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ALEXANDRE E. VOSKUYL, MD, PhD,
Associate Professor of Rheumatology,
Department of Rheumatology 4-A42,
VU University Medical Center, POB 7057,
1007 MB Amsterdam, The Netherlands;
MAARTEN BOERS, MD, PhD,
Professor of Clinical Epidemiology,
Department of Rheumatology and Department of
Clinical Epidemiology and Biostatistics,
VU University Medical Center,
Amsterdam, The Netherlands.
E-mail:eae.voskuyl@vumc.nl
Address reprint requests to Dr. Voskuyl.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with structural damage of joints. The process of joint destruction can be visualized with plain radiographs and more recently with magnetic resonance imaging (MRI), although the latter method is used infrequently in the clinical setting of patient care. Numerous studies have documented the course and prognostic factors associated with progression of radiographic joint damage in RA^1-6. These studies clearly show that the rate of progression of joint damage correlates strongly with disease duration and disease activity. Most studies suggest progression is highest in the first 3 years of the disease³, in particular in the first year after diagnosis. Only about 20 to 30% of the patients have no radiographic damage after 3 years⁷. Higher cumulative disease activity is associated with a higher progression of joint damage, but the relationship between disease activity and damage progression is highly individualized⁸.

Treatment of RA is directed towards suppression of signs and symptoms of synovitis, prevention of structural damage, and improvement and maintenance of functionality. Several treatment strategies are currently available and have been shown to reduce the progression of damage. Although the evidence is sound^9,10, a review of this evidence is not without problems¹¹. Prognostic factors available at the time of diagnosis that have been associated with progression of joint damage in early RA include disease activity, presence of elevated levels of IgM rheumatoid factor, C-reactive protein, HLA-DR4/shared epitope, and the presence and severity of baseline radiographic damage^1-6. In daily care, decisions about the efficacy of antirheumatic treatment are taken by evaluating disease activity and by evaluating the progression of joint damage. However, in the clinical setting of early RA, most rheumatologists now feel we should not let the window of opportunity (to prevent damage) close while waiting for reliable documentation that progression is actually occurring. Thus accurate determination of the presence or absence of joint damage at baseline becomes more important as this could guide the choice of initial treatment strategy in individual patients.

Like all measures, the scoring of radiographic abnormalities is affected by interobserver and intraobserver variation. In trials it is customary to involve 2 independent, experienced observers. Whether radiographs should be scored in chronological order or in random order is still a matter of discussion¹². Second, measurement error should be taken into account when progression of joint damage has to be defined. For this purpose, Lassere, et al proposed to calculate the smallest detectable difference¹³.

In this issue of The Journal, Paulus, et al addressed in an observational study the problem of classifying 179 patients with early RA as having erosive or non-erosive disease within 6 months of symptom onset¹⁴. Radiographs of hands and feet were performed on at least 2 occasions with a mean lag time of 6 months; joints were assessed by the Sharp method¹⁵ in random order by 2 observers. The authors show that single time-point radiographs taken within 6 months of symptom onset did not correlate with progression rates; correlations between 7 and 18 months were weak, but were better for erosion scores between 19 and 72 months. According to the authors, the correlations were not affected by differences in observation time. As expected, the proportion of radiographs without evidence of damage decreased as disease duration increased. When the individual radiographs were examined, the scores of the baseline radiograph had little relationship to the probability of subsequent progression of joint damage. Finally, the smallest detectable difference of joint scores was larger than the mean progression rate per year, showing that evaluating radiographs early in the disease is associated with a high degree of error. The authors conclude that single time-point radiographs are of no value for the decision whether or not to treat a patient aggressively; they suggest in their discussion that multiple radiographs taken late (> 18 months) in the disease course may give a better indication of the aggressiveness of joint damage.

We compliment the authors on the size and scope of this observational study, and concur with their general conclusion, especially in the sense that "no damage at baseline" should not lead the physician to choose "mild" initial antirheumatic therapy, for reasons stated above. The authors suggest that it is possible to give an indication whether the disease is aggressive when multiple radiographs are taken later in the disease course. However, it is difficult to draw such a conclusion from an uncontrolled study. The main reason is confounding by indication. For instance, not all patients were treated with antirheumatic drugs, which are thought to retard progression, and treatment regimens differed among patients at followup, which is likely to have influenced progression of damage. No doubt the treating physician assessed each patient's prognosis on the basis of all available clinical information, including disease activity, rheumatoid factor status, and radiographs, and initiated treatment based on this assessment. The subsequent course and treatment decisions were presumably based on the patient's response. Thus the value of the initial radiograph in this study can only be properly ascertained when initial treatment and disease activity are accounted for. The authors confirm this in the discussion, where they state that the 3 to 5 year outcomes were surprisingly good, with no progression in 31% of the patients. In our interpretation it is very likely that patients with a poor prognosis — and therefore a higher chance of radiographic progression — had more aggressive treatment, which influenced prognosis, and led to less actual progression than expected. In addition, prognostic indicators, i.e., high disease activity, high IgM rheumatoid factor serum concentrations, presence of shared epitope, and high baseline radiographic damage, work less well than before, because prognosis is being improved.

Other problems in the observational design that may hinder the interpretation of the results include quality of films that was not uniform due to lack of standardization among all participating centers, standardization of defining symptom onset, and only 31% of the patients having a progression of joint damage higher than the smallest detectable difference; but these do not detract from the main finding of the study.

This observation, that progression of radiographic joint damage cannot be predicted reliably in an early stage of the disease, is disappointing for clinicians eager to "tailor" treatment of the individual patient. It underscores the need for better predictors: evidence is accumulating for cartilage and bone destruction markers, and perhaps MRI signs^16,17. Bone and cartilage markers have been found to strongly predict damage independent of disease activity, both in active RA¹⁸ and in remission^19,20. Research is under way to determine the value of these predictors in clinical practice.

REFERENCES

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19. Molenaar ET, Lems WF, Dijkmans BA, de Koning MH, van de Stadt RJ, Voskuyl AE. Levels of markers of bone resorption are moderately increased in patients with inactive rheumatoid arthritis. Rheumatology 2000;39:742-4. [MEDLINE]

20. Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PB, Dijkmans BA. Progression of radiological damage in patients with rheumatoid arthritis in clinical remission [abstract]. Arthritis Rheum 2001;44 Suppl 9:S174. [MEDLINE]