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Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 60, No. 4, April 2009, pp 1042–1051
DOI 10.1002/art.24417
© 2009, American College of Rheumatology
Microanatomic Studies to Define Predictive Factors for the
Topography of Periarticular Erosion Formation in
Inflammatory Arthritis
Dennis McGonagle,1 Ai Lyn Tan,1 Uffe Møller Døhn,2 Mikkel Østergaard,2
and Michael Benjamin3
corresponded to CT-determined erosion formation in
the MCP and PIP joints of patients with RA, in whom
erosions adjacent to the CLs were more common than
dorsal or volar erosions.
Conclusion. Periarticular erosion formation may
not necessarily depend on the presence of a bare area
and has a propensity to occur adjacent to ligaments in
which bone microdamage is common. These findings
suggest that periligamentous locations prone to microdamage may critically influence the topography of erosion formation in inflammatory arthritis.
Objective. The microanatomic basis for formation
of erosions in inflammatory arthritis is incompletely
understood but is thought to be related to bare areas
and the associated cartilage–synovium junction. The
purpose of this study was to test the hypothesis that
erosion-prone sites are associated with microdamage in
macroscopically normal joints.
Methods. Histologic evaluation of erosion-prone
sites was performed on 20 collateral ligaments (CLs)
from the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) joints of 5 normal cadavers. In
addition, the MCP joints (n ⴝ 17) and PIP joints (n ⴝ
3) of 20 patients with rheumatoid arthritis (RA) were
assessed by computed tomography (CT) to ascertain
whether the topography of erosion formation in patients
with RA corresponded to the cadaveric findings.
Results. Absence of a bare area was noted in
cadaveric tissue at the periligamentous erosion-prone
regions, especially in the distal MCP joints and both
distal and proximal PIP joints. Nevertheless, these sites
exhibited soft-tissue pathologic features and bony
microdamage/cyst formation. Other significant findings
included the presence of pannus without inflammatory
changes in the regions in which a bare area was absent,
and the replacement of bare area regions with fibrovascular synovial tissue in joints without inflammatory
changes. The sites of cadaveric tissue microdamage
Erosion formation in a periarticular distribution
in the small joints is well recognized in rheumatoid
arthritis (RA), seronegative spondylarthritis (especially
psoriatic arthritis [PsA]), and also in a subgroup of
patients with erosive osteoarthritis (OA) of the hand.
The importance of such joint erosion (a key component
of this destructive process) has been central to both the
clinical and the scientific understanding of RA (1). For
example, erosion formation is important for diagnosing
RA, is a valuable prognostic marker, and is a useful
outcome measure in clinical trials (2–4). Furthermore,
an improved understanding of the pathophysiologic basis of erosion is regarded as a central precept for
elucidating the pathogenic mechanisms of RA (5). In the
case of PsA, formation of periarticular erosions has also
been linked to a poor prognosis (6).
The current model for erosion formation is one
that encompasses aberrant adaptive immune responses
that are associated with synovial fibroblast dysfunction
and osteoclast activation that culminates in bone destruction (7). The cellular immunopathologic processes
leading to erosion are believed to occur at a distinct
microanatomic territory, termed a “bare area,” in which
synovium comes into direct contact with bone, thus
1
Dennis McGonagle, PhD, FRCPI, Ai Lyn Tan, MBBCh,
MD, MRCP: University of Leeds, and Chapel Allerton Hospital,
Leeds, UK; 2Uffe Møller Døhn, MD, PhD, Mikkel Østergaard, MD,
PhD, DMSc: Hvidovre and Herlev University Hospitals, Copenhagen,
Denmark; 3Michael Benjamin, PhD: Cardiff University, Cardiff, UK.
Address correspondence and reprint requests to Dennis
McGonagle, PhD, FRCPI, Academic Unit of Musculoskeletal Disease,
Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK.
E-mail: d.g.mcgonagle@leeds.ac.uk.
Submitted for publication September 18, 2008; accepted in
revised form January 7, 2009.
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PREDICTORS OF PERIARTICULAR EROSION FORMATION IN ARTHRITIS
allowing osteoclast activation and erosion formation (8).
Another key concept is that a cartilage–pannus junction
is formed at this bare area during the destructive phase
of RA (9). However, these concepts have mainly been
formulated in studies of the large joints, such as the
knee, because these are typically affected in RA (10).
Additionally, these concepts have been developed by
performing histologic studies in patients with longstanding disease, without the use of normal control tissue.
We have previously utilized magnetic resonance
imaging (MRI) to rekindle interest in another possible
microanatomic factor in erosion formation (11). The
results from MRI showed that erosion formation in the
metacarpophalangeal (MCP) joints of patients with RA
is not random but, rather, occurs with a high frequency
adjacent to the collateral ligament (CL) origins of the
MCP joints, which are also sites of bony compression
(11). With the use of MRI in normal individuals, we also
noted a small degree of bone damage adjacent to the
CLs at the same MCP anatomic location, but the
histologic basis for such “erosion-like” changes has not
been defined. Given that the CLs in MCP joints are
relatively large structures, we postulated that synovitis in
RA drove the inherent tendency for bone erosion to
occur at certain predisposed locations (11).
In view of our previous MRI findings and the lack
of detailed knowledge about the microanatomy of the
CLs associated with MCP joints, we carried out the
present study to investigate the microanatomic factors
that could contribute to erosion formation in the joints.
In this study, we assessed the CLs in the context of the
“enthesis organ” concept, which recognizes that structures immediately adjacent to attachment sites may be
subject to compression since they contribute to reducing
stress concentration at the enthesis itself, and that these
sites are lined by buffering cartilage (12,13). Herein we
show that sites prone to compression, in which a bare
area may be absent, are associated with microdamage
and cyst formation. We also show that these sites
correspond to the topography of erosions in RA, as
defined by computed tomography (CT). Collectively,
these findings indicate that factors related to the anatomy of the small joints of the finger are major contributory factors in erosion formation, and thus such predictive factors may be relevant across the whole
spectrum of arthritic diseases.
PATIENTS AND METHODS
Histologic analysis of cadaveric tissue from the small
joints of the hands. Ten MCP and 10 proximal interphalangeal
(PIP) CLs were collected from 5 embalmed cadavers (mean
1043
age 90 years, range 74–101 years; 2 male, 3 female) donated to
Cardiff University for anatomic investigation under the provision of the 1984 Anatomy Act and the 1961 Human Tissue Act.
The embalming fluid contained 4% formaldehyde and 25%
alcohol as active fixative agents. None of the cadavers had any
grossly visible pathologic features in the joints examined,
although medical histories were not available. For both the
MCP and the PIP joints, the ligaments came from the same
finger in each cadaver. In all cases, both the radial and the
ulnar CLs were removed separately by hemisecting the joint in
the mid-sagittal plane. In this way, the relationship of each
ligament to the bones of the joint was retained; a total of 20
ligaments was thus examined.
After removing the ligaments in this manner, the tissue
was further fixed in 10% neutral buffered formalin for ⬃1
week, decalcified in 5% nitric acid, rinsed briefly in tap water,
and dehydrated with graded alcohols (70%, 90%, and
laboratory-grade absolute alcohol). The dehydrated tissue was
cleared in xylene and embedded in paraffin wax for routine
histology. Coronal sections (8 ␮m thick) were cut throughout
each block, so that the entirety of each CL could be examined.
Six sections were collected at 1-mm intervals and mounted on
glass slides. Three slides were stained with Masson’s trichrome
(for general histology) and 3 with toluidine blue (to highlight
the presence of a [fibro]cartilaginous matrix by its metachromasia).
Sections at all sample points of each of the 20 ligaments were systematically examined, and particular attention
was paid to the presence and location of bone damage.
Abnormalities were scored as erosions in areas in which the
bone surface was absent, and scored as cysts when these
regions were filled with fibrous connective tissue. The bare
areas were defined as regions within the confines of the joint
capsule in which synovial membrane was reflected onto the
bone in relation to the CLs. Thus, we were able to note
whether any bone cysts or erosions communicated with the
joint cavity, lay beneath articular cartilage, or occurred at one
of the CL entheses. We also assessed the histologic structure of
any bare areas.
Topography of radiographic erosions in RA. Seventeen
patients with established RA fulfilling the American College of
Rheumatology (formerly, the American Rheumatism Association) 1987 criteria (3) underwent CT of their second to fifth
MCP joints, using a Philips Mx8000 IDT multidetector unit
(Philips Medical Systems, Cleveland, OH) as previously reported (14). Thirteen patients were female and 4 were male
(median age 52 years, range 33–78 years), and the median
disease duration was 8 years (range 4–22 years). In addition,
CT scans of the second to fifth PIP joints were obtained from
a further 3 patients with RA (1 female, 2 male; median age 59
years, range 51–64 years), whose median disease duration was
5 years (range 4–7 years). Images with a voxel size of 0.4 mm ⫻
0.4 mm ⫻ 1.0 mm were obtained. Axial and coronal reconstructions with a slice thickness of 1.0 mm were created and
used for image evaluation.
The CT images were evaluated for erosions by an
observer (MØ) who was blinded to the clinical and radiographic data. Erosions in both the coronal and the axial planes
were marked on preformed scoring sheets. Erosions were
defined as sharply demarcated areas of focal bone loss visualized in 2 planes, with a cortical break (loss of cortex) in at least
1044
McGONAGLE ET AL
Figure 1. Normal anatomy of erosion-prone sites adjacent to the collateral ligaments of the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) joints of normal cadavers. a, Coronal section of an ulnar collateral ligament (UCL) of an MCP joint, showing how the deep
surface of the ligament is compressed against the articular cartilage (AC) extending around the side of the metacarpal (M). The cartilage on the side
of the MCP head articulates with the ligament, instead of with articular cartilage on the adjacent phalanx. There is a small bare area (BA) at the
metacarpal end of the ligament, but no bare area at the phalangeal end. The ligament insertion (LI) thus lies directly adjacent to the articular
cartilage on the base of the proximal phalanx (PP). Note the large synovial fold (S) extending into the joint cavity (JC). Bar ⫽ 1 mm. Inset,
Higher-magnification view of the boxed area in a, showing opposing surfaces of the articular cartilage and the collateral ligament. The upper region
is the deep surface of the ligament, showing the presence of fibrocartilage cells, while the lower region is the hyaline articular cartilage, against which
the ligament presses. Upper bar ⫽ 25 ␮m; lower bar ⫽ 100 ␮m. b, Coronal section of the radial collateral ligament (RCL) of a PIP joint, showing
how the deep surface of the ligament is compressed against the periosteal fibrocartilage (PF) extending from articular cartilage around the side of
the proximal phalanx. Note the complete absence of a bare area at both ends of the ligament. IP ⫽ intermediate phalanx. Bar ⫽ 2 mm.
1 plane. Erosion sites were documented according to location,
and designated as being either distal or proximal to the joint on
the coronal plane or as dorsal, volar, radial, or ulnar on the
axial plane, resulting in a total of 8 quadrants in a joint (4
quadrants each on the proximal and on the distal parts of the
joint). In those cases in which a large erosion spanned more
than 1 location, all locations were documented.
Statistical analysis. McNemar’s test was used to compare the proportion of the sites of CT-determined erosions.
The results of significance tests are presented as a guideline
only. All analyses were performed with SPSS, version 12.0.1
(Chicago, IL).
RESULTS
Histologic findings. Proximal MCP joint anatomy.
The CLs of the fingers are divided into the CL proper
and the accessory CL. In both the MCP and the PIP
joints, the CLs proper are much more substantial than
the accessory CLs, and therefore the CL proper was the
principal focus of interest. Histologically, the synovium
from all specimens did not show any evidence of florid
inflammation. In the MCP joints, articular cartilage
PREDICTORS OF PERIARTICULAR EROSION FORMATION IN ARTHRITIS
1045
Figure 2. Pannus formation and normal anatomy in association with the collateral ligaments of the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) joints of normal cadavers. a, Coronal section of a radial collateral ligament (RCL) of an MCP joint, showing the absence of
a bare area at either end of the ligament in this particular specimen (the size of bare areas varied from specimen to specimen), and showing the
continuity of ligament enthesis fibrocartilage (EF) and articular cartilage (AC) on the metacarpal head (M) and the base of the proximal phalanx
(PP). Bar ⫽ 2 mm. b, Left, Bare area associated with the metacarpal end of an ulnar collateral ligament of an MCP joint, in which there is a thick
subsynovial layer of highly vascularized connective tissue (arrows) beneath a surface layer of synoviocytes (S). There is also scalloping (asterisks)
of the bone cortex (B), but no frank erosion. Right, A more common view of a typical bare area, in which there is little subsynovial tissue. This
example is of the distal (phalangeal) end of an MCP joint in association with a radial collateral ligament. Bars ⫽ 100 ␮m. c, Metacarpal end of the
radial collateral ligament of an MCP joint, showing the absence of a bare area. Pannus invasion of cartilage is evident, without inflammatory change.
Bar ⫽ 500 ␮m. Inset, Higher-magnification view of the boxed area in c, showing pannus (P) invading the surface of articular cartilage. ME ⫽
metacarpal enthesis of the collateral ligament. Bar ⫽ 100 ␮m. d, Radial collateral ligament of a PIP joint attaching immediately adjacent to articular
cartilage on the intermediate phalanx (IP). No bare area is evident, but pannus is invading the cartilage, indicating that pannus formation does not
rely on a bare area region and is present in normal joints of elderly subjects. Bar ⫽ 100 ␮m.
covering the metacarpal bones extended around the side
of the bones to a varying degree. Thus, the cartilage
pressed directly against the ligament adjacent to its
origin, i.e., its proximal enthesis (Figure 1a). This was
related to the presence of an enthesis organ at this site,
as evidenced by the existence of small sesamoid fibrocartilage within the ligament (Figure 1a, inset). In some
specimens, the contact area between cartilage and ligament was 2–3 mm. In 2 cases, a high level of ligamentjoint compression was suggested by the presence of
sesamoid bone covered with hyaline cartilage near the
deep surface of the ligament.
Proximal PIP joint anatomy. In the PIP joints,
cartilage extended around the side of the proximal
phalanges, although this was typically fibrocartilage
rather than hyaline cartilage (Figure 1b). In addition, the
bony surface was almost completely covered by fibrocartilage that extended from the articular cartilage margin to include the fibrocartilage at the proximal attachment site of the CLs (Figure 1b).
1046
McGONAGLE ET AL
Figure 3. Presence of bony erosions/cysts and cartilage destruction in association with the collateral ligaments of the metacarpophalangeal (MCP)
and proximal interphalangeal (PIP) joints of normal cadavers. a, Coronal section of an ulnar collateral ligament (UCL) of an MCP joint, showing
the presence of an erosion (arrow) on the metacarpal (M). PP ⫽ proximal phalanx. Bar ⫽ 2 mm. b, A further example of an erosion at an ulnar
collateral ligament of an MCP joint. The bone defect (arrow) lies beneath the articular cartilage (AC). Bar ⫽ 500 ␮m. c, An erosion (arrow)
associated with the radial collateral ligament (RCL) of a PIP joint, extending through the articular cartilage near its junction with the periosteal
fibrocartilage on the proximal phalanx. Bar ⫽ 500 ␮m. Inset, Higher-magnification view of the adjacent part of the ligament in c, showing the
presence of fibrocartilage cells (FC). Bar ⫽ 50 ␮m. d, A bone cyst (arrow) beneath the articular cartilage that extends around the side of the
metacarpal head, with evidence of pressing against the ulnar collateral ligament. Bar ⫽ 500 ␮m.
Distal MCP and PIP joint anatomy. The insertion
of the CLs was much closer to the joint line than to the
origin, in both the MCP and the PIP joints (Figures 1a
and b). Similar to the findings in the proximal side of the
PIP joint, the insertional enthesis fibrocartilage of the
CLs in both joints often merged imperceptibly with
articular cartilage (Figures 1a and b and 2a).
Bare areas in the proximal region of the MCP joints.
A bare area was a universal feature of the proximal
aspect of the MCP joints, on both the ulnar side and the
radial side (Figure 1a). However, it could be quite small
and locally absent in some of the joints. Consequently, it
is possible for articular cartilage to lie immediately
adjacent to the entheseal fibrocartilage of the ligament
(Figure 2a).
The traditional view of the structure of a bare
area at this site is that it is represented by a thin covering
of synovial membrane immediately adjacent to the bone
surface, with little underlying connective tissue. However, in at least some sections from all MCP joints, there
was a thick layer of connective tissue beneath the
synovium (compare the panels in Figure 2b). This subsynovial tissue often exhibited hyperplasia and/or vascular changes. This region was also associated with subtle
damage or, in a few cases, scalloping of the bone cortex
(Figure 2b).
PREDICTORS OF PERIARTICULAR EROSION FORMATION IN ARTHRITIS
1047
Figure 4. Sites of bony erosions/cysts associated with the collateral ligaments of the metacarpophalangeal (MCP) and proximal interphalangeal
(PIP) joints of normal cadavers. a, A bony erosion (arrow) at the radial collateral ligament (RCL) of a PIP joint, located at the origin of the ligament
from the proximal phalanx (PP). IP ⫽ intermediate phalanx. Bar ⫽ 3 mm. b, An enlarged view of the erosion in a, at a site immediately adjacent
to the articular cartilage (AC) of the proximal phalanx. A synovial membrane with a thick underlying layer of connective tissue (arrows) lines
the bone surface. Bar ⫽ 500 ␮m. c, An erosion developing adjacent to the articular cartilage on the metacarpal in an MCP joint, adjacent to the
ulnar collateral ligament (UCL). Bar ⫽ 200 ␮m. d, An erosion (arrow) developing at the insertion of the ulnar collateral ligament of a PIP joint,
immediately adjacent to the articular cartilage on the intermediate phalanx. Note the complete absence of any bare area. Bar ⫽ 200 ␮m.
Bare areas in other regions. In serial sections, bare
areas were minimal on the proximal part of the PIP
joint, and bare areas were completely absent in 1 subject.
Moreover, bare areas were often completely absent in
the distal parts of the MCP and PIP joints.
Features at the cartilage–synovium junction. We
noted classic pannus tissue in cadaveric material in
which there was no obvious inflammatory cell infiltration (Figures 2c and d). Indeed, some degree of synovial
erosion of cartilage was universal in the MCP joints and
was present in the majority (4 of 5) of the PIP joints.
Intriguingly, pannus tissue invasion of articular cartilage
was found to occur at sites in which a bare area was
completely absent (Figures 2c and d), suggesting that
pannus formation is independent of that particular anatomic territory. Thus, pannus formation does not depend
on the presence of immediately adjacent synovial tissue.
Distribution of bony erosions or cyst formation.
Small bony erosions and/or cysts were seen in association with 2 of 5 radial CLs of the MCP joints and 4 of 5
ulnar CLs. In the PIP joints, erosions/cysts were present
in association with 4 of 5 radial ligaments and 2 of 5 ulnar
ligaments. Erosions or cysts were observed on both sides
of the MCP and PIP joints, although more typically they
were found to be present proximally. Those on the proximal aspect of both joints were either intracapsular (adjacent to or beneath articular cartilage [Figures 3 and
4a–c]) or sited at the CL enthesis. Those erosions or
1048
McGONAGLE ET AL
Figure 5. a, Distribution of sites of erosion in the metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA), showing that
erosions were found in the proximal part of the MCP joint as formed by the base of the metacarpal, and the distal part of the MCP joint as formed
by the head of the proximal phalanx. Most of the erosions were found on the radial and ulnar sides of the joint proximally (P ⬍ 0.0001 versus dorsal
and volar), but they were more randomly distributed distally (P ⫽ 0.064 between sites). b, Computed tomography scans of the axial (upper) and
coronal (lower) planes of the second and third MCP joints of a patient with RA, demonstrating erosions on the radial (R) side of the proximal part
of the joints. Note that on the coronal sections, the erosions were adjacent to the collateral ligaments. U ⫽ ulnar.
cysts at the distal side of both joints were usually at or
adjacent to the ligament attachment site (Figure 4d).
Importantly, such erosions/cysts were not always
related to bare areas, since they could be found beneath
cartilage (Figures 3b and d) and in regions of joints in
which no bare area was present at all (Figure 4d).
Furthermore, erosion formation was evident at sites
usually covered by fibrocartilage, suggesting that the
effects of tissue compression by ligaments can lead to
microscopic loss of cartilage and underlying bone (Figures 3c and 4b and d).
CT findings. In 530 quadrants assessed by CT, no
erosions were found. In total, 77 erosions spanning 110
quadrants were identified by CT. Forty-eight erosions
(62%) were on the proximal part of the MCP joint (i.e.,
the head of the metacarpal) and 29 (38%) were on the
distal part of the joint (i.e., the base of the proximal
phalanx). Erosions typically occurred on the radial and
ulnar sides of the MCP joints, adjacent to the CLs, which
corresponded to the sites of bony damage in normal
joints; the total number of quadrants with erosions
found at such sites was 76, compared with 34 on the
dorsal and volar sides (P ⬍ 0.0001). The difference in
the proportion of erosions between sites was most
striking proximally. On the proximal part of the MCP
joint, the total number of radial and ulnar quadrants
with erosions was 48, compared with 16 dorsal and volar
quadrants with erosions (P ⬍ 0.0001) (Figure 5).
There was also a predilection, on the proximal
side, for erosions in the radial site, with erosions present
in 33 radial quadrants, as compared with only 15 ulnar
quadrants with erosions (P ⬍ 0.0001). Distally, the
erosions were more randomly distributed, with a total of
28 radial and ulnar quadrants with erosions (17 radial
quadrants and 11 ulnar quadrants; P ⫽ 0.21) and a total
of 18 dorsal and volar quadrants with erosions (P ⫽
0.064).
Of the 12 PIP joints assessed in 3 patients with
RA, there were 7 erosions in the PIP joints of 2 of the
patients. The erosions were evident adjacent to ligaments, spanning over mainly the lateral sites, with 6
radial and ulnar quadrants with erosions as compared
with 3 dorsal and volar quadrants with erosions.
DISCUSSION
The purpose of this study was to determine
whether an understanding of normal joint microanatomy
PREDICTORS OF PERIARTICULAR EROSION FORMATION IN ARTHRITIS
1049
Figure 6. a, The traditional concept of a bare area (BA) and erosion formation in the small joints of patients with rheumatoid arthritis. An extensive
bare area is depicted on the proximal side of the joint, and its covering synovial membrane (S) tapers down at the cartilage–pannus junction (CPJ).
Multiple layers of flattened synoviocytes are piled up as pannus (P) over the edge of the articular cartilage (AC). Erosions form via the activity of
osteoclasts (OC) on the bone surface (B). CL ⫽ collateral ligament. b, The ligament compression concept of erosion formation is proposed as a
mechanism to better understand the full spectrum of damage related to erosions. The bare area is shown in relation to an enthesis organ associated
with enthesis fibrocartilage (EF) at the origin of the collateral ligament. Thus, in a proximal interphalangeal joint, there is sesamoid fibrocartilage
(SF) in the deep part of the ligament pressing against corresponding periosteal fibrocartilage (PF), while in a metacarpophalangeal joint, there is
extension of the hyaline articular cartilage. The erosion (E) forms in a region in which the collateral ligament presses against the proximal side of
the joint or is related to capsular compression distally at the enthesis fibrocartilage. Thus, erosions form at sites that are prone to microdamage. The
bare area is depicted as small on the proximal side of the joint and completely absent on the distal side. Furthermore, the bare area on the proximal
side of the joint has a thick and well-vascularized layer of subsynovial tissue (ST). Note also that pannus is present in the absence of any bare area.
could help to explain the propensity for erosion formation in arthritis of the small joints. Similar to our
previous findings in the normal joints of younger subjects assessed by MRI (11), the present study showed a
propensity for microdamage at the corresponding location associated with the CLs in the finger joints of
normal elderly subjects. Radiographic CT erosions in
patients with well-established RA also showed a strong
predilection for the same anatomic territory. Of note,
these erosion-prone sites that are subject to bony compression were often characterized by the absence of a
bare area, since we observed that articular cartilage was
continuous with ligament enthesis organ–related cartilage. These findings have implications for understanding
the pathophysiology of joint erosion formation.
Herein we presented 2 different lines of experimental evidence to address the question of how small
erosions may begin in inflammatory arthritis, including
RA. A detailed evaluation of the microanatomic structure of the digits of elderly individuals without ostensible
arthritis was undertaken, and the findings were related
to those from microradiographic analysis of the same
joints in patients with RA. Given that studies have
previously shown that erosions are present in both
established and early RA, that small cysts/erosions are
present in normal joints in young patients without
arthritis, and that, as shown in the present study, microscopic erosions are present in the same topographic
distribution in normal joints, there is an intriguing
possibility that erosion formation in early RA may be
stress-associated or stress-induced. Although onset of
RA at an older age seems to have a pattern of erosion
similar to that in early RA, direct proof that erosion
formation is stress-induced in younger subjects is lacking, so that these data and suppositions must be considered controversial.
The traditional paradigm for bone destruction
in RA is that a bare area exists between the cartilage
and immediately adjacent bone, and that the proliferation of cartilage–pannus junction stromal tissue and
invasion of cartilage, coupled with osteoclastic activation, culminates in joint destruction (8–10) (Figure 6a).
1050
Furthermore, it has been suggested that the initial
event in erosion formation is the maturation and activation of osteoclast precursors within the inflamed synovial milieu, leading to erosion of the superficial bone
cortex (5). The present study provided some support
for this traditional paradigm, since bare areas were
evident, especially in the proximal MCP joint. Nevertheless, our findings suggest that factors related to CL
locations could also be important in the propensity for
erosion formation. Of particular note, it was evident that
erosion-prone sites may be lined by cartilage, presumably to minimize bone damage; consequently, a bare
area could be completely absent at erosion-prone sites.
Therefore, how might this be relevant to pathologic erosion formation in arthritis? The presence of
microdamage in normal fingers at sites that are prone to
erosion in RA supports the idea that synovitis could
exacerbate joint damage and lead to clinically recognizable erosion (Figure 6b). This common biomechanical
and functional thread also likely underscores the propensity for periarticular erosions in seronegative arthritis and even OA (15,16). Indeed, it was recognized more
than 40 years ago that radiographic erosions tended to
occur adjacent to the capsule, but this important anatomic observation went largely unnoticed (17).
Although we noted the presence of microdamage
adjacent to sites prone to bony compression, it is by no
means clear that compression is directly linked to erosion formation. However, this anatomic configuration of
the small joints could also underscore the observation
that MCP and PIP joint disease in RA is associated with
a more destructive phenotype than that in the knees
(18). Furthermore, it is likely that similar anatomic and
biomechanical considerations are operational in other
joints, which likely underscores the propensity for erosion formation in the shoulder joint at sites of supraspinatus tendon compression of the humeral head (13,19).
We thus propose that inflammation drives the inherent
propensity for damage to occur at characteristically predisposed sites in patients with arthritis of the small joints.
We made a number of other observations that
could be relevant to our understanding of joint damage.
We noted that pannus-like tissue represented an agerelated phenomenon and could apparently invade cartilage in which a bare area was completely absent. It
should be noted that pannus invasion was evident in
joints in which there was no obvious inflammatory
reaction, as has been previously noted in fibrocartilage
of the Achilles enthesis (20). Of course, it is possible that
the affected joints were subject to inflammation at some
earlier time, which could have explained this histologic
McGONAGLE ET AL
feature. Pannus has been envisaged as a fibrovascular
proliferative tissue that invades articular cartilage at the
cartilage–synovium junction. Its formation has been
considered to be characteristic of RA, but it has also
been reported in OA, which may also be characterized
by synovitis (21). It must also be pointed out that the
pannus tissue evident microscopically in the present
study is likely to differ substantially from the inflamed
tissue associated with RA, in which florid destruction of
articular cartilage has been documented.
Additionally, we found that the bare area, when
present, was sometimes less than bare and was occupied
by thickened fibrovascular synovial tissue and could
show signs of bone scalloping. Finally, in animal models,
it has been suggested that bony canals adjacent to the
bare area may be responsible for a flux of cells into the
joint cavity from the bone marrow that culminates in
synovial hyperplasia (22). We only noted one such
region in the bare area of a single MCP joint, and thus
we cannot confirm the importance of this feature in
humans.
A limitation of our study was that the histologic
evaluation was conducted on joint tissue from dissectionroom cadavers who were, as expected, elderly subjects,
and the CT scans were from relatively younger patients with RA. Ethical considerations obviously preclude us from access to whole joints from patients with
early RA in whom little damage has occurred. However, the location of large erosions over the metacarpal heads on CT corresponded to the site of small
erosions/cysts in cadaveric tissue. Therefore, the link
between the elderly cadaveric specimens and the RA
joint tissue from younger patients is that, in the presence
of inflammation and synovitis, the process of bone
microdamage that is observed in normal joints could be
accelerated, resulting in the erosive phenotype typical
of RA.
Furthermore, the relevance of our observations is
supported by clinical studies showing that patients with
late-onset RA or those with older age at onset of RA
have a pattern of disease similar to that seen in young
subjects (23), indicating that these findings could be of
general relevance. Finally, previous histologic studies of
the erosion mechanisms in RA have been in subjects
with well-established disease, but the present study was
focused on relating normal joint microanatomy to the
patterns of radiographic disease expression. The validity
of such an approach is supported by previous MRI
studies showing that erosion-like changes can form in
normal joints adjacent to CLs in younger subjects (11).
To summarize, we propose that there are factors
PREDICTORS OF PERIARTICULAR EROSION FORMATION IN ARTHRITIS
that modulate the normal physiologic and adaptive
biomechanical responses at certain predisposed sites
and contribute to the erosive phenotype, as shown in
Figure 6 (24). Traditional defined concepts, such as the
bare area and the cartilage–pannus junction, may be
neither essential nor necessary for the erosive process in
the hands. This has implications for a better understanding of the link between joint inflammation and damage
and identifies a novel mechanism that may contribute to
the development of joint erosion.
ACKNOWLEDGMENTS
We thank radiographer Jakob Møller and radiologist
Maria Hasselquist from the Department of Diagnostic Radiology, Copenhagen University Hospital, Herlev, Denmark, for
acquiring the CT images, and Elizabeth Hensor for statistical
advice.
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.
Acquisition of data. McGonagle, Døhn, Østergaard, Benjamin.
Analysis and interpretation of data. McGonagle, Tan, Døhn,
Østergaard, Benjamin.
Manuscript preparation. McGonagle, Tan, Døhn, Østergaard,
Benjamin.
Statistical analysis. Tan.
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defined, factors, formation, arthritis, inflammatory, erosion, prediction, periarticular, studies, topography, microanatomy
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