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The concept of a Вsynovio-entheseal complex and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond.

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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: d.g.mcgonagle@leeds.ac.uk.
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. McGonagle, Lories, Tan, Benjamin.
17.
18.
19.
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