthesitis in PsA is rendered difficult History of enthesitis in PsA because enthesitis may not be associ- When Wright defined psoriatic arthritis ated with significant swelling, and con- (PsA) as a distinct entity from rheuma- sequently may be difficult to distinguish toid arthritis (RA), one of the defin- between fibromyalgia, mechanically re- ing features was axial disease which lated or degenerative related enthesopa- was present in up to 40% of cases (1, thy, but which are more common in 2). Radiographic assessment of axial subjects with high BMIs, which is often disease showed the presence of spi- the case in PsA (6). Nevertheless clini- nal fusion at different entheses around cal enthesitis has been documented in the spine thus pointing to an important a third of a PsA population (7). There role for the enthesis in axial changes. are a number of enthesitis indices, all Moll and Wright were able to lump the of which rely on subject assessment of (SpA) including response to pressure over insertion sites, PsA, , reactive so a “gold standard” assessment is not arthritis and inflammatory bowel -dis available (8-13). ease associated arthritis together based on the axial disease proclivity, but also Imaging enthesitis in PsA as a the tendency for peripheral enthesitis diagnostic test (3). Given that physicians tend to only The original studies from the 1990s Competing interests: none declared. recognise superficial easily accessible by Jevtic and colleagues looking at the

S-36 The enthesis in PsA / D. McGonagle & A.L. Tan hands, and the Leeds group studying Fig. 1. High resolu- the knees, suggested that MRI could tion MRI of the Achil- les tendon (T) of a differentiate between PsA and RA 32-year-old male with based on enthesitis and extracapsular psoriatic arthritis as- inflammation (14, 15). However, for sociated with swelling subjects with oligoarthritis the diagno- around the heel. There is diffuse sis remains largely clinical, and for sub- inflammation (arrows) jects with polyarthritis the main diag- around the entheseal nostic tests used are rheumatoid factor attachment with swell- and anti-citrullinated protein antibodies ing and disruption of the tendon near the in- to exclude RA. Numerous studies have sertion (arrowheads). shown that enthesitis and osteitis were A layer of fibrocarti- more common in PsA compared to RA lage (FC) forms part of the enthesis organ be- (Fig. 1), and that diffuse peri entheseal tween the tendon and osteitis was a useful differentiating the calcaneal , factor, but some studies have failed to which is the avascu- show that osteitis was statistically more lar region of maximal mechanical stressing. common in PsA (16), perhaps reflect- There is bone oedema ing Wright’s original observation that a (histologically an os- small proportion of ‘PsA’ is in fact coin- teitis) (asterisk) in the cidental RA with psoriasis (17). calcaneum adjacent to the enthesis. The avas- The differences between PsA and osteo- cular nature of the FC arthritis (OA) are similarly not com- leads to its sparing in pletely well defined. Although imaging the very earliest stages studies show some differences between of disease. PsA and OA (18, 19), the changes may not be sufficient in certain patients to consider imaging as a diagnostic tool in distinguishing these common arthropa- thies (20). The basis that enthesitis as a don, including the A1-3 pulleys which as a surrogate for RA, with extensive primary site of pathology suggests that could explain the . Previ- and bone erosions. However there may be a PsA-OA overlap pheno- ous studies have reported enthesitis in the early histological assessment of en- type (21), making clinical differentia- other sites in dactylitis, including the thesitis permitted the demonstration of tion difficult in some patients. collateral ligaments and dorsal tendons a primary enthesitis that subsequently (25, 26). These findings in the nails and spread to the adjacent tissues. In this Classification of controversial dactylitis are faithfully recapitulated particular model a population of innate enthesitis associations in several animal models of inflamma- lymphoid like cells (ILC) were docu- For a long time, it was unclear why nail tory arthritis, that begins at the enthesis mented at the entheses and these were disease predicted both PsA develop- (27). likely key to driving the disease process ment and more common distal inter- (31). phalangeal (DIP) joint involvement in Animal models with PsA features: ILC type cells are pivotal to gut and PsA. The enthesitis theory of disease primary enthesitis skin barrier tissue repair via the elab- provided an anatomical explanation, In recent years, animal models have oration of key pro inflammatory cy- since it was shown that the DIP joint been developed which demonstrate the tokines including IL-22 (32). Since the entheses, including the extensor ten- primacy of enthesitis in SpA like dis- human enthesis exhibits extensive mi- dons, collateral ligaments and dermal ease. The arthritis in the DBA-1 male crodamage in the cadaveric setting, it is ligaments, provide an elaborate anchor- mice and that in TNF-transgenic (tg) tempting to suggest that IL-23-related age mechanism to the nail (22). Moreo- mice was shown to start at the enthesis signalling at the enthesis is key to tissue ver nail involvement is associated with (27-30). The most exciting translation- repair but that the signalling might be diffuse remote systemic al model is that of arthritis following altered in disease. in the lower limbs (23). systemic over expression of the IL-23 The SKG mouse model was also pre- Recently high resolution MRI has been cytokine in the liver which resulted in viously reported as RA like and is due used to explore flexor tenosynovitis 3 cardinal manifestations including a to aberrant T cell gain of function (33). which is the most striking abnormal- primary enthesitis, skin rash and aor- A recent modification of this model ity in dactylitis (24). It was observed tic root inflammation (31). Of note the showed a primary enthesitis and also that microscopic enthesitis was seen in same model, analogous to the TNF tg dactylitis and nail disease, both of the minipulleys around the flexor ten- model, had previously been reported which link to enthesitis in humans (34-

S-37 The enthesis in PsA / D. McGonagle & A.L. Tan

36). Two further models, the B10Q (37) er for predicting PsA development but lated sites. J Anat 2001; 199: 503-26. and the K5.Stat3C:F759 mice have further work is needed. 5. BENJAMIN M, MORIGGL B, BRENNER E, EM- ERY P, McGONAGLE D, REDMAN S: The “en- shown similar psoriatic presentations An emerging question is whether the thesis organ” concept: why enthesopathies with a key role for enthesitis (38). treatment of skin psoriasis with agents may not present as focal insertional disor- that are known to be effective for PsA ders. Arthritis Rheum 2004; 50: 3306-13. Enthesitis points towards 6. ROUSSOU E, CIURTIN C: Clinical overlap be- also may prevent arthritis develop- tween fibromyalgia tender points and enthesi- a unified biomechancial concept ment, or at least lead to the regression tis sites in patients with spondyloarthritis who The presence of at the of subclincal . A recent present with inflammatory back pain. Clin enthesis points to complex compres- ultrasound study provided the first Exp Rheumatol 2012; 30 (Suppl. 74): 24-30. 7. GLADMAN DD, CHANDRAN V: Observa- sive, tension and shearing forces (Fig. evidence for this and showed that anti tional cohort studies: lessons learnt from the 1) (39). Fibrocartilage also is present TNF and methotrexate were associated University of Toronto Psoriatic Arthritis Pro- where tendons wrap around bony pul- with the regression of clinically occult gram. Rheumatology (Oxford) 2011; 50: 25- leys especially in the ankle and foot, enthesopathy (44). This places Derma- 31. 8. MANDER M, SIMPSON JM, McLELLAN A, and it also is present in other PsA target tologists at the forefront of therapy for WALKER D, GOODACRE JA, DICK WC: Stud- sites (4). These most notably include the possible prevention of enthesopa- ies with an enthesis index as a method of the sacro-iliac and the sterno- thy that may evolve to PsA, but further clinical assessment in ankylosing spondyli- clavicular joints, both of which can studies are needed. tis. Ann Rheum Dis 1987; 46: 197-202. 9. HEALY PJ, HELLIWELL PS: Measuring clini- be affected in PsA, and are synovial cal enthesitis in psoriatic arthritis: assess- joints that have a perpendicular orien- Lessons from therapies ment of existing measures and development tation to the ground, and consequently Over the last few years, several stud- of an instrument specific to psoriatic arthritis. Arthritis Rheum 2008; 59: 686-91. experience the same types of stress to ies have indicated that clinically deter- 10. MAKSYMOWYCH WP, MALLON C, MORROW the underlying bone. This strongly sug- mined enthesitis may respond to thera- S et al.: Development and validation of the gests that the enthesis and enthesis or- pies that target both IL23 and IL17 (30, Spondyloarthritis Research Consortium of gan concepts point towards a unifying 46). Small molecules and PDE4 inhibi- Canada (SPARCC) Enthesitis Index. Ann Rheum Dis 2009; 68: 948-53. biomechanical basis for PsA. Clearly tors also effectively target enthesitis 11. HEUFT-DORENBOSCH L, SPOORENBERG A, biomechanics may be important since and nail and dactylitic disease (47). It van TUBERGEN A et al.: Assessment of en- subjects with higher BMIs who have is not well understood why some pa- thesitis in ankylosing spondylitis. Ann Rheum psoriasis have a higher risk of PsA (40). tients with PsA who are well-treated Dis 2003; 62: 127-32. 12. BRAUN J, BRANDT J, LISTING J et al.: Treat- Injury is also associated with a risk of with diminution of joint swelling and ment of active ankylosing spondylitis with PsA (41, 42). In the animal model set- normalisation of CRP, complain of per- infliximab: a randomised controlled -multi ting, it has recently been shown that sistent entheseal symptoms (21). centre trial. Lancet 2002; 359: 1187-93. 13. GORMAN JD, SACK KE, DAVIS JC, Jr.: Treat- biomechanics alone are key to the de- ment of ankylosing spondylitis by inhibition velopment of SpA (43). Conclusions of tumor necrosis factor alpha. N Engl J Med In recent years a wealth of experimental 2002; 346: 1349-56. Imaging enthesitis in psoriasis data has emerged showing the primacy 14. McGONAGLE D, GIBBON W, O’CONNOR P, GREEN M, PEASE C, EMERY P: Character- to predict PsA of enthesitis in animal models of PsA. istic magnetic resonance imaging entheseal Given the continually emerging data Experimental and clinical data has also changes of knee synovitis in spondylarthrop- that strengthens the enthesitis concept, emerged showing the close functional athy. Arthritis Rheum 1998; 41: 694-700. more research is taking place on the link between enthesitis and nail dis- 15. JEVTIC V, WATT I, ROZMAN B, KOS-GOLJA M, DEMSAR F, JARH O: Distinctive radiologi- importance of enthesitis in early PsA. ease and dactylitis. The assessment of cal features of small hand joints in rheuma- Enthesopathy in subjects with psoria- human enthesitis is largely confined to toid arthritis and seronegative spondyloar- sis is very common and indeed much imaging, and there is a need to evalu- thritis demonstrated by contrast-enhanced more common than synovial changes. ate the pathophysiological basis for (Gd-DTPA) magnetic resonance imaging. Skeletal Radiol 1995; 24: 351-5. Of note, sonography shows that about disease localisation to this site in man. 16. MARZO-ORTEGA H, TANNER SF, RHODES 40% of psoriasis cases have enthesopa- LA et al.: Magnetic resonance imaging in thy, but clinical studies indicate that References the assessment of metacarpophalangeal joint fewer than 2% of psoriasis cases get 1. WRIGHT V: Psoriatic arthritis. A comparative disease in early psoriatic and rheumatoid ar- radiographic study of rheumatoid arthritis thritis. Scand J Rheumatol 2009; 38: 79-83. PsA each year (44, 45). The need to and arthritis associated with psoriasis. Ann 17. WRIGHT V: Psoriatic arthritis; a comparative define which groups develop PsA is of Rheum Dis 1961; 20: 123-32. study of rheumatoid arthritis, psoriasis, and particular relevance for early therapy 2. MOLL JM, WRIGHT V: Psoriatic arthritis. arthritis associated with psoriasis. AMA Arch and prevention. Semin Arthritis Rheum 1973; 3: 55-78. Derm 1959; 80: 27-35. 3. MOLL JM, HASLOCK I, MACRAE IF, WRIGHT 18. TAN AL, GRAINGER AJ, TANNER SF, EMERY We and others have shown that about V: Associations between ankylosing spondyli- P, MCGONAGLE D: A high-resolution mag- 10% of psoriasis cases have power tis, psoriatic arthritis, Reiter’s disease, the in- netic resonance imaging study of distal inter- Doppler changes on ultrasound at large testinal , and Behçet’s syndrome. phalangeal joint arthropathy in psoriatic ar- thritis and osteoarthritis: are they the same? entheses reflecting inflammation, but Medicine (Baltimore). 1974; 53: 343-64. 4. BENJAMIN M, McGONAGLE D: The anatomi- Arthritis Rheum 2006; 54: 1328-33. that this is not seen in normals (23). cal basis for disease localisation in seronega- 19. TAN AL, TANNER SF, WALLER ML et al.: This may be the best imaging biomark- tive at entheses and re- High-resolution [18F]fluoride positron emis-

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sion tomography of the distal interphalangeal inflammatory joint and intestinal diseases. onset of arthritis in a mouse model. J Invest joint in psoriatic arthritis--a bone-enthesis- J Exp Med 2008; 205: 331-7. Dermatol 2015; 135: 445-53. nail complex. Rheumatology (Oxford) 2013; 29. BRAEM K, CARTER S, LORIES RJ: Spontane- 39. BENJAMIN M, RALPHS JR: Fibrocartilage 52: 898-904. ous arthritis and ankylosis in male DBA/1 in tendons and ligaments--an adaptation to 20. BRAUM LS, McGONAGLE D, BRUNS A et al.: mice: further evidence for a role of behavio- compressive load. J Anat 1998; 193: 481-94. Characterisation of hand small joints arthrop- ral factors in “stress-induced arthritis”. Biol 40. BHOLE VM, CHOI HK, BURNS LC et al.: athy using high-resolution MRI--limited dis- Proced Online 2012; 14: 10. Differences in body mass index among in- crimination between osteoarthritis and psori- 30. EBIHARA S, DATE F, DONG Y, ONO M: Inter- dividuals with PsA, psoriasis, RA and the atic arthritis. Eur Radiol 2013; 23: 1686-93. leukin-17 is a critical target for the treatment general population. Rheumatology (Oxford). 21. McGONAGLE D, HERMANN KG, TAN AL: of ankylosing enthesitis and psoriasis-like 2012; 51: 552-6. Differentiation between osteoarthritis and dermatitis in mice. Autoimmunity 2015; 48: 41. NG J, TAN AL, McGONAGLE D: Unifocal pso- psoriatic arthritis: implications for pathogen- 259-66. riatic arthritis development in identical twins esis and treatment in the biologic therapy era. 31. SHERLOCK JP, JOYCE-SHAIKH B, TURNER following site specific injury: evidence sup- Rheumatology (Oxford) 2015; 54: 29-38. SP et al.: IL-23 induces spondyloarthropa- porting biomechanical triggering events in 22. TAN AL, BENJAMIN M, TOUMI H et al.: The thy by acting on ROR-gammat+ CD3+CD4- genetically susceptible hosts. Ann Rheum Dis relationship between the extensor tendon en- CD8- entheseal resident T cells. Nat Med 2015; 74: 948-9. thesis and the nail in distal interphalangeal 2012; 18: 1069-76. 42. PATTISON E, HARRISON BJ, GRIFFITHS CE, joint disease in psoriatic arthritis--a high- 32. AHLFORS H, MORRISON PJ, DUARTE JH et SILMAN AJ, BRUCE IN: Environmental risk resolution MRI and histological study. Rheu- al.: IL-22 fate reporter reveals origin and con- factors for the development of psoriatic ar- matology (Oxford) 2007; 46: 253-6. trol of IL-22 production in homeostasis and thritis: results from a case-control study. Ann 23. ASH ZR, TINAZZI I, GALLEGO CC et al.: infection. J Immunol 2014; 193: 4602-13. Rheum Dis 2008; 67: 672-6. Psoriasis patients with nail disease have a 33. SAKAGUCHI N, TAKAHASHI T, HATA H et al.: 43. JACQUES P, LAMBRECHT S, VERHEUGEN E greater magnitude of underlying systemic Altered thymic T-cell selection due to a muta- et al.: Proof of concept: enthesitis and new subclinical enthesopathy than those with nor- tion of the ZAP-70 gene causes autoimmune bone formation in spondyloarthritis are driv- mal nails. Ann Rheum Dis 2012; 71: 553-6. arthritis in mice. Nature 2003; 426: 454-60. en by mechanical strain and stromal cells. 24. TAN AL, FUKUBA E, HALLIDAY NA, TAN- 34. BENHAM H, REHAUME LM, HASNAIN SZ et Ann Rheum Dis 2014; 73: 437-45. NER SF, EMERY P, McGONAGLE D: High- al.: Interleukin-23 mediates the intestinal re- 44. ACQUACALDA E, ALBERT C, MONTAUDIE H resolution MRI assessment of dactylitis in sponse to microbial beta-1,3-glucan and the et al.: Ultrasound study of entheses in psoria- psoriatic arthritis shows flexor tendon pulley development of spondyloarthritis pathology sis patients with or without musculoskeletal and sheath-related enthesitis. Ann Rheum Dis in SKG mice. Arthritis Rheumatol 2014; 66: symptoms: A prospective study. Joint Bone 2015; 74: 185-9. 1755-67. Spine 2015; 82: 267-71. 25. McGONAGLE D, MARZO-ORTEGA H, BEN- 35. RUUTU M, THOMAS G, STECK R et al.: beta- 45. GISONDI P, TINAZZI I, El-DALATI G et al.: JAMIN M, EMERY P: Report on the Second glucan triggers spondylarthritis and Crohn’s Lower limb enthesopathy in patients with international Enthesitis Workshop. Arthritis disease-like ileitis in SKG mice. Arthritis psoriasis without clinical signs of arthropa- Rheum 2003; 48: 896-905. Rheum 2012; 64: 2211-22. thy: a hospital-based case-control study. Ann 26. ESHED I, BOLLOW M, McGONAGLE DG et 36. REHAUME LM, MONDOT S, AGUIRRE de Rheum Dis 2008; 67: 26-30. al.: MRI of enthesitis of the appendicular CARCER D et al.: ZAP-70 genotype disrupts 46. KAVANAUGH A, PUIG L, GOTTLIEB AB et skeleton in spondyloarthritis. Ann Rheum Dis the relationship between microbiota and al.: Maintenance of clinical efficacy and ra- 2007; 66: 1553-9. host, leading to spondyloarthritis and ileitis diographic benefit through 2 years of usteki- 27. LORIES RJ, MATTHYS P, de VLAM K, DERESE in SKG mice. Arthritis Rheumatol 2014; 66: numab therapy in patients with active psori- I, LUYTEN FP: Ankylosing enthesitis, dacty- 2780-92. atic arthritis: Results from the PSUMMIT 1 litis, and onychoperiostitis in male DBA/1 37. KHMALADZE I, KELKKA T, GUERARD S et trial. Arthritis Care Res (Hoboken) 2015 Jun mice: a model of psoriatic arthritis. Ann al.: Mannan induces ROS-regulated, IL-17A- 19 [Epub ahead of print]. Rheum Dis 2004; 63: 595-8. dependent psoriasis arthritis-like disease in 47. KAVANAUGH A, MEASE PJ, GOMEZ-REINO 28. ARMAKA M, APOSTOLAKI M, JACQUES P, mice. Proc Natl Acad Sci USA 2014; 111: JJ et al.: Treatment of psoriatic arthritis in a KONTOYIANNIS DL, ELEWAUT D, KOLLIAS E3669-78. phase 3 randomised, placebo-controlled trial G: Mesenchymal cell targeting by TNF as 38. YAMAMOTO M, NAKAJIMA K, TAKAISHI M with apremilast, an oral phosphodiesterase 4 a common pathogenic principle in chronic et al.: Psoriatic inflammation facilitates the inhibitor. Ann Rheum Dis 2014; 73: 1020-6.

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