What is MRI bone oedema in rheumatoid arthritis and why does it matter?
© BioMed Central Ltd 2006
Published: 5 December 2006
MRI bone oedema occurs in various forms of inflammatory and non-inflammatory arthritis and probably represents a cellular infiltrate within bone. It is common in early rheumatoid arthritis and is associated with erosive progression and poor functional outcome. Histopathological studies suggest that a cellular infiltrate comprising lymphocytes and osteoclasts may be detected in subchondral bone and could mediate the development of erosions from the marrow towards the joint surface. There is emerging evidence from animal models that such an infiltrate corresponds with MRI bone oedema, pointing towards the bone marrow as a site for important pathology driving joint damage in rheumatoid arthritis.
In the mid-17th century, a Dutch apprentice to a textile merchant, Anton van Leeuwenhoek, was the first to see and describe bacteria, yeasts and the circulation of blood corpuscles in capillaries using a new tool, the light microscope . The subsequent elucidation of the microbiological basis of infectious disease can be traced back, in part, to his pioneering work in imaging. A parallel exists between the invention of the microscope and the development of magnetic resonance imaging (MRI), which allows new ways to explore biological systems. In rheumatoid arthritis (RA), MRI provides information about synovitis and erosion in early disease [2, 3] when inflammatory and destructive articular change is typically subradiographic. In addition, it has revealed something new and unexpected; the appearance referred to as bone oedema. This MRI finding has been reported in other conditions, such as osteonecrosis , osteoarthritis , and ankylosing spondylitis , and in the sports medicine setting where it appears associated with mechanical stress . However, in RA there is evidence to suggest that bone oedema represents a pivotal change occurring within subchondral bone that may be associated with early events in disease pathogenesis, which have not previously been accessible to any form of imaging.
Just as the existence of micro-organisms was not expected prior to the invention of the microscope, so the presence and importance of bone oedema could not have been predicted using the other sonographic and radiographic imaging techniques used to investigate RA. MRI is unique in that it images protons, which are usually contained within water molecules (hence 'oedema'), these in turn frequently being contained within cells . Although ultrasound can be used to image synovitis by detecting thickening of the synovial membrane  and can reveal increased synovial blood flow using Doppler imaging , cellular infiltration within bone remains invisible. Radiography, while an excellent technique for imaging cortical bone, also cannot detect subcortical cellular infiltrates, which are not necessarily associated with periarticular osteopenia . Histology could be used to examine subchondral bone but resection of this tissue is almost never done in early RA and the primary focus for tissue immunohistochemistry has been the accessible synovium. There are currently no published studies comparing the histopathology of subchondral bone in RA with MRI appearances (specifically bone oedema) but these are underway. Unfortunately, they are likely to include patients with longstanding disease where erosive and secondary degenerative change could complicate the picture. In ankylosing spondylitis, such a study has recently been published, describing preoperative bone oedema in three of eight ankylosing spondylitis patients with longstanding disease who underwent spinal surgery involving resection of zygapophyseal joints . Concordance was observed between bone oedema and a mononuclear inflammatory infiltrate in bone marrow, but only when the latter was relatively intense, suggesting that the MRI feature is only apparent above a certain threshold.
Until recently, it was necessary to go back to literature published in the early 1980s for a description of the histology of subchondral bone in RA. Barrie  in 1981 described "diffuse osteitis" within subchondral bone in 35% of patients undergoing metatarsal head resection. In the November 2005 issue of Arthritis and Rheumatism, Bugatti and colleagues  published a similar immunohistochemical study of RA subchondral bone (from specimens obtained at the time of joint replacement), using contemporary techniques. They found lymphoid aggregates on the subchondral side of the joint in established RA, often associated with osteoclasts within the bone marrow abutting the cortex. They concluded that "an inflammatory lymphoid infiltrate... is a characteristic feature of RA subchondral bone marrow... raising the hypothesis that subchondral bone marrow inflammation might develop independent of the propagation of synovial tissue."
The MRI finding of bone oedema has been an important driver in refocusing interest towards the subchondral bone in early RA. A cohort study published in 1998  revealed bone oedema to be present at the carpus in 64% of RA patients within 6 months of disease onset and in 45% after 6 years . There was clear evidence at one and six years after disease onset [15, 16] that bone oedema was a pre-erosive lesion. The bone oedema score at presentation and one year later was correlated with radiographic erosion and joint space narrowing scores six years later  and, interestingly, even with function, as measured by the physical function component of the short-form-36 score . A later study also showed a link between bone oedema scores and tendon function at eight years in these patients . Others have also found bone oedema to be common in RA , and it was described by Ostendorf and colleagues  at the metatarsal heads within only two months of the onset of symptoms. Tamai and colleagues  recently confirmed its association with disease severity as indicated by inflammatory markers such as C-reactive protein and interleukin-6 levels in early RA. At the other end of the spectrum of disease duration, we have recently described florid bone oedema, at the site of intended surgery, in RA patients awaiting joint replacement or fusion. These data suggested that bone oedema may be especially associated with painful and aggressive disease . Taken together, these lines of evidence suggest that the process we recognize as MRI bone oedema is widespread and relatively common in early and late disease and tied to the development of long term joint damage. Before the advent of MRI, this process sited in the subchondral bone was unsuspected and certainly not accorded any significance in terms of disease pathogenesis.
New work is now emerging to link the entity of bone oedema with current theories of the immunopathogenesis of RA. Hirohata and colleagues , in a highly accessed article published in Arthritis Research and Therapy in early 2006, described a study of bone marrow cells aspirated from the iliac crests of RA patients. CD34+ stem cells that were abnormally sensitive to tumor necrosis factor (TNF)α  were found to express high levels of the nuclear factor kappa B (NFκB) transcription factor, contrasting with cells from osteoarthritis patients where NFκB expression was normal and TNF sensitivity not observed. These authors suggested that a bone marrow stem cell abnormality could underlie RA and proposed a disease model where such cells could, under the influence of TNF, differentiate into fibroblast-like cells, and travel to the synovial membrane where they might appear as type B synoviocytes and promote synovitis . Alternatively, they could travel via the systemic circulation to the subchondral bone marrow and initiate inflammatory and pre-erosive changes from there, possibly including activation of osteoclasts as described by Schwarz and colleagues .
Finally, animal studies are emerging to clarify the role of the bone marrow as a site of pathology in RA. Marinova-Mutafchieva and colleagues  described an inflammatory infiltrate in the subchondral bone of TNF-transgenic mice where TNF-responsive mesenchymal cells were identified within enlarged bony canals connecting bone marrow to synovium. Most recently, Proulx and colleagues  examined TNF-transgenic mice using a high-resolution 7 Tesla MRI scanner. They described the presence of bone oedema and correlated this histologically with a highly cellular infiltrate within the bone marrow. Another form of imaging, high-resolution multipinhole single-photon-emission computed tomography (MPH-SPECT), has revealed accelerated bone turnover within the joints of interleukin-1 receptor antagonist deficient mice . In a single patient with early RA, increased uptake in a central, interarticular distribution was detected by MPH-SPECT when the MRI signal for bone marrow on short tau inversion recovery (STIR) images was normal, raising the possibility that even earlier changes in the subchondral bone could be apparent using this sensitive, high-resolution technique .
high-resolution multipinhole single-photon-emission computed tomography
magnetic resonance imaging
nuclear factor kappa B
tumor necrosis factor
The authors wish to thank Professor P Conaghan for use of the MRI scan in Figure 2.
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