Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis, affecting ∼1% of the population (1). It is a heterogeneous disorder in terms of both clinical presentation and outcome. In some patients a mild, nonerosive form of RA associated with little disability develops. Other patients have persistent and aggressive disease that produces severe articular damage after only a few years (2), often requiring joint replacement surgery. The ability to predict aggressive disease when a patient first presents is an important clinical goal, because this would allow potent and potentially toxic disease-suppressing medication to be targeted to patients who are most in need. This predictive ability has become even more desirable from a medico-economic viewpoint with the advent of anti–tumor necrosis factor α therapies, which have powerful antierosive effects (3) but are costly, are sometimes associated with adverse effects, and should not be prescribed for patients in whom the potential to develop erosions is absent.
Clinical and demographic factors that have been identified as predictors of poor outcome include female sex, rheumatoid factor (RF) positivity, evidence of active inflammation (including high tender and swollen joint counts, an elevated erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP] level [4, 5]), and the presence of HLA–DRB1*04/01 alleles bearing the shared epitope (6). Unfortunately, despite the development of multifactorial predictive models using these parameters (7), it is still difficult to identify individual patients in whom severe disease will develop, because the majority of patients presenting with early RA will be female, RF-positive (within the first year), and will have active joint inflammation. Early detection of radiographic erosions is powerfully associated with poor outcome (4), but in many patients radiographic erosions are not apparent until at least 12 months after symptom onset.
We and other investigators have studied MRI as a potential tool for prognostication in RA (8–13). For the past 6 years, we prospectively studied a cohort of patients with early RA, monitoring their clinical and radiographic progression as well as the MRI appearance of their dominant wrists. Baseline MRI scores for synovitis, tendinitis, bone edema, and bone erosion, when combined as a total MRI score, were found to predict MRI and radiographic erosion scores at 1 and 2 years (9, 11). However, these outcome erosion scores were confined to the area of the MRI examination (the dominant wrist) and did not reflect the degree of whole-body erosion. We now report results of our data analysis at 6 years, investigating whether MRI of this single area at presentation can be a predictor of long-term overall radiographic joint damage, as measured by the modified Sharp score (14, 15).
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- PATIENTS AND METHODS
This study is the first to show that MRI scanning is useful in predicting whole-body radiographic outcome as measured by the modified Sharp/van der Heijde score in patients with RA. Both the MRI score for bone edema and the sum score for MRI bone edema plus MRI erosion, which were derived from scans of the dominant wrist obtained when patients first presented with symptoms of arthritis, were separately predictive of the total modified Sharp score 6 years later. Patients from this cohort represented a spectrum of disease activity at baseline, with a median swollen joint count of 15 and a median CRP level of 18 mg/liter (normal <1 mg/liter) (8). Baseline total modified Sharp scores were relatively low, but almost half of the patients had radiographic erosions scored at the hands or feet, suggesting an adverse prognosis. Standard clinical and radiographic variables predicted 45% of the variance of the 6-year Sharp score, but this was improved to 59% with the addition of MRI data. This result shows that MRI, which samples a small area (the dominant wrist), may be useful in helping to predict generalized joint damage in patients presenting with RA.
An initial concern over using MRI to quantify joint inflammation and damage has been the difficulty in obtaining reproducible scores for erosions, edema, and synovitis using the various scoring systems developed (24). Scoring MRI at the wrist is a complex task, requiring a detailed knowledge of the 3-dimensional anatomy of the carpal bones and joints as well as an understanding of the different sequences used, the signal characteristics of the tissues being imaged, and potential sources of error that are intrinsic to the modality itself. The latter include phenomena such as partial voluming, where signal from 2 sharply contrasting areas is “averaged” in the intervening zone, homogeneity of fat saturation, and variations in Gd-DTPA uptake, which need to be interpreted by a trained reader. This makes MRI scoring considerably more difficult than scoring radiographs to assess joint damage. Fortunately, throughout this study, interobserver reliability for MRI scoring has been high, with ICCs ranging from 0.7 to 0.85. Our MRI scores were obtained by 2 radiologists specializing in the musculoskeletal system who have an interest in MRI interpretation. We also used a scoring system that was sensitive to change in early disease, because erosions were counted and scored for size, ensuring that even minor progression could be detected.
In this study, MRI scans and plain radiographs were read without reference to previous scans or radiographs from the same patient. This approach could decrease sensitivity for scoring abnormalities such as erosions, because a reader with access to previous images could be alerted to a particular site and therefore examine it more carefully. The advantage for our method might be improved specificity, because a reader may be less likely to score an indistinct lesion as an erosion than they would be if they knew that previous images had also shown a defect in that area. Most radiographic studies of RA progression have allowed readers access to other films in the series, and we intend to reexamine our data in that manner to further explore issues of reliability.
Are erosions seen on MRI the same lesions as those detected by plain radiography? The answer to this question seems to be yes, in the main, as illustrated by studies comparing MRI findings with those of miniarthroscopy and ultrasound (25, 26). However, cortical bone, which is so well-visualized on plain radiographs as a white line, appears on MRI as a low signal region that may be confused with focal (and potentially transient) subcortical bone marrow edema (11). Other sources of false-positive MRI erosions include degenerative bone cysts and active synovitis adjacent to irregular bony margins.
Results from this study reveal high levels of concordance between MRI and radiography erosion scores at baseline and 6 years, when radiography scores were assessed from the same area as MRI scores (the dominant wrist) and also from a larger area (both hands and feet). The modified Sharp score includes scores for both erosions and joint space narrowing and is thus influenced by preexisting degenerative change at sites such as the first MTP joint. This may account for the finding that MRI and radiography scores correlated less well at baseline, when Sharp scores reflected joint space narrowing that was not noticed using the current MRI scoring system. By 6 years, however, rheumatoid articular damage had eclipsed minor degenerative change on radiography and paralleled bony erosive change as scored on MRI. Another reason for the initial relative discordance of MRI and radiography scores is that MRI reveals erosions much earlier: 45% of this cohort had MRI erosions at the dominant wrist at baseline, and only 15% had radiographic erosions at the wrist (8).
Bone marrow edema has been recognized as being important in RA only since the advent of MRI (27). It occurs in many non-RA contexts, including trauma and degenerative joint disease; it also occurs adjacent to enthesopathy and possibly in normal subjects (28). However, is all bone edema the same? In the setting of RA it has been estimated to occur in 68–75% of patients with early disease (8, 27). In our cohort it was confirmed as a preerosive lesion at 1 year (9) and again at 6 years, when the risk of developing erosion in a bone involved by edema at baseline was 6.5-fold that of erosion occurring without preceding edema. Although the level of bone edema for the group as a whole remained static throughout the study, individuals had high scores for bone edema at various time points, and this was often a transient phenomenon (i.e., it was not observed on their subsequent MRI scans). Thus, in those cases in which bone edema was not identified at baseline but erosion had occurred at 6 years, it is possible that transient but undetected bone edema had occurred as a preceding event. More frequent MRI scans over a period of years would be needed to explore the link between bone edema and erosion and to determine the degree of causality.
The mechanism underlying the association between bone edema and erosion remains to be determined, but bone edema in this context could represent an intraosseous cellular infiltrate capable of eroding cartilage and bone from the subchondral aspect of the joint. Evidence for such an infiltrate has been described in animal models of RA, in which TNF-responsive mesenchymal cells were identified within enlarged bony canals connecting bone marrow to synovium (29). Unfortunately, there are no MRI studies of animal models of early RA, and such studies are urgently needed. The histologic features associated with bone edema in early RA in humans are yet to be described because of difficulty obtaining material to examine, but Lee et al reported a decrease in bone edema in patients with RA who are in clinical remission, supporting its link to disease activity (30). McGonagle et al suggested that synovitis might lead to bone edema and subsequent erosion (28). Consistent with this is the observation from this cohort that all patients with bone edema at baseline also had synovitis, which was present in 93% of the total group (8). However, not all patients with baseline synovitis eventually experienced joint erosion, suggesting that the proposed linear causal relationship, with synovitis leading to bone edema leading to erosion, is too simplistic.
Why, in this cohort, was baseline MRI synovitis not predictive of radiographic erosion scores at 6 years? Data obtained previously from the same patients showed that MRI synovitis at baseline was predictive of MRI erosion scores at 1 year (10) but not of radiographic erosion scores at 1 or 2 years (9, 11). Other investigators have also demonstrated a link between early MRI synovitis and subsequent MRI erosion occurring after 1 year (12, 31). Conaghan et al recently reported that the area under the curve for MRI synovitis measured over 12 months in patients with early RA was a predictor of bone damage progression at MCP joints (31).
There are several possible explanations for the lack of a predictive association between synovitis and radiographic erosions in our cohort. First, this may not have been detected because the number of patients followed for 6 years was small, and a Type II error could have occurred. Second, a single “snapshot” of synovitis at baseline is unlikely to reflect subsequent levels of joint inflammation, which is why measurements of area under the curve are more informative. Indeed, Conaghan et al also did not demonstrate that baseline synovitis, as a single measure, predicted erosive progression in their patients (31). Third, this study is the first to follow up patients for a period as long as 6 years. It is possible that other processes are combining with synovitis to drive medium-term erosive progression. Our data suggest that bone edema could be a marker of such a process. The concept of a nonsynovitis mechanism contributing to erosion in RA is not new (32, 33). Kirwan postulated separate mechanisms underlying synovial inflammation and articular damage based on results of his study of low-dose steroid use in early RA, in which groups treated with prednisolone exhibited less radiographic progression than did groups treated with other disease-modifying antirheumatic drugs (DMARDs), despite the same control of synovitis (33).
In our group of patients, results of MRI scans were available to treating physicians, which may have modified their treatment decisions. Because this was not designed as an interventional study, no attempt was made to standardize DMARD therapy. Thus, the possibility exists that early aggressive therapy could have been instituted in those patients with MRI erosions on initial scans, potentially resulting in lower Sharp scores at 6 years. This would weaken an association between initial MRI scores and final radiographic outcome, suggesting that the observed association is, if anything, an underestimate of the true effect. In this cohort, analysis of the effect of treatment on outcome was performed at 1 year (9) and revealed that patients receiving DMARDs at that point were significantly more likely to have erosive disease on MRI, but this simply reflects earlier DMARD use in those with clinically aggressive disease. None of these patients received anti-TNF therapy, which is not currently funded in New Zealand.
In summary, this is the first study to show that carpal bone edema scored on MRI scans obtained at the time of first presentation of RA can be used to help predict the total radiographic outcome at the hands and feet at 6 years, as measured by the modified Sharp score. Using a modeling approach for predicting outcome, the addition of MRI variables to baseline clinical measures of disease activity improved the prediction of variance of 6-year Sharp score data. Thus, MRI scans of the dominant carpus might be a useful addition to standard investigations of patients with RA at the first presentation, although larger studies are needed to confirm this. We did not find MRI synovitis at baseline to be a predictor of radiographic erosion at 6 years, and this could suggest that other mechanisms in addition to synovitis operate in the intermediate term to promote articular damage. Bone marrow edema, which was strongly associated with subsequent erosion at individual sites in the carpus, could represent evidence of such a process centered in the subchondral region. MRI is proving to be a useful tool with which to investigate disease processes in RA and has the potential for clinical use in determining the prognosis and targeting aggressive therapy to patients with the most destructive disease.