A 1-year follow-up study of dynamic magnetic resonance imaging in early rheumatoid arthritis reveals synovitis to be increased in shared epitope-positive patients and predictive of erosions at 1 year

J. Huang, N. Stewart, J. Crabbe, E. Robinson, L. McLean, S. Yeoman, P. L. J. Tan and F. M. McQueen

Department of Rheumatology, Auckland Hospital, Private Bag 92024, Auckland 1, New Zealand


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Dynamic magnetic resonance imaging (MRI) allows visualization of the synovial membrane and measurement of synovitis within the joint. A cohort of patients with early rheumatoid arthritis (RA) were studied using MRI of the dominant wrist and clinical assessments. Associations between synovitis and the shared epitope genotype (SE) were looked for and synovitis as a predictor of joint erosion was examined.

Methods. Gadolinium-enhanced MRI scans of the dominant wrist were performed in 42 early RA patients at baseline (median disease duration = 4 months) and after 1 yr. Images were obtained at 42-s intervals over the first 6 min after gadolinium-diethylenetriamine pentaacetic acid injection using six cuts in the coronal plane, 2 mm apart. The site of maximal synovial enhancement was selected as the region of interest (ROI). The rate of enhancement (E-rate) was calculated and compared with synovitis scores from static MRI scans, clinical disease activity scores and HLA-DRB1*04/01 genotyping [sequence-specific primer polymerase chain reaction (SSP-PCR) and DNA sequencing].

Results. Reproducibility of the E-rate measurement was assessed by re-evaluating 10 randomly selected scans in a blinded fashion. Intra-observer reliability was high with an intraclass correlation coefficient of 0.91, 95% confidence interval (CI) 0.65–0.97. The E-rate correlated strongly at baseline with the maximum level of synovial enhancement (E-max) (r = 0.88, P < 0.0001) and the static MRI synovitis score (r = 0.52, P = 0.0004). There was also a weaker but significant correlation between E-rate and the pain score (r = 0.29, P = 0.04). The E-rate fell from baseline to 1 yr (P = 0.02) concordant with clinical improvement after treatment with standard therapies. E-rate scores were higher in SE+ than SE - patients (F1,25 = 5.19, P = 0.03) and were predictive of MRI erosions at 1 yr [chi-square = 5.0 (1 d.f.), P = 0.03]. The baseline C-reactive protein (CRP) was also predictive of MRI erosions at 1 yr to a similar degree [chi-square = 4.7 (1 d.f.), P = 0.03] but the mean static synovitis score at baseline was the strongest predictor [chi-square = 9.2 (1 d.f.), P = 0.003].

Conclusions. These results show that dynamic MRI can be used to score synovitis objectively in early RA patients. Synovitis was greater in SE+ patients, suggesting an early genetic influence on joint inflammation, and was predictive for the development of erosions at 1 yr.

KEY WORDS: Magnetic resonance imaging, Rheumatoid arthritis, Synovitis, Shared epitope.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Synovitis is a major feature of early rheumatoid arthritis (RA) and usually involves the carpus and the small joints of the hands [1]. Measuring the degree of synovitis has traditionally depended on clinical examination. However, joint tenderness and swelling scores are relatively subjective with considerable inter-observer variability and bias arising from the observer–patient interaction [2]. Dynamic magnetic resonance imaging (MRI) scanning provides a non-invasive tool for imaging the inflamed synovium which enhances after the intravenous (i.v.) injection of a contrast agent (gadolinium). Estimation of synovial volume [3–5] and enhancement post-contrast [6–9] have been proposed as measures to quantify synovitis more objectively than traditional means.

Several studies have examined dynamic MRI scans of the knee in RA patients [6–8] and in two of these correlations were found between the rate of increase of synovial enhancement and histological features of synovitis [7, 8]. However, there has been debate over how to calculate the rate of enhancement [8] and whether enhancement correlates with clinical indicators of inflammation [6, 8, 9]. Some studies of knee synovitis have compared MRI features with histological findings from arthroplasty specimens taken from patients with long-standing ‘burnt out’ disease and may not be applicable to early RA [7, 10]. The assessment of synovitis at the wrist using synovial enhancement from dynamic MRI scans has been described in two reports [6, 11]. Both studied small numbers of patients who were heterogeneous with respect to disease duration. Because of technical difficulties in obtaining synovial biopsies, histological features of synovitis and MRI findings have not been compared at the wrist. However, if dynamic MRI is to be applied to the measurement of synovitis in RA, the wrist is an important site to investigate as it is more frequently involved than the knee in early disease [1].

The degree of synovitis in early RA is likely to be an important indicator of prognosis. Many studies have recognized high joint activity scores at disease onset to be associated with long-term erosive joint damage [12, 13]. Carriage of the HLA-DRB1*04/01 genotype containing the shared epitope (SE) has also been shown to be associated with a poor prognosis by some groups [14, 15] but not others [16]. In this paper, we present the first longitudinal study of dynamic MRI of the wrist in early RA. We have looked for associations between MRI evidence of synovitis and clinical measures of joint inflammation. We have also investigated MRI synovitis as a prognostic factor in early disease and its relationship to SE genotype.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population and clinical assessments
An inception cohort of 42 patients with early RA has been studied since symptom onset. Details of recruitment, baseline demographics and clinical assessments have been described previously [17, 18]. To summarize briefly, all patients fulfilled 1987 American Rheumatism Association (ARA) criteria for RA [19] and had had symptoms for 6 months or less (median 4 months) at entry to the study. All patients were assessed clinically at baseline by a rheumatologist and standard laboratory investigations were performed to determine disease activity. These were repeated at 1 yr and Table 1Go summarizes the demographics of the group at both time points.


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TABLE 1. Patient characteristics at baseline and 1 yr (n = 42)

 

Dynamic MRI scans
A MRI scan of the dominant wrist was obtained using a 1.5 Tesla MR scanner (GE Signa Horizon) with a dedicated, phased array wrist coil (GE Medical Systems, Wisconsin, USA). The patient was placed supine within the scanner with the hand by the side and care was taken by the technician to place the hand in a true sagittal plane. Dynamic scans were performed using a coronal fat-suppressed fast multi-planar spoiled grass (FMP SPGR) technique. The scans were localized using the initial axial spin echo localizing sequence. The slices were arranged to cover the carpal bones centred on a slice through the mid-lunate. The 1-yr scans were set up to match the baseline scans.

The imaging parameters used were: TR 150 ms, TE 9.1 ms, flip angle 60 degrees, matrix size 256 x 256, slice thickness 3 mm and a gap of 2 mm between slices. Each sequence consisted of six slices and was obtained in 42 s. The field of view was 12 cm and included the distal radioulnar, radiocarpal and mid-carpal joints as well as the metacarpal bases. The small field of view was chosen to optimize resolution and did not include metacarpophalangeal joints. A pre-contrast scan (42 s, six slices) was performed (time 0 on Fig. 1Go), then 10 ml of gadodiamide (0.5 mmol/ml) (OmniscanR, Nycomed, New Zealand Ltd) was injected i.v. through a 23-gauge cannula in the opposite arm. This injection was given over a period of 20–30 s with a subsequent flush of 10 ml of normal saline, before the commencement of the next scan sequence (time 42 s, Fig. 1Go). Nine sequences were obtained, each of 42-s duration with a total imaging time of 6 min, 30 s. The last sequence of six images (slices) was examined and the slice with the greatest degree of synovial enhancement (usually from the mid-coronal position) was chosen for measurements of pixel intensity.



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FIG. 1. Typical enhancement curve for inflamed synovial membrane. Signal intensity (SI) increases rapidly from a take-off point (SI0) to SIt measured after time t (42 s).

 
Analysis of data was performed on a GE Advantage Windows 2.1 workstation. A region of interest (ROI) circle (8–12 mm2) was placed over the region of maximal synovial enhancement within the carpus by a musculoskeletal radiologist. A curve was obtained, plotting pixel intensity of the image against time, following gadolinium injection. The curve was typically S-shaped (Fig. 1Go) with an initial flat region of slow uptake which occurred just after the contrast injection, while contrast circulated to the ROI (time 0–42 s). Then a rapid linear increase was observed over the next 40–80 s after the take-off point (SI0 to SIt in Fig. 1Go) followed by a slower increase to a maximum level of enhancement (E-max) reached at approximately 120 s. The rate of increase in pixel intensity over the initial linear region of the curve (E-rate) was calculated as follows:

where SI0 is the signal intensity at the take-off point and SIt is the signal intensity reached after time t (42 s). E-rate was strongly correlated with E-max; r = 0.88, P = 0.0001. Data were also re-examined using the relative rate of enhancement (‘E-ratio’) as described by other groups [6, 7, 11]. However, this measure did not give a good indication of the rate of increase in signal intensity as spuriously elevated values were found in patients with low baseline readings (data available on request).

Static MRI scans
Static MRI scans of the dominant wrist were obtained at the same visit and results have been reported elsewhere [18]. Coronal and axial T1 sequences were performed, followed by axial fat-suppressed fast spin echo T2, then coronal fat-suppressed T1 sequences after injection of gadolinium. MRI scans were scored independently and without reference to radiographs, according to a system which has been described previously [17], by two musculoskeletal radiologists who were blinded to clinical and genetic data. Briefly, synovitis was scored at seven individual sites on the basis of synovial thickening and enhancement post-gadolinium (Table 2Go). Erosions were scored at each of the 10 carpal bones and the five metacarpal bases. Where observers differed as to the presence or absence of erosions, scans were reviewed and a consensus opinion obtained. Inter-observer and intra-observer reliability of the scoring system was high at baseline and 1 yr [17, 18].


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TABLE 2. Synovitis scoring system for static MRI scans (post-gadolinium)

 

Genetic studies
The methodology used for HLA-DRB1 typing has already been described [17]. Briefly, DNA was extracted from anticoagulated blood obtained from each patient at recruitment. Low-resolution typing was performed using sequence-specific primer polymerase chain reaction (SSP-PCR) with a standardized panel of 24 oligonucleotide primer pairs [20]. In subjects with alleles of the DRB1*04 or 01 groups, the sequence of the subtype-determining region of exon 2 of the DRB1 gene(s) was obtained by direct sequencing of PCR products [21]. A comparison of high-resolution HLA-DRB1 typing methods in this group has been reported elsewhere [22].

Statistics
Clinical disease activity measures were found to have skewed distributions so medians were used as measures of central tendency. However, normal distributions for the E-rate and static synovitis score allowed the use of parametric methods including Pearsons' correlations which were calculated and combined using Fisher's transformation [23].

Intraclass correlation coefficients were calculated to investigate the intra-observer reliability for positioning the ROI at the area of maximal synovial enhancement [24]. The repeatability index [2 standard deviations (S.D.) of the differences between repeated measurements] [25, 26] was used to investigate the variability of the E-rate measurement and the significance of its fall from baseline to 1 yr. Paired t-tests and Wilcoxon signed ranks tests were used to investigate the change from baseline to year 1 in E-rate and clinical measures.

Repeated measures analyses [27] using a mixed model approach were used to investigate the differences in rates of enhancement and mean static synovitis scores between SE+ and SE- patients at baseline and 1 yr. Logistic regression was used to investigate whether baseline measures predicted the presence of erosions at 1 yr.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Reproducibility of E-rate as a measure of synovitis at the wrist
Dynamic MRI scans of the dominant carpus were obtained in 42 patients with active recent-onset RA at entry into the study (baseline median symptom duration of 4 months) and in 41 patients after 1 yr. One patient was unable to complete the second scan because of severe joint pain. A ROI was defined for each scan as the point of maximum enhancement within the synovial membrane (Fig. 2A–FGo). The rate of enhancement (E-rate) of synovium at the ROI was obtained from serial scans taken at 42-s intervals over a 6-min period (Figs 1Go and 2Go) according to methods described by Gaffney et al. [8] (see Patients and methods). Determining the ROI was seen as a crucial step in calculating the E-rate and this was performed by a musculoskeletal radiologist. To test the reproducibility of this measurement, 10 scans were picked randomly and the ROI was reselected in a blinded fashion. The E-rate was then recalculated at that point and a comparison made with previous measurements. The intra-observer reliability was found to be high with an intraclass correlation of 0.91; 95% confidence interval (CI) 0.65–0.97.



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FIG. 2. Serial dynamic MRI scans of the dominant carpus in a patient with early RA (coronal section). (A–F) Increasing synovial enhancement at the ROI (circle 1) over 210 s after contrast injection. Scans were taken at 42-s intervals. (G) Signal intensity (mean pixel value) vs image number showing characteristic enhancement profile for synovitis.

 

Measurement of E-rate: possible influence of contrast dose
A standard dose of gadolinium of 5 mmol (10 ml of 0.5 mmol/ml) was used in this study for each patient. The mean body weight for the group was 75.2 kg (S.D. 13.8) making this a mean dose of 0.07 mmol/kg. To examine whether variation in body weight (and therefore blood volume) could have influenced E-rate, we looked for correlations between these variables. There was no correlation between E-rate and weight at baseline (r = - 0.2, P = 0.2). However, there was a correlation at 1 yr (r = -0.3, P = 0.04). As the dose of gadolinium given to each patient was the same at baseline and 1 yr, this was not felt to represent the influence of blood volume but rather to imply that weight is a marker of disease activity (lower weight, more active disease with higher E-rate). Consistent with this premise, weight at baseline was found to be an independent predictor of erosions at 1 yr (see below). Figure 3Go shows sample signal intensity curves for four patients with similar weights at baseline to illustrate this. Patients A and B had very flat curves, consistent with their lack of disease activity, contrasting with patients C and D who had rapidly rising curves, high E-rates and active disease.



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FIG. 3. Baseline signal intensity curves from four study patients showing the association between the slope of the curve (E-rate) and disease activity, irrespective of body weight. (A) Weight 84 kg; Ritchie score 2; ESR 30 mm/h; E-rate 1.42. (B) Weight 72 kg; Ritchie score 8; ESR 24 mm/h; E-rate 1.33. (C) Weight 75 kg; Ritchie score 13; ESR 36 mm/h; E-rate 26.9. (D) Weight 68 kg; Ritchie score 15; ESR 46 mm/h; E-rate 18.0.

 

E-rate at baseline and 1 yr
The E-rate fell from baseline to 1 yr (P = 0.05) (Table 3Go) coinciding with a fall in clinical parameters of joint inflammation including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and Ritchie score. The use of disease-modifying anti-rheumatic drugs (DMARDs) increased from 50% to 71% during this period (Table 1Go). The change in E-rate correlated significantly only with the change in ESR (r = 0.3, P = 0.04) but not with the change in CRP or Ritchie score (r = 0.2, 0.01; P = 0.2, 1.0, respectively). The significance of the fall in E-rate was re-examined using the methods of Ruckmann et al. [25] and Bland and Altman [26]. The change in E-rate from baseline to 1 yr was compared with the repeatability index (2 S.D. of the differences between repeated measurements) (Fig. 4Go). More than 50% of the values fell within the repeatability index, suggesting that the change in E-rate over the first year may not have been significant. However, for those with higher baseline E-rate measurements, the change in E-rate was greater and more frequently fell outside the repeatability index, suggesting that for those with the most active disease, a true fall may have occurred.


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TABLE 3. MRI and clinical scores reflecting disease activity at baseline and 1 yr

 


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FIG. 4. Change in E-rate over 1 yr plotted against baseline E-rate showing the region of the repeatability index (between dotted lines). This index represents 2 S.D. of the differences of repeated measures and provides an indication of the expected variability of the measure. Changes in E-rate are only likely to be real if they fall outside the repeatability index and this was most frequently observed in those with high baseline E-rate (see text).

 

Dynamic MRI synovitis (E-rate) correlated with static MRI synovitis score
Synovitis from dynamic scans (E-rate) was compared with synovitis assessed on static MRI scans taken at the same time. Synovitis scoring was performed by two musculoskeletal radiologists using a validated scoring system [17, 18] with synovitis rated as 0, 1 or 2 at each of seven individual sites and then summated to provide the total score for the carpus (Table 2Go). A mean of the two radiologists' scores was taken as the static synovitis score for each patient. E-rate correlated significantly with the static synovitis score at baseline (r = 0.52, P = 0.0004) and at 1 yr (r = 0.56, P = 0.0001).

E-rate correlated with pain score at baseline and 1 yr
The relationship between E-rate and clinical measures was examined at baseline and 1 yr (Table 4Go). E-rate correlated only with pain score at baseline (r = 0.29, P = 0.05). At 1 yr, E-rate correlated with a number of clinical measures including the Ritchie score [28], swollen joint score, Health Assessment Questionnaire (HAQ) score [29], pain score and the disease activity score (DAS) [30]. There were no significant correlations between baseline E-rate and any of the 1-yr clinical scores.


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TABLE 4. Correlationsa between E-rate and clinical scores of disease activity at baseline and 1 yr

 

E-rate was higher in SE+ patients than SE- patients at baseline
Of the 42 patients studied, 32 were SE+ at the HLADRB1*04 or *01 loci. These patients were found to have higher E-rate levels than SE– patients at both time points (F1,25 = 5.19, P = 0.03) (Fig. 5Go). Static synovitis scores and CRP were also compared between SE+ and SE- patients at both times, but no significant difference was found. Interestingly, despite the higher E-rate in SE+ patients, there was no association between carriage of the SE and the presence or number of erosions at either time point.



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FIG. 5. Box plot to show E-rate in SE+ and SE- patients at baseline and 1 yr. Mean (* and median (-) values were higher in SE+ patients (P = 0.03).

 

Increased synovitis at baseline predicts erosions at 1 yr
Carpal MRI scans from this group of patients were also scored for the presence of erosions at 1 yr by two radiologists using a validated scoring system and these results have been published elsewhere [18]. The E-rate from baseline dynamic MRI scans was found to predict the development of erosions on static MRI scans at 1 yr [chi-square = 5.0 (1 d.f.), P = 0.03], implying that those patients with the greatest degree of carpal synovitis were most at risk for long-term erosive damage (Fig. 6AGo, BGo). Baseline CRP and weight were also independently predictive of erosion at 1 yr [chi-square = 4.7 (1 d.f.), P = 0.03 and chi-square = 6.0 (1 d.f.), P = 0.01], but the strongest single predictor was the static synovitis score at baseline [chi-square = 9.2 (1 d.f.), P = 0.003].



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FIG. 6. Dynamic MRI of the dominant carpus (coronal section) in a patient with early RA. (A) Baseline scan reveals high signal intensity of synovial membrane at the ROI (circle 1) contrasting with low signal intensity of bone marrow (circle 2). White arrows indicate intense synovitis at intercarpal joints adjacent to the hamate and trapezoid carpal bones. (B) Repeat scan at 1 yr shows that new erosions have developed at the trapezoid and hamate (also confirmed on static T1-weighted images). These are filled with enhancing synovium.

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Dynamic MRI allows imaging of the synovial membrane in patients with inflammatory arthritis and was first evaluated at the knee. Tamai et al. [7] proposed the ‘E-ratio’ as a measure of synovitis, calculated from the rate of increase of synovial enhancement after contrast injection, divided by the baseline signal intensity of the synovial membrane. They described the typical S-shaped enhancement curve which is characteristic of inflamed synovial membrane and contrasts with patterns of bone marrow and synovial blood vessel enhancement over time [7–9]. They found a correlation between the E-ratio and features of synovitis on biopsy such as leucocyte infiltration and proliferation of blood vessels. Gaffney et al. [8] re-evaluated the calculations used to measure synovitis in their MRI study of 21 patients with knee synovitis and proposed that the initial rate of synovial enhancement be used as an absolute measure, rather than relative to a baseline which was highly variable. This enhancement rate correlated with features of inflammation on multiple synovial biopsies from the involved joints. Both studies involved patients with variable disease duration and the authors commented on difficulties in scoring histology because of inhomogeneity of inflammatory changes within the synovial membrane.

Synovitis at the wrist has long been recognized as an early feature of RA [1] and dynamic imaging of this site has been studied by a number of groups. Ostergaard et al. [3–5] used synovial volume, measured either by a manual outlining method or using computer-assisted technology, as a surrogate marker of synovitis and found this to be associated with joint swelling and tenderness. Sugimoto et al. [31] also found a weak association between the volume of enhancing pannus measured at all the joints of the hand and clinical markers of disease activity. Other workers [6, 11] have used synovial enhancement at the wrist as a marker for joint inflammation. We have followed the method of Gaffney et al. [8] in adopting the E-rate as a measure of synovitis in our group of 42 patients with very early RA who have been studied longitudinally over the first year of their disease. We found that E-rate correlated closely with the maximum level of synovial enhancement (E-max) and as such it was felt to be a good indicator of synovial inflammation. In contrast, the E-ratio calculated from our results did not correlate with the E-max, being inappropriately elevated in patients with low baseline enhancement, and was therefore abandoned.

Our method involved the delineation of a ROI at the point of maximal synovial enhancement within the wrist by a musculoskeletal radiologist and subsequent computer analysis of pixel intensity at that region over the next 6 min. Although this relies on the skill of the observer in selecting the appropriate tissue and site for analysis, a high degree of reproducibility was found with an intraclass correlation coefficient of 0.9. However, this correlation only relates to measurements made by the same reader on the same sets of MRI images (i.e. assesses variability in the placement of the ROI) and further variability could well occur if MRI scans were repeated on the same day or on two consecutive days. Unfortunately, such a precise examination of the reliability of this measurement was beyond the scope of the present study for economic reasons but should be incorporated into future studies.

The dose of gadolinium used in this study was a standard dose of 5 mmol (10 ml of 0.5 mmol/ml) which is used in our institution for all adults weighing less than 110 kg. This provided a mean dose for the group of 0.07 mmol/kg. Most authors have cited the use of 0.1 mmol/kg of body weight [6–8], but at least one group have used 0.05 mmol/kg [4]. We did not find any significant association between E-rate and body weight at baseline, making it unlikely that the slightly higher dose of gadolinium in patients with lower body weight could have influenced the E-rate. Those patients in the group with relatively inactive disease had flat signal intensity curves, regardless of weight, implying that E-rate was determined predominantly by joint inflammation. There was an increasing association between body weight and E-rate as disease progressed, suggesting that low weight is a marker of increased disease activity. This was consistent with the finding that body weight was an independent predictor of carpal erosions at 1 yr.

MRI evidence of synovitis (E-rate) correlated with the pain score in our patients at baseline and 1 yr, but only with other clinical measures of inflammation at the 1 yr time point. Clinical parameters of disease activity fell during the 1-yr study implying improvement which may have been associated with drug therapy (Table 1Go). The E-rate also decreased during this time concordant with clinical improvement, but the extent of the fall was in most cases within the range of the repeatability index, suggesting that it may not have been a real reduction. Few other studies have compared MRI and clinical measures of synovitis during early disease. Reiser et al. [6] did not find any correlation between signal intensity gradient and clinical indicators of inflammation in their RA patients who had MRI scans at the wrist or knee, but interestingly they used the E-ratio which also yielded negative results from our data. Lee et al. [11] noted a 48% fall in E30-ratio in three of their RA patients who achieved remission on DMARD therapy, but detailed clinical assessments were not presented.

We have already studied synovitis in this cohort of patients from static MRI wrist scans and quantified it by scoring at seven joints within the carpus [17, 18]. We found 93% of patients to have synovitis at baseline using this method, falling to 85% at 1 yr (unpublished data). Static synovitis scores were strongly correlated with dynamic synovitis scores (E-rate) from the same patients, as expected, but did not correlate with pain scores. These disparate results are not surprising as the E-rate is a different parameter from the static synovitis score. It provides a more accurate indication of the intensity of inflammation at one specific point within the carpus, while the static synovitis score is cruder and more subjective but allows examination of many joints and a wider view of the carpus as a whole. The pain score is the one global clinical score that would be expected to reflect intensity of inflammation, even in a very localized area, and therefore its correlation with the E-rate is predictable.

The HLADR4*01/04 genotype bearing the SE has been shown in some studies to be associated with poor outcome in RA [14, 15]. We have already examined the influence of the SE on the development of MRI and radiological erosions in this cohort of patients and have found no association at baseline or 1 yr [17, 18]. Thus, it is a little surprising that there should appear to be an association between carriage of SE and the intensity of baseline synovitis on dynamic scanning (E-rate). The SE sequence is expressed on the surface of HLA-DR molecules on antigen-presenting cells and is likely to be directly in contact with the critical antigen and matching T cell receptors during early immunopathological events of RA [16]. Subsequent immune activation would be associated with release of pro-inflammatory cytokines, angiogenesis and the ingress of inflammatory cells resulting in the typical features of inflammation. These features are recognized on dynamic MRI scanning as being proportional to the rate of enhancement of the synovial membrane. Therefore, our finding of a higher E-rate in SE+ patients would support the hypothesis that the SE has a role in facilitating early immune activation. However, because of the variability demonstrated in the E-rate measure (Fig. 3Go), this finding may simply represent a type I statistical error and needs to be re-examined in a larger cohort of patients.

Finally, we have investigated whether the degree of synovitis, measured from MRI scans, might be a useful prognostic tool in early RA for predicting the development of erosions. We found that both the E-rate and CRP at baseline predicted MRI erosions at 1 yr. However, the static synovitis score [18] was the strongest predictor. If all three measures were examined using logistic regression, then only the static synovitis score was found to have an effect over and above that of the other two. Site-specific data have also been analysed from this cohort and an association found between synovitis at a specific carpal joint at baseline and erosion at an adjacent bone after 1 yr [odds ratio (OR) = 2.14] [18] confirming this. Ostergaard et al. [5] made a similar observation in 26 RA patients observed over 1 yr. In their study, MRI synovial membrane volume was used as a measure of baseline synovitis and this was found to predict the rate of erosive progression over 1 yr.

In summary, we have shown that dynamic MRI can provide useful information about the degree of synovitis at the wrist in early RA. The E-rate measurement, obtained from the intensity of synovial enhancement after uptake of gadolinium, allows objective quantitation of synovitis and has been found to correlate with the pain score. It may have an important role in monitoring responses to new anti-rheumatic agents, including biologics, allowing a direct measurement of anti-inflammatory activity to be made, in contrast to using indirect clinical measures such as CRP. We have examined three indicators of synovitis at baseline (E-rate, CRP and static synovitis score) and found all to be predictive of erosion on MRI at 1 yr, but the static synovitis score was the most powerful predictor. We also observed the E-rate to be highest in the SE+ patients in this cohort and this finding warrants further study with a larger patient group.


    Acknowledgments
 
The authors wish to acknowledge the assistance of the following clinicians who have referred patients for this study: Dr Mike Butler, Dr David Caughey, Dr Nora Lynch, Dr Alan Doube, Dr Hamish Hart, Dr Peter Gow, Dr Raoul Stuart, Dr Terry Macedo, Dr Max Robertson, Dr Roger Reynolds, Dr Bob Grigor. We are also most grateful to the technical staff at the Auckland Radiology Group and in particular Mrs Rika Nel, MRI technologist who supervised the MRI scans. We also acknowledge the contribution of Mrs Ma Wei (Technician, Department of Molecular Medicine) who performed HLADRB1*04/01 genotyping and Mr Rob McVie who assisted in collation and analysis of data. This study was supported by grants from the Health Research Council of New Zealand, the Arthritis Foundation of New Zealand, the Auckland Medical Research Foundation, the Auckland Radiology Group and Sanofi-Winthrop.


    Notes
 
Correspondence to: F. McQueen. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Gordon DA, Hastings DE. Rheumatoid arthritis. Clinical features: Early, progressive and late disease. In: Klippel JH, Dieppe PA, eds. Rheumatology. London: Mosby-Year Book Europe, 1994;3.4.1–14.
  2. Eberl DR, Fasching V, Rahlfs V, Schleyer I, Wolf R. Repeatability and objectivity of various measurements in rheumatoid arthritis: A comparative study. Arthritis Rheum1976;19:1278–86.[ISI][Medline]
  3. Ostergaard M, Hansen M, Stoltenberg M, Lorenzen I. Quantitative assessment of the synovial membrane in the rheumatoid wrist: an easily obtained MRI score reflects the synovial volume. Br J Rheumatol1996;35:965–71.[ISI][Medline]
  4. Ostergaard M, Stoltenberg M, Lovgreen-Nielsen, Volck B, Jensen CH, Lorenzen IB. Magnetic resonance imaging-determined synovial membrane volumes in rheumatoid arthritis and osteoarthritis. Arthritis Rheum1997;40:1856–67.[ISI][Medline]
  5. Ostergaard M, Hansen M, Stoltenberg M et al. Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum1999;42:918–29.[ISI][Medline]
  6. Reiser MF, Bongartz GP, Erlemann R et al. Gadolinium-DPTA in rheumatoid arthritis and related diseases: first results with dynamic magnetic resonance imaging. Skel Radiol1989;18:591–7.[ISI][Medline]
  7. Tamai K, Yamato M, Yamaguchi T, Ohno W. Dynamic magnetic resonance imaging for the evaluation of synovitis in patients with rheumatoid arthritis. Arthritis Rheum1994;37:1151–7.[ISI][Medline]
  8. Gaffney K, Cookson J, Blake D, Coumbe A, Blades S. Quantification of rheumatoid synovitis by magnetic resonance imaging. Arthritis Rheum1995;38:1610–7.[ISI][Medline]
  9. Gaffney K, Cookson J, Blades S, Coumbe A, Blake D. Quantitative assessment of the rheumatoid synovial microvascular bed by gadolinium-DPTA enhanced magnetic resonance imaging. Ann Rheum Dis1998;57:152–7.[Abstract/Free Full Text]
  10. Konig H, Sieper J, Wolf KJ. Rheumatoid arthritis: evaluation of hypervascular and fibrous pannus with dynamic magnetic resonance imaging enhanced with Gd-DTPA. Radiology1990;176:473–7.[Abstract]
  11. Lee J, Lee SK, Suh JS, Yoon M, Song JH, Lee CH. Magnetic resonance imaging of the wrist in defining remission of rheumatoid arthritis. J Rheumatol1997;24:1303–8.[ISI][Medline]
  12. van der Heijde DMJM, van Riel PLCM, van Leeuwen MA, van't Hof MA, van Rijswijk MH, van der Putte LBA. Prognostic factors for radiographic joint damage and physical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients. Br J Rheumatol1992;31:519–25.[ISI][Medline]
  13. van Zeben D, Breedveld FC. Prognostic factors in rheumatoid arthritis. J Rheumatol1996;23:31–3.[ISI]
  14. Nepom GT, Gersuk V, Nepom BS. Prognostic implications of HLA genotyping in the early assessment of patients with rheumatoid arthritis. J Rheumatol1996;23(Suppl. 44):5–9.[ISI]
  15. Gough A, Faint J, Salmon M et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum1994;37:1166–70.[ISI][Medline]
  16. Eberhardt K, Fex E, Wollheim FA. Associations of HLA-DRB and DQB genes with 2 and 5 year outcome in rheumatoid arthritis. Ann Rheum Dis1996;55:34–9.[Abstract]
  17. McQueen FM, Stewart N, Crabbe J et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom-onset. Ann Rheum Dis1998;57:350–6.[Abstract/Free Full Text]
  18. McQueen FM, Stewart N, Crabbe J et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann Rheum Dis1999;58:156–63.[Abstract/Free Full Text]
  19. Arnett FC, Edworthy SM, Bloch DA et al. The ARA 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  20. Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence specific primers (PCR-SSP) in 2 hours: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens1992;39:225–35.[ISI][Medline]
  21. Voorter CEM, Rozemuller EH, de Bruyn-Geraets D, van der Zwan A-W, Tilanus MGJ, van den Berg-Loonen EM. Comparison of DRB sequence-based typing using different strategies. Tissue Antigens1997;49:471–6.[ISI][Medline]
  22. Seccombe A, Wei M, Tan P, Yeoman S, McQueen F, McLean L. Comparison of four methods for high resolution HLA-DRB1 typing in early rheumatoid arthritis. Aust NZ J Med1998;28:747.
  23. Snedecor G, Cochran W. Statistical methods, 6th ed. Ames, IA, USA: Iowa State University Press, 1967;186–8.
  24. Shrout PE, Fleiss JL. Intraclass correlations: Uses in assessing rater reliability. Psychol Bull1979;86:420–8.[ISI]
  25. Ruckmann A, Ehle B, Trampisch H. How to evaluate measuring methods in the case of non-defined external validity. J Rheumatol1995;22:1998–2000.[ISI][Medline]
  26. Bland J, Altman D. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet1986;I:307–10.
  27. Liang KY, Zeger SL. Longitudinal data analysis using generalised linear models. Biometrika1986;42:805–20.
  28. Ritchie DM, Boyle JA, McInnes JM et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med1968;37:393–406.[Medline]
  29. Pincus T, Summey JA, Soraci SA, Hummon NP, Wallston KA. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum1983;26:1346–53.[ISI][Medline]
  30. van der Heidje DM, van't Hof MA, van Riel PL et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis1990;49:916–20.[Abstract]
  31. Sugimoto H, Takeda A, Kano S. Assessment of disease activity in rheumatoid arthritis using magnetic resonance imaging: quantification of pannus volume in the hands. Br J Rheumatol1998;37:854–61.[ISI][Medline]
Submitted 27 July 1999; revised version accepted 1 November 1999.