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Ann Rheum Dis 2000;59:985–994 985 Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from MEETING REPORT

Enthesitis and ankylosis in : What is the target of the immune response?

J Braun, M A Khan, J Sieper

A report from a symposium held at Klinikum Benjamin Franklin, Free University, Berlin, Germany, 25–26 February 2000

This symposium was organised by J Braun and seal structures are aVected in sacroiliac inflam- J Sieper (Free University, Berlin) to review the mation has not yet been entirely clarified. To current knowledge of the anatomical, inflam- answer some of the most critical questions an matory, microbiological, and immunological expert symposium on enthesitis was organised: events in enthesitis. + Why are related structures aVected? The term “” is relatively new + Is the presence of fibrocartilage essential? and its medical history short, but some impor- + Do we have to change the concept of tant contributions can be listed (box 1). enthesitis or that of enthesis? More struc- tures are aVected than the conventional concept of enthesis implies. What about the Box 1 History of “enthesopathy” blood supply of such structures? Is enthesitis an inflammatory process? Is it 1966 Enthesopathy first used by Niepel + + due to an immune response, trauma/ 1970 Entheses centrally aVected in anky- + mechanical stress, or both? losing spondylitis, in contrast with rheu- Where does the inflammation start? matoid (RA; Heberden oration + Is the new formation and ankylosis a lecture by Ball) + pathological process itself, or is it no more

1975 Some enthesitis in sacroiliitis http://ard.bmj.com/ + than a reaction to severe and persistent (François) inflammation? 1983 Syndrome of seronegative en- + What is the link between inflammation and thesopathy and in children + new bone formation? (Rosenberg) Which molecules might be the target of an 1982 Sacroiliitis starts in the subchondral + + immune response? bone (Shichikawa) + 1991 Enthesopathy discriminative

Anatomy on September 26, 2021 by guest. Protected copyright. feature of spondyloarthropathy (SpA; To understand the pathology of SpA, detailed European Spondyloarthropathy Study knowledge about the of the aVected Group criteria, Dougados) structures is needed. + 1998 Entheses more commonly aVected The enthesis is defined as the site of in arthritis in SpA compared with RA insertion of a , , capsule, (McGonagle) or fascia to bone. Thus a variety of anatomical Department of sites can be symptomatically aVected in , UK enthesopathy (box 2). B Franklin, Free The are among the University, Berlin, The anatomy of peripheral entheses was dis- Germany most common inflammatory rheumatic dis- cussed by Benjamin, CardiV. There are basi- 1 J Braun eases. In addition to the strong genetic predis- M A Khan position, partly due to HLA-B27,2 there are J Sieper characteristic clinical features of SpA3: inflam- Box 2 Entheseal structures most matory back pain often due to sacroiliitis4 and commonly aVected in SpA Correspondence to: enthesitis occurring mostly at various well Professor J Braun, + defined locations, predominantly of the legs, Department of + Fascia plantaris Rheumatology, Medizinische such as the Achilles tendon, the plantar + Pes anserinus Klinik IV, aponeurosis, the , the trochanter regions of Universitätsklinikum + Trochanter major the femur, and several pelvic sites.5 Thus Benjamin Franklin, + Ischial tuberositas Hindenburgdamm 30, 12200 entheses are ubiquitous, resulting in a diversity + Iliac crest Berlin, Germany of associated pathological manifestations. [email protected] Epicondylus humeri lateralis Sacroiliitis is the most common early sign of + Accepted 9 August 2000 SpA.6 Whether or not ligamentous and enthe-

www.annrheumdis.com 986 Braun, Khan, Sieper Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from cally two major types of entheses (table 1): the dense fibrous that attaches fibrocartilaginous and the fibrous type.7 The the tendon or ligament to the bone,8 whereas fibrous type of enthesis is characterised by pure the fibrocartilaginous type is characterised by a transitional zone of fibrocartilage (FC) at the bony interface (fig 1). Fibrous entheses are typical of the metaphyses and diaphyses of long , but most entheses are fibro- cartilaginous—for example, the sites of tendon insertions into the epiphyses of long bones.9 FC is most typical of and where the angle of attachment changes throughout the range of joint movement. The site at which capsules insert into the bone can also be regarded as an enthesis containing FC.10 The fibrocartilaginous entheses have four components: + The tendon with characteristic sparse longi- tudinally orientated fibroblasts—that is, dense fibrous connective tissue + A zone of uncalcified FC where the morphology changes to that of + An abrupt transition to calcified FC + Bone. As shown by Benjamin some ligaments have both types of insertion, such as the medial collateral ligament of the knee joint.11 This liga- ment has a fibrocartilaginous enthesis on the femoral but a purely fibrous attach- ment to the tibial . An immuno- histochemical study of the medial collateral ligament during the postnatal growth period of rats showed that the entheseal at the femoral attachment is initially derived from the cartilaginous bone rudiment. However, it was found to be quickly eroded on its deep surface by endochondral ossification as bone formed at the attachment site. Later, it was replaced by FC. Thus enthesis FC is a dynamic tissue with

the inherent ability to promote bone formation. http://ard.bmj.com/ This is of particular interest in SpA with regard to ankylosis. It is not clear whether enthesitis in SpA involves only insertions containing FC. The embryologic development of enthesis is characterised by the primitive tendon or ligament attaching to the cartilage. Metaplasia of fibroblasts at this attachment site results in the formation of FC, and this process then on September 26, 2021 by guest. Protected copyright. extends further into the tendon or ligament, while the remainder of the cartilage undergoes endochondral ossification. The regions of ten- dons and ligaments that make up the entheses are dynamic structures with a high capacity for tissue turnover so as to respond continually to changing mechanical factors. There is a sharp borderline between calcified and uncalcified cartilage, which is called the tidemark. In contrast with the tidemark region, the junction between calcified FC and bone is highly irregular, with little direct continuity of collagen fibres penetrating directly into the Figure 1 (A) Low power view of the attachment of the Achilles tendon to the to bone trabeculae. These Sharpey fibres may show the complexity of structures that jointly comprise the enthesis. These structures include the enthesis fibrocartilage (EF), sesamoid fibrocartilage (SF), periosteal fibrocartilage provide additional anchoring support to bone. (PF), and the retrocalcaneal bursa (RB). Toluidine blue. Scale bar 0.5 cm. (B) A high The uncalcified FC zone creates a vascular and power view of the enthesis of the supraspinatus tendon in the region of the tidemark (T). cellular barrier. This is prominent at sites This highly basophilic line is a calcification front separating the zones of calcified and uncalcified fibrocartilage. It is relatively straight and this contrasts with the irregularity of where joint movement results in a great deal of the junction between the calcified fibrocartilage (CF) and the underlying bone (B) bending of ligaments/tendons, probably be- (junction marked with *). It is such interdigitations that help to hold the two tissues cause the FC helps to reduce wear and tear by together. Note that the fibrocartilage cells (FC) are more conspicuous in the region of uncalcified fibrocartilage. Haematoxylin and eosin. Scale bar 100 µm. (Courtesy of Dr M stress dissipation, as does the articular carti- Benjamin, University of CardiV, Wales.) lage. The tidemark between the uncalcified and

www.annrheumdis.com Enthesitis and ankylosis in spondyloarthropathy 987 Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from Table 1 The two types of enthesis Should the anatomical concept be changed because the does not accept histological Fibrocartilaginous enthesis Fibrous enthesis borders? In contrast, it seems more logical to Origin Cartilage Tendon, ligament, periosteal change the concept of the disease. Thus the Traject of fibres End within cartilage Penetrate into bundle bone concept of specific inflammation in SpA should Attachment site Epiphyses, apophyses Metaphyses, diaphyses Collagen type II I no longer remain restricted to entheses but has Present Absent to be extended to subchondral bone, the bone Example Achilles tendon, annulus fibrosus Perivertebral ligaments marrow, and the . One common SIJ* ligament SIJ ligament denominator for these structures is the pres- ence of FC (fig 1). Thus FC might be the cen- *SIJ = . trally involved anatomical structure in SpA. the calcified FC is very close to the subchon- This needs to be further investigated. dral bone. Tendon/ligament failures at FC Another important anatomical feature is the entheses, clinically and experimentally, often ubiquitous presence of blood vessels at the sites occur at the level of the subchondral bone, sug- where synovium, joint capsule, subchondral gesting that this region is weaker than the tran- bone, and come close, as shown sitional region between soft and hard tissue.12 by D Gardener in the case of a normal The overall significance of this barrier between sacroiliac joint (fig 2). If the transport of bone and ligament, and fibroblasts, antigens such as bacteria associated with reac- is not clear. tive arthritis to these structures is the initial At the insertion site of the Achilles tendon, trigger of inflammation it is there where the bloodstream takes them. three types of FC can be diVerentiated: two are Furthermore, common ossification proc- located in the distal tendon (entheseal and esses, such as , are preceded by sesamoid) and one proximal to the heel bone 16 13 vascular invasion. Ball already described (periosteal ). The entheseal FC allows for a capillary-like vessels that are seen close to the gradual transition of mechanical properties bone and pass through the enthesis to the mar- between tendon and bone. The periosteal and row to Haversian canals. Although the vessels sesamoid FC, which lie anterior and posterior histologically seem quite scanty, the vascular to the retrocalcaneal respec- bed of the entheses seems fairly large according tively, help the tendon to withstand compres- to early experiments using labelled phospho- sion against the heel.9 As proposed by Ben- rus.17 There is a definite role for new blood jamin, these associated fibrocartilages can also vessels in endochondral bone formation. As be considered as a part of the enthesis.5 discussed by Braun, vascular endothelial The suggestion of Khan was discussed to growth factor, an essential mediator of angio- broaden the concept of enthesis even further to genesis in growing cartilage,18 has not been include the sites of the cartilage attachment to searched for in these regions to date. bone. This proposal would imply that the Although the topic was not directly dis- chondral-subchondral junction of bone where cussed during the workshop, entheses probably

cartilage, rather than exclusively ligament/ derive their nutrition from a number of http://ard.bmj.com/ tendon, attaches to the bone, is also regarded as sources: (a) small perforating vessels that are an enthesis. The basis of this idea comes from branches of surrounding periosteal the histopathological studies of Shichikawa et that form an anastomosis around the base of al14 and recent magnetic resonance imaging the enthesis, (b) vessels in the associated bone (MRI) studies, in which patients with early marrow, and (c) vessels that supply from the stages of SpA commonly show inflammatory pure fibrous region of the tendon or ligament. 15 Entheses are well innervated with propriocep-

subchondral bone changes. on September 26, 2021 by guest. Protected copyright. tive and pain receptors.

Histopathology The histopathology of spinal entheses was dis- cussed by François, from Brussels, Belgium. , pannus formation, superficial carti- lage destruction, myxoid bone marrow, en- thesitis, intra-articular fibrous strands, new bone formation, and bony ankylosis all occur in (AS) sacroiliac (fig 3). Cartilaginous fusion is also seen in con- trol groups but occurs earlier in AS. As reported by Francois, mild but destructive synovitis and myxoid subchondral bone mar- row are the earliest changes identified histo- logically.19 20 There is only limited inflamma- tion not only at entheseal sites in the sacroiliac joint.20 Similarly, in the experience of Braun using MRI,21 in early cases sacroiliac inflamma- Figure 2 Low power view of a normal sacroiliac joint showing the tion starts near the joint capsule (fig 3). As (left) and its attachment to the cartilage (centre), the bone marrow at the right bottom with the attached subchondral bone and cartilage above and numerous blood vessels in the already pointed out, vessels are abundant in the subchondral area. (Courtesy of Professor D Gardener, University of Edinburgh, Scotland.) region where subchondral bone, capsule, and

www.annrheumdis.com 988 Braun, Khan, Sieper Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from at its chondroid enthesis, in the deeper peri- vertebral ligaments, and at their insertion by Sharpey’s fibres. An unusual form of chon- droid metaplasia contributes to ankylosis and bony fusion. inflammation and bone destruction occur at entheseal sites, and inflammatory fibroblastoid cell infiltrates in- vade the bone that is adjacent to the entheseal site, and also the subchondral bone.21 The pre- cise role and origin of these cells is incom- pletely understood. Studies by de Vlam from Gent, Belgium, suggest that ankylosis of the zygoapophyseal joint occurs before the appearance of bony syndesmophytes at the same level.22 Claudepierre, from Paris, France, studied orthopaedic surgery specimens from eight patients with SpA, four with RA, and three with (OA). Inflammatory infiltrates Figure 3 Sacroiliac joint biopsy specimen of a 29 year old male patient with ankylosing and oedema were clearly predominant in the spondylitis and bilateral inflammatory low back pain located to the right side and a disease duration of 7.5 years. The biopsy specimen shows a subchondral cellular infiltrate partly bone marrow of SpA specimens close to the invading the cartilage. and activated are seen in the infiltrate. In enthesis, and the inflammatory cells were between are areas of calcification and bone formation. (Haematoxylin and eosin staining, predominantly T lymphocytes.23 There was a × magnification 250 .) four- to fivefold increase of CD3+ T cells in SpA compared with RA. The CD3+ cells were clearly more common than CD20+ cells in SpA, but not in RA. In comparison with earlier studies in sacroiliitis24 CD8+ T cells were more commonly found in hip joints.23 A possible explanation is the diVerent stage of disease of the patients undergoing endoprosthesis. FitzGerald, from Dublin, Ireland, studied synovial changes in (PsA), focusing on T cells and on the increased vascu- larity of the synovium. CD4+ T cells predomi- nate in the synovial membrane during active disease, but CD8+ cells outnumber CD4+ cells by 2:1 in the synovial fluid. The CD8+ T cells appear to be clonally expanded, and an

antigen-specific T cell mediated immune event http://ard.bmj.com/ seems to occur in the synovial membrane in PsA.25 The extensive pathological studies of AS and PsA by Fassbender26 27 indicate that the new Figure 4 T weighted magnetic resonance image after 1 bone formation in these takes the form application of gadolinium-DTPA, performed when the patient reported pronounced left sided, low back complaints of desmal ossification at the enthesis junction for the first time (starting about four weeks ago, severity with bone, and also by endochondral ossifica- index of 8 on a visual analogue scale of 0 to 10), showed a tion at sites where cartilage is present. Signs of on September 26, 2021 by guest. Protected copyright. high and steep contrast enhancement (Fenh 94%) in the left subchondral zone on the iliac side, in the left joint space, inflammation are not present at these sites. and at the left posterior joint capsule, with extension to the BMP-6 transgenic mice that develop PsA-like pericapsular tendinous and muscular attachments. The left arthropathy with florid periostitis show an anterior aspect likewise shows signs of moderate capsulitis. 28 The linear contrast enhancement of the right anterior analogous joint histopathology. portion of the capsular ligaments that extends to the Fassbender published several papers to- anterior iliac may still be regarded as normal gether with Schilling on the subject in the capsular enhancement. Because MRI depicted no signs of chronic inflammatory changes and the anterior joint spaces 1970s, in which the entheses were recognised on both sides were still smoothly demarcated, the overall as an essential part of the SpA concept, which appearance was classified as MRI stage 0X/0B according they introduced into German rheumatology. 74 to Brandt et al. Schilling recently discussed the relation be- bone marrow come together in the sacroiliac tween the SAPHO syndrome and the SpA joint (fig 4). concept.29 Destruction of adjacent articular tissues is followed by scarring by fibrous tissue, woven Biochemistry bone, and new cartilage. The original The axial skeletal hyaline and FC resist fuse, and this is the predominant mechanism of compressive forces resulting from mechanical early ankylosis. In the spine the diarthrodial stress. FC cells are large and oval and often joints exhibit either synovitis or enthesitis, with packed with intermediate filaments which are capsular ossification, myxoid bone marrow aVected in the transduction of physical forces.30 changes, chondroid metaplasia, , During diVerentiation FC cells accumulate at a and ossification. Inflammatory changes are time that corresponds to increasing mechanical seen all along the annulus fibrosus, particularly load. Entheseal FC cells are surrounded by a

www.annrheumdis.com Enthesitis and ankylosis in spondyloarthropathy 989 Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from metachromatic pericellular matrix, in which teins. They are present in the extracellular proteoglycan molecules are visible.31 At the matrix of cartilage, and also in entheses and entheses these cells do not communicate with tendons. They include the collagen binding each other via gap junctions in contrast with proteoglycans such as decorin, biglycan, fibro- the midsubstance of a tendon.32 In the enthesis, modulin, and lumican, that play a major part in as in articular cartilage, its ability to resist interlinking collagen fibres and in the assembly compression is linked to the presence of aggre- of the collagen network. This family also can and type II collagen in the extracellular includes molecules not containing GAG matrix. These molecules have been demon- chains, and some of them, such as chondro- strated at several entheses by reverse adherin and osteoadherin, are likely to have a transcriptase-polymerase chain reaction, west- role in mediating signals from matrix to ern blotting, and/or immunohistochemistry. At chondrocytes for monitoring tissue function most sites, they are synthesised by FC cells that and maintaining structural integrity. appear relatively late in development by fibro- A molecule called cartilage oligomeric ma- blast metaplasia. In the inner annulus, how- trix protein (COMP), which is expressed in ever, FC cells are derived from cartilage and tendon, binds to collagen mol- that is present during early development.11 ecules to help form collagen fibres.35 36 The Fibrous and fibrocartilaginous regions of a molecule has five binding sites and, possibly, tendon respond diVerently in their extent of may induce pathogenic complexes. In early cell division and matrix synthesis to the stages of OA, chondrocytes express more addition of growth factors such as IGF1 that COMP, fibronectin, and a protein called class are aimed at encouraging repair.14 There are II associated invariant chain peptide, possibly marked changes in the as a repair-type response. The proteoglycan (GAG) distribution: both types of enthesis fragment release in the urine is high in the early have dermatan sulphate throughout life but stages, and it decreases at later stages when OA only the fibrocartilaginous insertions have changes can be seen by roentgenography. keratan sulphate (after 45 days of develop- Heinegard pointed out that he had not studied ment) and chondroitin 4 and 6 sulphate.33 The SpA, but, from his perspective, COMP at latter, as pointed out by Benjamin, is the most cartilage-bone interface is also worth investi- consistent surface marker of FC.34 Of interest, gating in SpA. much of the GAG is associated with the large There is a need to characterise further the aggregating proteoglycan that is biochemistry of the enthesis, which has not characteristic of articular cartilage. The many been well defined, partly because of the relative GAG side chains attached to the core protein inaccessibility of this site (box 3). Any age aggrecan, in turn linked to a central hyaluron related diVerences in gene expression also need molecule, create a highly negative charge. This to be investigated as SpA are uncommon after leads to the formation of domains with high the age of 40, which may reflect biochemical osmotic pressure and the ability to imbibe changes at the enthesis with passage of time, water significantly in order to withstand such as progressive cross linking of human ten-

compression. don collagen with increasing age. The distribu- http://ard.bmj.com/ Types I and III collagen are the major colla- tion and expression of proteoglycan aggrecan gens found in the Achilles tendon and its FC; and type II collagen are important because their major function is to provide tensile autoimmunity to these molecules in mice can strength. FC has properties intermediate with result in arthritis. Interestingly, both these those of very dense connective tissue and hya- antigens are expressed in the FC within the line cartilage.9 Type II collagen mRNA was enthesis and also at other sites of inflammation consistently found at the enthesis but not at in SpA. mid-tendon, and proteoglycan aggrecan on September 26, 2021 by guest. Protected copyright. mRNA was found at a higher level in the enthesis than in mid-tendon.33 The ability of Box 3 Biochemistry of the enthesis the entheseal FC to resist compression is the Collagens I, II, III, V, VI, IX, X, XI result of the presence of type II collagen and + Decorin aggrecan in the , synthe- + Biglycan sised by FC cells that develop by fibroblast + Fibromodulin metaplasia. + Lumican Heinegård from Lund University, Sweden, + Versican reviewed the biochemistry of cartilage matrix. + Aggrecan The matrix, a composite tissue with mechani- + cal function, can remodel itself by the actions of chondrocytes to respond to changing functional requirements. Its major constituents Animal models are the collagen fibres that provide tensile Zhang, from McGill University, Montreal, properties, and the negatively charged aggre- Canada, discussed the BALB/C mice that can macromolecules that provide osmotic develop arthritis and spondylitis reminiscent of pressure to retain water and restrict its human SpA in response to immunisation with movement. Minor components that have a key human proteoglycan aggrecan in complete role in regulating the matrix assembly and in Freund’s adjuvant,37 and also when one uses signalling the chondrocytes about the condi- only its G1 domain instead of the whole aggre- tion of the matrix, include a family of leucine- can molecule. The inflammatory lesions are rich proteins called leucine-rich repeat pro- characterised by initial mononuclear cell infil-

www.annrheumdis.com 990 Braun, Khan, Sieper Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from tration into the outer margins of the annulus showed such changes. Furthermore, cartilage fibrosus at the entheseal insertions to the metaplasia could be detected at vertebrae, as seen in AS. The inflammation is enthesis. The paws showed severe destructive associated with angiogenesis that progresses to lesions in 25% of the animals, along with carti- destructive lesions of the end plates and lage metaplasia, synchondrosis, invasion of progressive discitis.38 Their studies of T cells fibroblastic tissue into subchondral bone, and specific for the G1 epitope have shown that inflammation of adjacent muscles, but there local generation and release of the immunogen was only mild synovitis. Thus in the animal or fragments thereof would lead to T cell hom- model the inflammatory process primarily ing, with resultant inflammatory damage that starts just beneath the cartilage and invades the would lead to further release of epitope, cartilage and the bone.43 attracting further disease inducing T cells.39 40 Eulderink, from Delft, the Netherlands, Moreover, cytokines may cleave hyaluronic described the joint histopathology of ankylos- acid, while metalloprotease and aggrecanase ing enthesitis, a naturally occurring progressive enzymes may cleave the interglobular region to stiVening of the and/or tarsal joints in release the G1 domain of aggrecan in enthesis, C57BL/10 mice.44 It is seen in up to 30% of cartilage, and disc. Zhang is currently studying male animals, and hardly at all in female peptides derived from the G1 domain that bind animals. In contrast with AS,45 the sacroiliac to human major histocompatibility complex joints, spine, eyes, or other organs are not molecules. According to him, this region can aVected. Ankylosing enthesitis usually starts at potentially provide 20 peptides that have the the age of 4 to 8 months, develops during a HLA-B27 binding motif. period of two to four weeks, and then remains Cellular immunity to proteoglycan was stable. In HLA-B*2702 transgenic mice an reported in patients with AS some years ago.40 increased frequency of this ankylosing en- Proteoglycans, including G1 or other homolo- thesopathy has been reported, but this does not gous proteins, can be found in anatomical sites markedly aVect the severity or the type of known to play a part in AS, such as the enthe- lesions.46 The disease starts with a short phase ses, the uvea, the aorta, and the aortic valve.41 of proliferative inflammation of the joints and Proteoglycans bind to , and the adjacent tissues of the paw that lasts for two to binding is stabilised by the associated link pro- three weeks. There is some fibrinous exudation tein which may play a part in autoimmune and leucocytic infiltration. This brief and processes in RA.42 The pattern and distribution scarcely destructive process leads to prolifera- of the proteoglycans, aggrecan and versican, tion of cartilaginous cells at entheseal attach- varies. For example, smooth muscle cells in ments of capsules, ligaments, and tendons to arterial tissues synthesise versican, and bone bone. Fusion of joint cartilage (synchondrosis), , cells at the mid-tendon level, and, marginal ankylosis, and subsequent ossification to a lesser extent, in the enthesis, also produce of the cartilage proliferations and some dermal versican, which serves the role of aggrecan in ossification lead to large bony bridging (syn- environments subjected to cyclical compres- desmophytes) and ligamentous calcification

sion. Such compression and relaxation also that limits joint mobility. This ankylosis mainly http://ard.bmj.com/ occurs in the anterior uveal tract of the eye in aVects the margins of the joints of the paw, order to focus the lens. Interestingly, molecules whereas the central cartilage of the aVected have been seen at that site in the eye that are joints remains intact for a long time.46 immunoreactive with antibodies to aggrecan and link protein. Thus trauma and/or inflam- Immunology mation due to , in the presence of The molecular and cellular mechanisms of dis- immunogenetic predisposition, may permit a ease causation are still unknown despite inten- loss of T cell tolerance that leads to immunity sive investigation.47 Some evidence indicates on September 26, 2021 by guest. Protected copyright. to the G1 domain of aggrecan, link protein, or that T cells and are involved,24 48 other molecules at the aVected sites, resulting but the role for bacterial antigens is less clear in tissue damage at specific sites in AS. because microbial DNA has been detected in Kriegsmann from the University of Mainz, peripheral joints but not the sacroiliac Germany, discussed joint pathology in HLA- joints.49 50 Furthermore, DNA of more bacteria B27 transgenic rats from the 21–4H line that than expected has been detected in both develop gut inflammation and rheumatic mani- arthritic51 and normal joints.52 festations resembling human SpA. He noted It is postulated that AS and related SpA that the primary event is synchondrosis—that result from autoreactive T cells that are is, fusion between the opposing articular carti- activated by external antigenic (bacterial) chal- lages of the joint, and all the 12 animals killed lenge, and then recognise endogenous peptides at 7 months of age showed fusion of vertebral presented by HLA-B27.47 This arthritogenic bodies by cartilaginous tissue. He speculated peptide hypothesis implies that arthritis is trig- that this may be due to alteration of cartilage gered by a T cell response to a specific biochemistry or surface properties. The next antigenic peptide or peptides (derived from the stages are the degeneration of the cartilage, triggering bacteria and/or from an autoantigen) proliferation of chondrocytes, and invasion of that can preferentially be bound to disease fibroblastic tissue from the subchondral bone. associated HLA-B27 subtypes, which are thus Syndesmophyte formation was seen in the presented in an HLA-B27 restricted fashion to spine. Synchondrosis and subchondral ero- eVector CD8+ T cells. Arthritis can be induced sions were present in the sacroiliac joints in in rodents by first priming the T cells to 50% of the animals, and 40% of knee joints respond to a foreign antigen, and then

www.annrheumdis.com Enthesitis and ankylosis in spondyloarthropathy 991 Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from tis,4 usually in combination with peripheral arthritis. Enthesitis seems to be most common in juvenile SpA, where it is a more obvious ini- tial feature than sacroiliitis.57 In the ESSG cri- teria only enthesitis of the legs was taken as indicative of SpA.3 The tarsal ankylosing enthesitis in the animals with ankylosing enthesitis resembles the ankylosing tarsitis of Mexican Mestizo children that was described by Burgos-Vargas, from Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. The enthesitis begins primarily in the feet, and the inflamma- tory phase of this enthesitis lasts for a mean duration of 1.9 months, though the range is quite wide. Some children have recurrent episodes of enthesitis aVecting many sites and lasting for a longer time. No treatment seems eVectively to stop this severely disabling disease process that results in bony ankylosis of joints Figure 5 Magnetic resonance imaging subtraction image of a 32 year old HLA-B27+ patient with undiVerentiated spondyloarthropathy showing acute plantaris (all the of the feet. Most of these children later get fully white appearing enhancement after gadolinium application corresponds to oedema and fledged ankylosing spondylitis, and 95% have inflammation). Reproduced with permission of the copyright holders from Akt Rheumatol HLA-B27—primarily, the B*2705 subtype. 2000;25:1–9. Leirisalo-Repo from Helsinki University, challenging the animal with the antigen Helsinki, Finland, described the clinical signifi- intra-articularly. This is similar to the situation cance of enthesitis in ReA, which is seen in up in human (ReA), in which T to 30% of such patients. This enthesitis seems cell responses are induced by the triggering to run a more chronic course than distinct microbe, and the microbial antigens reach the arthritis. She carried out a case-control study joints, probably via macrophages. The severity of 405 patients with acute joint symptoms after and persistence of the resulting arthritis are campylobacter infection, the commonest gut determined by genetic factors. infection in Finland, and of 405 uninfected As pointed out by Sieper, Berlin, exposure to controls. Acute joint symptoms were seen in bacteria which trigger disease seems to be cru- 25.4% of patients and only 2% of controls. cial to the pathogenesis of SpA. He put forward Among the campylobacter infected patients, a hypothesis, needing further validation by 7.4% developed ReA, 5.4% had “reactive” future studies, that in HLA-B27+ patients with , 3% had isolated “reactive” sacroilii- SpA, a primary entheseal based pathology of tis, and 1% had isolated “reactive” enthesitis; synovial joints may result in secondary synovial these conditions were not seen among controls. changes that masquerade as synovitis. On the The results indicate that enthesitis can be the http://ard.bmj.com/ other hand, in HLA-B27− patients, the pri- only clinical manifestation in some patients mary target may be the synovium, and the per- with reactive musculoskeletal complications sistence of bacteria or their antigenic compo- triggered by an enteric infection. From the nents in the joints may be suYcient to induce studies of Leirisalo-Repo in salmonella trig- synovitis. The articular and extra-articular dis- gered ReA we know that about 15% of patients ease spectrum in HLA-B27+ patients may develop chronic SpA.58 result, at least in part, from an autoimmune on September 26, 2021 by guest. Protected copyright. response to a cross reacting autoantigen Imaging triggered by bacterial immunogen(s) that may What can we learn from modern imaging tech- not necessarily persist (a “hit and run” event). niques for the localisation of inflammation in Given that a mostly silent bacterial infection SpA? In peripheral enthesitis, inflammatory not readily controlled by the host’s immune processes in tendons and ligaments can be visu- system due to, for example, lower tumour alised by ultrasound59 and MRI,60 but it is also necrosis factor á (TNFá) production,53 54 is the possible to document enthesitis in more hidden initial event, either the microbes themselves or sites, such as the plantar aponeurosis (fig 5). antigen-specific T cells would be expected to Although there is limited clinical evidence be transported by the bloodstream55 to the that reactive enthesitis or sacroiliitis exists entheses and cause inflammation in this without arthritis being present, the interesting borderline tissue.56 hypothesis by McGonagle and colleagues implies that knee arthritis is mainly a feature of extensive enthesitis.61 62 Anatomically this may Clinical epidemiology indeed be the case because the knee joint has Clinically, there is no doubt that entheseal numerous intra-articular entheseal structures structures play a part in SpA. The exact preva- (including the chondral-subchondral junc- lence of enthesopathy in SpA and its subsets is tions, cruciate and meniscal attachments) and diYcult to assess because it is often impossible entheseal sites (including the joint capsules, to delineate the clinical symptoms to defined and insertions of numerous tendons and anatomical structures. However, on the basis of ligaments) adjacent to it. In a comparative MRI published data we can assume that 10–60% of study knee arthritis of extra-articular ligamen- patients with SpA have clinically overt enthesi- tous and entheseal structures was detected

www.annrheumdis.com 992 Braun, Khan, Sieper Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from more commonly in patients with SpA than in (c) the synovium may not be the primary target those with RA .61 There are no histological data in AS and related SpA. on this issue so far. Olivieri, from Potenza, Italy, McGonagle, New bone formation from Leeds, UK, Bollow and Braun, from Ber- Development of new bone formation is the lin, discussed the imaging modalities of en- main factor in the spinal immobility associated thesitis. The conventional radiographic fea- with SpA. Ball, in his classic studies on tures of enthesitis include soft tissue swelling, enthesitis, suggested that the new bone forma- osteopenia at entheseal bone insertions, bone tion is a reaction to the previous homeostasis cortex irregularity at insertion, and adjacent and repair of skeletal structures. As discussed periostitis, as well as entheseal soft tissue calci- by Häupl from the Charité, Berlin, transform- fication and new bone formation. These enthe- ing growth factor â (TGFâ) may provide pro- seal changes are not as readily appreciated in tective signals early during the inflammatory large joints as they are in the small joints of the process but induces non-specific fibrosis upon hands, especially among patients with PsA. In chronic disease progression. TGFâ mRNA has contrast, conventional radiography and com- been detected in sacroiliac joints of patients 21 puted tomography mainly detect chronic with SpA. Overexpression of TGFâ and bone changes. Dynamic (gadolinium enhanced) morphogenic proteins (BMPs) may induce MRI and the use of short term inversion recov- pathological ossification, or promote disc degeneration. BMPs play a major part in ossi- ery and other fat suppression techniques show 66 67 that the inflammatory response associated with fication processes, while the related growth and diVerentiation factors influence tendon enthesitis may be quite extensive. It aVects not 68 only the adjacent soft tissues but also the and ligament formation. BMP-2 and BMP-4 promote callus during healing processes after underlying bone marrow, where it can some- 69 times extend to a considerable distance away . BMP-2 also enhances tendon to bone healing, but the presence of BMP-7 is from the enthesis insertion. inappropriate for tendon repair as it may The earliest lesion in AS is usually detectable induce pathological ossification.70 As noted in the sacroiliac joint, where the joint capsule earlier, the BMP-6 transgenic mice develop enthesis and subchondral bone are probably florid periostitis, suggesting that this cytokine the earliest sites a ected. MRI provides V may be important in new bone formation.28 evidence of bone marrow oedema and inflam- The importance of enthesitis and new bone mation of structures in and around the joint formation as skeletal phenomena in SpA has capsule in some patients. The lumbar spine gained further support from another transgenic may also be aVected early and skip lesions may animal model not discussed at this symposium. be evident. This indicates that the spinal A disease phenotype similar to human AS, with disease in early AS does not always extend in a polyenthesitis, occurs in transgenic mice71 orderly fashion from the sacroiliac joint up- expressing a truncated TNFá gene obtained wards. Dynamic MRI is very helpful in the from a mouse strain called . 21 63 Peromyscus leucopus

early diagnosis of sacroiliitis and spinal dis- These observations confirm the importance of http://ard.bmj.com/ 64 65 ease in AS when conventional radiographs the role of proinflammatory and pro- are still normal, and the degree of gadolinium osteoblastic cytokines in enthesitis associated enhancement correlates with the diVuse histo- disease. 48 logical changes. The entheseal bone oedema Again, the important role of angiogenesis for may be evident at sites devoid of synovium, bone formation has recently been shown by such as the , and also at entheses demonstrating that vascular invasion of carti- adjacent to synovial joints. However, it may lage is necessary for proper bone formation.72 also be a non-specific response to biomechani- This point was also emphasised in a recent on September 26, 2021 by guest. Protected copyright. cal factors, as in trauma or osteoarthritis, or paper by Benjamin and colleagues, who due to joint inflammation, fracture, infection, showed that ossification processes in the Achil- or malignancy. les tendon of young rats are a physiological part Entheseal structures have a low water of normal development. Bony spurs form with- content and are therefore not well visualised on out inflammatory reactions and they form by MRI; only the adjacent soft tissue and bone endochondral ossification of enthesis FC pre- changes are best seen. High frequency real time ceded by vascular invasion.73 ultrasonography is a relatively inexpensive method for assessing enthesitis, as it can dem- Treatment onstrate entheseal swelling, tendonitis, peri- Successful treatment in an open study of 11 tendinous soft tissue swelling, , and patients with AS with the anti-TNFá mono- ligamentous and periosteal swelling. Enthesitis clonal antibody infliximab (Remicade) in a is associated with alterations of the normal dose of 5 mg/kg body weight intravenously fibrillar echo texture owing to decreased echo- infused on three occasions (weeks 0, 2, and 6) genicity of the enthesis by inflammation and was reported by Braun, Berlin.74 The patients oedema, and possibly bone erosion or new with AS had severe disease that had not bone formation at the insertion. Combined responded to conventional treatment, includ- MRI and ultrasonographic studies suggest that ing sulfasalazine. The response was monitored (a) entheseal soft tissue abnormalities may over 12 weeks by visual analogue scale for pain, predate the onset of bone oedema, (b) SpA BASDAI—a disease activity index, BASFI—a associated periostitis may be secondary to the functional index, BASMI—a metrology index, diVuse enthesitis associated bone changes, and serum C reactive protein and IL1. Dramatic

www.annrheumdis.com Enthesitis and ankylosis in spondyloarthropathy 993 Ann Rheum Dis: first published as 10.1136/ard.59.12.985 on 1 December 2000. Downloaded from improvement, starting on the day after the first 23 Laloux L, Voisin MC, Allain J, Martin N, Kerboull L, Chevalier X, et al. Comparative histological study of infusion, was noted in all 10 patients who com- enthesitis in spondyloarthropathies [abstract]. Arthritis pleted the study; one patient was withdrawn Rheum 1999;42:S402. 24 Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, from the study because of rash. Improvement Herbst H, et al. Use of immunohistologic and in situ was still present at week 12 in nine of the hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing patients. Pain and swelling due to enthesitis spondylitis. Arthritis Rheum 1995;38:499–505. clearly improved in two patients. Similar results 25 Costello P, Bresnihan B, O’Farrelly C, FitzGerald O. 75 Predominance of CD8+ T lymphocytes in psoriatic arthri- have been reported from Belgium. Thus anti- tis. J Rheumatol 1999;26:1117–24. TNFá treatment seems to be eVective in active 26 Fassbender HG, Fassbender R. Synovial characteristics of seronegative spondarthritides. Clin Invest Med 1992;70: AS, and deserves to be studied further in a 706. controlled study, and also in other forms of 27 Ceponis A, Konttinen YT, Imai S, Tamulaitiene M, Li TF, 76 Xu JW, et al. Synovial lining, endothelial and inflammatory SpA. As discussed by Khan, this is potentially mononuclear cell proliferation in synovial membranes in the biggest breakthrough in the treatment of psoriatic and reactive arthritis: a comparative quantitative morphometric study. Br J Rheumatol 1998;37:170–8. severe AS since the introduction of phenyl- 28 Maerker-Hermann E, Fassbender HG, Kessler S, butazone more than 40 years ago. Thomssen H, Meyer-zum-Büschenfelde KH, Blessing M. Transgenic mice with an epidermal overexpression of bone morphogenic protein-6 present with psoriatic skin lesions We thank Dr M Benjamin and Dr R Francois for reading the and osteoarthropathy [abstract]. Arthritis Rheum 1997;40: manuscript and much helpful advice and discussion. S261. Professors Braun and Sieper are supported by grants from the 29 Schilling F, Kessler S. Das SAPHO-Syndrom—Klinisch- Bundesministerium für Forschung und Technologie. rheumatologische und radiologische DiVerenzierung und Klassifizierung eines Krankengutes von 86 Fällen. Z Rheu- matol 2000;59:1–28. 1 Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, 30 Rufai A, Ralphs JR, Benjamin M. Ultrastructure of fibrocar- Distler A, et al. Prevalence of spondylarthropathies in HLA tilages at the insertion of the rat Achilles tendon. J Anat B27-positive and -negative blood donors. Arthritis Rheum 1996;189:185–91. 1998;41:58–67. 31 Ralphs JR, Benjamin M, Waggett AD, Russell DC, Messner 2 Brown MA, Kennedy LG, MacGregor AJ, Darke C, K, Gao J. Regional diVerences in cell shape and gap junc- Duncan E, Shatford JL, et al. Susceptibility to ankylosing tion expression in rat Achilles tendon: relation to fibrocar- spondylitis in twins: the role of genes, HLA, and the envi- tilage diVerentiation. J Anat 1998;193:215–22. ronment. Arthritis Rheum 1997;40:1823–8. 3 Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor 32 Rufai A, Benjamin M, Ralphs JR. The development of fibrocartilage in the rat . Anat Embryol B, Calin A, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondy- (Berl) 1995;192:53–62. larthropathy. Arthritis Rheum 1991;34:1218–27. 33 Milz S, Putz R, Ralphs JR, Benjamin M. in 4 Braun J, Sieper J. The sacroiliac joint in the spondylar- the extensor tendons of the human metacarpophalangeal thropathies. Curr Opin Rheumatol 1996;7:275–83. joints. Anat Rec 1999;256:139–45. 5 McGonagle D, Khan MA, Marzo-Ortega H, O’Connor PO, 34 Benjamin M, Ralphs JR. The cell and developmental Gibbon W, Emery P. Enthesitis in spondyloarthropathy. biology of tendons and ligaments. Int Rev Cytol 2000;196: Curr Opin Rheumatol 1999;11:244–50. 85–130. 6 Brandt J, Bollow M, Häberle HJ, Sieper J, Braun J. Not all 35 Carlsen S, Hansson AS, Olsson H, Heinegard D, Holmdahl patients with sacroiliitis have spondyloarthropathy - a clini- R. Cartilage oligomeric matrix protein (COMP)-induced cal study of inflammatory back pain and arthritis of the arthritis in rats. Clin Exp Immunol 1998;114:477–84. lower limbs. Rheumatology (Oxford) 1999;38:831–6. 36 Smith RK, Heinegard D. Cartilage oligomeric matrix 7 Benjamin M, Evans EJ, Copp L. The histology of tendon protein (COMP) levels in digital sheath synovial fluid and attachments in man. J Anat 1986;149:89–100. serum with tendon . Equine Vet J 2000;32:52–8. 8 Rufai A, Ralphs JR, Benjamin M. Structure and histopathol- 37 Leroux JY, Guerassimov A, Cartman A, Delaunay N, Web- ogy of the insertional region of the human Achilles tendon. ber C, Rosenberg LC, et al. Immunity to the G1 globular J Orthop Res 1995;13:585–93. domain of the cartilage proteoglycan aggrecan can induce 9 Benjamin M, Ralphs JR. Fibrocartilage in tendons and inflammatory erosive and spondylitis in ligaments—an adaptation to compressive load. J Anat BALB/c mice but immunity to G1 is inhibited by 1998;193:481–94. covalently bound keratan sulfate in vitro and in vivo. J Clin

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