Rheumatoid arthritis (RA) is characterized by the presence of disease activity and bone destruction. The pattern of disease activity varies considerably between patients (1, 2). Disease activity can be persistent, but exacerbations and periods of low disease activity or even remission can also occur. In the majority of patients, RA causes progressive joint destruction, deformities, and disability. Only a minority of patients achieve a permanent remission (3). The process of bone destruction in RA is correlated with arthritis activity (4), although evidence is accumulating that bone destruction can occur independently of arthritis activity (5–7).
Two sets of criteria for clinical remission are currently being used: the criteria proposed by the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) (8) and the criteria based on the Disease Activity Score (DAS) (9). In general, it is estimated that remission occurs in 10–20% of patients with RA (3, 9–12). The occurrence of clinical remission has been studied in patients with early RA and short-term followup (9, 12) and in long-term cohort studies (10). All of these studies were undertaken in groups of patients with various levels of disease activity, and in particular those with high levels of disease activity. However, only a relatively small number of patients with RA in clinical remission have been studied prospectively, and knowledge about factors that are possibly associated with remission is limited. Stopping use of second-line antirheumatic drugs during remission increases the chance of a disease flare (13).
Achieving clinical remission is an important milestone, but such remission is unsatisfactory if joint destruction is not halted. Whether the absence of arthritis activity prevents further joint damage is still a matter of debate. To our knowledge, longitudinal studies investigating the relationship between joint damage and clinical remission are lacking. The present study was undertaken over a 2-year followup period in a cohort of patients with RA in clinical remission, in order to determine whether radiologic joint damage worsens during remission.
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The main conclusion to be drawn from the present study is that radiologic progression can occur during a state of persistent remission as defined by our remission criteria, but also as defined by the ACR and DAS criteria.
Studies with large numbers of patients with RA in clinical remission are limited and give rise to several intriguing questions (10, 13). The first question is whether a state of clinical remission is persistent. In about half of our patients, clinical remission persisted in the second year of the study. However, remission persisted in 68% of patients with a DAS AUC of <1.6 over the first year. As expected, this confirms that repeated observations are more reliable than a single observation (e.g., at baseline) as an indicator of a stable low level of disease activity.
The radiologic progression observed over 1 year in our group of patients with RA in remission is consistent with that in patients with active RA treated with combination therapy or tumor necrosis factor–blocking agents. In the Combinatietherapie Bij Reumatoïde Artritis (COBRA) study, patients treated with sulfasalazine had, after 1 year, a median score for progression of 6 (range 0–54), whereas patients treated with combination therapy of methotrexate, sulfasalazine, and prednisone had a median score of 2 (range 0–43) (24). In the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study, the mean (±SD) score for progression over 1 year was between −0.7 ± 3.8 and 1.6 ± 8.5 in patients treated with infliximab, whereas in patients treated with methotrexate only it was 7.0 ± 10.3 (25). In the etanercept study, the mean score for progression over 1 year was 1.0 in patients treated with etanercept, whereas in patients treated with methotrexate it was 1.6 (26).
It is interesting to note the differences between the frequency of patients fulfilling the ACR remission criteria and the DAS remission criteria, both at baseline and after followup. Although one of the ACR remission criteria (fatigue) was not evaluated in our patients, and comparison between the remission criteria used may therefore be somewhat difficult, the observed differences stress the need for consensus on the use of remission criteria in the near future.
Stratification according to disease activity revealed that progression of joint damage was present in both the group of patients with an exacerbation of RA and the group of patients with RA in persistent clinical remission. In fact, the major part of radiologic progression can be attributed to disease activity, but some patients had considerable progression despite persistent remission. The relationship between disease activity and radiologic progression is consistent with that observed in previous studies (4, 27). However, the unique finding in this study of radiologic progression during persistent clinical remission supports the hypothesis that synovitis and joint destruction are 2 different and independent processes (5–7). Other support for this hypothesis comes from studies on bone markers, showing that levels of bone markers are increased in patients with RA in remission (15), and that a reduction of the levels of bone markers is associated with a reduction in long-term joint damage, independent of arthritis activity (28, 29).
The results of the present study impact the whole concept of remission, including radiologic parameters. The ultimate goal of therapy is to achieve a state of inactive disease, both clinically and structurally. Perhaps structure should be included in a new definition of remission. Also, more attention should be focused on the evolution of remission during followup, to determine the influence of exacerbations and smaller fluctuations in disease activity on structure and long-term outcome.
In conclusion, half of patients with RA in clinical remission can expect a relapse within 2 years, which often is preceded by an increase in the DAS. Radiologic progression occurs in relation to disease activity, but persistent remission is not fully protective. It is proposed that structure is an important dimension of the concept of remission.
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We thank the following rheumatologists for their participation: Dr. J. M. W. Hazes, Leiden University Medical Centre, Leiden, and Erasmus University Medical Centre, Rotterdam; Dr. A. J. Peeters, Reinier de Graaf Gasthuis, Delft; Drs. J. P. Terwiel and C. Mallee, Spaarne Ziekenhuis and Kennemer Gasthuis, Haarlem; and Drs. M. L. Westedt and I. Speijer, Bronovo Ziekenhuis, Den Haag.