Methotrexate plus etanercept effective in inducing clinical remission in patients with early moderate-to-severe RA

The first phase of a double-blind, randomized, parallel-group, multicenter, outpatient study demonstrated that treatment with the combination of etanercept and methotrexate was more effective in inducing both clinical remission and radiographic nonprogression than methotrexate alone in patients with early moderate-to-severe rheumatoid arthritis (RA).

Key Points

The first phase of a double-blind, randomized, parallel-group, multicenter, outpatient study demonstrated that treatment with the combination of etanercept and methotrexate was more effective in inducing both clinical remission and radiographic nonprogression than methotrexate alone in patients with early moderate-to-severe rheumatoid arthritis (RA). These study results were published in Lancet.

The 24-month Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) trial enrolled 542 patients with RA disease duration of ≥3 months but ≤2 years. Eligible patients had a disease activity score in 28 joints (DAS28) of ≥3.2. Patients were excluded from the study if they had previously been treated with methotrexate, etanercept, or another tumor necrosis factor (TNF) antagonist or if they had been treated with other disease-modifying antirheumatic drugs (DMARDs) or corticosteroid injections in the 4 weeks before baseline.

Patients were randomized to treatment with either subcutaneous (SC) etanercept 50 mg/wk plus oral methotrexate for 52 weeks or with oral methotrexate alone for 52 weeks. Methotrexate was initiated at a dose of 7.5 mg/wk and was titrated over 8 weeks to a maximum dose of 20 mg/wk.

At 52 weeks, a significantly greater percentage of patients treated with etanercept plus methotrexate had achieved clinical remission (50%; 95% CI, 44%–56%) compared with patients treated with methotrexate alone (28%; 95% CI, 23%–33%; effect difference, 22.05%; 95% CI, 13.96%–30.15%; P<.0001). This treatment difference was observed as early as Week 2 and was thereafter observed at all time points.

A significantly greater proportion of patients in the combination group demonstrated radiographic nonprogression (defined as mTSS ≤0.5) (80%; 95% CI, 75%–85%) compared with patients in the methotrexate monotherapy group (59%; 95% CI, 53%–65%; effect difference, 20.98%; 95% CI, 12.97%–29.09%; P<.0001).

Among patients treated with combination therapy, 55% demonstrated a normal health assessment questionnaire disability index (defined as ≤0.5) at 52 weeks versus 39% of patients treated with methotrexate alone (effect difference, 16.10%; 95% CI, 7.44%–24.76%; P=.0004). Improvement in this index from baseline to end of study was demonstrated in 61% of patients in the combination group compared with 44% of patients in the methotrexate monotherapy group (P<.0001).

Among patients treated with etanercept plus methotrexate, 59% had no swollen joints at 52 weeks compared with 38% of patients treated with methotrexate alone (P<.0001).

The incidences of serious adverse events and malignant diseases were similar between treatment groups.

The investigators pointed out several study limitations that may have affected interpretation of the results. Because patients were not permitted to decrease the dose of their primary medication (except in cases of adverse events) and were not allowed to change the route of methotrexate administration (from oral to SC), it may be difficult to extrapolate these results to a real-world setting. However, the investigators suggested that, based on these trial results, clinical remission may be "an achievable goal in patients with early severe rheumatoid arthritis within the first year of therapy with etanercept plus methotrexate."

SOURCE

Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): A randomised, double-blind, parallel treatment trial. Lancet. 2008 [Epub ahead of print].