Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure

Abstract

Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42-0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low.

Figure 1

Ineffectiveness of re-employed courses in relation to dose of original course. Bars show the association of treatment termination of re-employed courses for ineffectiveness with the dose of the original methotrexate (MTX) course (total numbers shown in the bars). This relationship is shown for all re-employed courses (black bars; P = 0.02, by logistic regression), patients in whom MTX was re-employed at higher doses (grey bars; P = 0.43), and patients in whom MTX was re-employed at doses lower than or equal to the original courses (white bars; P = 0.01).

Figure 2

Cumulative retention rates of methotrexate therapies. Kaplan-Meier analysis of retention rates of methotrexate. The different panels show (a) the overall drug retention, (b) retention of drug effectiveness, and (c) retention of drug safety for original therapy (grey lines; oMTX) and re-employed therapy (black lines; rMTX). Overall retention rates were similar between the two groups (panel a: P = 0.31, by log-rank test). Likewise, retention because of safety was similar between groups (panel c: P = 0.23). Retention because of effectiveness was better for the rMTX group (panel b: P < 0.01).

Figure 3

Adjusted cumulative retention rates of MTX therapies. Based on a Cox proportional hazards regression model, cumulative retention rates for original therapies (grey lines; oMTX) and re-employed therapies (black lines; rMTX) are shown adjusted for the use in 1999 or later and methotrexate dose (lines for oMTX and rMTX are plotted at the cohort mean of these covariates). Re-employed courses showed a significant lower Hazard Ratio of treatment discontinuation compared to the original courses (P = 0.04). All courses that were ongoing, lost to follow up, or terminated because of incompliance were censored in this analysis.