What to do after methotrexate failure?

This review evaluated the different therapeutic options in the treatment of rheumatoid arthritis (RA) after the failure of initial methotrexate therapy.

Disease-modifying anti-rheumatic drugs (DMARDs) are a group of medications commonly used in patients with RA. DMARDs suppress the immune response against self and slow the progression of RA. Methotrexate is usually chosen as first-line DMARD therapy for RA. Methotrexate elicits good or even excellent disease response in 20 to 30% of patients treated, however many do not respond to this course of initial therapy, and develop progressive joint damage despite treatment.

Several different DMARDs have been added to the therapeutic arsenal of RA over the past decade, including different immune-suppressing drugs and recently developed targeted biological therapies. However, no consensus exists regarding the optimal treatment course after failure of initial methotrexate therapy. 

Several studies have demonstrated that a combination of several DMARDs including methotrexate is more effective than metho­trexate therapy alone for the treatment of early RA (disease duration of 1 year or less). This suggests that adding one or more DMARDs to methotrexate could be a reasonable next step following methotrexate failure. However, in a randomized trial including 247 patients after methotrexate failure, the addition of sulphasalazine and hydroxychloroquine to methotrexate (referred to as triple therapy) showed response in only 22% of patients, and did not result in improved clinical responses compared to when methotrexate was simply replaced by another DMARD.

Meanwhile, the treatment of RA was revolutionized by the advent of targeted biologic therapies, including anti-TNF agents (TNF or tumor necrosis factor is a key factor in the destructive inflammation in RA). Many of the new anti-TNF agents, such as infliximab (Remicade), have been demonstrated as more effective than triple therapy for the treatment of early RA. Therefore, anti-TNF biologic agents were widely regarded as the logical next step in patients for whom methotrexate had failed. Indeed, the 2010 European League Against Rheumatism (EULAR) guidelines for the treatment of RA clearly identified the addition of anti-TNF agents as the most appropriate next step. However, trials published in the past few years cast some doubt on this strategy. In one trial, 487 patients with newly diagnosed RA were initially given methotrexate, and if insufficient response was achieved at 3 months they were randomized to receive either sulphasalazine and hydroxychloroquine (triple therapy) or infliximab in addition to methotrexate. While clinical results were superior for infliximab one year into the trial, after 2 years only minor differ­ences were noted in clinical benefit between the treatment groups. Imaging scans however did indicate greater progression of joint damage with triple therapy compared to infliximab. In a separate trial investigating patients with long-standing RA, 353 patients with an average disease duration of 5 years and showing insufficient response to methotrexate treatment, were randomized to receive triple therapy or the anti-TNF agent etanercept (Enbrel). The trial reported similar clinical outcomes between the addition of etanercept to methotrexate and triple therapy. Perhaps the most interesting aspect of this trial was that in the event of insufficient response after 24 weeks, patients were switched to the opposite treatment strategy. Patients not responding to triple therapy often switch to biological agents, however switching from a biologic agent to standard triple therapy rarely occurs in clinical practice. Interestingly, results clearly demonstrated that switching to triple therapy in the case of insufficient response to biological treatment was just as effective as switching from triple therapy to a biological agent.

This review concluded that both triple therapy and the addition of anti-TNF agents are viable treatment strategies after methotrexate failure.