Department of Rheumatology, Evangelisches Fachkrankenhaus, Rosenstrasse 2, D-40882 Ratingen, Germany
SIR, We have read with interest the article of Kirwan et al. [1]. As part of a double-blind study comparing 7.5 mg prednisolone/day with placebo in addition to DMARD treatment, the authors investigated the relationship between joint swelling as measured clinically and radiographically and (i) joint erosions as measured with the Larsen score [2] and (ii) joint space narrowing (JSN) in a way very similar to that originally described by Sharp [3]. They found a better correlation of joint swelling to JSN progression than to erosion progression, and complete cessation of erosion progression (slight reduction in the Larsen score) in the prednisolone-treated patients (n=11) in contrast to clear progression in the placebo group (n=14). There was no difference, however, between the two treatment groups in JSN progression. Patients on placebo showed a correlation between clinical signs of synovitis and progression in the Larsen score and, to a greater extent, in the JSN score. In contrast, prednisolone-treated patients demonstrated no correlation between clinical synovitis and change in the Larsen score and only a slight correlation with JSN.
From these data, the authors conclude that there is a disassociation between inflammation and erosion progression (though there is an association with JSN progression) and that prednisolone inhibits erosion progression but not JSN progression, or inhibits JSN progression to a lesser degree. Apart from the fact that these far-reaching conclusions are based on a very small study (11 and 14 patients in each group, only PIP and MCP joints evaluated), in our view there are several methodological problems.
First, the Larsen scoring system includes soft tissue swelling (without erosions) in grade 1, which does not represent structural damage. Patients entering a clinical study are likely to have joint swelling in the MCP and PIP joints that are Larsen grade 1. With prednisolone treatment, the number of swollen joints and, therefore, the Larsen score might be more reduced than in the placebo group, leading to the slight reduction in the score observed in this group independently of erosion progression. For this evaluation, the Sharp erosion score or the modified Larsen score [4], eliminating soft tissue swelling from the scoring system, would have been more appropriate and might have produced different results.
Secondly, the authors take for granted that JSN represents cartilage loss. However, JSN in the PIP and MCP joints may be caused much more by laxity of capsules, tendons and muscles, leading to slight subluxation with narrowing of the joint space, as seen on radiographs. This can occur without any cartilage destruction. Indeed, laxity of the capsule is a consequence of joint swelling with or without effusion; therefore, the correlation between swelling and JSN progression is not surprising.
Several studies have shown a good correlation of joint swelling at baseline and over time with radiographic progression. In the Kirwan et al. study [1], the placebo-treated group had a higher baseline and cumulative synovitis score, which can easily explain the higher erosion progression rate observed in the placebo group. A faster reduction of synovitis by prednisolone added to DMARD treatment than by DMARD treatment alone is our explanation for the slower erosion progression during the first year of treatment in the low-dose prednisolone treatment study [5]. This same observation, with a faster reduction of joint swelling in the prednisolone group, was also seen in Kirwan's main study [6].
Unpublished data from a long-term one-centre study over 10 yr in 115 patients, analysed on an individual joint basis, indicate a clear correlation between swelling and erosion progression: joints that were never swollen did not develop erosions. This is in agreement with clinical experience. According to Kirwan et al. the erosive process may be more likely to be associated with macrophage (and pannus) infiltration than with lymphocytes; however, does prednisolone exert more effect on macrophages and pannus than on lymphocyte infiltration? In conclusion, the data of Kirwan et al. do not prove the concept of a disassociation of inflammation and erosive damage (that can be prevented by steroid treatment). Prednisolone is still regarded as the most potent anti-inflammatory drug, and its inhibitory effect on erosion progression seems to be related to this potency.
Notes
Accepted 22 August 2001
References
Rheumatology Unit, University of Bristol Division of Medicine and
1 Department of Clinical Radiology, United Bristol Healthcare NHS Trust, Bristol Royal Infirmary, Bristol BS2 8HW, UK
We thank Professor Rau and Dr Wassenberg for their interest in our paper [1]. It is true that one swallow does not make a summer, and it is not often that a single report can be claimed to prove a point. We emphasized in our discussion that 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 could be considered proven. Nevertheless, we think that Rau and Wassenberg, who are themselves making important contributions in this area, have misunderstood the nature of our arguments. We will review their points in order.
First, soft tissue swelling is included in the Larsen grade 1 in the written descriptions, but is not included in the standard atlas that we used to undertake the original radiographic analysis. In this, only peri-articular osteoporosis and slight joint space narrowing are illustrated. We applied these criteria conservatively and scored few grade 1 joints. Nevertheless, it can be seen that this would tend to inflate a relationship between erosions and joint space narrowing, not soft tissue swelling. Such a bias (very small, if present at all) would tend to go against the findings of our paper and is therefore not relevant to its conclusions.
Secondly, we agree that we have used joint space narrowing as a surrogate for cartilage loss and that there may be alternative interpretations. Nevertheless, whatever the cause, it appears to behave as a different marker of the disease process compared with erosion formation, and it is related more to clinical signs of inflammation. Oral glucocorticoids do not break this relationship, even though they do stop the progression of erosions.
Thirdly, Rau and Wassenberg are mistaken in their suggestion that baseline characteristics differed between our patient groups. In our paper we reported there were no significant differences in baseline data between the groups with regard to articular index (treated mean 201 vs untreated mean 204, P=0.942), plasma viscosity (1.85 vs 1.79, P=0.405), HAQ scores (1.21 vs 1.40, P=0.466), log Larsen scores (0.39 vs 0.42, P=0.896), log joint space narrowing (0.32 vs 0.41, P=0.551) and number who were non-erosive (73.1% vs 73.3%). Baseline differences between the groups could not have explained our findings, particularly as these groups were randomly allocated to treatment in a double-blind fashion.
We have reviewed some preliminary data from the randomized, placebo-controlled trial of low-dose glucocorticoid undertaken by Rau, Wassenberg and colleagues, published to date in abstract form only [2]. We calculated the percentage increase in joint space narrowing (JSN) and in erosions in patients treated for 12 and 24 months (Table 1). Even in their own study, which used a different method of counting erosions and JSN, prednisolone seems to have suppressed erosions (62% increase vs 152%) but not JSN (95 vs 93% increase).
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