The concept of a Вsynovio-entheseal complex and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 56, No. 8, August 2007, pp 2482–2491 DOI 10.1002/art.22758 © 2007, American College of Rheumatology SPECIAL ARTICLE The Concept of a “Synovio-Entheseal Complex” and Its Implications for Understanding Joint Inflammation and Damage in Psoriatic Arthritis and Beyond Dennis McGonagle,1 Rik J. U. Lories,2 Ai Lyn Tan,3 and Michael Benjamin4 of synovitis and the propensity for erosions in early RA (7). This concept of such tissue-specific factors or “autoinflammatory factors” (as distinct from autoimmunity, which is principally played out in the primary and secondary lymphoid organs) allowed for the development of a new classification scheme for all inflammatory disorders (8). Such tissue-specific factors might also underscore common inflammatory or tissue repair pathways that may be shared by both inflammatory and degenerative disorders (9). Thus, the purpose of the present article is to develop the idea that joint-specific factors could trigger innate immune responses and may be pivotal players in the phenotypic expression of PsA, the related SpA, RA, and even OA. The concept is centered on an anatomic unit we have called the synovio-entheseal complex (SEC) and is described in relation to PsA and other types of arthropathy. Introduction The pathogenesis of tissue inflammation and damage in rheumatic diseases that are associated with the major histocompatibility complex (MHC), including rheumatoid arthritis (RA) and the spondylarthritides (SpA), has mainly been viewed in relation to an autoimmune effector mechanism (1–3). However, because synovial joints serve to promote movement, it is logical to assume that aberrant functioning of their constituent parts could contribute to inflammation. Although such “wear and tear” mechanisms are well recognized as contributory factors in osteoarthritis (OA), it is less clear that factors intrinsic to the biomechanical functioning of synovial joints could be significant in diseases considered to be autoimmune. Investigators in our group previously proposed that the primary basis for the pathogenesis of psoriatic arthritis (PsA) and SpA could be biomechanical rather than autoimmune (4–6). This was based on our interpretation of magnetic resonance imaging (MRI) in knee disease in early SpA, which showed specific patterns of inflammation. Moreover, such observations were not confined to SpA, because the anatomic locations of ligaments and tendons also affected both the magnitude The original concept of enthesitis and synovitis In the last decade, it has become clear that enthesitis is well recognized in synovial joints of patients with PsA (6,10,11). The original conceptual link between enthesitis and synovitis was envisioned in terms of liberation of proinflammatory mediators from focal bony attachment sites, which could trigger a secondary synovitis (4,12). In light of new findings, it now appears that the immunopathogenetic interrelationship between synovium and entheses is more complex than first imagined and is relevant far beyond understanding the pathogenesis of PsA. The enthesis often comprises more than a focal insertion and forms part of an “enthesis organ” (Figure 1). However, the functional interdependence of an enthesis with adjacent synovium and how this critically influences the phenotypic expression of joint disease have not been fully appreciated. It must be recognized that it is still unclear whether every diseased joint in every patient with SpA Dr. McGonagle’s work was supported by the Medical Research Council, UK. Dr. Lories’ work was supported by grant G.0340.03 and a postdoctoral fellowship from the Fund for Scientific Research–Flanders. 1 Dennis McGonagle, FRCPI, PhD, University of Leeds, Leeds, UK, and Calderdale Royal Hospital, Halifax, UK; 2Rik J. U. Lories, MD, PhD, Katholieke Universiteit Leuven, Leuven, Belgium; 3 Ai Lyn Tan, MRCP, MD, University of Leeds, Leeds, UK; 4Michael Benjamin, PhD, Cardiff University, Cardiff, UK. Address correspondence and reprint requests to Dennis McGonagle, FRCPI, PhD, Professor of Investigative Rheumatology, Academic Unit of Musculoskeletal Disease, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. E-mail: firstname.lastname@example.org. Submitted for publication December 13, 2006; accepted in revised form April 20, 2007. 2482 THE SYNOVIO-ENTHESEAL COMPLEX 2483 with polyenthesitis when the joints are visualized with high-resolution MRI (11). Several ultrasound studies have also shown that clinically unrecognized enthesitis (often asymptomatic) is extremely common in attachment sites adjacent to the knee joints and other sites that are amenable to sonography (14–17). Furthermore, an immunohistologic study of joints obtained at the time of Figure 1. Diagrammatic representation of the synovio-entheseal complex, using the Achilles tendon enthesis organ to illustrate the concept. The synovial membrane (SM), which is intimately related to the enthesis (E) itself, lines much of the retrocalcaneal bursa (B), except in the region where the sesamoid fibrocartilage (SF) in the deep part of the tendon presses against the periosteal fibrocartilage (PF) covering the superior tuberosity. Macrophages (M) are an integral part of the synovium, and their anatomic proximity to fibrocartilage adjacent to insertions could contribute to an inflammatory response in relation to degenerative changes (DC) in the walls of the bursa or at the enthesis itself. Although a young healthy enthesis is probably avascular, blood vessel invasion (VI) of the enthesis is common in older individuals (24). The blood vessels may come from the underlying bone at sites of focal absence of the subchondral bone plate (FAB), as depicted, or they may invade from tissue on the surface of the tendon, including synovium. has entheseal inflammation, although several MRI studies have suggested a link between enthesitis and synovitis in individual swollen joints in patients with PsA and those with SpA (6,11). This relationship was clearly shown in the knee joint and the distal interphalangeal (DIP) joints of the fingers (6,11), but it was less clearly demonstrated in the proximal interphalangeal joints (10) and has not been shown at all for the small joints of the wrist (13). The inability to show enthesitis in all cases may reflect limitations in the spatial resolution of MRI for small joints because of the close proximity of entheses, synovium, and cartilage–pannus junctions at these sites. In support of this assertion is the observation that DIP joint arthropathy in PsA is universally associated Figure 2. The synovio-entheseal complex in health and disease. In the setting of health, the synovium plays a pivotal role in the nourishment and lubrication of entheseal fibrocartilage, in a manner identical to its function for articular cartilage. In the setting of disease, however, this close functional interdependence could lead to joint inflammation. Tissue damage or necrosis leads to the release of many endogenous proinflammatory molecules, including hyaluronate and fibronectin fragments, RNA and DNA, high mobility group box chromosomal protein 1, glycoprotein 96, Hsp60, Hsp70, cellular uric acid, and others (22). Access of molecules from damaged tissue to the synovium may play a key role in the triggering and perpetuation of inflammation and damage, especially in the presence of intercurrent infections and fortuitous major histocompatibility complex associations, which could lead to subsequent adaptive immune responses. PRRs ⫽ pattern recognition receptors; TLRs ⫽ Toll-like receptors. 2484 arthroplasty suggested that inflammatory changes of bone related to enthesitis were ubiquitous in patients with SpA (18). Taken together, these findings suggest the importance of entheseal disease in synovial joints in general in SpA. The SEC, joint inflammation, and damage The synovium in health. The normal synovium comprises a lining layer and a sublining layer. The lining layer has 2 populations of cells: type A cells, which are macrophages, and type B cells, which are fibroblastic. The sublining layer consists of loose connective tissue, fat, and blood vessels and has considerable potential to undergo angiogenesis and accrue a massive inflammatory cell infiltrate in the event of joint insults (19). Unlike other joint structures, healthy synovium is non–load-bearing and participates in cartilage nourishment and joint lubrication. This involves the synthesis of lubricin, hyaluronan, and other molecules (20) (Figure 2). Synovial macrophages form a key cellular component of the innate immune response and can be activated by a myriad of proinflammatory signals. At the molecular level, cellular activation is related to ligand binding to macrophage receptors, including Toll-like receptors and other pattern-recognition receptors, proinflammatory cytokines, and immune complexes, and to tissue injury or necrosis (21). It is of particular interest that the ligands for innate immune response activation may include fragments of hyaluronan, fibronectin, and other molecules that are released from damaged connective tissue (22). There is thus an emerging concept of a molecular link between joint damage and subsequent innate immune activation leading to joint inflammation, but the sites of such damage in vivo have not been defined. Tropism for inflammatory response localization within the synovium is illustrated by the diversity of factors that lead to synovitis in the adjacent joint. The joint insults may be periarticular or bone related and include the presence of tumors or inflammation. Thus, adjacent osteomyelitis or osteoid osteomas may be associated with secondary synovitis (12). Indeed, irrespective of the initial joint insult or its precise anatomic location, synovitis with associated joint effusion is the final common pathway, reflecting the fact that the synovial membrane can be quickly primed for innate immunologic responses (19). The enthesis in health. Key differences in the microanatomy, vascularity, and cell composition of entheses and synovia can be summarized as follows. First, MCGONAGLE ET AL tendons, ligaments, and joint capsules are composed of dense regular connective tissue, whereas the synovium has a subintimal layer of loose connective tissue. Consequently, diffuse swelling and joint effusions cannot readily occur at the former sites. Second, healthy entheses are avascular at the fibrocartilaginous point of attachment (23), but synovia are well vascularized. From the perspective of immunology, the avascularity of entheses parallels that of articular cartilage, where the presence of blood vessels and immune cells conflicts with the requirements of load bearing and smooth movement. However, in contrast to articular cartilage, there appears to be significant vascular invasion of enthesis fibrocartilage with aging (24). This is likely to be a physiologic response accompanying microdamage with the aim of effecting tissue repair (24). Third, unlike synovia, the healthy enthesis lacks resident macrophages at its fibrocartilaginous bony attachment site (25). However, adjacent fascia, bone marrow, and synovia do have populations of macrophages and/or dendritic cells. Finally, in recent years, it has become clear that the enthesis is often more than a focal attachment and can form part of an elaborate “enthesis organ” that may include functional integration with a synovial membrane (26,27) (Figure 1). This is best exemplified at the Achilles tendon enthesis, where the components of the enthesis organ consist of the enthesis itself, together with periosteal and sesamoid fibrocartilages, the retrocalcaneal bursa, and the tip of Kager’s fat pad. Collectively, these structures help to dissipate load over a wide area. Thus, although there is no neighboring synovial joint lined by articular cartilage at this location, the enthesis is still intimately related to synovium, because a synovial membrane covers the tip of the protruding fat pad (Figure 1). An enthesis organ involving synovium is also present at numerous other sites, some of which are illustrated diagrammatically in Figure 3. It should also be remembered that the very fact that most tendons and ligaments attach to bone in the immediate vicinity of synovial joints (rather than some distance from them) gives their entheses a close anatomic relationship to synovia, even if the synovium does not form part of a distinctive enthesis organ. Given the extent and complexity of entheses, it is likely that the presence of synovium and synovial fluid in the retrocalcaneal bursa and bursae associated with other attachment sites reflects a physiologic role identical to that in synovial joints (Figure 2). Where a bursa is present adjacent to an enthesis, type A and type B THE SYNOVIO-ENTHESEAL COMPLEX 2485 Figure 3. Examples of synovio-entheseal complexes (SECs), highlighting the intimate relationship between each enthesis/enthesis organ/functional enthesis and a neighboring synovial membrane. Each tendon/ligament (together with any associated adipose tissue) is shown in yellow, articular hyaline cartilage is shown in dark blue, fibrocartilage is shown in light blue, synovial membrane (SM) is shown in red, and bone is shown in black. In each case, note the proximity of the enthesis or functional enthesis (i.e., the region where a tendon presses against a bone but does not attach to it) to a synovial cavity (SC). a, An SEC in the extensor tendon (ET) of an interphalangeal joint, as seen in a sagittal section of a finger. Synovium lines the deep surface of the tendon except in the region of the sesamoid fibrocartilage (SF), which, in a flexed finger, is compressed against articular cartilage. b, A complex enthesis organ is associated with the insertion of the tendon of the flexor hallucis longus (FHL) at the base of the distal phalanx of the big toe. Immediately adjacent to its enthesis, the tendon merges with the volar plate (VP), in which a sesamoid bone (SB) is prominent. This bone is covered on its joint side with articular cartilage that forms a part of the interphalangeal (IP) joint. However, on its deep surface, the sesamoid bone is covered by thick sesamoid fibrocartilage (SF) that articulates with a similar (but thinner) fibrocartilage on the adjacent surface of the tendon. The two are separated by the synovial cavity of the tendon sheath, which is lined by a synovial membrane except over the fibrocartilage. c, Variation of the SEC at a functional enthesis, where a tendon (T) wraps around a bony pulley (e.g., the tibialis posterior tendon curving around the medial malleolus) and is associated with a tendon sheath lined by a synovial membrane. In each of the 3 examples, a unifying anatomic basis for the SEC complex is that it minimizes the presence of innate immune cells, especially macrophages, at sites of high stressing. EF ⫽ enthesis fibrocartilage; AT ⫽ adipose tissue; PF ⫽ periosteal fibrocartilage. synoviocytes are likely to be involved in maintaining the rheologic properties of synovial fluid, lubricating and nourishing periosteal and sesamoid fibrocartilages (Figure 2). Because of the emerging evidence for anatomic, functional, and physiologic interdependence between synovial membrane and entheses, we propose that the 2 structures could be viewed as forming a “synovioentheseal complex.” Although such a structure appears to be advantageous in health, the very fact that a tissue prone to microdamage is closely juxtaposed to synovium means that, in effect, the SEC region is walking an immunologic tightrope and may be a region within the joint that is particularly prone to inflammation. Implications of the SEC for synovitis in PsA The structure and cellular composition of the healthy enthesis and the synovium are diametric opposites. By virtue of respective cellular compositions, the healthy enthesis is generally antiinflammatory and the synovium intrinsically proinflammatory. Thus, when a mechanically stressed enthesis is injured, any associated inflammatory reaction would be expected to man- ifest prominently within the juxtaposed synovium. This principle is well illustrated in OA, where joint injury leads to the shedding of articular cartilage “shards” that are thought to play a role in associated secondary synovitis (28). Recently, we showed that extensive microdamage and altered vascularity are present at numerous entheses in elderly individuals, which probably relates to a lifetime of mechanical loading (24). We and others similarly noted that fibrocartilage adjacent to insertions that are closely juxtaposed to synovium are also sites of microdamage (29,30). Indeed, Rufai et al suggested that this could trigger retrocalcaneal bursitis (30). The mechanism whereby factors related to SEC microdamage could directly contribute to the initiation of joint inflammation at the molecular level has been elucidated in recent years, as previously stated. It turns out that not only are Toll and other pattern-recognition receptors activated in response to bacterial molecules including lipopolysaccharide, but also that the same receptors can serve as ligands for molecules released from damaged tissue (22) (Figure 2). 2486 MCGONAGLE ET AL Lessons from animal models The central tenet of the SEC model is that primary entheseal abnormalities trigger secondary joint synovitis. This is virtually impossible to study in humans, but such study is feasible in animal models of disease. No animal model exactly mimics human arthritis, and issues such as the relative quantities of fibrocartilage at associated entheses and the extent of microdamage in small animal joints compared with human joints remain unresolved. However, these models provide the researcher with experimental systems for studying specific aspects of the disease process. Some recent observations in different animal models support the hypothesis that the SEC is a unifying factor in understanding PsAassociated synovitis. Spontaneous arthritis in aging male DBA/1 mice is characterized by oligoarthritis of the hindpaw toes and more rarely involves the ankles. Investigators in our group previously reported striking similarities between this murine disease and human PsA (31). In addition to observing enthesitis leading to joint ankylosis (which presents clinically as arthritis), investigators in our group also recognized dactylitis with extensive subcutaneous edema and onychoperiostitis, both of which are typical of PsA (31). Histomorphologic analysis demonstrated that ankylosis as a result of enthesitis is the hallmark of this murine disease, and that synovitis is not necessary for the appearance of clinical arthritis (31). Two stages can be recognized in this model. First is the development of an acute inflammatory reaction, with diffuse subcutaneous edema around tendons and muscles and infiltration of neutrophils and macrophagelike cells (Figure 4). Of particular interest are the foci of intense cell infiltration that are observed adjacent to entheses (31). This acute inflammatory process usually extends into the synovium (Figure 4). Synovitis is similarly characterized by cell infiltration without any hyperplasia of the lining layer. In most cases, this acute inflammatory process subsides rapidly, and the second phase of the disease process develops. This is characterized by endochondral ossification that starts at the enthesis and culminates in joint ankylosis. In the fused joint, the synovium generally shows little involvement. As ankylosis progresses, increased cellularity is sometimes noticed in the synovium, with mainly fibroblastlike cells present in the sublining layer. Mild hyperplasia of the lining layer is rare (Figure 4). In late stages of disease, the synovium may disappear in the bridging bony structure between both articular surfaces. The dual response of the synovium in the inflammatory and Figure 4. Enthesitis and synovitis in different stages of spontaneous arthritis in male DBA/1 mice. A, Acute subcutaneous inflammation extending into the entheseal region, with diffuse cell infiltration. B, Details of an inflammatory cell infiltrate. Inset shows highermagnification view of boxed area. Arrows show enthesis-associated inflammatory changes extending into the synovium. C, Limited synovial hyperplasia and cell infiltration (arrow) during progression of endochondral bone formation at the enthesis. D, Joint ankylosis extending into the disappearing synovium in late stages of the disease. AC ⫽ articular cartilage; SC ⫽ synovial cavity. (Hematoxylin and eosin stained; original magnification ⫻ 400 in A and B; ⫻ 200 in C; ⫻ 100 in D.) remodeling stages provides strong support for the concept of secondary synovial inflammation in the SEC. Therefore, the DBA/1 mouse model is characterized by excessive tissue responses. In humans, it is possible that an intrinsic but overexuberant repair response also underlines the propensity for site-specific SEC disease. Other recent models support the SEC concept of synovitis in PsA, including inducible genetic deletion of the activator protein 1 transcription factor components, c-Jun and JunB, which results in the development of psoriasis-like skin lesions and PsA-like arthritis in mice (32). The histomorphologic presentation of arthritis in this model has not been extensively reported but is suggestive of both enthesitis-related diseases, including osteitis, and synovium-related disease (32). When the mice were crossed into a T cell–deficient background, arthritis was milder, with an absence of erosions. However, skin disease remained unchanged. Interestingly, these observations in an animal model of PsA are reminiscent of those in HLA–B27–associated SpA in humans, in which the MHC appears to modulate the severity of bone disease (33). The animal model sup- THE SYNOVIO-ENTHESEAL COMPLEX 2487 ports the assertion that innate immune activation within the SEC is critical for the phenotypic expression of PsA, and that adaptive immune responses, as orchestrated by T cells, modify the clinical phenotype. In other words, the model shows how SEC-related, tissue-specific factors rather than the adaptive immune response may be primary in PsA. This is in contrast to classically recognized, antigen-driven autoimmunity, including thyroid disease and idiopathic thrombocytopenic purpura and other neonatal autoimmune conditions, in which autoantibodies may attack ostensibly normal tissue (8). Synovial immunopathology in relation to the SEC Many investigators still view synovitis in PsA and SpA as being related to a primary synovial immunopathology independent of entheseal-related disease, largely similar to the concept of RA (20). Both macroscopic and microscopic synovial abnormalities have been described, including less hyperplasia of the lining layer compared with that observed in RA (34–36). Two of these studies demonstrated more subsynovial tissue edema and greater vascularity in PsA (34,35), but the other study did not (36). One recent study showed that neutrophilic synovial inflammation was much more common in PsA than in RA (37). Both B cells and T cells have been observed in the synovium of patients with PsA, but specific synovial T cell clonal expansions that might confirm that joint autoantigens drive the immune response have not been shown (38). Furthermore, the assertion that PsA is related to HLA–Cw6 has been challenged by a recent large study that showed a milder spectrum of joint disease in patients carrying this gene (39). There is, therefore, evidence for a distinct pattern of synovitis in PsA but a lack of evidence for autoimmunity. The notion that synovitis in PsA is unique is also supported by results of macroscopic and microscopic studies showing that the pattern of blood vessels in PsA is disorganized compared with that in RA. This has been interpreted as representing some fundamental angiogenic perturbation that drives synovitis in PsA (40,41). However, the question of whether synovial angiogenesis in PsA is abnormal compared with that in RA remains controversial, because this difference in angiogenesis is not supported by some important studies (36,42). Examining both the immunologic and vascular features of synovitis from the SEC perspective offers a novel view of putative immunopathogenetic mechanisms of PsA-related joint disease, at least in some settings. These differing angiogenic features could be attributable Figure 5. Proposed time line for development of clinical rheumatoid arthritis (RA) and psoriatic arthritis (PsA) (or reactive arthritis) in relation to the synovio-entheseal complex (SEC). The light gray area represents the hitherto poorly understood preclinical disease phases. The dark gray area represents RA or PsA at the time of clinical presentation with joint swelling and pain. The evolution of RA appears to be a gradual process, as suggested by the presence of autoantibodies and an elevated level of C-reactive protein months before clinical presentation. In contrast, the onset of spondylarthropathy (including some types of PsA) can be clearly traced to an inciting event within the preceding days or weeks. Recognized triggering stimuli for PsA include acute infection and joint injury. Therefore, compared with early RA, early PsA is characterized by a relatively abrupt onset of inflammation and marked angiogenesis. It is thus proposed that the propensity for microdamage and microtrauma in the SEC contributes directly to the onset of synovitis in spondylarthritis (i.e., the kinetics of the inflammatory responses lead to a different clinical phenotype in early disease). As stated in the text, this mechanism is supported in only a subset of patients with PsA. to a relatively slow onset of synovitis in early RA and a more abrupt onset in early PsA and reactive arthritis, in which identical vascular changes have been reported (Figure 5). In RA, synovitis generally develops slowly, as indicated by a subclinical disease phase; this scenario would permit more ordered angiogenesis (43). This is supported by both the demonstration of synovitis during early disease in joints that apparently are not involved and the presence of autoantibodies that predate clinical synovitis by years (43,44). In contrast, the quick onset of synovitis associated with the enthesitis that occurs in SpA (especially reactive arthritis and some types of PsA, including guttate-related disease that follows streptococcal infections) might lead to a massive and abrupt angiogenesis and hence the formation of a more disorganized network of vessels. This is supported by the recognition that reactive arthritis occurs within 1 day to 1 month of an inciting infection. The good prognosis in reactive arthri- 2488 tis, in which the angiogenic phenotype is identical to PsA, also provides evidence against an intrinsic angiogenic phenotype being critical for disease perpetuation. According to the SEC-centered view, some hitherto poorly understood event, including recent SEC microdamage or tissue repair, could stochastically trigger innate immunity and a relatively fast onset of synovitis (Figure 5). This type of scenario in both psoriasis and PsA is not without support, given the association of preceding joint or skin injury (Koebner’s phenomenon) with the expression of joint disease at different sites (45,46). Thus, some aspects of the angiogenic phenotype in PsA could be linked to the kinetics of the synovitis response, which could, in turn, be related to the SEC (Figure 5). It is not contended that the SEC provides an exclusive view of synovitis in PsA, because one study noted tortuous synovial blood vessels in the setting of chronic PsA compared with chronic RA, suggesting that the vascular pattern could represent more than just a difference in the rate at which synovitis develops and is maintained throughout disease (47). It also must be acknowledged that some studies support the notion that PsA-related synovitis may have a long preclinical phase, because pericapsular bony abnormalities, presumably related to the existence of an enthesis organ, are a feature of asymptomatic patients with skin disease only (48). Clearly, this is an area for further research, especially on unaffected joints in PsA, and illustrates how the kinetics of synovitis could influence the apparent clinical phenotype in some settings. The recent demonstration of altered vascularity at enthesis insertions also raises the possibility that putative angiogenic phenotypes in the skin and synovium could also equally apply to the enthesis in PsA. Although the fibrocartilage at entheses has been viewed as avascular, it appears that microdamage and ensuing repair responses at normal insertions could be associated with significant neovascularity at this site (24). Therefore, somewhat surprisingly, aberrant vascular responses at entheses could play a role in PsA, and any “vascular phenotype” in disease may be directly relevant to the SEC concept. Therefore, it is tempting to speculate that aberrant vascular responses during normal SEC-related repair responses could contribute to a normal repair response being converted into a pathologic one. The SEC in RA and OA In the last decade, results of several clinical and animal studies have suggested that transformed synovial MCGONAGLE ET AL Figure 6. Schematic diagram showing how the synovio-entheseal complex (SEC) may influence erosion formation in rheumatoid arthritis (RA). The collateral ligament (CL) presses on the bone adjacent to the ligament origin and is thus characterized by a sesamoid fibrocartilage (SF) on its deep surface. The rest of the ligament is lined by a synovial membrane (SM). Direct SEC stressing on bone likely contributes to erosion (E) formation at these characteristic sites in early RA. The site of erosion is typically where the collateral ligament presses against a periosteal fibrocartilage (PF) that extends the articular cartilage (dark blue) around the sides of the bone. EF ⫽ enthesis fibrocartilage; SC ⫽ synovial cavity; IP ⫽ interphalangeal. fibroblasts play a pivotal role in the pathogenesis of joint erosion in RA (49,50). If this were exclusively the case, then erosions would be expected to develop at random locations adjacent to the cartilage–pannus junction in small joints. However, the erosions that develop in small joints in early RA are typically seen adjacent to the SEC that is formed by the collateral ligament attachments, adjacent cartilages, bone, and synovium (Figure 6). Mechanistically, this is still poorly understood, but bone microdamage next to the SEC may be a major contributory factor (24). In support of this possibility is the observation that cysts tend to develop adjacent to the SEC region in normal joints (7). It therefore appears that RA-associated synovitis drives the inherent propensity for damage to occur at such sites (7). It is worth noting that erosions that develop in patients with inflammatory OA, as determined by high- THE SYNOVIO-ENTHESEAL COMPLEX resolution MRI of the interphalangeal joints, may be seen at the same location adjacent to the SEC (51). In small-joint OA, some patterns of bone edema that originate at the SEC also extend to the subchondral regions, thus providing a link between the SEC and possible cartilage damage (29). Therefore, for small joints, it appears that chronic synovitis, irrespective of the triggering or perpetuating factors, leads to the same phenotypic expression of SEC periarticular erosions that is observed in early arthritis. More work is needed to elucidate the precise role of the SEC in the pathogenesis of joint damage other than SpA. Implications of the SEC for monitoring disease What does the SEC concept mean in terms of clinical practice? Because the enthesis and synovium are so functionally integrated, serial evaluation of periarticular joint erosion in PsA is valuable, because halting the progression of erosion represents an arrest, or at least an abrogation, of the SEC-related inflammatory response, even if its origin relates to precipitating factors that are not related to the synovia (52–54). In addition to synovitis and erosions, outcome measures must include new bone formation at entheses and joint ankylosis, because these are features of SpA in particular. New bone formation could be completely independent of synovitis, given the evidence that inflammation and remodeling occur at 2 different time points in animal models of SpA (55). In view of the intimate relationship and functional integration of synovia and entheses, it seems clear that studies of synovial fluid or synovial tissue (e.g., biologic studies of T cells) are still relevant surrogates for understanding PsA. However, such studies in humans must be performed in the context of understanding the functional complexity of the SEC rather than in the context of pure synovia-based immunopathology. Implications of the SEC for synovitis ablation Until recently, successful therapy for RA was envisaged almost exclusively in terms of controlling autoimmune mechanisms and thereby ablating inflammation. However, it has been shown at 2 different sites in patients with RA that the SEC not only influences the magnitude and severity of synovitis within joints but also determines the effectiveness of therapy. In RA, synovitis is most pronounced adjacent to the collateral ligaments that form an SEC in the metacarpophalangeal joints of the hand (7). In the suprapatellar bursa of the knee, the SEC formed in part by the quadriceps tendon insertion 2489 on the patella also influences the magnitude of local synovitis (56). Following therapy for knee joint synovitis with either methotrexate or leflunomide, synovitis adjacent to the patella proved more difficult to suppress in comparison with that at remote sites in the suprapatellar bursa (56). This observation has enhanced the concept that site-specific factors could contribute to innate immune activation and thus help sustain disease. It also suggests that factors intrinsic to the joints that are independent of autoimmunity in RA may make a major contribution to the phenotypic expression of disease and determine whether remission can be induced (8). This viewpoint of non–autoimmune-related factors is supported by work on the K/BxN mouse model of RA, in which alterations in synovial vascularity predate ostensible evidence of autoimmunity (57). Conclusions In the original enthesis-based model for SpA, synovitis was viewed as being principally related to the release of inflammation mediators from attachment sites. Indeed, florid inflammatory reactions at entheses suggest that this may be a factor in joint disease (11). However, in the years since the introduction of the original enthesitis model, there have been tremendous advances in understanding joint disease, from the macroscopic level to the microscopic level (58). Although genetic factors are important in inflammatory arthritis, this area has been extensively covered over the years (59–61). Herein, we focused on tissue-specific factors in the joint that could contribute to innate immune activation. We viewed the interrelationship between the synovium and the enthesis and suggest that the spectrum of synovial joint disease can usefully be conceptualized in relation to the SEC. Currently available imaging techniques are limited in defining the changes occurring at an enthesis in the environment of inflamed synovium, and it remains to be seen whether synovitis is always associated with SEC-related disease, or whether microdamage to the synovium, for example, could trigger synovitis independently. Rheumatologists increasingly recognize the key role of joint-specific factors in autoimmune diseases such as RA (62). It appears that local microenvironmental response to the stressing of SEC tissue (which may include cell injury) dictates, to a variable degree, the clinical expression of disease, especially in PsA/SpA but also in other conditions. The issue of whether aberrant repair responses at SEC sites without prior significant microtrauma are also important in initiating or driving MCGONAGLE ET AL 2490 inflammation awaits elucidation. Although RA and PsA historically have been classified as autoimmune diseases, the SEC concept supports the importance of jointspecific factors that serve as danger signals triggering innate immune responses that lead to either disease localization or specific patterns of disease expression. For example, the role of joint-specific factors centered on the SEC explains why MHC associations and primary immunologic synovial perturbations are generally not well reproduced in PsA (38,63). This SEC-based model thus allows for an improved conceptual understanding of arthritis in general. 12. 13. 14. 15. 16. AUTHOR CONTRIBUTIONS Dr. McGonagle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. McGonagle, Lories, Tan, Benjamin. Acquisition of data. McGonagle, Lories, Tan, Benjamin. Analysis and interpretation of data. McGonagle, Lories, Tan, Benjamin. Manuscript preparation. 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