Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritis.код для вставкиСкачать
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: email@example.com. Submitted for publication September 18, 2008; accepted in revised form January 7, 2009. 1042 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. 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