Vienna, Austria - When it comes to the early treatment of rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs (DMARDs), a new study "reveals that 'early' cannot be early enough," say the investigators, led by Prof Josef Smolen (Vienna University, Austria) [ 1 ].
"This study extends all previous notions on the importance of early DMARD therapy in RA by revealing the existence of a therapeutic window of opportunity within the first few months of the disease," they comment in the July 2004 issue of Rheumatology. Preliminary results from this study were first presented at the EULAR 2002 meeting and reported at the time by rheuma wire .
An accompanying editorial says this is an important study with important results [ 2 ]. It "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," comment Dr Gerd Burmester and colleagues (Free University of Berlin, Germany). It also suggests that "very early treatment in patients with RA, or at high risk of RA, can act as a kind of prevention."
Burmester tells rheuma wire that this study "confirms the concept of a therapeutic window of opportunity. These results come from 1 center and from a limited number of patients, and so of course we need more data, but to ask for hundreds of patients in 1 center is unfair."
"It cannot give a definitive answer, but it goes in the right direction," he comments. "It was a very well-conducted study, and it shows quite clearly that even a couple of weeks or months in early RA is crucial to avoid joint destruction. It also confirms our approach of viewing early RA as a medical emergency and seeing patients with potential RA as early as possible, even when the diagnosis is still unclear."
There has been a recent trend toward diagnosing and treating RA earlier and earlier, but the term "early" hasn't really been defined, and some trials have included patients with a duration of 1 to 5 years. "Even a few years ago, a disease duration of up to 3 years was considered the appropriate time span," say the editorialists. Recent trial results have focused attention on the first year of the disease, but here there is a dilemma, they point out, "as the diagnosis of RA may not be definite before at least a year has passed." But now the focus has narrowed even further, to very early RA (VERA), defined as having a maximum duration of symptoms of 12 weeks.
This latest study shows that it is these very first few months of the disease that are critical. The observations "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," the editorialists conclude.
The latest trial compared a group of patients with VERA who had a mean disease duration of 3 months (range 2 to 4 months) with a matched group of patients who had RA with a mean duration of 12 months (range 9 months to 3 years), referred to as the late-early RA (LERA) group.
Each group had 20 patients at baseline, and 20 in each group completed the 1-year follow-up, but by the third year, some were lost to follow-up, so the 3-year observations were made on 17 patients in each group. The authors also repeated the VERA part of the study in a second group of patients, to see whether the findings would be duplicated (they were).
Both groups had similar disease activity scores (DAS) at baseline, with a mean of about 9 swollen and tender joints, and 75% of both groups tested positive for rheumatoid factor. They differed, however, in the x-ray findings—not surprisingly, comment the authors. At baseline, 25% of the VERA group and 50% of the LERA group had radiologically visible erosions.
All the patients were DMARD na¿ve and received routine treatment for RA from a rheumatologist, consisting of traditional DMARDs (methotrexate, sulfasalazine, chloroquine, cyclosporin A, or a combination) as well as nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, all at the physician's discretion. (The biologics weren't licensed in Europe at the time the study began). The initial distribution of DMARDs between the 2 groups was similar, but as the study progressed, there was 3 times more switching due to inefficacy in the LERA group than the VERA group (p<0.05), the researchers note.
Despite the fact that the 2 groups had similar disease and received similar treatment, there was a big difference in the responses seen.
At baseline, both groups had DAS28 scores in the high range (more than half in each group had DAS28 scores >5). After 3 months of DMARD therapy, the DAS28 decreased by about 40% compared with baseline in the VERA group but fell by an insignificant 12% in the LERA group, the authors comment. At 1 year, there was a significant difference in the response to treatment, with DAS28 scores falling by -2.72 in the VERA group compared with -1.61 in the LERA group (p<0.05). For the VERA group, the mean DAS28 score reached the low range, and it stayed there for the next 2 years. Such low mean disease activity was never achieved in the LERA group, they add.
The x-ray findings also show significant differences between the 2 groups, with the VERA group showing a greater retardation of radiographic damage. During the 3-year observation period, changes from baseline were significantly higher (more than 4-fold) in the LERA patients when compared with the VERA group (p<0.05), the authors note. The biggest increase in radiographic damage in the LERA group was seen within the first year, but after that the increase paralleled that seen in the VERA group. In contrast, the slope of radiographic progression in VERA was linear throughout the observation period.
Both groups started with a similar disability score on the Stanford Health Assessment Questionnaire (HAQ). A significant difference in this score in favor of the VERA group was seen after only 3 months of DMARD therapy, and this significant difference was maintained throughout the 3 years. So, while both groups started with a similar disability score (0.9), this score was 150% higher in the LERA group than in the VERA group after 3 years, the authors report.
A similar development was seen for pain assessment and for both the physicians' as well as the patients' global assessments, with significant differences between the VERA and the LERA groups, the authors comment. However, the difference in swollen joint counts was not significant, although numerically it favored the VERA group.
The acute-phase response, as measured by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), was decreased significantly in both groups after only 3 months of DMARD therapy, and the decrease continued throughout the study. At 3 years, the levels of both biochemical markers were close to normal and not significantly different between the 2 groups.
http://www.medscape.com/viewarticle/537861_print