Department of Rheumatology and Clinical Immunology, CharitéUniversity Medicine Berlin, Humboldt-University and Free University of Berlin, Schumannstrasse 20/21, D-10117 Berlin, Germany
Correspondence to: G. R. Burmester. E-mail: gerd.burmester{at}charite.de
The modern differentiation of rheumatoid arthritis (RA) from other joint diseases still dates from as early as 1907 [1]. As there is no distinctive feature in the early phase of the disease, it is unknown when rheumatoid arthritis really develops as a separate entity. Experience from early arthritis registers and from specialized early arthritis clinics has shown that the classification criteria of the American College of Rheumatology (ACR) from 1987 are not, or not sufficiently, able to distinguish early stages of RA from other forms of joint inflammation [2, 3]. Indeed, use as a diagnostic tool has never been claimed for the ACR classification criteria at all. Therefore, diagnosis of RA is generally based upon the opinion of the rheumatologist who may additionally take the ACR classification criteria into account. Yet, the earlier a diagnosis is attempted the more atypical symptomatic patterns are present, and uncertainty and inhomogeneity among experts is usually high [4, 5]. A crucial problem is the definition of the term early when considering a chronic disease. A few years ago, a disease duration of up to 3 yr was considered the appropriate time-span. More recent meta-analyses and reassessments of clinical trials have shown, however, that the course of the disease still seems to differ notably within this period of time. In this context, the difference in treatment outcome has been found to be the strongest surrogate indicator for an earlier phase of disease [6].
Treatment with disease-modifying anti-rheumatic drugs (DMARDs) appears to be more successful in patients with a disease duration of up to 1 yr as compared with treatment outcome in patients with symptoms lasting for 1 or 2 yr. Thus, the therapeutic effect seems to depend less on the pharmacological capacity of a given DMARD than on the starting point of its administration within the process of disease development. At least two conclusions have been drawn from these observations. First, the hypothesis of a window of opportunity describing a period of time when the underlying inflammatory process is more susceptible to drug influences than at later time-points [79]. In this early phase, the process of autoimmunologically induced inflammation is not yet fully established with regard to both pathogenic as well as mechanical aspects (i.e. the extent of proliferation of and cellular infiltration into the inflamed synovia) [10]. As a definite diagnosis of RA cannot be confirmed at this stage, however, other rheumatologists opted to define more precise goals for the diagnostic approach. According to this hypothesis, in the initial phase of joint inflammation it is more useful to identify persisting, progressive courses of arthritis and reliable predictors of an establishing RA [1114]. In its most pronounced form this second line of discussion refuses any entity of early RA. It proposes to consider early arthritis as a condition which is unclassified and which might differentiate into several outcomes such as psoriatic arthritis, arthritis in spondyloarthropathy, RA or even a spontaneous abortion of symptoms [1]. Both the concept of a transiently unclassified early arthritis and the concept of a window of opportunity in early RA partly reflect the same experimentally and empirically obtained findings and transcribe them into scientific instructions for diagnostic and therapeutic decisions. The dilemma is reflected by the fact that diagnosis of RA might not be definite before at least a year has passed [1, 15]. At that time, the window of opportunity may be closed and the chance for better treatment success might have been missed. The gap has opened even more widely as, in addition to early RA (ERA), very early RA (VERA) has been defined with a maximum duration of symptoms of 12 weeks [16]. In the future, there will be better immunological and genomic predictors for the classification of arthritis subgroups and for a developing RA including autoantibody profiles (i.e. anti-citrullin antibodies). At present, however, we have to face the risk of over-treatment or under-treatment, starting DMARD therapy early in the wrong patients or too late in the right patients, respectively. Regarding the practical care of patients with early polyarthritis further concerns arise because DMARDs have not been approved for unclassified arthritis.
Considering the difficult therapeutic decisions in patients with a probable early RA, the study of Nell et al. [17], published in this issue, represents a remarkable scientific approach with important results. It addresses the question: When should we start DMARD treatment and is there a window of opportunity? The study design, a prospective, observer-blinded cohort study of early and very early RA patients, closely followed the conditions of daily rheumatological care. No instructions for particular therapeutic interventions were given except those for the routine treatment of RA, e.g. an algorithm for choosing methotrexate, sulphasalazine, chloroquine and cyclosporin A or combinations in the case of insufficient effectiveness. Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids could be added, at the physician's discretion. The case cohort consisted of patients who had had arthritis complaints for 3 to 4 months (very early rheumatoid arthritisVERA). For each of these patients one gender- and age-matched patient was included in a control group with a mean disease duration of 12 months (late early rheumatoid arthritisLERA). The delay resulted from late referral, and all patients were DMARD naïve. The upper and lower limits of the VERA group and the 25th and 75th percentile of disease duration in the LERA group did not overlap. Seventeen pairs were analysed after 36 months and at interim visits. Primary end-points were defined as change in disease activity score of 28 joints (DAS28) and the extent of structural damage assessed radiologically by the Larsen score. In addition, well-evaluated outcome measurement instruments like improvement criteria of the American College of Rheumatology (ACR), the Health Assessment Questionnaire (HAQ) and visual analogue pain scales were used. Diagnosis of rheumatoid arthritis was performed by the treating rheumatologist who was not informed about the ongoing trial setting. All patients fulfilled the ACR classification criteria for RA at baseline or during the follow-up period within the first year. In other words, in some patients the diagnosis was not established by the ACR criteria at baseline but was performed by the rheumatologist. The problem of early diagnosis was not the intended focus of this study, but here, more detailed information about the diagnostic criteria would have been helpful for the comparison with predictors of RA defined or proposed elsewhere [1114, 18]. Three-quarters of patients in both groups were tested positive for rheumatoid factor (RF). The mean number of swollen and tender joints was about nine, and a quarter of patients in the VERA group had radiologically visible erosions. Apart from the erosions, this group was similar to the LERA group. The presence of RF and a polyarticular inflammation in early arthritis are regarded as strong predictors of a persisting erosive disease [11, 12]. Thus, patients with at least a high probability for establishing RA were included in both groups. The important message is the following: starting on a similar DAS at baseline, defined by the onset of DMARD therapy, more patients in the VERA than in the LERA group had a good DAS response and a better retardation of radiological progression. A comparable number of patients in both groups received NSAIDs or corticosteroids, although the dosage of these drugs is not reported. The strongest differences in therapeutic effects between VERA and LERA patients occurred during the first 3 months of DMARD treatment. In addition, after 3 yr of observation the VERA patients remained on a disease activity level that was significantly lower than patients of the LERA group.
The authors stress the interesting fact that, among the response parameters, the inflammation-related acute phase parameters as well as joint swelling did not significantly differ between the LERA and VERA groups. These results support the assumption that the process of structural damage may be in some respects independent of the inflammation. The dissociation of structural damage and inflammation has been hypothesized about recently [19]. We agree with the authors conclusion that there is a window of opportunity in the very early inflammation phase. Considering the baseline data of disease severity in both groups and the significantly different therapeutic effect of a comparable treatment regimen, spontaneous self-limiting conditions are unlikely. The study results indicate that very early treatment in patients with RA, or at high risk of RA, can act as a kind of prevention. Proof of prevention is a difficult scientific task. Nell et al. [17] support their hypothesis by a very early treatment regimen in a second VERA group with similar characteristics to the first VERA group and similar therapeutic effects in both groups. The reported results of the 17 matched pairs demonstrate the urgent need for early referral to rheumatologists and early aggressive treatment with DMARDs even in a phase when the diagnosis of RA is still uncertain.
Concerning safety issues, in this study DMARD switches in the VERA group occurred slightly more often due to adverse events than in the LERA group. More detailed information about side-effects is not given by the authors. After all, over-treatment seems to be the more acceptable risk than missing the chance of a better treatment effect. Following recommendations for early referral to the rheumatologist [20], advice for treatment strategies for early and not finally diagnosed polyarthritis including DMARDs and perhaps even biological therapies should be developed by the scientific community. Further experience from prospective controlled treatment trials needs to be obtained for this purpose. Certainly, an approach with a study design without randomization has possible biases such as selection and indication and would have to balance them. On the other hand, studies with a less experimental concept are close to the real-life situation and thus have a higher external validity. The trial design of matched pairs should be repeated in the future by matching not only for gender and age but also for genomic and additional immunological markers according to improved scientific knowledge. The study of Nell et al. clearly points out the particularity of RA in its initial phase and suggests that even a short delay of DMARD therapy will have irreversible consequences for patients. We think that this important study will give new impetus to a more active diagnostic strategy and more aggressive treatment in the near future.
References
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