Clinical outcomes in patients with rheumatoid arthritis (RA) who are treated with etanercept (Enbrel) in combination with methotrexate (MTX) appear to be independent of MTX dosage, according to European investigators.
Consequently, they said, lower doses of MTX when used in combination with etanercept can be considered while maintaining efficacy and quality of life.
In a subanalysis of two large randomized trials of etanercept in RA, clinical responses measured in various ways "were similar for patients treated with etanercept plus MTX combination therapy, regardless of the MTX dose used," wrote Gaia Gallo, from Pfizer Europe, Rome, and colleagues online in RMD Open.
"Low-dose MTX (<10 mg/week) is sufficient to achieve efficacy outcomes similar to higher doses of MTX (10.0-17.5 mg/week, or >17.5 mg) when used in combination with etanercept," they concluded from their pooled analysis.
Following induction with MTX, "a maintenance dose of MTX <10 mg/week is sufficient to retain efficacy when used in combination with etanercept," they added.
The researchers pooled data from two clinical trials -- the Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis (COMET) study and the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) -- in which RA patients were randomized to receive MTX monotherapy or a combination of MTX and etanercept for 24 consecutive months.
Patients in the MTX arms in both trials received 7.5 mg/week, which could be increased to 15 mg/week and again to 20 mg/week if response was inadequate. Following dose titration, MTX dosage remained stable unless adverse events necessitated a reduction.
Patients within the MTX arm and within the etanercept-plus-MTX arm in the pooled TEMPO and COMET studies were divided into three groups according to their MTX dosage at 24 months: low dose (<10.0 mg/week); medium dose (10.0- 17.5 mg/week); or high dose (>17.5 mg /week).
There were 276 patients in the etanercept-plus-MTX arm and 218 in the methotrexate arm.
Outcomes at 24 months evaluated for each subgroup were Disease Activity Score in 28 joints (DAS28), attainment of low disease activity (LDA) and remission, and American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, and 70) responses. Changes from baseline in the Health Assessment Questionnaire Disease Index (HAQ-DI) and EuroQol 5-Dimensions (EQ-5D) visual analogue scale (VAS) were also evaluated.
At 24 months, 55% of patients were receiving 10.0 to 17.5 mg/week of MTX, with a mean dosage of 11.0 mg/week and a median dosage of 10.0 mg/week.
"Clinical responses as measured by DAS28 LDA and remission rates, ACR 20/50/70 rates and change from baseline in DAS28 were similar for patients treated with etanercept-plus-MTX combination therapy, regardless of the MTX-e dose used," noted Gallo and colleagues.
At 24 months, more than 60% of patients randomized to etanercept plus MTX achieved DAS28 remission or LDA -- 68% in the low-dose MTX group, 69% in the medium-dose group, and 70% in the high-dose group.
More patients randomized to etanercept-plus-MTX combination therapy achieved DAS28 remission or LDA, or DAS28 remission only, compared with those randomly assigned to MTX monotherapy at all time points. Rates of DAS28 LDA did not appear to be related either to the MTX dose in either of the MTX arms of the study.
In the etanercept-plus-MTX arm, the rates of ACR20, ACR50, and ACR70 "were largely unaffected by the MTX dose at 6, 12, and 24 months," the authors wrote. ACR20 responses were achieved by 89% to 93% in each MTX dose group; ACR50 response in 73% to 79%, and ACR70 response in 56% to 59%.
"Rates of ACR 20, 50, or 70 were paradoxically inversely related to the dose in patients receiving MTX-e monotherapy," they added. Patients receiving any dose of MTX monotherapy were less likely to achieve ACR 20, 50, or 70 compared with those receiving etanercept plus MTX at 24 months.
Improvements from baseline in DAS28, HAQ-DI, and EQ-5D VAS were not dependent on MTX dosage in the etanercept-plus-MTX combination arm. Improvements from baseline to month 24 were of greater magnitude in those receiving etanercept plus MTX than in those receiving MTX monotherapy in all patient-reported outcome measures.
A lack of pharmacokinetic alternations to etanercept with concomitant MTX "could help to explain why increased efficacy of etanercept plus MTX over MTX monotherapy was not MTX dose-dependent in this study," the investigators postulated.
In addition, they noted that as a potential limitation, the study population may have been biased toward treatment responders, as evidenced by the stable dose of MTX over time in the two studies. In addition, pooling data from two studies with diverse patient populations (early disease in COMET, late disease in TEMPO) may have produced a result different from that of assessing the trials separately.
Two authors are full-time employees of Pfizer, and another is a full-time employee of Quanticate International, which was contracted by Pfizer to provide statistical input to the study and manuscript. One author was a former employee of Pfizer. Others report lecture fees/consultancy fees from Merck, UCB, Bristol-Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boehringer Ingelheim, Takeda, Zydus, and Eli Lilly.
This post-hoc analysis was sponsored by Pfizer.
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