Radiographic scoring included the Larsen score, joint space narrowing and soft tissue ... Synovitis, Diffuse cartilage loss, Erosions, Glucocorticoids, Pathology.
Rheumatology 2001;40:297±301
The relationship between soft tissue swelling, joint space narrowing and erosive damage in hand X-rays of patients with rheumatoid arthritis J. Kirwan, M. Byron and I. Watt1 Rheumatology Unit, University of Bristol Division of Medicine and 1Department of Clinical Radiology, United Bristol Healthcare NHS Trust, Bristol Royal In®rmary, Bristol, UK Abstract 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 in¯ammation 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 wtransformed score = log10 (original score + 1)x. 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 coef®cient. Results. There was a difference in the rate of progression in the Larsen score between placebo- and prednisolone-treated patients, but there was no signi®cant 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-signi®cant 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 = 2 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 = 2 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.
There is a broad correlation between the clinical and radiological severities of rheumatoid arthritis (RA) w1x.
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 w2±7x. Recent clinical w2±5x studies describe disassociation between clinical synovitis, the serum acute-phase response and radiological progression, whilst others w8, 9x do report
Submitted 12 November 1999; revised version accepted 2 October 2000. Correspondence to: J. Kirwan, University of Bristol Division of Medicine, Bristol Royal In®rmary, Bristol BS2 8HW, UK.
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correlation between joint swelling and radiological damage. The latter studies examined joints in groups, a process which in¯ates apparent relationships. In a study that analysed data in relation to individual joints w10x, the correlation between persistent synovitis and erosive progression was weak (r = 0.248, explained variance 6%). Furthermore, imaging studies have identi®ed different types of synovial pathology within the same joint w11x, and histological studies have shown that erosions are more likely to be associated with in®ltration by macrophages than lymphocytes w6x. One explanation for these observations is that the clinical signs and symptoms of in¯ammation are caused by synovial pathological processes different from those that cause the erosive joint damage seen on radiographs. However, persistent, sustained intra-articular in¯ammation may be responsible for the diffuse cartilage loss w10, 12x 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.
Methods 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 w2x. 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, ®ve 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 w2x. 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 ®lms in random order from 10 randomly selected patients. All identifying markings were covered. Each joint was scored by the method of Larsen w13x, 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, de®nite = 2, marked = 3, not scorable = X), following a prede®ned sequence. This was then repeated for each joint in the same sequence, identifying joint space narrowing (none = 0, minimal = 1, de®nite = 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 in¯ammation was assessed every 3 months by the method of Thompson et al. w14x, in which joints are recorded as being in¯amed if both soft tissue swelling and tenderness are present simultaneously. This method has been validated within and between observers w14x, correlates well with the acute phase response w14x, and has been used in other multicentre studies w15x. After publication of the original study report w2x, 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 prednisolonetreated patients were analysed separately. The Larsen scores were compared after log transformation wtransformed score = log10 (original score + 1)x. 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% con®dence 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 coef®cient.
Results Twenty-®ve 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 signi®cant 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)
Synovitis and progressive erosions in RA
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 signi®cant 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 w2x. (In this subset of patients there was a small but statistically nonsigni®cant 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 signi®cant differences between them (P = 0.466 and 0.254 for 0 and 2 yr respectively). The correlation coef®cients 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 signi®cantly 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). 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-signi®cant correlation with
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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 = 2 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 = 2 0.003).
FIG. 1. Mean proportionate change in Larsen scores. Vertical bars show 95% CI.
FIG. 2. Mean proportionate change in joint space narrowing. Vertical bars show 95% CI.
TABLE 1. Mean (S.D.) clinical and radiographic scores for placebo- and prednisolone-treated patients Placebo Number of patients Cumulative clinical synovitis score Cumulative radiographic soft tissue swelling score Mean joint space narrowing, year 0 Mean joint space narrowing, year 2 Mean of Larsen scores after log transformation, year 0 Mean of Larsen scores after log transformation, year 2
14 23.3 (12.0) 17.6 (12.3) 3.27 (5.62) 7.67 (9.23) 1.61 (2.91) 4.22 (3.11)
Prednisolone 11 15.8 (10.2) 11.2 (7.3) 2.00 (2.71) 4.31 (5.09) 1.46 (1.69) 1.16 (2.13)
P (t-test) 0.045 0.326 0.466 0.254 0.896 0.037
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TABLE 2. Correlation between clinical and radiographic features in placebo-treated patients Cumulative radiographic soft tissue swelling score Cumulative clinical synovitis score Cumulative radiographic soft tissue swelling score Change in Larsen score
Change in Larsen score
0.472***
0.281*** 0.140
Change in joint space narrowing 0.342*** 0.192** 0.322***
**P
