Long-term structural benefits from Short-Term aggressive treatment of early Rheumatoid Arthritis
Early treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is standard in modern rheumatology practices. Several reports have suggested that treatment with combinations of DMARDs is superior to treatment with sequential single DMARDs in suppressing disease activity and slowing destruction of the joints. One such report from the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that in a 56-week intervention, a combination of prednisolone, methotrexate, and sulfasalazine was superior to sulfasalazine alone (Boers et al, Lancet 350:309-318, 1997). In the February issue of Arthritis and Rheumatism, these investigators presented results from the 5-year follow-of patients in the COBRA trial (Landewe et al, Arthritis Rheum 46:347-356, 2002).
Methods: The COBRA study was a multicenter, randomized, double-blind, controlled trial in patients with early, active RA and no prior treatment with a DMARD or corticosteroid. COBRA treatment consisted of prednisolone (initially 60 mg/day, tapered to 7.5 mg/day, then stopped at week 28), low dose methotrexate (MTX; 7.5 mg/wk, then tapered and stopped at week 40), and sulfasalazine maintenance therapy (SSZ; 2 gm/day). COBRA intervention ended at week 56, but blinding was maintained until week 80. In the period between weeks 56 and 80, rheumatologists were allowed to select therapy for individual patients with no limiting regulation. During the trial and the follow-up, disease activity was reported in the form of the 28-joint Disease Activity Score (DAS28). This is a composite index of a 28-joint swollen joint count, a 28 joint tender joint count, the erythrocyte sedimentation rate (ESR), and the patients global assessment of well-being. Functional disability was measured with the 24-item Health Assessment Questionnaire (HAQ). Radiographic damage was assessed using the Sharp/van der Heijde method.
Results: At the beginning of the 5-year follow-up, patients in the COBRA group had lower time-averaged DAS28 scores and radiographic damage (Sharp score) compared with patients in the SSZ monotherapy group, while the functional ability score (HAQ) was not different in the two groups. During the 4-5 year followup period, the time-averaged DAS28 score decreased more in the SSZ group (0.17 points per year) than in the COBRA group (0.07/yr). However, the Sharp progression rate was higher in the SSZ group (8.6 points per year) than in the COBRA group (5.6/yr). After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28.
Conclusion: Aggressive short-term combination therapy (COBRA) early in disease was effective in reducing and sustaining a lower rate of radiographic progression (35% lower) than monotherapy with SSZ over 4-5 years. This reduction in COBRA treated patients could not be explained by differences in DMARD therapy utilized during the follow-up period, nor by differences in disease activity during the double-blind treatment period. After COBRA therapy was stopped, the rate of radiologic progression did not return to the rate observed during the year of double-blind treatment, but rather stabilized at a lower level.
Editorial Comment: These findings support the concept that the rate of radiologic progression can be re-set pharmacologically if effective, aggressive treatment is introduced early in the disease process. The SSZ group could not “catch up” with the COBRA group during followup – that is, they continued to have a higher rate of radiographic progression – even though fairly similar treatments were administered during the 5 year followup with respect to the type and amount of DMARDs and steroids. This is an interesting observation, though somewhat flawed by the absence of a defined treatment protocol during the followup, and compels us even more avidly to treat our RA patients early with the goal of attaining excellent control of disease activity.
In conclusion, brief but intensive combination therapy early in the course of RA can have long-term structural benefits.