Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial

Abstract

Objective: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA.

Methods: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped-up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was ≥3.2.

Results: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean ± SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 ± 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 ± 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean ± SD change in modified Sharp score 0.2 ± 1.1 versus 1.1 ± 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 ± 1.3 versus 3.2 ± 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 ± 4.1 versus 1.1 ± 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar.

Conclusion: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy.

Figure 1

Flow diagram showing the distribution of the study subjects from initial assessment to analysis of the study data. Details are given according to the Consolidated Standards of Reporting Trials (CONSORT) statement for reporting randomized controlled trials. Although 89 participants had a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of 3.2 at week 24, only 81 continued in the study past week 24. Off medication means the subject was off any/all active study drugs. TB, tuberculosis; MTX, methotrexate; ETN, etanercept; SSZ, sulfasalazine; HCQ, hydroxychloroquine; SAE, serious adverse event; AE, adverse event; MM, MTX monotherapy.

Figure 2

Disease Activity Scores in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) throughout the study period, by treatment group. Patients received immediate (IM) combination therapy (broken line), methotrexate (MTX) monotherapy (solid black line), or initial MTX therapy with step-up (SU) to combination therapy (solid gray line) (see Patients and Methods for details). Values are the mean ± 95% confidence interval.

Figure 3

Percentages of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70) at year 2. Patients received immediate combination therapy (hatched bars), initial methotrexate (MTX) therapy with step-up to combination therapy (shaded bars), or methotrexate (MTX) monotherapy (solid bars) (see Patients and Methods for details). Numbers across the top of the bars are the values represented by the bars themselves. Comparisons across groups for the numbers of patients achieving ACR20, ACR50, and ACR70 improvement were not significant (P = 0.66, 0.23, and 0.51, respectively).