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To the Editor:

I read with interest the editorial by Kirwan (1) in relation to an accompanying article in Arthritis & Rheumatism. Dr. Kirwan uses the results reported by Molenaar et al (2), along with other selected references, to promote the hypothesis that clinical activity and radiologic joint destruction are mediated by different disease processes.

However, I believe that this hypothesis can be challenged by published studies which suggest that these two processes are closely linked, if not identical. Several studies have demonstrated a close association between the acute-phase response and clinical disease activity (3–5), and other studies demonstrate the association of cumulative acute-phase response with the radiologic progression of joint destruction (4–6). Joint inflammation has been associated with the occurrence of joint erosions in rheumatoid arthritis (RA) (5–8). Unfortunately, standard disease-modifying antirheumatic drug (DMARD) treatments have only a modest impact on joint damage in rheumatoid arthritis (RA). This is probably because most treatments do not result in the level of disease suppression that approximates the American College of Rheumatology (ACR) criteria for remission (9) or at least do not maintain it for a long enough period to achieve regression of joint damage (10–12). Our own results demonstrated that synovial membrane pathology could be returned to close to normal, and that this could be associated with retardation of radiologic damage (13, 14). We came to this conclusion upon examining the synovial membrane immunopathology in a selected group of RA patients in whom remission was achieved according to the ACR criteria and was maintained for a significant length of time.

A recent report by Aken et al (15) showed less radiologic progression in patients with early initiation of DMARD treatment than in patients who received delayed DMARD treatment. However, the rate of joint destruction during years 1–4 of the study did not differ between the two treatment groups. Why were the results in the early-treatment group not better in the long term? The answer may lie in the low remission rate for both treatment groups and the significant acute-phase response in both treatment groups up to 4 years, with similar percentages of change in erythrocyte sedimentation rate in both treatment groups over 4 years. In other words, in neither the early nor the delayed treatment group was the disease activity reduced sufficiently, or for a long enough period to favorably affect the rate of radiologic progression.

So what of the study by Molenaar et al (2), which Kirwan suggests supports the concept of different pathologic processes mediating clinical activity and radiologic progression. First, we are not informed in this report of the error rate in repeated scoring of radiographs of the hands and feet using the Sharp/van der Heijde method (16). What is the minimal detectable difference with this scoring method? When the results of this study are examined more closely, it appears that those patients whose RA remained in persistent remission over the 2-year observation period had a significantly better radiologic outcome over 1 and 2 years than did those with exacerbations of their disease activity over that period. It is questionable whether a change in the mean Sharp/van der Heijde score of 0.7 (1-year followup) or 1.1–1.2 (2-year followup) in the RA patients with persistent remission is actually greater than the error rate in the radiologic scoring technique. This study also showed that the area under the curve (AUC) for the Disease Activity Score (DAS) (17) was significantly higher in patients with relevant radiologic progression than in patients with low or no progression. In addition, the DAS AUC was a stronger predictor of radiologic progression than was the absence of persistent remission. Surely this is consistent with the hypothesis that lack of sustained disease activity suppression is related to radiologic suppression, again suggesting that the two pathologic processes are linked, if not identical. If the authors had provided other evidence of how completely disease activity was suppressed over the observation period, possibly by an AUC assessment of C-reactive protein, it would be possible to assess whether any apparent radiologic progression in the sustained-remission RA patient group (a small number of outliers in Figure [2]) was due to incomplete disease activity suppression.

In conclusion, the published evidence (including that referenced by Kirwan) does not necessarily support his hypothesis of different disease pathologies mediating disease activity and radiologic damage. The study results are equally consistent with the hypothesis that the pathology underlying joint inflammation and radiologic damage are linked if not identical. It may be that this reflects the inadequacies of standard DMARD treatments to completely suppress disease activity for long enough periods to favorably alter radiologic outcomes. Perhaps future studies of treatment with biologic agents will further address this issue, if such treatment aims at the goal of attaining and maintaining remission for a significant period of time, with restoration of synovial membrane pathology to close to that of normal synovium.

  • 1
    Kirwan JR. The synovium in rheumatoid arthritis: evidence for (at least) two pathologies [editorial]. Arthritis Rheum 2004; 50: 14.
  • 2
    Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M, Dijkmans BA. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum 2004; 50: 3642.
  • 3
    Mallya RK, de Beer FC, Hamilton ED, Mace BE, Pepys MB. Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentrations of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 1982; 9: 2248.
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    Dawes PT, Fowler PD, Clarke S, Fisher J, Lawton A, Shadforth MF. Rheumatoid arthritis: treatment which controls the C-reactive protein and erythrocyte sedimentation rate reduces radiological progression. Br J Rheumatol 1986; 25: 449.
  • 5
    Van Leeuwen MA, van der Heijde DM, van Rijswijk MH, Houtman PM, van Riel PL, van de Putte LB, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis: a comparison of radiologic damage, physical disability, joint counts and acute phase reactants. J Rheumatol 1994; 21: 4259.
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    Hassell AB, Davis MJ, Fowler PD, Clarke S, Fisher J, Shadforth MF, et al. The relationship between serial measures of disease activity and outcome in rheumatoid arthritis. Q J Med 1993; 86: 6017.
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    Drossaers-Bakker KW, de Buck M, van Zeben D, Zwinderman AH, Breedveld FC, Hazes JM. Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis Rheum 1999; 42: 185460.
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    Brennan P, Harrison B, Barrett E, Chakrovarty K, Scott D, Silman AJ. A simple algorithm to predict the development of radiological erosions in patients with early rheumatoid arthritis: prospective cohort study. BMJ 1996; 313: 4716.
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    American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002; 46: 32846.
  • 10
    Prevoo ML, van Gestel AM, van't Hof MA, van Rijswijk MH, van der Putte LB, van Riel PL. Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 1996; 35: 11015.
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    Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis 1995; 54: 9447.
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    Pincus T, Wolfe F. “No evidence of disease” in rheumatoid arthritis using methotrexate in combination with other drugs: a contemporary goal for rheumatology care? Clin Exp Rheumatol 1997; 15: 5916.
  • 13
    Smith MD, Kraan MC, Slavotinek J, Au V, Weedon H, Parker A, et al. Treatment-induced remission is characterized by a reduction macrophage content of synovial biopsies. Rheumatology (Oxford) 2001; 40: 36774.
  • 14
    Smith MD, Slavotinek J, Au V, Weedon H, Parker A, Coleman M, et al. Successful treatment of rheumatoid arthritis is associated with a reduction in synovial membrane cytokines and cell adhesion molecule expression. Rheumatology (Oxford) 2001; 40: 96577.
  • 15
    Van Aken J, Lard LR, Le Cessie S, Hazes JM, Breedveld FC, Huizinga TW. Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis. Ann Rheum Dis 2004; 63: 2749.
  • 16
    Van der Heijde DM. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 1999; 26: 7435.
  • 17
    Van der Heijde DM, van't Hof MA, van Riel PL, Theunisse LM, Lubberts EW, van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990; 49: 91620.

Malcolm D. Smith PhD*, * Flinders Medical Center and Repatriation General Hospital, Daw Park, South Australia.