Combo Drug Treatment Scores for Early Rheumatoid Arthritis

By Judith Groch
LEEDS, England, 16 july 2008 -- Combining methotrexate and etanercept (Enbrel) for early moderate-to-severe rheumatoid arthritis improved remission and progression rates within a year, a randomized trial found.
At one year those treated with etanercept, an anti-TNF agent, plus methotrexate were 22% more likely to achieve remission as those given methotrexate alone, Paul Emery, M.D., of the University of Leeds, and colleagues reported online in The Lancet.
The industry-funded study included 542 outpatients who were methotrexate-naive and had had early moderate-to-severe RA for three to 24 months. Patients ages 18 or older were enrolled at 70 sites in Europe, Latin America, Asia, and Australia from October 2004 to February 2006.
After randomization masked to both patients and care persons, 268 patients were assigned to methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by the eighth week, and 274 were randomized to combined treatment with methotrexate (same titration) plus etanercept at 50 mg a week.
This study was supported by Wyeth Research, which was responsible for the collection and analysis of data. Wyeth is a marketer of Enbrel.
Altogether, there was severe disease in 487 evaluable patients (DAS 28>5.1).
Coprimary endpoints at 52 weeks were remission measured with the Disease Activity Score in 28 joints (DAS 28) and radiographic non-progression measured by a modified total Sharp score.
Of 265 patients given combined treatments and who were available for assessment, 132 or 50% (95% CI 44% to 56%) achieved clinical remission, while 94% had a good to moderate response.
The 50% response compared with a 28% response among 73 of 263 patients (95% CI 23% to 33%) taking methotrexate alone, making the difference for the effect 22.05% (95% CI 13.96% to 30.15%, P<0.0001).
In the combined treatment group, 80% (196 of 246) showed no radiographic progression of joint damage at 52 weeks compared with 59% of the monotherapy patients. The 21% difference favored combined treatment (95% CI 12.97% to 29.09%, P<0.0001).
Serious adverse events, worsening of rheumatoid arthritis, breast cancer, chest pain, pneumonia, infections, for example, were about 12% in both groups.
The cumulative proportion of patients working full- or part-time at baseline but who stopped working at least once was 9% for those given combined therapy versus 24% for those given monotherapy. Additionally, a lower risk of joint damage might reduce the need for future joint-replacement surgery, the researchers said.
The effect of rheumatoid arthritis is especially significant for women ages 55 to 64, because their rates for stopping work early are high, they added.
Study limitations included the fact that unlike patients treated in the real world, study participants could not decrease the dose of their primary medication other than for adverse events. Thus the combination regimen might have had a similar positive effect with lower methotrexate doses.
Additionally, administration of methotrexate could not be changed from oral to subcutaneous for higher doses, so that results might have differed with a parenteral procedure.
The analyses in this report are of treatment group averages rather than individual patients' responses, including lack of radiographic progression. These results do not indicate that rheumatoid disease was completely eliminated, although more patients continued employment when taking combined treatment versus monotherapy, the researchers said.
Within one year of treatment with methotrexate plus etanercept, both clinical remission and radiographic non-progression were achievable goals in patients with early severe rheumatoid arthritis, Dr. Emery's team said. Results for the combination-therapy group also suggest patients' ability to remain employed.
Furthermore, they added, "these outcomes appear to be achieved without exposing patients to significant additional risk."
In an accompanying commentary, Joel M. Kremer, M.D., of Albany (N.Y.) Medical College, wrote that the study authors acknowledged that the therapeutic value of methotrexate might have been enhanced if methotrexate had been given parenterally rather than orally, because the bioavailability of methotrexate diminishes with oral dosing in the range of the mean doses administered in this study.
Therefore the relevant question is whether the difference between the clinical and radiographic response to methotrexate alone versus combination therapy is worth the additional cost, inconvenience, and potential toxic effects.
Thus the difficulty is to show better outcomes in patients with a lesser disease burden who are given expensive drugs in combination with methotrexate over truly long-term treatment.
The answers, Dr. Kremer wrote, lie with data collection in national registries throughout Europe that use one-payer governmental systems, which can mandate participation. These systems are crucial for buttressing the shorter-term substantial results, such as those reported by Emery and colleagues, with real-world data over much longer treatment periods.
"Experts in health economics can apply rigorous formulae . . . to establish whether the promising data reported in these investigations are sustained, and whether the new biological agents are cost effective," Dr. Kremer said. "The answers are not yet entirely in."
Dr. Emery reported that he has served as a Wyeth consultant and has received Wyeth research grants. Other researchers served as Wyeth consultants or were Wyeth employees at the time of this trial. Dr. Kremer, the comment author, reported no conflicts of interest.
Primary source: The LancetSource reference:Emery P, et al "Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept on active, early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial" The Lancet 2008; DOI: 10.1016/S0140-6736(08)61000-4. Additional source: The LancetSource reference: Kremer J "COMET's path, and the new biologicals in rheumatoid arthritis" The Lancet 2008; DOI: 10.1016/S0140-6736(08)61001-6.