"[P]atients who do not achieve a moderate or low disease activity after 3 months of treatment, especially when taking traditional DMARDs such as MTX, are not likely to achieve a good outcome in terms of low disease activity or remission at 1 year. It is conceivable that such patients may benefit from rapid switching to alternative therapies," said lead author Daniel Aletaha, MD, at the Medical University of Vienna, Austria.
60% of responders known within first 3 months
The research team led by Dr. Smolen, also included Julia Fonovits, MS, at the Medical University of Vienna, and Edward C. Keystone, MD, at the University of Toronto. Pooled data from 1342 patients with early RA treated in clinical trials of methotrexate (MTX), tumor necrosis factor inhibitor monotherapy with adalimumab or etanercept, or the combination of adalimumab or infliximab plus MTX were used to assess whether disease activity at baseline or during the first 3 months of therapy predicted disease activity at 1 year after treatment initiation.
The results of this analysis were validated using data from clinical trials of MTX and of TNF inhibitor plus MTX in late RA (n = 712). Disease activity was measured using the Simplified Disease Activity Index (SDAI), the Disease Activity Score 28-joint assessment (DAS28) and the Clinical Disease Activity Index.
The analysis showed that
- disease activity at 1 year is significantly related to baseline and to 3-month disease activity
- TNF inhibitor plus MTX was more effective than MTX alone over a broader range of baseline disease activity
- 60% of the patients who met ACR20 improvement criteria at 6 months had already done so at 3 months
"This suggests that for the majority of patients, the response achieved within the first 3 months is highly predictive of the degree of clinical outcome at 1 year," the authors wrote. Baseline SDAI values were not useful as predictors of remission at 1 year. SDAI at 3 months was more useful. Patients in the lowest SDAI quartile at 3 months were four times as likely to be in remission at 1 year as those in the highest SDAI quartile. "Moreover, as a group, patients who achieved low disease activity or remission at 1 year were already well into the moderate disease activity category (SDAI 11 to <e;26) at 3 months."
The validation studies showed that this relationship also holds for RA patients with late-stage disease. "These data not only validated the results obtained in the early RA population, but also revealed that disease duration does not bear a major influence on the association obtained (ie, these findings support the generalizability of our results," Dr. Aletaha noted.
Data support strategy of sequential regimens
The investigators also found that in the patients with longstanding RA "the relationship between disease activity at baseline, and especially at 3 months, with disease activity at 1 year was similar to that observed in MTX-naïve patients," suggesting that even partly effective reduction of disease activity from an initial regimen is likely to set the stage for better results from a subsequent regimen. The authors see this as an argument in favor of an initial 3-month course of MTX in all patients regardless of baseline activity.
"[T]hose with good prospects for achieving low disease activity or remission will benefit from such therapy, while those with worse prospects may still experience a reduction of their disease activity from baseline, even if it is only a moderate reduction. This lower disease activity level resets the baseline for subsequent treatment with a biologic agent plus MTX and increases the likelihood of achieving a satisfying disease activity status," they conclude. They suggest that sequential drug therapy might provide better control of RA disease activity, "taking advantage of the fact that disease activity may become progressively reduced with every new treatment course."
"The available data suggests that it is better to give more treatment in early RA than to give monotherapy in patients with active disease. But many patients respond well to methotrexate monotherapy. Therefore, it might be reasonable to assume that clinical measures like SDAI combined with a step-up approach at 3 months would give more benefit than monotherapy or even than starting intensive treatments in all patients. But that must be set against the lack of evidence that step-up treatment is more effective than parallel treatment," Dr. Scott said.
"I agree with the need for a paradigm shift from monotherapy towards more intensive early treatment," he added. "I suspect this is more important than the exact nature of the intensive treatment. I would focus on the intensive aspect rather than the measures or approach. But by providing more data around the area there is likely to be gradual advance. Within the UK, the available data suggests too little intensive treatment is used."
Correlation of Simplified Disease Activity Index (SDAI) at Baseline and 3 Months with 1-Year Outcome: Patients With Early RA (n = 1342)
| Assessment | Correlation With 1-Year SDAI* |
| Baseline | 0.220 |
| 1 month | 0.432 |
| 2 months | 0.516 |
| 3 months | 0.593 |
| 6 months | 0.719 |
*Correlation coefficients determined by Spearman's rank correlation. All are significant at P<.0001.
Source: Arthritis Rheum. 2007;56:3226-3235.1
Correlation of Simplified Disease Activity Index (SDAI) at Baseline and 3 Months With 1-Year Outcome: Patients With Late RA (n = 712)
| Assessment | Correlation With 1-Year SDAI* |
| Baseline | 0.340 |
| 1 month | 0.446 |
| 2 months | 0.535 |
| 3 months | 0.553 |
| 6 months | 0.606 |
*Correlation coefficients determined by Spearman's rank correlation. All are aignificant at P<.0001.
Source: Arthritis Rheum. 2007;56:3226-3235.1
Reference
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