Radiography has been the imaging modality of choice in rheumatoid arthritis (RA), primarily because of its reproducibility and feasibility with respect to detecting structural damage. Newer imaging modalities such as MRI, however, permit simultaneous imaging of key structures other than of bone that are important in inflammatory arthritis, allowing dissection of the inter-relationship between osteitis, synovitis and erosions , and providing insight into the pathogenesis of inflammatory joint disease .
MRI is the most sensitive imaging modality for the assessment of structures critical in the evolution of inflammatory disease [3–5], with studies confirming the superiority of MRI when compared with plain film radiography. The multiplane, multislice capability of MRI allows visualization of the area of interest in three orthogonal planes. This confers an advantage– MRI is able to provide superior detail of both the bone and surrounding soft tissue of the joint, capabilities not shared by any other imaging modality, whereas avoiding ionizing radiation exposure for the patient. This significant increase in imaging sensitivity has increased the power of studies to show earlier differences between treatment groups. As a result, MRI is increasingly utilized in clinical studies, both in terms of identifying features for entry into clinical trials as well as monitoring disease progression over time.
This article will examine recent MRI developments in the research and clinical setting, encompassing validation evidence in clinical trials as well as the issues surrounding the utility of MRI in clinical practice.
Recent validation studies
As with all imaging techniques and biomarkers, it is important that abnormalities on MRI are representative of the underlying disease process so that the results are clinically meaningful. Effective ways to achieve this goal include correlation of imaging results with histology (criterion validity) or correlation with other modalities measuring a similar pathology (construct validity).
Validation of synovitis on MRI has been extensively addressed using arthroscopy and synovial biopsy and comparing these with MRI synovial volume estimates [6–9]. This has been performed in knees as well as in the metacarpophalangeal (MCP) joints using miniarthroscopy, macroscopic evaluation and histology. Ostendorf et al. found that synovial enhancement post intravenous gadolinium contrast (Gd-DTPA) on MRI correlated with macroscopic signs of synovitis, and joint space narrowing on MRI was significantly correlated with bony changes on arthroscopy.
The clinical relevance of synovitis in terms of its role as an erosion precursor is now well studied. Recently, however, MRI has played a key role in explaining structural disease progression in RA patients with subclinical synovitis. Brown et al.[10••] have shown in an RA cohort that MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage. Such a study reinforces the utility of MRI for the accurate evaluation of disease status and the prediction of structural outcome. An example of synovitis is shown in Fig. 1.
Erosions on MRI and ultrasound have been validated against the surrogate gold standard, computed tomography (CT), by both Dohn et al. and Perry et al.. Dohn et al. showed that MRI and US demonstrated high specificities (96 and 91%, respectively) when compared with CT in detecting MCP bone erosions in RA patients, even in radiographically nonerosive joints (96 and 92%). Perry et al. compared MRI and CT in RA wrists, showing that most erosions were detected using both modalities but that erosion scores were higher on CT than MRI, especially at the metacarpal bases. The results of these studies study support the assertion that erosions seen on MRI represent a loss of calcified tissue with cortical destruction, that is, they are true erosions, and the increased sensitivity of CT in some regions such as the metacarpal bases may be because it is better able to clearly delineate bony margins.
MRI has been compared with conventional radiography for erosion identification and sensitivity to change of erosion detection over time with studies confirming the superiority of MRI. Ejbjerg et al., for example, showed that both ‘few joint’ (unilateral wrist and 2nd–5th MCP joints) and ‘many joint’ [bilateral wrist and MCP joints plus unilateral metatarsophalangeal (MTP) joints] combination approaches were significantly more sensitive than radiography for erosion detection over time, strengthening the case for MRI as a tool for outcome measurement in RA clinical trials. Similar results have been shown for low-field MRI by Olech et al.. Examples of erosions are shown in Fig. 2.
Bone oedema (increased signal intensity of bone on T2 weighted images after fat suppression) has recently been the subject of validation work using bone samples obtained prior to joint replacement surgery. McQueen et al. obtained preoperative contrast-enhanced MRI scans in 11 RA patients who were having orthopaedic surgery to the hands/wrist or feet, correlating the presence of bone oedema with histological findings on bone samples obtained at the time of surgery. Results have shown that bone oedema represents osteitis (a cellular inflammatory infiltrate in subchondral bone) that may be a precursor to erosive change [16,17••]. If the osteitis is successfully treated then there may be no obvious sequelae, but if it persists then trabecular bone is destroyed and an erosion results. Hence this lesion spans the spectrum from activity (osteitis) through to damage (trabecular loss) [18–20]. Figure 3 shows examples of bone marrow oedema in the carpus .
Scoring of MRI pathology in rheumatoid arthritis
Synovitis, bone oedema and erosions on MRI have been defined by the Outcome Measures in Rheumatology (OMERACT) MRI Task Force and a scoring system, termed the RA MRI score (RAMRIS), has been validated and evaluated for sensitivity to change in a longitudinal setting. The RAMRIS does not, however, include a scoring system for tendons or a score for cartilage loss; this latter problem relates to problems with adequate image resolution of cartilage in small joints. Recently, however, Haarvardsholm et al. have published a novel scoring system for tenosynovitis based on semiquantitative scoring (0–3) of flexor and extensor tenosynovitis at the wrist in 10 anatomical areas. The maximum width of postcontrast enhancement within each anatomical area on axial T1-weighted images was scored, producing a potential maximum score of 30. This system was also tested for reliability in a longitudinal setting and provides a useful adjunct for the conventional RAMRIS. The evaluation of cartilage changes on MRI, however, remains an important research goal.
Clinical trials using MRI as an outcome measure
Clinical trials that are designed to monitor response to therapy in RA patients have used serial plain film radiography of the hands and feet, as radiography is a widely available and reproducible technique . More recently, studies have incorporated MRI into trial design. From an ethical standpoint, placebo arms cannot be included in modern RA clinical trials, and therefore trials must now compare active treatment arms. This often results in slower rates of progression and smaller differences between treatment groups. As a result, trials need to be substantially longer with larger patient numbers to achieve statistical significance. The advantage of using MRI compared with radiography stems from its greater sensitivity for erosive damage, which increases the power of a study that is, the ability to differentiate between two treatment arms. As a result, fewer patients may be required and study duration is reduced.
The first randomized therapeutic trial using MRI as an outcome measure was published by Conaghan et al. in early RA. MRI was used to follow synovitis and erosions in patients randomized to methotrexate +/− intraarticular corticosteroid. During the randomized phase the combination arm had reduced synovitis scores and significantly fewer joints with new erosions on MRI compared with the methotrexate alone arm. There was a close correlation between the degree of synovitis and the number of new erosions, with the area under the curve for MRI synovitis the only significant predictor of bone damage progression. Subsequently, there have been further studies describing the effect of therapy on MRI outcomes in RA and an overview of these are shown in Table 1[1,24–48].
Disease-modifying antirheumatic drugs
A demonstrative sample of these studies is discussed in further lines. Lee et al. used MRI to monitor disease in 10 patients newly commenced on methotrexate and hydroxychloroquine, showing that the four patients who achieved clinical remission showed a decrease in synovial proliferation and bone marrow oedema on MRI, with no new erosions over 12 months. Ostergaard et al. used MRI of the knee to assess changes following intraarticular corticosteroid, showing a decrease in synovial volume, and the same group have also examined MRI response to the interleukin-1 receptor antagonist, anakinra . Kalden–Nemeth  used MRI of wrist/knee/ankle to monitor patients treated with biologic therapy, showing that changes in synovium signal intensity correlated well with clinical markers of inflammation. Quinn et al. assessed efficacy of very early treatment with infliximab in addition to methotrexate in poor prognosis RA patients. Synovitis and structural damage in the form of erosions on MRI were significantly reduced by this therapeutic combination at 1 year when compared with the group receiving methotrexate alone. Durez et al. compared three treatment arms (involving methotrexate, infliximab and methylprednisolone) in an early RA study using MRI to monitor synovitis, bone oedema and erosions over time, showing significant differences between arms. Zikou et al. have followed hand synovitis with MRI in patients treated with adalimumab and Lisbona et al. used MRI to show that etanercept reduced synovitis in active RA patients after only 6 weeks.
Utility in clinical practice
Despite considerable evidence supporting the use of MRI in RA, cost and accessibility are still the main barriers to the widespread application of MRI in clinical practice. Low-field extremity MRI (eMRI) offers a potential solution to these barriers . Extremity low-field magnets often require less physical space and shielding and use low-field magnets (such as the 0.2 T C scan or the 1.0 T OrthOne). New machines will contain high-field strength magnets in a similar small machine. Cost is significantly reduced and the machine can be situated conveniently in a suitable clinic room, rather than requiring a purpose-built home as for conventional MRI. Patient comfort is enhanced as a result of the extremity design of the magnet. Figure 4 shows a T1-weighted sequence of an RA carpus acquired using a 0.2 T C scan machine.
Despite the clear advantages, there are shortcomings . Because of the reduction in the magnet strength, there is reduced signal to noise (SNR) that may potentially reduce image clarity. In addition, low-field MRI has a reduced number of image acquisition techniques and is not able to achieve frequency-selective fat saturation sequences (the optimum way for detecting bone oedema). The low-field systems therefore use a Short Tau Inversion Recovery (STIR) sequence, which provides a type of fat suppression image, but the images are affected by reduced SNR, limiting spatial resolution. Despite these limitations, it appears that low-field MRI is equivalent to high-field MRI for the assessment of erosions, although it is less sensitive for oedema and requires contrast to adequately identify synovitis . The OMERACT MRI group has published data demonstrating equivalent scores for images obtained in RA patients using high and low-field systems ; these results included patients in cross-sectional and longitudinal exercises.
The only published study to date using eMRI as an outcome measure for the assessment of therapeutic response was an open-label, pilot protocol of RA patients who switched to infliximab after an incomplete response to etanercept . In addition to standard radiography, eMRI of the metacarpophalangeal joints 2–3 and wrist of the most severely affected hand was performed. At week 14, there were no marked differences in the median number of erosions seen on MRI between the patients who received infliximab and those who continued on etanercept but the numbers in the study were small as it was a pilot design.
Recent work has further validated MRI, confirming that both bone oedema and erosions on MRI represent osteitis and cortical bone defects; this adds to what was already known about the validity of contrast enhanced synovium representing synovitis. An increasing number of studies have used MRI as an outcome measure and it is anticipated that in the future, MRI will become part of standard measures for RA clinical trials. Low-field eMRI represents a well tolerated, comfortable and convenient method for imaging assessment in clinical practice with further work required to provide useful clinical algorithms.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 189–190).
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