The relationship between soft tissue swelling, joint space narrowing and erosive damage in hand X-rays of patients with rheumatoid arthritis

Transcription

1 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. Watt 1 Rheumatology Unit, University of Bristol Division of Medicine and 1 Department 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 = log 10 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 = , P < 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 = ). 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. Submitted 12 November 1999; revised version accepted 2 October Correspondence to: J. Kirwan, University of Bristol Division of Medicine, Bristol Royal In rmary, Bristol BS2 8HW, UK. 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 297 ß 2001 British Society for Rheumatology

2 298 J. Kirwan et al. 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 = log 10 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)

3 Synovitis and progressive erosions in RA 299 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 = and 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 = and 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 = 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 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 = ; P < 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 = ). 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 Prednisolone P t-test) Number of patients Cumulative clinical synovitis score ) ) Cumulative radiographic soft tissue swelling score ) ) Mean joint space narrowing, year ) ) Mean joint space narrowing, year ) ) Mean of Larsen scores after log transformation, year ) ) Mean of Larsen scores after log transformation, year ) ) 0.037

4 300 J. Kirwan et al. TABLE 2. Correlation between clinical and radiographic features in placebo-treated patients Cumulative radiographic soft tissue swelling score Change in Larsen score Change in joint space narrowing Cumulative clinical synovitis score 0.472*** 0.281*** 0.342*** Cumulative radiographic soft tissue swelling score ** Change in Larsen score 0.322*** **P<0.01, ***P< TABLE 3. Correlation between clinical and radiographic features in prednisolone-treated patients Cumulative radiographic soft tissue swelling score Change in Larsen score Change in joint space narrowing Cumulative clinical synovitis score 0.427*** Cumulative radiographic soft tissue swelling score *** Change in Larsen score ***P< Because some of the data had mildly skewed distributions, log transformation wnew value = log 10 old value + 1)x was applied to all the data and the analysis was repeated. Minor differences were noted in the correlation coef cients, all adding greater support to the conclusions. Discussion 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 w14x, 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 ndings in other groups of patients should be sought before these hypotheses can be considered proven. Some published studies of the histology w5, 6x and magnetic resonance imaging w11x 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 in ammation 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 in ammation, as recently reviewed by Weyland w16x. The production of high synovial uid concentrations of cytokines and matrix metalloproteinases could cause generalized cartilage loss. However, as proposed by Gay and colleagues in 1993 w17x, synovial hyperplasia and macrophage in ltration may offer a separate and localized pathological mechanism for cartilage and bone destruction. How invasive, broblast-like synoviocytes might cause

5 Synovitis and progressive erosions in RA 301 joint damage was reviewed by Firestein w18x. 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 t with clinical observations. In particular, the nding that differences in synovial histology in biopsies from knee joints correlate with overall radiographic progression in patients is relevant w5, 6x. 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 w5, 6x. It is therefore feasible that these different pathological mechanisms of in ammation and localized tissue destruction might relate separately to the clinical signs of joint in ammation 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 w19±21x. 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. References 1. Scott DL, Spector TD, Pullar T, McConkey B. What should we hope to achieve when treating rheumatoid arthritis? Ann Rheum Dis 1989;48:256± Van Leeuwen MA, van der Heijde DM, Rijswijk MH et al. Inter-relationships of outcome measures and process variables in early rheumatoid arthritisða comparison of radiological damage, physical disability, joint counts and acute phase reactants. J Rheumatol 1994;21:425±9. 3. Kirwan JR and the ARC Low Dose Glucocorticoid Study Group. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:142±6. 4. Hickling P, Jacoby RK, Kirwan JR and The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Br J Rheumatol 1998;37:930±6. 5. Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence thatthe pathogenesisofsynovial in ammation and articular erosion may differ. Br J Rheumatol 1996; 35:1263±8. 6. Mulherin D, FitzGerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 1996;39:115± McGonagle D, Gibbon W, O'Connor P et al. A preliminary study of ultrasound aspiration of bone erosion in early rheumatoid arthritis. Rheumatology 1999;38:329± van der Heide A, Remme CA, Hofman DM, Jacobs JWG, Bijlsma JWJ. Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis. Arthritis Rheum 1995;38:1466± Hassell AB, Plant MJ, Clarke S et al. Small joint synovitis in rheumatoid arthritis: should it be assessed separately? Br J Rheumatol 1995;34:51± Kirwan JR. The relationship between synovitis and erosions in rheumatoid arthritis. Br J Rheumatol 1997; 36:225± Jevtic V, Rozman B, Watt I, Presetnik M. Use of contrast enhanced MRI in the assessment of therapeutic response to a disease-modifying and anti-rheumatic drug. Br J Rheumatol 1995;34:956± Fell HD, Jubb RW. The effect of synovial tissue on the breakdown of articular cartilage in organ culture. Arthritis Rheum 1978;20:1359± Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference lms. Acta Radiol 1977;18:481± Thompson PW, Silman AJ, Kirwan JR, Currey HLF. Articular indices of joint in ammation in rheumatoid arthritis: correlation with the acute phase response. Arthritis Rheum 1987;30:618± Prevoo MLL, van Riel PLCM, van't Hof MA et al. Validity and reliability of joint indices. A longitudinal study in patients with recent onset rheumatoid arthritis. Br J Rheumatol 1993;32:589± Weyland CM. New insights into the pathogenesis of rheumatoid arthritis. Rheumatology 2000;39 Suppl. 1): 3± Gay S, Gay RE, Koopman WJ. Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction? Ann Rheum Dis 1993;52:S39±S Firestein GS. Invasive broblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 1996;39:1781± Wassenberg S, Rau R, Ratingen HZ. Low dose prednisolone therapy LDPT) retards radiographically detectable destruction in early rheumatoid arthritis. Arthritis Rheum 1999;42:S van Everdingen AA, Jacobs JWG, van Reesema, DR Bijlsma JWJ. Low dose glucocorticoids in early RA inhibit radiological joint damage. Arthritis Rheum 1999;42:S Zeidler H, Rau R, Stinfeld P for the Low Dose Prednisolone Therapy LDPT) Study Group. Ef cacy and safety of low dose prednisolone in early rheumatoid arthritis RA). Arthritis Rheum 1999;42:S271.