Enthesitis in spondyloarthropathy Dennis McGonagle, MRCPI* Muhammad Asim Khan, MD, FRCP‘ Helena Marzo- Ortega, MRCP; Philip O'Connor, FRCR,* Wayne Gibbon, FRCR,’ and Paul Emery, FRCP* Inflammation atthe insertions of igaments, tendons, or joint ceapeules to bone, which is termed enthesits, is a characteris: tic feature of spondyloarthropathy. Because of the relative inaccessibility of the enthesis, the inflammatory, microbiologic, and immunologic events at that site have been poory defined. Recent magnetic resonance imaging studies have drawn attention tothe ubiquitous nature of enthesiti in spondy- loarthropathies, especially adjacent to synovial joints. This may have implications for the mechanisms of synovitis in spondy- loarthropathies. Magnetic resonance imaging studies also suggest that enthesits lesions may be extensive, which could ‘explain the difuse nature of bone changes seen in some patients with spondyloarthropathies. The importance of enthe- Sitis as a skeletal phenomenon in spondyloarthropathies has ‘gained futher suppor from transgenic models in which either tumor necrosis factor-a or bone morphogenetic protein’6 ‘overexpression result in entheseal-associated polyarthropathy. (Cur Opin Rrevmao! 1999, 1244-250 © 1999 Linco Win & Wits, Deparmant of Rheumatology, Urey of Leds Lends UK; Dapariment of Mating, Case Westen Reserve Unvort Seve! of oseine, Cera CConsapondance to Danis MeGonagl, MRCP, Dsparmen of Rheunatiogy, ‘Univer of Leads, 36 Carendon Rot, Leeds LS2 9NZ, UK: e-rat DIG MeGenuglostoedsacuh ‘Curent Opinion in Rheumatology 1990 112 Abbreviations ‘AS anycsing spond Soa Spondyoartpany ISSN 1040-6711 © 1999 Upprcot Wane & Wikis 244 The enthesis is the point of insertion of the cendon ligament, joint capsule, or fascia to bone [1] Enthesopathy is seen in many arthropathies, buc inflam- matory enthesopathy, which is termed enthests, is the cardinal feature of spondyloarthropathy (SpA) [1] Recent studies have drawn attention to enthesitis as a possible unifying inflammatory lesion in the muscu- loskeletal lesions associated with SpA [2¢,3¢]. This review article focuses on the concept of enthesiis and its role in the pathogenesis of SpA, and investigators anticipate that future studies of che early enchesitis lesion will advance our pathogenic understanding of inflammatory arthritis Derivation of the term enthesis and history of enthesitis According to Lampman [4], the word entkesitis came into use to signify traumatic changes to tendon insertions, a tennis elbow, because the word enthesis means “insertion or implantation.” Gzech physicians first used the term in the 19608 to deseribe the inflammatory symptoms at insertional sites that are an important feacure of ankylos- ing spondylitis (AS) and related SpA. Although the term enthesoparhy was initially used, the term enshesitis was subsequently preferred. Ball [5] popularized the use of entkestis io the English language in his now-famous Heberden oration in 1970. In 1973, a few years after Ball's observations on the importance of enthesitis in SpA, the striking HLA-B27 association was described [6,7]. Paradoxically, although the importance of the enthesitis lesion had just been emphasized, its possible relationship to HLA-B27 has never been addressed. This, in part, could explain why so many untested and unproven hypotheses exist regarding the role of HLA-B27 in SpA. Clinically, however, the concept of enthesitis had gained sufficient recognition to be included as a classification diagnostic criterion for SpA in 1991 [8] and for subsets of juvenile chronic arthritis [9] Embryology ‘The earliest stage of the embryologic development of the enthesis is characterized by the primitive tendon or ligament attaching to the cartilage. Metaplasia of fibrob- lasts at this attachment site results in the formation of fibrocartilage, and this process then extends further intothe cendon or ligament while the remainder of the earti= lage undergoes endochondral ossification [10 Anatomy ‘Two forms of enthesis exist: 1) fibrous and 2) fibrocarti- Iagenous [114]. Fibrous attachments are found at the metaphyses and diaphyses of long bones and, in these collagen fibrils, attach directly co the bone. In fibrocarti- lagenous entheses, a conspicuous transitional zone is present and on the basis of this the enthesis is divided into the following four regions: 1) Tendon with characteristic sparse longitudinally orientated fibroblasts 2) A region of fibrocartilage where the cell morphol- ogy changes toa chondrocyte 3) A fairly abrupt region of transition from fibrocarti- lage to calcified fibrocartilage, which is seen as a discrete tidemark 4) Bone Evidence shows that ehe enthesis is anchored into the adjoining bone by collagen fibrils that penetrate into the trabeculae, Historically, these Sharpey fibers were thought to provide additional anchoring support to bone, although the functional significan: remains unknown, e of these, if any Although the enthesis is considered a discrete or focal insertion to bone, studies of large entheseal insertions clearly show that these can be inserted over a wide ates Fibrocartilage is scen not only at the enthesis point of attachment but also along the bone adjacene to the ‘enthesis, where it is thought to provide support in resist- ing compressive forces on the adjacent bone [114]. ‘This has been best scudied in Achilles cendon insertion, where sesamoid (posterior) and periosteal (anterior) rocartilage is well described [12]. The blood supply of entheses is derived from the surrounding periosteal vessels, which form an anastomosis around the base of the enthesis from which small, perforating vessels nourish it, Additional blood supply is obtained from the bone marrow vascularity and from the tendon blood supply. The perfusion of the enthesis is less than that of synovium or bone, Enthe: well innervated with both pain receptors and propiore- ceptive nerve fibers [13] Al structures in general are Physiology Fibroblast-containing tissues are generally considered relatively metabolically inactive compared with others; however, che tendons and figaments that make up the enthesis are continually responding co mechanical factors in the external environment, indicating the ‘dynamic nature of this region [14]. ‘Phe response of ligs- ments to inereased physical activity is to increase in al. 245 Enthestis in spondyloarthropathy McGonag weight and size. Conversely, during periods of immobi« lization, ligaments decrease in fibrocartilage content and strength of entheseal attachments [14]. This response is reminiscent of articular cartilage, ‘The need for a high capacity for tissue turnover at the enthesis is partly explained by histologic studies thar commonly show tentheseal and bone damage related co repeated mechan- ical stressing [15]. Although the biomechanies of the eathesis are poorly defined, the forces transmitted through a large enthesis, eg, the patellar tendon or Achilles tendon, are considerable, and the need for continuous repair mechanisms is obvious. The high race Of tissue attrition at the enthesis may partly explain why this is a common target for many diseases of the skeletal Biochemistry “The biochemistry of entheses in general seems to reflect the cell eyp variey of methods, including immunohistochemistry and Western blotting, have recently been used to charaecerize the proteins expressed at the enthesis [16#8]. Apart from immunohistochemistry, the characterization of the biochemistry of entheses is difficult because no clear cutoff point exists between the various cissues, Nevertheless, Waggere er af, [16e8] elegantly demon- strated differences between the point of entheseal attach- ment and the neighboring tendon. Collagen types 1, 3 and 6, decorin, biglyean, fibromodulin, and lumican found in che midtendon and encheseal insertion. In contrast, MRNA for type 2 collagen way consistently fnund ae the enthesis bur not che midtendon, ‘The patt and distribution of versican and aggrecan was quite the opposite. with high levels of aggrecan mRNA at the tenthesis und low levels in the midtendon, whereas the converse was erue for versican. ‘The distribution of aggre ean and type 2 collagen exp experimental autoimmunity to both results in a disease phenotype similar to that of human SpA. Other investiga tors have identified collagen types 9, 10, and 11 at knee ligament insertion sites in animals [17] within the each region of the enthesis. A essivn is noteworthy because Ankylosing spondylitis is rare after the age of 40 years, eflect biochemical changes at the enthesis with time, To date, studies have shown progressive crosslinking of human cendon collagen with increasing age [18]. Further characterization of the biochemistry of tentheses and investigation of age-related differences in iene expression, which could help elucidate the patho- genesis of AS, are needed. whieh could Ubiquity of entheseal insertions Before one considers the possible scope of enthess associated pathology, one must consider the ubiquitous nature of entheseal insertions, When one thinks of tentheses, one most frequently considers large structutes,248 Spondyloarthropathies 4g, the Achilles tendon, plantar fascia, and patellar tendon; however, entheseal insertions are particularly Aumerous adjacent to and within synovial joints commonly involved in SpA. For example, the knee joint, which is frequently involved in SpA, has several intra-articular entheseal structures, including the cruci- ate-associated and meniscal-associaced ligaments and numerous entheseal structures adjacent co it, including the joint capsules, insertions of tendons from the muscles taking origin in the pelvis, and origins of many muscles associated with leg movement. Anatomically, diseases of entheseal struccures in the vicinity of synovial joints might be expected to result in secondary synovial and cartilage changes. Because entheseal inser~ tions are so numerous at synovial joints and because Clinical differentiation between them may be impossi- ble, a primary, entheseal-based pathology could masquerade as synovitis. Pathology Several histologic studies of the pathology of SpA and enthesitis have been performed and are well reviewed; the most widely quoted study is that performed by Ball [5]. These have demonstrated soft tissue inflammation and bone destruction at the site of entheseal insertion to bone. Pannus, or fibroblastoid, tissue and inflammatory cell infiltrates invading the bone adjacent to the enthe- siy attachment are well described [5]. Histologie abnor- inalities within the soft tissues of the tendon or ligament are described less often but nevertheless occur. Extensive bone marrow changes in the spine have also been reported in some patients with AS [19}; however, the difficulty of reconciling some of the skeletal changes in patients with SpA with enthesitis, particularly the extensive radiographic bone changes, has recently been pointed out {20}. Radiographic and magnetic resonance (MR) imaging studies have suggested that the inflam- matory response in SpA may occur at a considerable distance from the enthesis, eg, the adjacent bone marrow. The extensive distribution of inflammatory changes at the enthesis, bone, periosteum, eartlage, and bone marrow makes virtually impossible the assessment of the inter-relationship of inflammatory changes at these various sites on a microscopic slide. As discussed later, MR imaging studies indieate that the extensive pathologic changes in Spa with enthestis. On MR images, knee joint enthesitis is associated with bone inflammation at a considerable distance from tendons and ligament attachments (Fig. 1) [24]. The recognition of a more extensive lesion associ- ated with enthesitis could explain the diverse histologic changes reported to date f¢ in some way associated Although the work of Ball [5] represents one of the most significant contributions in research into SpA, a degree of caution is needed in the interpretation of these histo- logic data and related studies on enthesitis. Biopsy spec- imens were invariably obtained from sites of radi- ographic abnormalities in patients with longstanding disease. The histologic lesions described therein may indicate a nonspecific response to inflammation, An immunohistochemistry assessment of early preradi- ‘ographic bone changes is needed. ‘An important feature of enthesits lesions is the devel- opment of new bone formation, which is the main factor in the immobility associated with AS. According to Ball [21], the bone formation is reaction to the previous bout of inflammation at che enthesis attachment. This bone formation, in effect, can lead to a new enthesis above the level of the existing one. Pathology in experimental models of spondyloarthropathies The assessment of early enthesitis lesions in human subjects has technical and ethical considerations. An alternative means of exploring the pathogenesis of enthesis-associated pathology is to evaluate animal ‘models with arthritis. Some studies have reported subele inflammatory changes at entheses in type 2 collagen models of arthritis [22,23]. Another strategy is the induc- tion of an inflammatory polyarthritis with the features of human SpA by inoculating mice with aggrecan [24] Both these antigens are expressed at the fibrocartilage within the enthesis and at other sites of inflammation in SpA. A scriking feature of enthesitis in SpA is that ie often culminares in new bone formation, But the mechanisms of this remain unknown. Cytokines, including trans: forming growth factor-B, and the bone morphogenetic proteins are thought to be important in this process. A-B bbone morphogenetic protein transgenic model with skin phenotype of psoriasis and florid periosttis has recently been described, suggesting that this cytokine could be important in new bone formation [25 Yet another model of enthesitis has been described; tumor necrosis factor transgenic mice develop a polyen- theseopathy with a phenotype similar to that of human. AS [26]. These combined observations confirm the importance of autoimmunity co native antigens and the tole of pro-inflammatory cytokines and pro-osteoblastic cytokines in the development of an entheseal-associated pathology. Imaging The radiographic features of enthesitis have played pivotal role in defining enthesis lesions and in che concept of SpA. ‘These are well described elsewhere and include entheseal bone insertion osteopenia, bone cortex irregularity at insertion, erosion, entheseal softEnthesitis in spondyloarthropathy McGonagle etal. 247 Fig. 1.72 fat-suppressed sagittal magnetic resonance images of the knee in early hheumatold arthritis (A) and early reactive arthritis ®) “The high ignite) 9 Arpresni nose (and he bones enor bc: Howe. a honnby ta cured sow Prominent ot isue charges ae sso preset ove of he bee ajacent ha ante patti intumes (The par tendon ori ness whit avons. The patel esos etensive tnd comsrricale wth th jt any, whch cod be reponse lors secondary nyo. Sok tse acer with rome! changes ote of he ont ent is ssendert tissue calcification, and new bone formation at the enthesis [27]. Periostitis nor relaced co a defined inser- tion is also a feature, Just ike radingraphic bone erosion in cheumatoid arthritis, entheseal changes are not readily appreciated in large joints bur nevertheless are discernible when a careful search is conducted; however, enthescal-associated bone changes are common in the small joints of the hands, especially in fc arthetis [28 ‘Computed tomogeaphy has not been used extensively 10 investigate enthesitis, but intraentheseal calcium or cerystal deposition has been used to confirm a di of gouty enthesopathy [29]. A pri gouty enthesitis with a cytokine: synovitis could explain some cases of gouty synovitis in which eryseals are nor recovered. y inflammatory nediated reactive Scintigraphic studies have shown diffuse inereased bone uptake in patients with SpA, bur an anaromie explana tion has nor been identified [30]. MR imaging has been used to assess enthesitis and has provided new insights The first MR imaging studies emphasized the extrivyn= ‘vial natue of inflammatory lesions in synovitic joints in patients with SpA bu did not identify enthesitis in the same joints (31.32 of farsuppresion MR imaging rechniques has allowed wo important pathogenic observations. First, the basis of the extracap- sislar changes in synovial joint inflammation in patients with SpA is commonly enthesitis [24]. Second, the inflammatory response associated with enchesitis may be quite extensive, involving the soft tissues and under- lying bone marrow at a considerable distance from the nthesis insertion [24], As already discussed, the extent of the MR imaging changes associated with enthesitis may exphiin the diffuse histologic changes in the bone marrow in both human and animal st wowever the MR imaging has some limitations in evaluating enthe- ses—the seruecures that make up entheses have a low248. Spondyloarthropathies signal on conventional MR imaging sequences, and the associated soft tissue and bone marrow changes are best seen, Bone edema as demonstrated on MR imaging is 3 nonspecific response to trauma, fracture, infection, neoplastic involvement, osteoarthritis, and joint inflam- ‘mation as seen in rheumatoid arthritis, In patients with sheumatoid arthritis, bone edema occurs adjacent to cartilage and is much less extensive than in patients with Spa. Entheseal bone edema could be related co inflammation per se or to biomechanical factors (eg, thae seen in patients with trauma or osteoarthritis). MR. imaging of patients with enthesopathy unrelaced to SpA. addresses this important question and answers whether bone edema in patients with SpA is mainly caused by inflammatory or biomechanical factors, Bone edema is evident in the sacroiliac joint; in entheyeal insertions adjacent to synovial joints; and at sites devoid of synovium, ¢g the plantar fascia. Ultrasonography is enthesitis and is complementary to MR imaging because it readily demonstrates tendon, ligament, and periosteum [33]. The sonographic appearance of enthe- sitis is associated with the loss of normal fibrillar chogenicity of the enthesis with hypoechoic thickening and edema with bone erosion or new bone formation at the insertion. Sonography may be a relatively inexpen- sive method for assessing enthesitis in patiencs with Spa. adily applicable to demonstrating, The variable and extensive abnormalities seen on MR imaging, lead one wo ask, Whe site of disease—the enthesis or the bone Combined MR imaging and sonography studies suggest that the primary lesion is related to inflammation at the enthesis insertion, with bone marrow changes being secundaty [34]. ‘This conclusion is based on the observa- tion thar bone edema evident on MR imaging is inva ably associated wich soft tissue changes at the enthesi however, some patients with entheseal soft tissu changes do not have bone edema. Furthermore, bone cortex erosion as detected on sonography follows bone edema detectable on MR imaging, suggesting that bone cortex erosion isa secondary Feature [34] is the primary anacomie “The earliest lesion in AS is at the sacroiliac joint. Extensive bone edema has been reported at this site [35]. The lumbae spine is also involved, and skip lesions may be evident, confirming that early AS docs not extend in a orderly fashion from the sacroiliac joint upward, Because the steroiise joint has large circumfer- ential capsular atcachments and an intraosseous Tiga ment, che authors postulate that the MR imaging ‘changes inthe sacroilae join are secondary to enthesitis because the characteristic feature of enthesitis in peripheral sites is extensive bone edema [36] “The MR imaging observations allow for the first time a unifying anatomic and pathologie explanation for the skeletal manifestations of early Spa. TI have allowed the wealth of clinical, immunologic, micro- biologic, and molecular data to be viewed from the perspective of a predominantly entheseal-based, rather than a synovial-based, pathology. Many of the synovial and cartilage changes reported in patients with SpA may be secondary co an inflammatory response with an epicenter located at the enthesis (Fig. 2) [34] Experimental data from several studies indicate that locally releaved cytokines in the joint cavity could precip- itate synovitis [38]. ‘The realization that the synovium may not be the primary target organ explains the failure o consistently identify bacterial products a that sie. Relationship of enthesitis to HLA-B27 “The primary location of the pathology of entheses in patients with SpA may have imporeant implications for understanding the pathogenesis of the disease. For example, the understanding of autoimmune diseases in general, eg, insulin-dependent diabetes mellitus and celiac disease, is based on the interplay between the immune system and tissues at the respective anatomic sites of disease in the pancreatic islets and the gut lamina propria. Exploring the relationship berween the immune system and sites of disease has resulted in significant advances in understanding the pathogenesis of these of HLAassociated entities, Compared with these condi- ions, all of which have only moderate HLA associations, the association between H/A-B27, and AS in particular, is striking. Although numerous proposed on putative pathogenic mechanisms, none have addressed possible interactions in the relationship to the anatomic sites of disease in patients with AS. vories have been Fig. 2. Inflammatory response at the onthesis Extacapsular fue Presonus mage Capsule -eiuataton tow anasto wsporse pray based whe ethan uid asocatod wth bane synoviae aus changes, hs proving ‘Spanabeeaplraton othe sane nates of Sp assed pethogyDespite major conceptual understanding of AS pacho- genesis, no data are available regarding on che site of inflammation. ‘The demonstration of a link between HLA-H27 entheseal changes, changes in the adjacent soft tissues, or bone matrow edema could have important implications for understanding the pathogens esis of disease. The future ‘The realization that the joint enthesis and capsule may play a central cole in che pathogenesis of joine inflamma tion may have important implications for both the ekassi- fication of inflammatory arthritis, and furure cherapy: Recognition of the central role of the enthesis hay permitced « reclassification of psoriatic archritiy based on pathology and also provides new avenues for researching the relationship hecween skin and joine disease [37]. “The prognosis of patients with cheumatoid arthritis is good in one subsee; this group may be pare of the wider spectrum of Spa [38h ‘The good prognosis of this zeoup was recently recognized ay being entheyeal-related, which may have important implications for both the selection of disease-modifying anti-rheumatie drug therapy in eacly arthritis and for expanding the spe of SpA (Fig, 3) [39¢]. The extent of the bone marcos lesion associated with and the Fietors chat determine this, need to be del thesit Fig. . 12 fat-suppressed coronal magnetic resonance image of the hand of a patient with sudden-onset polyarthritis with {the ee of imaging, ths pati me the Anrcan Colege of Areursoiony trae hema ars. Pomneat ede ie resort at tha caplet {onatlchment (white arows), and ie rome! eeracapsuar anges ae ‘Sho enon wht aster) Cincaly, he sun ons ot demas, tssocaion ‘an preceding iection and good pogross we emniscant of eacte ath Und ho magnet resonance nga ertnena bose patlogy suppers ths Enthositis In spondyloarthropathy McGonagle ef al. 248 noninflammatory entheseopathies. H/A-B27 may be important in the pathogenesis of these changes How es the concept of enthesitis be pur into context with respect to Future research in the rheumatic diseases? A comparison with cardiovascular medicine is an obvious choice; 10 years ago, the vascular endoth lium was viewed ay an inest structure of marginal rele- vance 10 disease of the cardiovascular system. Research into the endothelium is now a fruictul and expanding area of research in medicine. Likewise, important patho- xenie understanding will come from evaluation af the centhesis and how enthesitis results in bone, cartibage, and synovial changes. Conclusions An entheseal-associated patholoxy may exp tand much of the synovial joine inflammation in patients with AS and related Spa. ‘The concept of inflann archritis in general must he extended co view the role of tentheseal of capsular changes in disease patho ‘The determination of the interaction berween mieroor= anisms and H/1-827 a¢ this site could eontribuce t a etter understanding. of the pathogenesis of AS. 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