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Rheumatology Advance Access originally published online on November 28, 2007
Rheumatology 2008 47(1):13-21; doi:10.1093/rheumatology/kem250
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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MRI of rheumatoid arthritis—image quantitation for the assessment of disease activity, progression and response to therapy

R. J. Hodgson1,2, P. O’Connor2 and R. Moots3

1MARIARC, University of Liverpool, Liverpool, 2Chapel Allerton Hospital, Leeds and 3Clinical Rheumatology, School of Clinical Sciences, University of Liverpool, Liverpool, UK.

Correspondence to: R. Hodgson, MARIARC, Pembroke Place, Liverpool L69 3GE, UK. E-mail: RichardHodgson{at}btinternet.com


   Abstract
Top
 Abstract
Introduction
 Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
 References
 
Magnetic resonance imaging (MRI) allows the direct visualization of many bone and soft tissue changes in rheumatoid arthritis. Synovitis volume, bone marrow oedema and bone erosions are suitable for serial measurement. The outcome measures in rheumatoid arthritis clinical trials (OMERACT) rheumatoid arthritis magnetic resonance imaging (RAMRIS) system is designed to allow straightforward, reproducible scoring of all these features. Alternatively, synovial volumes may be directly and quickly measured using semi-automated techniques. There is the potential for similar systems for measuring erosions. Dynamic contrast enhanced MRI depends on the rate of enhancement of the synovium after intravenous contrast agent. Measurements depend on the underlying physiology of the inflamed synovium, in particular the vascularity and capillary permeability which are expected to closely mirror inflammatory activity in the joint. Measurements from MRI have been shown to correlate with clinical, laboratory, imaging and histological measures of inflammation, predict erosive progression and respond rapidly to various types of treatment. They are, therefore, expected to be good measures of disease activity, progression and response to therapy.

KEY WORDS: MRI, Dynamic contrast enhanced MRI, Image analysis, Rheumatoid arthritis


   Introduction
Top
 Abstract
 Introduction
Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
 References
 
Imaging techniques have played an important role in assessing disease progression and response to treatment in rheumatoid arthritis (RA) for many years [1]. Plain X-rays have been widely used together with scoring systems designed to quantify disease and measure progression and response to treatment [2]. However, these rely on relatively late disease features such as bone erosion and joint space narrowing.

Magnetic resonance imaging (MRI) can directly visualize the bone and soft tissues in three dimensions, and has the potential to measure inflammatory activity and joint destruction. Ultrasound, bone scintigraphy and positron emission tomography (PET) are also sensitive techniques for assessing RA, and the relative roles of the different imaging modalities have yet to be established. Ultrasound can rapidly assess multiple joints and is well established in the clinical assessment of synovitis and tenosynovitis, although it is less sensitive than MRI for detecting erosions and cannot assess marrow oedema [3]. Doppler imaging provides information on disease activity. Reproducible quantitation is difficult due to the operator dependence of the technique, however, recent 3D systems may overcome this limitation [4]. Bone scintigraphy can assess the whole body, although the specificity is relatively low and MRI is more sensitive for detecting erosions [3]. F-18 fluro-2-deoxyglucose (18FDG)-PET provides unique information about metabolic activity and is inherently quantitative [5]. Its sensitivity for detecting joint inflammation and response to treatment relative to MRI is yet to be determined.

In this article, we review the MRI quantitation of synovitis, bone marrow oedema and bone erosions using scoring systems, direct volume measurement and dynamic contrast enhanced MRI. For each system we discuss suitable MRI protocols, measurement techniques and reproducibility. Discussion of scoring systems will be limited to the widely accepted RA MRI Scoring (RAMRIS) technique. Direct volume measurements and dynamic contrast enhanced MRI are less mature and an overview of the different techniques is included. These quantitative techniques are rarely used in routine clinical practice at the present time, but they have been applied to clinical trials, the results of which are summarized here.


   Scoring systems
Top
 Abstract
 Introduction
 Scoring systems
Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
 References
 
The Outcome Measures in RA Clinical Trials (OMERACT) group have devised and tested a RAMRIS system for the wrist and MCP joints. This aims to provide a well-defined, reproducible measurement system suitable for multi-centre use [6]. Of the various measurements considered, bone erosions, bone marrow oedema and synovitis volume provided acceptable reproducibility [7].

OMERACT defines a core set of MR sequences [8]. T1-weighted images acquired before and after the administration of gadolinium-based, intravenous contrast are required to demonstrate enhancing synovitis. These images are also helpful for identifying cortical defects, a defining characteristic of bone erosions. Erosions must be visible in two planes to meet the RAMRIS criteria, hence axial and coronal images are recommended. Small erosions need images from thin slices for reliable visualization and the OMERACT studies used slice thickness of 3 mm [7, 9, 10]. Bone marrow oedema is best assessed on pre-contrast fat-suppressed T2-weighted images, typically in the coronal plane. Figure 1 shows examples of synovitis, erosions and marrow oedema on T1-weighted post-contrast images. Studies looking at low-field (0.2 T) MR systems for OMERACT scoring have shown good correlation with standard field systems (1.5 T) for scoring synovitis and erosions but not marrow oedema [11, 12]. Contrast dose affects the synovitis scores [13], hence a standard dose of 0.1 mmol/kg is usually used [7, 9, 10]. Although the RAMRIS system is specific to the wrist and MCP joints, it has been modified for use in the feet, and there is some evidence to suggest that, as with X-rays [14], MRI of the feet may be more sensitive, revealing changes in the feet even if the hands are not involved [15]. Scoring of the feet may therefore be of use in early disease.


Figure 1
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  		FIG. 1. T1-weighted post-contrast fat-suppressed images through the wrist and MCP joints of a patient with long-standing, active RA. (A) coronal, (B) sagittal and (C) axial sections showing examples of synovitis (s), erosion (e) and bone marrow oedema (o). Images acquired using 3D fat-suppressed VIBE sequence at 3 T (TR = 8 ms, TE = 4 ms, flip-angle = 30°, 0.5 mm isotropic resolution).

 
The score for each of synovitis, bone erosions and bone marrow oedema is made up from the sum of scores from individual joints. Synovitis is scored 0–3 in each of the distal radioulnar, radiocarpal, intercarpal-carpometacarpal and 2nd–5th MCP joints. Bone changes are scored in each of the carpal bones, distal radius, distal ulna and metacarpal bases. Erosions are scored 0–10 and oedema 0–3 as a fraction of the bone involved within 1 cm of the joint line.

The reliability of the OMERACT scoring system has been assessed in several studies and shows low intra-reader variation (interclass correlation coefficient, ICC > 0.9) [16]. The results for inter-reader correlation are less good with substantial variation between studies for synovitis (ICC 0.58–0.78), erosions (ICC 0.3–0.83) and oedema (ICC 0.32–0.95) [7, 9, 16, 17]. This variation may in part reflect the different characteristics of the patients groups studied [9]. There is also controversy over the relative reliability of wrist and MCP scores [7, 9, 18]. Studies looking at changes in OMERACT scores have shown slightly poorer inter-reader correlation [9, 18]. Smallest detectable differences have been estimated at less than 36% [9, 18, 19] for all measures, which has been compared favourably with clinical scores [9]. Recently, atlases have been produced to standardize scoring and facilitate inter-reader and inter-site comparisons [20, 21]. The reliability studies were performed before this, so performance may be improved by using the atlas; however, this remains to be demonstrated.

Several studies have applied the OMERACT scoring system to diagnosis, measurement of disease activity, prognosis and response to treatment (Tables 1 and 2). Low-grade changes have occasionally been seen in normal subjects [30]. Higher scores for oedema in the MCP joints have been found in RA compared with other types of inflammatory arthritis [23], suggesting a potential use in diagnosis. Synovitis and marrow oedema scores correlate with other measures of inflammation such as ESR, CRP and radiolabelled nanocolloid uptake while erosion score correlates with ESR [25]. OMERACT scores appear more sensitive to early erosions than plain X-rays [31], but not to long-term progression [29]. Importantly, synovitis, oedema and erosion scores all predict erosive progression [26, 27]. In patients receiving anti-TNF-{alpha} therapy there was a significant reduction in scores of synovitis (after 3 months) and marrow oedema (after 1 month) with significantly less erosive progression at 1 yr [28, 32].


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  		TABLE 1. Selected cross-sectional studies performed using the OMERACT RAMRIS system

 

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  		TABLE 2. Selected longitudinal studies performed using the OMERACT RAMRIS system

 
OMERACT scores are the most mature quantitation system for RA. They are straightforward, appear moderately reliable and sensitive, correlate with other measures of inflammatory activity, predict erosive progression and respond to treatment. They are robust, have been extensively validated and are suitable for multi-centre trials. They have the advantage of assessing synovitis, marrow oedema and erosions. Despite this, surprisingly few clinical trials to date have used OMERACT scoring, perhaps because of the relatively poor sensitivity to synovial change. Alternative methods for assessing synovitis are available (see subsequently) but there are no significantly better methods of assessing erosions and currently no alternative methods of assessing marrow oedema, an important marker for erosive progression.


   Volume measurements
Top
 Abstract
 Introduction
 Scoring systems
 Volume measurements
Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
 References
 
Synovial volume
In an effort to improve on the reproducibility and sensitivity of scoring systems, various techniques have been put forward for the direct measurement (in cubic millimetres or millilitres) of synovial volume.

As with OMERACT scoring, visualization of the inflamed synovium for volume measurement requires intravenous contrast to reliably exclude other tissues. Synovial volumes measured using unenhanced images are larger than those measured from enhanced images [33] due to variable additional contributions from underlying connective tissue, poorly vascularized, fibrous pannus and joint fluid. Enhancing synovitis is generally measured as it corresponds to active, inflamed tissue and is therefore expected to be a better marker of disease activity. Higher contrast doses improve synovial conspicuity and slightly increase the measured volume of enhancing tissue [34]. Strongly T1-weighted MR sequences optimize contrast between the enhancing synovitis and the surrounding tissues. While the precise protocol affects the delineation of the edges of the synovium, in particular the outer border, this is rarely important unless comparing images acquired with different imaging parameters. The delay between contrast administration and scanning is important as the volume of enhancing synovitis increases initially (see subsequently) before stabilizing after about 4 min. After 6–11 min contrast reaches the synovial fluid [35, 36], obscuring the synovium/fluid interface. Imaging is, therefore, best performed between these times. Post-contrast images are the most important but pre-contrast images [33, 35] or subtraction images [37] can be helpful to confirm enhancement. Subtraction images increase the conspicuity of enhancing synovitis, making differentiation from fatty marrow easier, although noise is increased and the anatomical relationships are less obvious. Movement during acquisition may introduce artefacts at the edges of subtracted images although these can be reduced by manual or automated registration prior to subtraction. In the absence of pre-contrast images, fat suppression may be useful [32]. Images oriented in the axial plane are often the most appropriate for analysis in the knee, wrist and hand [33, 37] although coronal sections are sometimes used in the wrist and hand [38]. Thin slices are advantageous, particularly at the edges of the synovium, and this can be achieved using 3D sequences [39, 40].

The most straightforward technique for measuring synovitis involves a skilled operator outlining the synovial tissue on each slice of an MR data set (Fig. 2). This has been reported in the knee, wrist and hand. Several studies have looked at the reproducibility of such measurements [37, 41, 42]. Intra-observer, inter-observer and inter-scan errors were around 5% in the knee [37] and slightly higher in the wrist [42] with combined reproducibility errors of 18% [37]. Changes of as little as 20% in synovial volume are detectable in the wrist [43], better than achievable using OMERACT scoring. Correlation between scoring and direct measurement ranged from moderate (r = 0.7) [43] to good (r = 0.88) [42]. In one study, synovitis volume measurement was a better predictor of erosive progression than OMERACT score [42].


Figure 2
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  		FIG. 2. Coronal (A), sagittal (B) and axial (C, D) sections through a 3D T1-weighted fat-suppressed image of the wrist and MCP joints. The volume of enhancing synovium has been manually outlined. Images acquired using 3D fat-suppressed VIBE sequence at 3T (TR = 8 ms, TE = 4 ms, flip-angle = 30°, 0.5 mm isotropic resolution).

 
Outlining the synovitis manually can take 1–2 hours per scan [33, 44, 45]. Thresholding in combination with rough manual outlining can substantially reduce analysis times, e.g. to 15 min [45]. Image intensity thresholds are set as percentage enhancements [45–47], relative to muscle [32, 48] or interactively [38, 49]. Other similarly enhancing tissues are excluded either by initial approximate outlining of the synovium [45, 48] or removal after thresholding [38, 49]. The choice of thresholding level is challenging and affects both reproducibility and accuracy. The reproducibility of such semi-automated measurements is poorer than manual outlining and is critically dependent on the threshold chosen, with an increase in overall reproducibility error of at least 6% compared with manual measurement [45]. This has been attributed to partial volume effects and synovial fluid enhancement, both of which could be minimized with a suitable imaging protocol. Volumes are significantly lower than those measured manually, but correlate well, particularly in the wrist. Automated identification using the technique of principle component analysis has also been successfully demonstrated [50]. An alternative approach to reducing imaging times by measuring the thickness of the synovium at 4 points, rather than the entire area of a slice [44], was less successful at reducing imaging times (45 min) and correlating with manual measures (r = 0.7). Semi-automated methods have been used to show correlations between synovial volume and clinical measures of disease activity [32, 38, 47, 49, 51] as well as responses to treatment [32, 49].

Several studies have produced interesting results using measurements of synovial volume (Tables 3 and 4). Significant differences have been shown between RA patients and normal controls [55] or arthralgia patients [52], although not between rheumatoid and other inflammatory arthritides [52]. Correlations have been demonstrated with pain [32, 51], tenderness [49, 51], swelling [38, 47, 49, 51] and global clinical scores [32, 49] as well as with ESR [38] and metabolic activity on PET [51]. A dependence on anatomical location has been observed [40]. Comparison with histology in the knee has shown that the volume of synovitis is related to disease activity and correlates with overall histological inflammation, specifically fibrin deposition and cellular infiltration [54]. Correlation with vascular proliferation was weaker and was not significant with perivascular oedema. Evidence for synovial volume as a marker for disease progression comes from the correlation between synovial volume and erosive progression [39, 56, 60]. Synovial volume has also been shown to change in response to treatment. The decrease in synovial volume after synovectomy correlated with the duration of clinical remission [35]. Reduction in the volume of enhancing synovitis has been demonstrated with DMARDs [60] including methotrexate [51, 61], oral steroids [51] and anti-TNF-{alpha} therapy [32, 49]. A rapid response has been demonstrated to intra-articular steroids, with a significant decrease in synovial volume after 1 day [37], with longer remission in patients with smaller pre-treatment volumes.


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  		TABLE 3. Selected cross-sectional studies performed using direct volume measurement

 

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  		TABLE 4. Selected longitudinal studies performed using direct volume measurement

 
Synovial volume correlates with histological markers of inflammation, rapidly demonstrates change with treatment and predicts erosive progression. It is, therefore, likely to represent a good marker for disease activity.

Bone erosion volume
Less work has been done looking at erosion volume compared with synovial volume, reflecting the difficulty in making accurate measurements of bone erosion.

Most studies have measured the volume of erosions by expert manual outlining. Post-contrast, T1-weighted images are useful for highlighting defects in the cortical bone necessary to diagnose an erosion [43]. They may, however, be insensitive to erosions filled with fibrous tissue [62]. Erosion volumes are usually measured in the coronal plane in the wrist [43, 58]. Although thin slices are expected to improve accuracy, this has not been clearly demonstrated [10].

Published work suggests reproducibility in the wrist is good, with intra-reader, inter-reader and inter-scan correlation coefficients over 0.9 and good correlation with OMERACT scores [18, 43]. Both volume measurements and OMERACT scores are capable of detecting a similar (20%) difference in erosion volume [43]. Inter-observer agreement is poorer in the MCP joints [10, 18], with little evidence of benefit from training [18] or thinner slices [10]. This has been attributed to difficulty in estimating the proximal bone outline prior to erosion [18]. Erosion volume has been shown to correlate with the Joint Alignment and Motion score [10].

A semi-automated technique has allowed erosion volume to be calculated after manual outlining of the approximate joint area, using the combination of T1-weighted spin-echo and gradient echo images [58, 63]. Volumes correlated with erosion scores. A fully automated method has been demonstrated in a rat model of inflammatory arthritis [64]. The automated and semi-automated methods for determining erosion volume do not distinguish between oedema and erosions [58, 64]. Little work has been published looking at the independent quantitation of bone marrow oedema, despite evidence that this is important in predicting erosive progression [26, 65].

Thus, there is currently little evidence of any improvement in accuracy by using volume measurements of erosions compared with OMERACT scoring, particularly in the MCP joints. Automated and semi-automated scores may, however, provide time-saving advantages and do offer the potential to objectively measure bone volume loss in the future.

Synovial fluid volume
Synovial fluid volumes have been measured in the knee in RA. Strongly T2-weighted, unenhanced images allow the delineation of joint fluid from adjacent synovitis [47, 48]. Fluid segmentation has been performed manually [37, 46, 47] or using threshold values after initial rough manual outlining [48]. Reproducibility errors have been similar to those for synovitis with combined inter-reader, inter-scan errors of about 15% [37, 41] with good correlation with aspirated fluid volume [47].

Synovial fluid volume measured using MRI has been linked to potential synovial and plasma markers for RA [53]. A reduction in synovial fluid volumes has been shown after intra-articular steroids [37], arthroscopic [35] and radiation [47, 48] synovectomy.

Thus, synovial fluid volume may be reliably measured and has been shown to respond to intra-articular treatment in the knee. However, it is unclear that effusion volume offers any advantage over synovitis volume, and fluid volumes are unlikely to be as useful in the wrist and hand.

Cartilage volume
There is little published work quantitatively assessing cartilage in RA. Generalized cartilage thinning and focal cartilage erosion have been demonstrated in RA [66]. However, although numerous techniques for measuring cartilage volume and quality have been used in osteoarthritis, few have been applied to RA. A study on the knee of patients with RA measuring cartilage volume by manual segmentation of 3D gradient-echo images achieved inter-operator and inter-scan coefficients of variation of around 35% [59]. Cartilage volumes were lower than historical controls, however, no significant reduction in cartilage volume was detected over 1 yr. Cartilage measurement in the wrist and hand is difficult due to the small size of the joints [67]. Joint space narrowing was therefore excluded from the OMERACT system as reliability was poor [6]. Cartilage volume has been measured in cadaveric MCP joints to an accuracy of 2%, and the technique was successfully attempted in a single patient with RA [68]. T2 measurement is widely used for assessing cartilage quality in osteoarthritis and has been shown to be reduced in juvenile RA [69].

While cartilage volume and T2 measurements in the knee in particular hold promise for the future, they have not yet been used to demonstrate changes in RA as a result of disease progression or response to treatment.

Synovial volume measurements are relatively precise and reproducible, and compare favourably with OMERACT scoring. They offer increased sensitivity to change and less subjectivity, particularly when using semi-automated techniques. They are, therefore, preferable to OMERACT scoring where appropriate facilities are available. However, they are more dependent on the imaging technique and data about multi-centre use is lacking at present. There is currently little evidence for any benefit of erosion volume measurement over OMERACT scoring. The role of synovial fluid and cartilage volume measurement has yet to be established.


   Dynamic contrast enhanced MRI
Top
 Abstract
 Introduction
 Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
Conclusion
 Acknowledgements
 References
 
Dynamic contrast enhanced MRI (DCE-MRI) involves the acquisition of sequential images in rapid succession every few seconds during and after the intravenous administration of contrast agent. This allows the time-course of the synovial enhancement to be analysed. Measurements made from the enhancement curve (Fig. 3) are sensitive to various physiological parameters, including synovial perfusion and capillary permeability. Consequently, they are expected to be good markers for inflammation in RA.


Figure 3
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  		FIG. 3. Enhancement curves from a series of DCE-MRI images of a patient with RA showing the early enhancement rate (EER), the maximum enhancement (ME) and the late (static) enhancement (SE). Enhancement is reduced after anti-TNF-{alpha} therapy.

 
The knee and wrist/MCPs have been most commonly assessed in recent studies (Tables 5 and 6). DCE-MRI of the knee is technically easier due to the larger volumes of synovitis. Contrast is usually administered as a rapid, intravenous, bolus injection. This increases sensitivity to synovial vascularity but necessitates rapid imaging. A contrast dose of 0.1 mmol/kg gadolinium is usually given, but 0.05–0.3 mmol/kg have been used [3, 42]. Higher doses increase enhancement, but the effect is non-linear [34]. Injection rate directly affects the DCE-MRI measurements, hence consistency is important and a power injector may be helpful [87]. The conflicting demands of joint coverage, temporal resolution and spatial resolution are particularly important in DCE-MRI. Inflamed synovitis enhances rapidly over the first 20–30 s after a bolus of intravenous contrast (Fig. 3) and a temporal resolution of under 10 s is advantageous to accurately characterize the initial enhancement phase. The small size of the wrist and MCP joints means a spatial resolution of at least 1mm is helpful (Fig. 1). 3D sequences with high resolution in all three planes improve reproducibility in serial studies. Typically, images of the wrist from 3 mm slices acquired in under 30 s are adequate, although a wide range of imaging protocols have been used in different studies with temporal resolutions of 2.6–70 s [25, 75] and slice thicknesses from 1 to 7 mm [70, 88]. Imaging is usually carried out at 1.5T, although field strengths between 0.2 and 3T [25, 71, 88] have been used. In general, increased signal at higher field strengths allows better spatial and/or temporal resolution. In addition to high temporal and spatial resolution, the imaging protocol must provide strongly T1-weighted images that are sensitive to the gadolinium. Most studies have therefore used rapid T1-weighted gradient-echo sequences with relatively short echo times and repetition times. Although high flip angles are traditionally used for DCE-MRI [87], lower flip angles perform better at short repetition times [89].


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  		TABLE 5. Selected cross-sectional studies performed using DCE-MRI of RA

 

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  		TABLE 6. Selected longitudinal studies performed using DCE-MRI of RA

 
The region of interest (ROI) of inflamed synovium from which the enhancement curve is determined may be chosen in different ways. This is important because there is evidence of variation in enhancement across the synovitis [25, 36, 79] corresponding to histological differences [78]. Combining multiple small ROIs improves results [25], analysing all the synovitis in a slice is better than using smaller ROIs [84] and multiple slices are better than a single slice [25]. Taken together these studies suggest the entire enhancing synovium should be included [90]. Because of the time involved in manually outlining all the inflamed synovium, several authors have used automated or semi-automated methods [40, 42, 50, 85].

Parameters that can be measured from the enhancement curve include the early enhancement rate, the maximum enhancement and the late or static enhancement (Fig. 3). The relative early enhancement rate (RER) is often used in preference to the absolute early enhancement rate as it is independent of the units of signal intensity and is proportional to the gadolinium concentration in the synovium (Tables 5 and 6). Theoretically the RER is more strongly dependent on synovial vascularity and capillary permeability than maximum enhancement or static enhancement and is therefore expected to be the best marker for disease activity in RA. Most studies measure the RER over a fixed time period between 30 and 60 s [42, 70, 72, 76, 78–81, 83–85]. Shorter periods increase the dependence on synovial vascularity but are technically more difficult. The relative enhancement at a fixed time [25, 26, 30, 91] is closely related to the RER. The early enhancement rate has been shown to correlate with erosions [74], ESR and pain [83], erosive progression [83] and effects of treatment [32, 85]. It has shown a better correlation with histology [78] and response to treatment [84] than the static enhancement. Direct measurements from the enhancement curve, such as the RER, have the disadvantage of depending on the precise imaging technique and equipment. They are also difficult to interpret as they have a complex dependence on the synovial pathophysiology. Recently, a different approach has been adopted by modelling the enhancement curves to determine underlying physiological parameters, including the volume transfer constant, Ktrans. This depends predictably on synovial vascularity and capillary permeability, and is therefore expected to be a good marker for inflammatory activity [75, 88, 92–94].

Good intra-reader [25, 26, 72, 79, 83, 95], inter-reader [79, 84] and inter-scan [95] reproducibility (ICC > 0.9) has been demonstrated for DCE-MRI measurements. A median combined inter-scan/inter-reader difference of 26% was observed in the RER [84].

Evidence for the value of DCE-MRI comes from correlation with other measures of inflammation (in particular histology), prediction of disease progression and demonstration of a response to treatment.

DCE-MRI parameters have been shown to correlate with clinical findings including joint swelling [77], pain [76, 77] and disease activity score (DAS) [71], Paulus [82], ACR [91] and HAQ [71] scores. The picture with ESR is more confused with some studies finding a correlation [25, 78, 83, 96] while others were unable to do so [42, 82, 95], perhaps reflecting the dependence of the ESR on disease throughout the body. While enhancement parameters have shown differences between patients with RA and osteoarthritis [75], they have been unable to distinguish RA from psoriatic arthritis [72].

The enhancement rate correlates with other imaging measures of synovial volume, erosion, vascularity, capillary permeability and metabolic activity. Static MRI measures of enhancement [70] and synovial volume [70, 83] correlate with RER, implying a link between synovial vascularity and volume. Correlations have also been demonstrated with marrow oedema [25] and erosions [74], suggesting rapidly enhancing tissue is associated with erosive disease. Power Doppler vascularity, which directly images blood flow in the larger synovial vessels, also correlates with DCE-MRI [80, 81]. Correlations between enhancement rate and radiolabelled nanocolloid uptake are unsurprising since both depend on synovial vascularity and capillary permeability [25]. FDG-PET activity also correlates with the RER [70], suggesting a link between enhancement rate and metabolic activity.

Some of the most compelling evidence that DCE-MRI is likely to be a useful marker for disease activity comes from comparative studies with histology. The enhancement rate has been shown to correlate with overall histological inflammation [78, 95]. Strong correlations have been demonstrated between RER and vascularity (e.g. vascular area, proliferation) and perivascular oedema [73, 76, 78, 97]. This is more marked than those seen with synovial volume (see above), and supports the strong dependence of the RER on synovial vascularity and capillary permeability. Other histological markers of acute inflammation which have been linked with DCE-MRI include cellular and polymorphonucleocyte infiltration and fibrin deposition [78, 97]. No correlation has been observed with the more chronic changes of fibrosis [78], while links with granulation tissue are controversial [78, 97].

Two studies have compared baseline DCE-MRI with progression of bone erosion (defined by OMERACT scores) and have demonstrated a correlation between enhancement rate and erosive progression after 1 yr (42 patients) [83] and 2 yrs (24 patients) [26]. This provides evidence that DCE-MRI predicts erosive progression.

Several studies have demonstrated the effects of treatment on DCE-MRI measurements. The earliest changes have been shown after intra-articular steroid injection—a longitudinal study (15 patients) showed a decrease in enhancement rate in the knee 7 days after treatment [84]. Other studies have looked at the effects of DMARDs. A randomized controlled trial of 34 patients compared leflunomide with methotrexate and demonstrated a significant fall in RER after 4 months of leflunomide treatment, significantly greater than the response to methotrexate [85]. A small group of patients showed a fall in enhancement rate 14 months after starting methotrexate and hydroxychloroquine [91]. In a group of 42 patients, half of whom received DMARD therapy, a fall in enhancement rate was seen after 1 yr [83]. Three studies have looked at the effects of anti-TNF-{alpha} therapy. All showed a change in DCE-MRI after treatment. A statistically significant fall in enhancement rate of synovitis in the wrist was seen after 14 weeks of treatment in 19 patients [32]. A study of 18 patients showed a decrease in RER significantly greater than the control group after 4 weeks [82]. A further study of 12 patients using pharmacokinetic modelling demonstrated a decrease in Ktrans with anti-TNF-{alpha} therapy but not with methotrexate [92]. DCE-MRI measurements have therefore been shown to respond to a variety of treatment regimens.

In summary, DCE-MRI should be performed using fast gradient-echo images with short echo times and repetition times allowing rapid imaging, ideally in 10 s or less. The relative early enhancement rate calculated from the entire volume of synovitis appears to be the best of the simple DCE-MRI measurements. It depends heavily on synovial vascularity and capillary permeability and as such is expected to be sensitive to inflammation. This is supported by correlation with clinical, laboratory, histological and other imaging measures of disease activity. Enhancement rates predict erosive progression and respond rapidly to treatment. They are therefore likely to be good measures of disease activity in RA.

The evidence to date suggests DCE-MRI is a more sensitive marker of disease activity than scored or measured synovial volume. It is therefore most likely to demonstrate changes in individual patients or cohorts. However, it is very dependent on the precise experimental protocol, contrast injection and measurement technique so further work is needed before it can be applied to multi-centre studies.


   Conclusion
Top
 Abstract
 Introduction
 Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
Acknowledgements
 References
 
MRI is well suited to providing quantitative measurements in RA because of its ability to visualize bone and soft tissues in three dimensions. The OMERACT scoring systems has been well validated and allows straightforward quantitation of bone erosions, bone marrow oedema and synovial volume, all of which predict erosive progression. Synovial volume can be measured directly by manually outlining the inflamed synovium, but this is time consuming. Semi-automated techniques have been developed that allow measurement in acceptable times. Such measurements may be more reproducible and sensitive than OMERACT scoring, correlate with histological inflammation and respond quickly to treatment. There is currently no clear advantage to direct measurement of erosion volume, but automated techniques under development may allow fast, objective measurements of bone loss. Finally, the use of dynamic contrast enhanced MRI provides measurements which reflect the underlying pathophysiology of the inflamed synovium and may provide the most responsive MR measurements of disease activity. DCE-MRI measurements have also been shown to correlate well with other measures of acute inflammation, predict erosive progression and to respond to treatment. However, the role of MRI measurements in routine clinical care for defining remission, determining optimal treatment and predicting long-term response to therapy remains to be established.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
References
 
The authors wish to thank the Royal College of Radiologists, UK for a Research Fellowship.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Scoring systems
 Volume measurements
 Dynamic contrast enhanced MRI
 Conclusion
 Acknowledgements
 References
 

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Submitted 2 May 2007; revised version accepted 8 August 2007.
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