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Rheumatology 2001; 40: 297-301
© 2001 British Society for Rheumatology
The relationship between soft tissue swelling, joint space narrowing and erosive damage in hand X-rays of patients with rheumatoid arthritis
Rheumatology Unit, University of Bristol Division of Medicine and
1 Department of Clinical Radiology, United Bristol Healthcare NHS Trust, Bristol Royal Infirmary, Bristol, UK
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Abstract |
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Objectives. To test the hypotheses that the progression of joint space narrowing behaves differently from the progression of erosions and that clinically and radiologically assessed soft tissue swelling relates more to diffuse cartilage loss than to erosive damage.
Methods. Radiographs and clinical data were obtained from 28 patients in a prospective, multicentre, randomized, placebo-controlled trial of prednisolone 7.5 mg daily over 2 yr. Radiographic scoring included the Larsen score, joint space narrowing and soft tissue swelling. Clinical joint inflammation in the hands was assessed every 3 months and cumulative synovitis score over the period of study was then calculated for each joint. The placebo-treated patients and the prednisolone-treated patients were analysed separately. The Larsen scores were compared after log transformation [transformed score=log10 (original score+1)]. Changes in Larsen scores and joint space narrowing scores were compared with the cumulative presence of clinical synovitis and radiological soft tissue swelling using the correlation coefficient.
Results. There was a difference in the rate of progression in the Larsen score between placebo- and prednisolone-treated patients, but there was no significant difference in the rate of joint space loss. In placebo-treated patients, measures of synovitis correlated more strongly with progression of joint space narrowing than with changes in the Larsen score. In prednisolone-treated patients there was no correlation between clinical synovitis and change in Larsen score (r=0.029) and only a slight and non-significant correlation with joint space narrowing (r=0.127). Radiographic evidence of soft tissue swelling remained correlated with joint space narrowing (r=0.279, P<0.001) but was not correlated with change in Larsen score (r=-0.113, P<0.001 for difference between correlations). The correlation between Larsen score progression and joint space narrowing seen in the non-treated patients was completely abolished in the glucocorticoid-treated group (r=-0.003).
Conclusions. The progression of joint space narrowing behaves differently from the progression of erosions. Prednisolone slows (or even stops) the progression of erosions (as assessed by the Larsen score) while making no difference to the progression of cartilage loss (as assessed by joint space narrowing). The results also suggest that synovitis, whether measured clinically or radiologically, is more closely related to diffuse cartilage loss than to erosion progression. Any link between synovitis and erosions is abolished by glucocorticoid therapy while the link between synovitis and cartilage loss is not, pointing to at least two different mechanisms for these observed radiological features.
KEY WORDS: Synovitis, Diffuse cartilage loss, Erosions, Glucocorticoids, Pathology.
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Introduction |
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There is a broad correlation between the clinical and radiological severities of rheumatoid arthritis (RA) [1]. However, evidence is accumulating to suggest that different pathological processes are involved in the clinical manifestations of synovitis and the progressive erosive radiological damage seen in RA [2–7]. Recent clinical [2–5] studies describe disassociation between clinical synovitis, the serum acute-phase response and radiological progression, whilst others [8, 9] do report correlation between joint swelling and radiological damage. The latter studies examined joints in groups, a process which inflates apparent relationships. In a study that analysed data in relation to individual joints [10], the correlation between persistent synovitis and erosive progression was weak (r=0.248, explained variance 6%). Furthermore, imaging studies have identified different types of synovial pathology within the same joint [11], and histological studies have shown that erosions are more likely to be associated with infiltration by macrophages than lymphocytes [6]. One explanation for these observations is that the clinical signs and symptoms of inflammation are caused by synovial pathological processes different from those that cause the erosive joint damage seen on radiographs. However, persistent, sustained intra-articular inflammation may be responsible for the diffuse cartilage loss [10, 12] manifest as radiographic joint space narrowing. We therefore hypothesized that (i) the progression of joint space narrowing might behave differently from the progression of erosions, and (ii) that clinically and radiologically assessed soft tissue swelling will relate more to diffuse cartilage loss than to erosive damage. The aim of this study was to use hand radiographs taken from a randomized controlled trial of prednisolone in RA to test these hypotheses.
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Methods |
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Radiographs and clinical data were obtained from a prospective, multicentre, randomized, placebo-controlled trial of prednisolone 7.5 mg daily that has been fully reported elsewhere [2]. That study included 128 patients aged 18–69 yr with RA of <2 yr duration and currently active disease. The 28 patients entered through one centre who had the required hand radiographs available were included in the present study. Clinical and radiographic data were available at baseline, 1 yr and 2 yr of follow-up for the following joints: four proximal interphalangeal (PIP) joints, five metacarpophalangeal (MCP) joints and the thumb interphalangeal joint.
Radiographs
Radiographic scoring was undertaken by two independent methods. All available radiographs were viewed jointly by the same experienced radiologist (IW) and rheumatologist (JRK), using the same viewing conditions [2]. To ensure similar conditions for assessing the radiographs from any one patient, and to avoid the possibility of bias that might develop over the several sittings required to read and score the radiographs, their presentation was in blocks of 30. Each block included 0, 1 and 2 yr films in random order from 10 randomly selected patients. All identifying markings were covered. Each joint was scored by the method of Larsen [13], which grades the degree of joint damage on a scale from 0 (radiologically normal joint) to 5 (maximum degree of joint destruction) with reference to a standard atlas of radiographs. Assessments were made by consensus between the observers and were recorded on coding sheets. The change in Larsen score between baseline and 2 yr was calculated for each joint.
As a separate exercise undertaken with radiographs marked and randomized in a similar manner, two experienced observers (IW and MB) scored each joint of both hands for soft tissue swelling (none=0, minimal=1, definite=2, marked=3, not scorable=X), following a predefined sequence. This was then repeated for each joint in the same sequence, identifying joint space narrowing (none=0, minimal=1, definite=2, no remaining joint space=3, fused=4, not scorable=X). The cumulative soft tissue swelling score over the period of study (i.e. sum total of the score for the three X-rays) was then calculated for each joint. The change in joint space narrowing was also calculated for each joint.
Clinical data
Joint inflammation was assessed every 3 months by the method of Thompson et al. [14], in which joints are recorded as being inflamed if both soft tissue swelling and tenderness are present simultaneously. This method has been validated within and between observers [14], correlates well with the acute phase response [14], and has been used in other multicentre studies [15]. After publication of the original study report [2], and as a separate exercise, the data relating to the hands (for the PIP joints, the MCP joints and the thumb interphalangeal joint) were taken from the original study record forms and entered into a new database. Joints were recorded as either showing synovitis (score=1) or not doing so (score=0) on each occasion of examination. The cumulative synovitis score over the period of study (i.e. the sum total of the scores for the nine visits) was then calculated for each joint.
Comparisons
The placebo-treated patients and the prednisolone-treated patients were analysed separately. The Larsen scores were compared after log transformation [transformed score=log10 (original score+1)]. The sum of the joint space narrowing scores for all joints taken together was used for the total joint space narrowing score for each patient on each occasion. Means and 95% confidence intervals (CI) were calculated and the groups compared using the unpaired t-test. Changes in Larsen scores and joint space narrowing scores were also compared with the cumulative presence of clinical synovitis and radiological soft tissue swelling using the correlation coefficient.
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Results |
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Twenty-five of the 28 patients had full clinical and radiological data for the analysis undertaken here. Eleven had received prednisolone and 14 had received placebo. There were no significant differences in baseline data between the groups with regard to articular index (treated group mean 201 versus untreated group mean 204, P=0.942), plasma viscosity (1.85 versus 1.79, P=0.405), HAQ (health assessment questionnaire) scores (1.21 versus 1.40, P=0.466), log Larsen score (0.39 versus 0.42, P=0.896), log joint space narrowing (0.32 versus 0.41, P=0.551) and percentage of patients who were non-erosive (73.1 versus 73.3).
The cumulative clinical synovitis and radiological soft tissue swelling scores for both groups are shown in Table 1
, together with the mean joint space narrowing and Larsen scores for years 0 and 2. Although patients treated with prednisolone had a lower cumulative clinical synovitis score (15.8 versus 23.3, P=0.045), the more striking significant difference between the patient groups was in the progression of Larsen scores (Fig. 1). There was a clear difference in the rate of progression in Larsen scores between the prednisolone- and placebo-treated groups (P=0.896 and 0.037 for 0 and 2 yr respectively), in agreement with the full study report [2]. (In this subset of patients there was a small but statistically non-significant reduction in the Larsen score for those treated with prednisolone). Joint space narrowing scores are shown in Fig. 2. Joint space was lost in both treatment groups, with no significant differences between them (P=0.466 and 0.254 for 0 and 2 yr respectively).
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The correlation coefficients comparing cumulative scores for radiographic soft tissue swelling (radiographic synovitis), clinical soft tissue swelling (clinical synovitis), radiographic joint space narrowing (cartilage loss) and Larsen score (erosion progression) are shown in Table 2
for patients who did not receive glucocorticoid treatment and in Table 3 for those who did. For placebo-treated patients (Table 2), clinical and radiographic assessments of soft tissue swelling were significantly correlated (r=0.472, P<0.001). Clinical synovitis correlated with change in Larsen score (r=0.281, P<0.01) but more strongly with changes in joint space narrowing (r=0.348, P<0.001). Radiographic soft tissue swelling did not correlate with change in Larsen score but was weakly related to change in joint space narrowing (r=0.192, P<0.01). In these patients, progression of Larsen score and change in joint space narrowing were correlated (r=0.322, P<0.001), but less so than the correlation between the two (clinical and radiographic) measures of soft tissue swelling (r=0.472, P=0.066 for the difference between correlations).
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In patients treated with glucocorticoids (Table 3
), cumulative clinical and radiographic measures of soft tissue swelling remained correlated with each other (r=0.427, P<0.001). There was no correlation between clinical synovitis and change in Larsen score (r=0.029) and only a slight and non-significant correlation with joint space narrowing (r=0.127). Radiographic evidence of soft tissue swelling remained correlated with joint space narrowing (r=0.279, P<0.001) but was not correlated with change in Larsen score (r=-0.113; P<0.001 for the difference between correlations). The correlation between Larsen score progression and joint space narrowing seen in the non-treated patients was completely abolished in the glucocorticoid-treated group (r=-0.003). Because some of the data had mildly skewed distributions, log transformation [new value=log10 (old value+1)] was applied to all the data and the analysis was repeated. Minor differences were noted in the correlation coefficients, all adding greater support to the conclusions.
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Discussion |
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This study examined the relationship between clinical and radiographic measures of synovitis and the two main destructive lesions of RA, erosions and cartilage loss. The results are based on clinical and radiological follow-up in a randomized, controlled trial. They support the hypothesis that the progression of joint space narrowing might behave differently from the progression of erosions. This study shows that prednisolone slows (or even stops) the progression of erosions (as assessed by Larsen scores) while making no difference to the progression of cartilage loss (as assessed by joint space narrowing). The results also suggest that synovitis, whether measured clinically or radiologically, is more closely related to diffuse cartilage loss than to erosion progression. Any link between synovitis and erosions is abolished by glucocorticoid therapy while the link between synovitis and cartilage loss is not, pointing to at least two different mechanisms for these observed radiological features.
Several precautions were taken to avoid systematic bias in these results. Firstly, clinical synovitis was assessed as part of a double-blind, randomized, controlled clinical trial. It was not linked in any way to the later radiological assessment of soft tissue swelling. Because the clinical scoring system has been validated as a whole [14], it may be less reliable when applied to individual joints. Therefore only the presence or absence of clinical synovitis (rather than any system of grading or weighting) was used in this study. Secondly, the progression of erosions, as assessed by the Larsen score, was performed with radiographs masked, viewed and scored in random order, and assessed at a time when the hypothesis being tested here had not been formulated. Thirdly, the assessment of joint space narrowing was similarly masked and randomized, and was performed over 2 yr later than the Larsen score assessments and the clinical evaluations.
It may be argued that a bias could have arisen in the results because radiological assessment of synovial swelling and joint space narrowing were undertaken at the same viewing session. However, radiographs were assessed in random order and it was the cumulative occurrence of soft tissue swelling over each patient's sequence of radiographs that was compared with the change in joint space narrowing over the 2 yr of observation. It is thus unlikely that this method of reading radiographs caused any systematic effect.
The observations from this limited study are clearly consistent with the hypotheses that were tested, but similar findings in other groups of patients should be sought before these hypotheses can be considered proven. Some published studies of the histology [5, 6] and magnetic resonance imaging [11] of rheumatoid synovium suggest that there may be areas of different pathology and that these may relate differently to the progression of erosions.
Our current understanding of the pathology of joint inflammation and damage centres on the role of T lymphocytes, macrophages and synoviocytes. T cells appear to be central to the initiation of early disease processes, and to the potentiation of inflammation, as recently reviewed by Weyland [16]. The production of high synovial fluid concentrations of cytokines and matrix metalloproteinases could cause generalized cartilage loss. However, as proposed by Gay and colleagues in 1993 [17], synovial hyperplasia and macrophage infiltration may offer a separate and localized pathological mechanism for cartilage and bone destruction. How invasive, fibroblast-like synoviocytes might cause joint damage was reviewed by Firestein [18]. Animal models of joint tissue destruction can proceed without concurrent T-cell involvement. Such localized destructive lesions may represent the clinical occurrence of erosions. Thus, plausible cellular mechanisms have been elucidated which might fit with clinical observations. In particular, the finding that differences in synovial histology in biopsies from knee joints correlate with overall radiographic progression in patients is relevant [5, 6]. An abundance of T cells was related to little progression of erosions, while an abundance of macrophages occurred in patients who subsequently had erosive progression [5, 6]. It is therefore feasible that these different pathological mechanisms of inflammation and localized tissue destruction might relate separately to the clinical signs of joint inflammation and erosion development, and that glucocorticoid treatment could affect them differently.
Two further studies of prednisolone in RA, as yet published only in abstract form, support a differential effect of glucocorticoids on conventional radiographic features [19–21]. Improved understanding of the role of new imaging techniques such as magnetic resonance imaging will provide substantially greater sensitivity in future investigations of disease mechanisms in patients.
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Notes |
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Correspondence to: J. Kirwan, University of Bristol Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
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