1 Department of Rheumatology, Vienna General Hospital, University of Vienna, 2 Department of Rheumatology, Lainz Hospital, Vienna, 3 Department of Radiology, Vienna General Hospital, University of Vienna, Austria.
Correspondence to: J. S. Smolen, Department of Rheumatology, Internal Medicine III, University of Vienna, Waehringer Guertel 1820, A-1090 Vienna, Austria. E-mail: Josef.Smolen{at}wienkav.at
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Abstract |
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Methods. In this case-control parallel-group study, 20 very early RA (VERA) patients with median disease duration of 3 months were age and gender matched to a group of 20 late early RA (LERA) patients with median disease duration of 12 months until first DMARD initiation. Follow-up time was 36 months. Primary outcome measures were the disease activity score (DAS28) and radiological joint destruction using the Larsen method.
Results. Already after 3 months of DMARD therapy we found a significant difference of improvement in favour of the VERA patients in the DAS28. This trend continued over the study period. At study end the DAS28 showed an improvement of 2.8±1.5 in the VERA vs 1.7±1.2 in the LERA group (Pc<0.05). The Larsen scores showed a statistically significant retardation of progression in the VERA compared with the LERA.
Conclusion. Our results indicate that there is a window of opportunity for highly successful treatment of RA in the first year, and especially within the first 3 months of therapy. Thus, early diagnosis and therapy may be the crucial step in achieving optimal control of disease progression and prognosis in RA.
KEY WORDS: Very early rheumatoid arthritis, Disease-modifying anti-rheumatic drugs, Larsen score, DAS28, Therapeutic window
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Introduction |
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Early application of DMARDs has revealed significant benefit when compared with their use later in the course of the disease [1620], and in fact today most rheumatologists strongly recommend early introduction [2125]. However, even early DMARD therapy does not fully prevent disease progression in the majority of the patients and, importantly, the term early is still ill-defined: in clinical trials of early RA, patients with disease durations of a few months to 5 yr were included [17, 20, 2630]. To date, though, there are no data actually comparing prospectively the outcome of very early intervention with only briefly delayed DMARD therapy in patients with early RA.
In the present study we have tested to see if such a window of opportunity exists and thus compared, in a parallel study design, disease activity, joint destruction and functional outcome in patients with very early RA with those of age- and gender-matched patients who have experienced a short delay in disease-specific therapy.
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Patients and methods |
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In this study we hypothesized that DMARD treatment introduced very early, as soon as only a few weeks after onset of symptoms, would be significantly superior when compared with a delay of DMARD initiation of only a few months, suggesting a therapeutic window of opportunity in this very early stage of the disease. For evaluation of efficacy, the core set of disease activity measures for RA clinical trials was used. Primary endpoints were defined as the difference in disease activity score and the change of radiological joint damage as assessed by the Larsen score.
The patient groups were followed during the same time period employing a similar therapeutic approach. Before inclusion of the first patient in 1997, a widely publicized Early Arthritis (EA) Action was launched [33], leading to a significant increase in early referrals to our specialized units. All patients received routine patient care from rheumatologists who were unaware of the comparative purpose of the study. However, as a general policy, all physicians of the clinics are instructed to treat patients with DMARDs as early as possible, as aggressively as their disease state requires and as current practice dictates, and to switch DMARDs as soon as it is deemed clinically appropriate, i.e. if active disease persists after 3 months of DMARD therapy at effective doses, such as 3 g of SSP/day or 15 mg of MTX/week. The choice of DMARD was left to the rheumatologists discretion. Neither the use of corticosteroids nor the use of NSAIDS was pre-defined.
For the two main patient cohorts, VERA1 and LERA, this study design balanced the treatment strategies, and allowed optimal investigation of real-life therapy with traditional DMARDs.
A final third group consisted of the next 20 consecutive VERA patients from the early arthritis clinic (VERA2). The additional VERA2 group allowed us to test the validity of data obtained in VERA1 patients.
This design seemed to be the appropriate way to address the clinically important question of the optimal time point of DMARD intervention, since a randomized trial of immediate versus delay of treatment for several months could be considered unethical on the basis of current clinical data.
The study has been approved by the Ethical Committee of the Vienna General Hospital and complies with the GCP guidelines according to the Declaration of Helsinki. A detailed design of the EA action has been reported previously [33]. All subjects gave written informed consent. Patients were assessed and managed at the rheumatological out-patient clinics of the General Hospital and the Lainz Hospital, both in Vienna, by a multidisciplinary team, including rheumatologists and a specialized occupational health therapist.
All patients were followed for a total of 3 yr. The date of DMARD start was defined as baseline.
Very early rheumatoid arthritisVERA1 patients
The first 20 consecutive patients in the early arthritis clinic seen within 3 months from symptom onset and diagnosed as RA constituted the VERA1 cohort of patients. Since the American College of Rheumatology (ACR) classification criteria for RA [34] do not apply at the very early stage of the disease [33, 3537], diagnosis of RA was made by the participating rheumatologists based on the clinical signs and symptoms and on laboratory tests, and ascertained by chart review after 1 yr. However, all patients fulfilled the ACR criteria at least at baseline and/or cumulatively during their first year of follow-up.
As soon as RA was diagnosed, patients were consequently treated with DMARDs. The date of DMARD start was defined as baseline.
Late early rheumatoid arthritisLERA-patients
Each of the 20 VERA1 patients described above was matched to the first RA patient seen in clinic who matched by age (±2 yr) and gender, and who was presenting in clinics for the first time with a symptom duration between 9 months and 3.5 yr, and had never received DMARDs before (LERA). Diagnosis was made by the rheumatologists in charge, and, as in the VERA1, all patients fulfilled the ACR criteria already at baseline and/or during their first year of follow-up.
Again, patients were treated with DMARDs as soon as RA was diagnosed, and the date of DMARD start defined as baseline.
VERA2 patients
In order to validate the data obtained from the VERA1 group, a second group of the next 20 consecutive very early arthritis patients (VERA2) was evaluated in the same way as VERA1 and LERA, but at a subsequent point in time.
Clinical and laboratory investigations
For evaluation of efficacy the core set of disease activity measures for RA clinical trials was used [3840]. All variables were assessed prospectively.
The primary endpoints were the difference in disease activity score [42] and the change of radiological joint damage as assessed by the Larsen score [43], an established surrogate of outcome [38, 39, 44]. Secondary endpoints were differences in core set variables including function-related quality of life by Health Assessment Questionnaire (HAQ), as well as the ACR and the European League Against Rheumatism (EULAR) response rates [45, 46].
Disease activity score (DAS28)
The DAS28 [41, 42], a composite score calculated from joint counts (TJC, tender joint count; SCJ, swollen joint count), acute phase response (erythrocyte sedimentation rate, ESR) and patient global assessment (PGA) was evaluated as a measure of RA activity [DAS28 = 0.56 x (TJC) + 0.28 x(
SJC) + 0.70 x ln(ESR) + 0.014 x PGA]. A DAS28 score of
3.2 is defined as low activity, >3.25.1 as moderate activity and >5.1 as high activity [42].
Radiographic assessment
Initial radiographs and radiographs at 12, 24 and 36 months, blinded for group and sequence, were assessed at the same time by a team of two experienced readers, one rheumatologist (KPM) and one radiologist (MU). In order to characterize precision of assessment, the complete sets of X-rays were reassessed at a different time point. Agreement between the assessments revealed a correlation coefficient of 0.86 [95% confidence interval (CI) 0.805 to 0.906].
Scoring was done according to the Larsen method on 42 joints in the hands/wrists and feet. Radiographs were compared with standard reference films and scored from 0 (normal) to 5 (mutilating changes) for each individual joint [43]. Accordingly, the possible range of the summary joint count score was 0210. The number of eroded joints (defined by Larsen scores 2) was also calculated. Joint involvement was expressed as mean Larsen scores and by eroded joint counts.
Functional assessment, pain and global assessment, joint counts, acute phase response and rheumatoid factor
Functional disability was assessed using the Stanford HAQ [47] in a validated German version [48].
Visual analogue scales (from 0 to 100 mm) were used for the evaluation of pain intensity and physicians as well as patients global assessment of disease activity.
Tender and swollen joint count scores were based on the 28 joint count [49, 50]. All joint counts were performed by an independent and blinded assessor.
Laboratory analyses according to standard techniques included the ESR and C-reactive protein (CRP) as measures of the acute phase response, and rheumatoid factor (RF) determined by nephelometry.
ACR and EULAR response criteria
The ACR 20, 50 and 70% [45] and the EULAR response criteria composed of categorical changes in the DAS28 [46] are validated criteria for the assessment of treatment response [51]. Both scores emphasize change in disease state, and are therefore useful for assessing clinically relevant improvement in disease activity.
Follow-up
For all groups follow-up data obtained at baseline, at 3 months and at yearly intervals thereafter will be shown, with the exception of radiographic assessment, which was assessed at yearly intervals only.
Our analyses of data at 1 yr after DMARD start are complete for all 40 VERA and LERA patients. During the second year two patients (one VERA1, one LERA) were lost to follow-up and another during the third year (one LERA). Two of these patients moved to other cities or countries and one was lost to follow-up because he did not return to our clinics and could not be accessed.
Statistical analysis
Differences in the DAS28 and the Larsen score were employed as primary outcome variables. Changes from baseline values of individual core set variables (including HAQ) as well as the ACR 20, 50 and 70%, and the EULAR response rates served as secondary endpoints. Changes from baseline values are presented as mean values ± standard deviation if not indicated otherwise.
Continuous variables were compared using the Wilcoxon signed rank test for paired data; binary variables were analysed using the McNemar test. To adjust for multiplicity, P values were corrected using the Bonferroni/Holm method in primary outcome variables (Pc).
Missing observations for each of the lost to follow-up patients and the data of the complementary paired patient from this exclusion point on were carried forward until the end of the observation period (LOCF). As an exception, results of Larsen scores exclude matched patient pairs with any missing data at the respective point in time. At 1 yr, however, Larsen scores were available for all patients.
SPSS statistical software (SPSS Inc., Chicago, IL) was used for statistical analysis. The reported P values are the results of two-sided tests. A P (Pc) value smaller than or equal to 5% was considered statistically significant.
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Results |
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Retardation of radiographic damage is greater in the VERA than LERA group
At baseline, Larsen scores were 3.5 ± 4.4 in the VERA1, and 11.3 ± 10.0 in the LERA group (Pc<0.05). After 36 months of DMARD therapy, Larsen scores increased by 3.6 ± 6.5 in the VERA1 and by 14.7 ± 9.9 in the LERA group (Fig. 2). Changes from baseline were significantly higher (more than four-fold) in the LERA patients when compared with the VERA group (Pc<0.05). While five VERA1 and 10 LERA patients had erosions (Larsen score 2) at baseline (P<0.05), the number of patients with erosions at 36 months was seven in the VERA1 and 15 in the LERA group (P<0.05). Thus, in both groups the frequency of patients with erosions increased by about 50%, but among VERA1 the number of patients with erosions was even lower at 3 yr than among LERA at baseline.
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Changes in functional outcome, but not joint counts or acute phase response, are more pronounced among VERA than LERA patients
The changes from baseline in variables assessed at 3 months and at the study endpoint at 36 months are shown in Table 2. As soon as 3 months after DMARD start in both groups, there was a significant difference in favour of the VERA1 group with respect to the disability score (HAQ), and this significant difference was maintained through year three. Thus, while both groups started with a similar disability score (0.9), this score was 150% higher in the LERA group (0.5) than in the VERA1 group (0.2) after 3 yr.
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The development of the acute phase response as measured by ESR and CRP is shown in Table 3. A decrease was demonstrated for both variables in both groups after only 3 months of DMARD therapy with continuing reduction until study end, when both the mean ESR and CRP values were quite close to their normal range, with no significant difference between the two groups.
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Patients lost to follow-up
A total of three patients were lost to follow-up during the 3-yr period of observation: one VERA and two LERA patients. Data for each of these patients plus their matched control were interpreted using the LOCF method but fully excluded for radiological analysis. We calculated all our data with the 17 complete pairs that continued treatment over 36 months (not shown). The results were very similar to the ones shown.
Switches of DMARD therapy due to lack of efficacy are common among LERA
The evolution of DMARD usage over time reflected the clinical data. The initial distribution of DMARDs was similar when the two groups were compared (Table 4). However, DMARDs of four VERA1 patients were subsequently switched once, and twice or three times in each one additional patient (the total number of regimen changes was nine). In contrast, among LERA patients, switching of DMARDs was necessary once in six patients, twice in two and three times in one patient (total changes 13). Interestingly, of the nine switches in the VERA1 group, six were due to adverse events and three due to inefficacy, while in the LERA group four switches were due to adverse events and nine due to inefficacy. Thus, DMARD switching due to lack of efficacy were three-fold (P<0.05) more frequent among LERA than VERA1 patients.
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Discussion |
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To establish whether there exists a window of opportunity within early disease, we formed two groups: one group of patients with very early RA, with a median of 3 months symptom duration before DMARD start, and a fully matched group of patients with late early RA, with a median symptom duration of 12 months, who would still have qualified for most previously published early RA trials.
The results obtained show that throughout the period of observation, and despite similar therapies, there were significant differences in disease activity, joint destruction and functional outcome in favour of very early therapy. Most importantly, the major differences between the two groups occurred within the first year and especially during the first 3 months of treatment. This was particularly true for functional disability, disease activity and radiographic progression of joint destruction.
This suggests that in very early arthritis, but not in arthritis lasting for just a short time longer, disease progression can be halted rapidly. Moreover, these therapy-driven data confirm epidemiological indications that arthritis of more than 1224 weeks duration will cause increasing damage [53, 54].
The data also suggest that, when treated very early, a large fraction of patients respond very well to traditional DMARDs (ACR 50% response in 60% of patients after 36 months), allowing levels of effectiveness to be achieved that approach or even exceed those obtained with the best recently introduced agents, including biological therapies, which were not licensed in Europe until almost the end of the inclusion period. These latter costly therapies could then be reserved for those patients who do not respond well to traditional approaches, and still be used relatively early for the benefit of the patients.
Could the excellent therapeutic results obtained among VERA1 patients have been due to spontaneous remissions or contamination of this group with non-RA patients? This is highly unlikely for several reasons: Firstly, with one exception, VERA1 patients had persistent arthritis for more than 6 weeks and 70% for at least 3 months, important time points for the differentiation between early RA and early non-RA [34, 53, 54]. Secondly, a good DAS28 response was not observed more frequently among VERA1 patients with 3 compared to those with >3 months disease duration at DMARD start (data not shown). Thirdly, RF status was similar in both groups, and numerically even higher among VERA1 patients, and corresponds well to other early RA cohorts [19]. Fourthly, the frequencies of patients with erosive disease increased by around 50% during the 3 yr of observation in both groups, further supporting the diagnosis of RA. Also, for both VERA and LERA patients, respectively, the data on joint damage at study start were similar to those published on investigations of similar cohorts of patients [17, 19, 20, 27, 53]. Finally, we could easily control for the results observed in the initial VERA1 group by assessing a second cohort of VERA2 patients: the differences between LERA and VERA1 were fully confirmed when the LERA group was compared with the VERA2 cohort.
All patients were referred to our clinics in the context of a widely publicized Early Arthritis Action [33]. At the time of study onset, we had set inclusion criteria for the VERA and the LERA group. The LERA was defined, similar to those of other trials on early RA, as patients with maximum symptom duration of 3 yr [17, 28, 29]. When we evaluated the data retrospectively to include only patients with symptom duration of less than 1 yr and compared those LERA with their matching VERA1 equivalent, results (not shown) did not differ significantly from those observed for the total group.
This study did not constitute a randomized controlled therapeutic trial but a real-life design. However, assessment was performed in a blinded manner by independent observers. There was no selection bias regarding the VERA group, since consecutive patients were included. The treating physicians were unaware of the comparative purpose of the study, and different from the evaluators. They were only required to treat all RA patients in the clinic according to the state of the art, and, in fact, VERA and LERA patients were initially treated in a similar fashion, while their worse clinical course forced a more frequent and more rapid change of DMARD regime in LERA compared to VERA patients.
Thus, the data obtained suggest that, compared with very early RA, it is more difficult to control RA ongoing for a prolonged time, even if this prolonged period is relatively short, i.e. a few months. This conclusion is supported by recent observations that first DMARD courses are particularly effective and more so than later DMARD courses [55, 56]. The data shown here suggest that the higher efficacy of first DMARD courses may be associated with their institution earlier in the disease course rather than with their earlier numerical sequence. Thus, our observations provide evidence that there exists a critical therapeutic window very early in the course of RA.
Interestingly, the surrogates of inflammatory disease activity did not differ between VERA and LERA patients: the acute phase response and joint swelling improved significantly in both groups of patients compared with baseline, but the changes observed in the VERA group were not significantly different from those of LERA patients at any point in time. Thus, although there exists a relationship between joint swelling and acute phase response on the one hand and radiographic damage on the other hand [5759], the lack of difference regarding the inflammatory variables compared with the highly significant difference in structural changes support the notion of a dissociation of inflammation and destruction as recently evidenced in experimental models of arthritis [60, 61]; this dissociation appears to be particularly present in very early disease when inflammation is active but cartilage and bone structures have not yet been fully attacked. Thus, the data suggest that, although inflammation may be halted to a similar degree in very early and later RA, destruction, once initiated and progressing, is partly autonomous. On the other hand, once disease was under control with DMARDs, i.e. after the first year, radiographic progression in later disease paralleled that in very early disease, suggesting that rapid reduction of inflammation is key also in established RA.
On the basis of publications on the efficacy of early DMARD therapy [16, 17, 19, 2325, 62], rheumatologists are now alerted to start DMARDs as early as possible. Nevertheless, many physicians even today still prefer to wait for a few months before institution of DMARDs [63, 64]. Moreover, patients are often referred late after onset of symptoms [63]. In fact, the delay of DMARD start among LERA patients in our study was solely due to late referral.
The present data extend all previous notions on the importance of early DMARD therapy and reveal that early cannot be early enough. Of course, as shown here, DMARDs can be highly effective even in later stages of RA; however, even when DMARD therapy is only briefly delayed, RA patients may never catch up for the loss of time in terms of destruction and function.
In conclusion, based on the data presented, the major tasks for the immediate future will be to alert physicians that early referral may be the most important joint protecting measure for patients with rheumatoid arthritis and that DMARD therapy should be instituted as early as possible, ideally within the first 3 months from onset of symptoms.
The authors have declared no conflicts of interest.
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References |
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