Oulu University Hospital, Oulu and 1 Rheumatism Foundation Hospital, Heinola, Finland.
Correspondence to: K. Palosaari, Department of Diagnostic Radiology, Oulu University Hospital, Kajaanintie 50, FIN-90029, BOX 50, Oulu, Finland. E-mail: kari.palosaari{at}oulu.fi
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Abstract |
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Methods. Twenty-eight early RA patients (median symptom duration 5 months, range 112 months) underwent MRI, NC scintigraphy, laboratory and clinical examinations. Static wrist MRI scans were retrospectively scored for synovitis, bone oedema and erosions by two independent readers using the recently published rheumatoid arthritis MRI scoring system (RAMRIS). Twenty NC scans were analysed quantitatively by measuring maximum 99Tcm-NC uptake in three small areas of each wrist. From the same locations on the wrists, dynamic MRI gadolinium-diethylenetriaminepenta-acetic acid (Gd-DTPA) enhancement rates (E-rate) were measured. The average 99Tcm-NC uptake of the whole wrist region was also measured and average E-rates were calculated. Correlations between MRI and NC scintigraphy measurements were calculated. Correlations between imaging methods of the wrist and the global measures of inflammation (laboratory and clinical examinations) were also assessed.
Results. Strong correlations emerged between maximal 99Tcm-NC uptake and MRI E-rates, reflecting similar performance of the methods in detecting local synovial inflammation. 99Tcm-NC uptake and MRI E-rate correlated with semiquantitative scoring of synovitis and bone oedema from static MRI scans. The erythrocyte sedimentation rate (ESR) correlated with MRI scores, E-rate and 99Tcm-NC uptake. No correlation between the clinical parameters and the imaging methods was detected. Inter-observer reliability for scoring synovial hypertrophy, bone oedema and bone erosions from static MR images were high (single-measure fixed-effects intra-class correlations 0.87, 0.93 and 0.91 respectively). Intra-observer reliability for E-rate and 99Tcm-NC measurements of 10 randomly picked scans was found to be high, with an intra-class correlation of 0.92; 95% confidence interval (CI) 0.840.96 and 0.99; 95% CI 0.981.00, respectively.
Conclusions. Objective information about wrist joint inflammation can be obtained with contrast-enhanced dynamic MRI and quantitative 99Tcm-labelled NC scintigraphy. MRI also allows visualization and semiquantitative scoring of bone oedema and erosions of the wrist. Dynamic MRI and NC scintigraphy are safe and easy to perform, and they can be used in a long-term follow-up of rheumatoid patients.
KEY WORDS: Dynamic MRI, NC scintigraphy, Rheumatoid arthritis
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Introduction |
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Whole-body radiolabelled albumin-nanocolloid (NC) scintigraphy has proved to be an effective method for identifying patients with active peripheral joint disease [2325], and an accurate method for quantifying nanocolloid uptake in inflamed tissue at the local joint level is available [26]. The mechanism of 99Tcm-NC uptake is not well understood, but labelled nanocolloid particles are thought to leave the circulation and to enter the extravascular compartment at sites of inflammation, where increased local vascular permeability of the synovial membrane prevails [27].
In this paper, use of 99Tcm-labelled NC scintigraphy in quantifying local joint inflammation in early RA patients is presented and the method is compared with contrast-enhanced dynamic and static MRI. The associations between methods of imaging the wrist and the global measures of inflammation (laboratory and clinical examinations) are also assessed.
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Material and methods |
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Assessment of dynamic MRI scans
For the subsequent MRI measurements, a blank anatomical illustration of the carpus with three circular areas (Fig. 1B) was prepared by the nuclear medicine specialist (RT). The three areas were selected based on the quantitative results of NC scanning. The purpose of this selection was to investigate if the nanocolloid uptake values in the different areas within the carpus correlated with the MRI measurements. On MRI image data, ROI circles (528 mm2) were placed over the region of maximal synovial enhancement within three pre-selected areas of the carpus. The ROI measurements of the MRI scans were performed by a radiologist (KP) who was blinded to the NC scintigraphy measurements, clinical data and laboratory results. Analysis of the dynamic data was done on a workstation using VIA 2.0 software (Philips Medical Systems, MR Technologies Finland, Vantaa, Finland) and it took about 20 min per patient. Three curves were obtained, plotting the mean pixel intensity of the ROI circle against the time following Gd injection (Fig. 1CF). In most patients, a rapid steep increase in signal intensity was observed after the first post-contrast sequence at 69 s, followed by a slower increase to the maximum level of enhancement.
For quantitative characterization of these curves, the rate of enhancement (E-rate) per second after the first post-contrast sequence (69 seconds) was calculated as follows:
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Evaluation of enhancement after the first post-contrast sequence was chosen, because a previous study revealed significant correlation (Spearman's r>0.60) between the early enhancement rate and the microscopic features of inflammation in the interval of 30 to 120 s after the Gd injection (maximal correlation at 35 to 55 s post-injection) [9]. To compare the results on dynamic MRI and clinical parameters, a single E-rate representing the whole volume of synovial tissue would be needed. However, because it was impossible to measure a single E-rate value from the whole volume of synovial tissue (12 image slices with multiple different sized areas of enhancing tissue at different locations), an average enhancement value from the three previously measured ROIs was calculated.
Scoring of static MRI images
MRI scoring of synovial hypertrophy, bone oedema and bone erosions of the wrist joint was done independently by two observers (KP and JV) by reading the STIR images (bone oedema) and static T1-weighted 3D GRE images obtained before and after contrast enhancement (synovitis and erosions) according to the OMERACT group RAMRIS scoring system [19]. Synovitis was scored on a scale of 03 at three different locations: Radioulnar joint, radiocarpal joint and intercarpalcarpometacarpal joints, (total maximum score 9). A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Measurements, in millimetres, of the maximum thickness of enhancing tissue perpendicular to the cortical surface were performed to guide the approximation of the presumed maximum volume of the synovial compartments. Carpal bones, distal radius, distal ulna and bases of metacarpals (15 locations) were scored separately for bone oedema (score 0 to 3 by the volume of oedema: 1, 133%; 2, 3466%; 3, 67100%) and bone erosions (score 0 to 10, based on the proportion of eroded bone compared with assessed bone volume: 0, no erosion; 1, 110% of the bone eroded; 2, 1120%, etc.) The maximum score for bone oedema was 45 and that for bone erosions 150. The metacarpophalangeal joints were not evaluated, as they were not completely covered in the image sets.
Statistics
The data were not normally distributed, and correlations between MRI, NC scintigraphy and clinical and laboratory assessments were therefore analysed using Spearman's rank correlation coefficient. Single-measure fixed-effect intraclass correlation coefficients were calculated to investigate the intra-observer reliability of dynamic MRI and quantitative NC scintigraphy measurements. Inter-observer reliability of scoring static MRI scans were calculated with the same method [30]. A level of P<0.05 was considered statistically significant. The SPSS 9.0 was used to conduct analyses.
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Results |
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Two readers scored the 28 baseline static MRI wrist scans separately. Inter-observer reliability for the MRI synovitis score was 0.87 (95% CI 0.740.94), while the bone oedema score was 0.93 (95% CI 0.850.97) and erosion score 0.91 (95% CI 0.820.96).
In separate readings, erosions were scored as present in 23 of the 28 MRI scans (82%) by reader 1 and in 20 of the 28 (71%) scans by reader 2. To reach maximum accuracy in scoring erosions and bone oedema, all of the 28 scans were reviewed for a consensus opinion. In the case of the five scans with controversy as to the presence or absence of erosions, the consensus reading showed one scan to reveal an erosion, giving a total of 21 erosive scans (75%). Bone marrow oedema was present according to consensus reading in 17 scans (61%). Synovitis was present according to one or both observers in all scans. The median scores for grading synovitis, bone oedema and erosions are presented in Table 4.
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Discussion |
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In our study, both quantitative NC scintigraphy and dynamic MRI were found to be feasible methods for detecting the degree of synovial membrane inflammation at the local joint level, even though they require manual processing on a workstation. High correlation between quantitative NC scintigraphy and dynamic MRI indicates a similar diagnostic performance of these imaging methods in detecting synovial inflammation of the wrist. Significant correlations between quantitative results obtained from NC scintigraphy, dynamic MRI and static semiquantitative MRI scores of synovitis and bone oedema further support the concept that these measures are linked to disease activity.
Because 99Tcm-NC image formation is based on the uptake of radiolabelled compound in inflamed tissue, it lacks the spatial resolution and visualization of anatomical structures achieved with MRI. Thus, evaluation of bone oedema and erosions is impossible. Another disadvantage of scintigraphy compared with MRI is the use of a radioactive compound, which exposes patients to small amounts of radiation. However, unlike with MRI, the whole body can be scanned at same time with 99Tcm-NC scintigraphy, and valuable information about possible inflammation in other joints is available. Whole-body 99Tcm-NC scintigraphy could be useful in assessing objectively global disease activity and in guiding clinicians to focus MRI on the most seriously involved joints. At present, analysis of the whole-body 99Tcm-NC scans of the patients is under way, and the results will be published in a forthcoming report.
Dynamic Gd-DTPA-enhanced MRI in quantifying synovial hypertrophy in patients with inflammatory arthritis was first published by Reiser et al. [2]. This group showed a rapid and marked increase of signal intensity in synovial proliferations over time, with a peak value at 56.3 ± 21 s post-injection. Four dynamic MRI studies have included histopathological references [3, 79], and only one study has examined the optimal timing of enhancement measurements in correlation with histological inflammatory activity [9]. This study showed the maximum correlation between synovial enhancement and histological inflammatory activity in an arthritic knee joint to occur at 35 to 55 s after the Gd injection, and the correlation continued to be significant until 2 to 2.5 min post-injection. In these studies, the dynamic data were collected from one to four pre-selected image slices. When imaging a wrist joint, the selection of only one slice is problematic because of the more complex anatomy of the wrist compared with the knee joint. In a quantitative assessment of synovial membrane in the wrist joint by Ostergaard et al. [14], the rate of early synovial enhancement could not be measured from a single pre-selected axial image slice in 14 out of 26 wrists. Therefore, despite the disadvantage of a relatively long acquisition time (69 s per sequence), we preferred to select multiple (12) continuous coronal image slices to cover most of the wrist joint volume.
The other approach to quantifying joint synovitis is to measure the synovial tissue volume of the wrist joint [14, 17]. Manual outlining and volume calculation of the enhanced synovial area of the joint is time-consuming, and several semiquantitative scoring methods have been used instead [13, 15]. The OMERACT group released a simple MRI scoring system (RAMRIS) of the wrist and metacarpophalangeal joints, which was validated in an international multicentre trial [20]. Overall the agreement between six groups was satisfactory for measures of synovitis, bone erosions and bone oedema. After practising with wrist MR images of five patients not involved in this study, we decided to employ the RAMRIS score sheet, even though the system is somewhat cruder than some grading systems published previously [13, 15] in terms of its inability to score cartilage thinning or damage and the exclusion of tendonitis and tenosynovitis. Our inter-reader agreement was somewhat better than agreement results published by the OMERACT group. However, we had two readers rather than the six readers of the OMERACT multicentre study, and we performed an inter-reader practice with consensus reading before the reading of the actual study images.
Regional heterogeneity of synovial inflammation in different parts of the arthritic knee joint has been reported previously. In a study by Ostergaard et al. [31], evaluation of the early synovial enhancement rate in small areas of synovial membrane revealed large variation compared with the total synovial membrane enhancement rate of a pre-selected image slice. To investigate this phenomenon and to examine the correlation between quantitative NC scintigraphy and MRI in more detail, three different areas of the wrist were selected for ROI measurements. In our study, similar variation of MRI enhancement rates and radiolabelled nanocolloid uptake were found in different parts of the wrist joint in most patients. The variation between the MRI enhancement rates of the different areas within wrists can be mostly explained by the regional heterogeneity in synovial hypertrophy tissue, but when measuring very small areas of synovial hypertrophy, a partial volume artefact may also have an effect on the measurements. One reason for this regional heterogeneity may be the complex anatomy of the wrist joint, as the joint is composed of several compartments including the first carpometacarpal, common carpometacarpal, intercarpal, radiocarpal and distal radioulnar compartments, which may be differently affected by the disease. In addition to inflammatory activity, the volume of synovial tissue may also contribute to 99Tcm-NC uptake.
To get a single overall measure of the joint inflammation, the average 99Tcm-NC uptake of the whole wrist region was measured. This average measure was used to study the correlation between NC scintigraphy and clinical parameters. However, from multiple wrist MR image slices we were unable to obtain a single enhancement measurement representing the whole volume of inflamed tissue, and we therefore calculated average enhancement values from the three previously selected areas for the comparison of dynamic MRI with clinical parameters, and presented them as average E-rates. The maximal E-rate and the maximal 99Tcm-NC uptake measured in the areas of the most intense enhancement/uptake were also compared with clinical and laboratory results. Measurement of several enhancement curves for average E-rate calculation is time-consuming and similar associations between maximum and average E-rates compared with other study parameters support the idea that a single measurement from the region of the most intense Gd enhancement is sufficient for assessing disease activity.
To determine MRI enhancement rates, implementation of a special rapid gradient-echo sequence, manual placement of ROI circles on the areas of most intense Gd enhancement and calculation of time-dependent enhancement curves by software is required. Obviously, this is more time-consuming than semiquantitative scoring of synovitis by the RAMRIS scoring system from static post-Gd scans. Although dynamic MRI provides more accurate information of the intensity of inflammation at one specific site within the carpus, the significant correlation between MRI E-rate measurements and more easily obtained semiquantitative MRI synovitis score in our study suggests that the RAMRIS system may be adequate in clinical trials and practices, when implementation of dynamic MRI is considered too time-consuming.
Synovitis was present according to one or both observers in all of our patients and bone marrow oedema was present according to consensus reading in 17 of 28 patients (61%). These results are similar compared to those in other papers [15, 37] and indicate a close association between synovitis and bone changes. MRI revealed carpal erosions in 75% of our RA patients who had had symptoms for less than a year (median 5 months). Other MRI studies have also shown that bony erosions develop very early in RA. McQueen et al. [34] reported 45% (19 of 42) of early RA patients to have MRI-detectable erosions at 4 months after the onset of symptoms, the corresponding percentage at 1 yr being 74%. Another study revealed that 18 out of 19 patients with symptoms for less than 1 yr had erosions on MRI of the dominant hand [35]. MRI increases the sensitivity of detecting erosions compared with plain radiography, and there has been some controversy concerning the specificity of erosions detected by MRI. Partial volume artefacts and bone surface irregularity may cause some false-positive findings, but they are mostly avoidable by scoring erosions only if they are present on two different planes (axial and coronal) or in more than one of the adjacent slices of the same sequence. Interestingly, MRI erosions have also been found in normal control subjects and in arthralgia patients [17, 36].
In our study, the MRI and NC scintigraphy parameters correlated with ESR. This may reflect systemic disease activity. A weaker correlation emerged between CRP and the average 99Tcm-NC uptake and between CRP and the wrist MRI synovitis and bone oedema scores. However, no correlation was found between CRP and MRI E-rates. There are conflicting reports concerning MRI and the laboratory parameters of inflammation. In an early RA study of 42 patients, MRI scores of the wrist correlated with CRP and ESR [15]. In some other papers, no correlation was found between the laboratory parameters of inflammation and dynamic MRI [8, 10, 31].
For each patient, NC scintigraphy and MR imaging were performed on the same day to ensure comparable imaging data, but a weakness in our study design was the relatively long time interval between the clinical assessment and imaging. This was due to the limited time capacity of our MRI unit. This may have an effect on non-existent correlation between clinical evaluation (i.e. tender/swollen joint count, HAQ) and imaging results. The involvement of several rheumatologists may also have affected the present results, but this reflects the situation in everyday practice in our institution. In a recent study by Cimmino et al. [33], significant correlations between MRI early enhancement rate and several clinical global disease activity measures (number of swollen and tender joints, the Ritchie Index, Disease Activity Score, HAQ, CRP, ESR, 2 globulins) were found. On the other hand, some other papers address the discrepancy between clinical evaluation and MRI. Gaffney et al. [8], who studied rheumatoid knee joints, noted no correlation between dynamic MRI and clinical assessment or laboratory parameters. When comparing dynamic MRI of the rheumatoid wrist with clinical parameters, Huang et al. [10] found a weak but significant correlation with the pain score, but not with the other clinical parameters. In a longitudinal study by Jevtic et al. [32], 58% congruence between the clinical and MRI findings was seen. In a 1-yr follow-up study of 34 RA and polyarthritis patients, a decrease in the swollen or tender joint count was detected, but finger synovitis and tenosynovitis on MRI persisted [16]. This may represent the difficulty and low sensitivity of clinical evaluation of disease activity. Nevertheless, the imaging of one joint may not be representative of the global disease activity of a polyarticular systemic disease.
In conclusion, dynamic MRI and quantitative NC scintigraphy show high intermodality correlation in evaluating synovial inflammation of the wrist joint in early RA patients. More detailed and comprehensive information about bone damage is achieved by MRI, but unlike with NC scintigraphy, the evaluation of several joints during the same session is impossible. Both techniques are relatively easy to perform, and they can be used in a long-term follow-up of rheumatoid patients.
The authors have declared no conflicts of interest.
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References |
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