Combinations of conventional and biologic DMARDs

The disease-modifying anti-rheumatic drug (DMARD) methotrexate is the drug of choice for initial treatment of RA and many individuals respond well to monotherapy with methotrexate. However, for adequate disease control it is sometimes necessary to use combinations of DMARDs, including methotrexate and other conventional DMARDs or methotrexate and selected biologics.


Methotrexate and other conventional DMARDs

A substantial body of evidence has shown that combinations of conventional DMARD treatments (one or more DMARDs combined with methotrexate) are safe and effective in the early treatment of RA.1

This research has demonstrated that aggressive early treatment with a combination of three conventional DMARDs (used with short-term glucocorticoid treatment) was significantly more effective than a single DMARD (methotrexate) in slowing disease progression (as determined by x-ray evidence of joint damage). Such aggressive treatment for the first 2 years after diagnosis was shown to limit joint damage for at least 5 years.2

This aggressive approach to early treatment has been shown to yield a range of benefits, including impressive rates of disease remission after 2 years, which were more likely to be sustained beyond 2 years compared with less aggressive treatment (a single conventional DMARD).3 Early combination DMARDs also reduced disability and improved long-term (5 years following diagnosis) productivity.4

Even when given as an initial 6-month cycle of treatment of combination DMARDs with glucocorticoids, this early aggressive approach resulted in sustained suppression of joint damage up to 5 years.5

Benefits of DMARD combinations after inadequate response to methotrexate. Results from a recent study published in the New England Journal of Medicine have demonstrated that a combination of conventional DMARDs, an approach called “triple therapy” which includes methotrexate, sulfasalazine, and hydroxychloroquine, can provide significant benefits in patients with RA who have failed to respond adequately to monotherapy with methotrexate. The 48-week, double-blind, randomized, controlled trial was conducted in 353 patients with RA who continued to have active disease despite treatment with methotrexate. Participants in the study were randomly assigned to a triple therapy combination of the conventional DMARDs, methotrexate, sulfasalazine, and hydroxychloroquine, or to etanercept (Enbrel) plus methotrexate. Subjects who did not have sufficient improvement by 24 weeks were switched to the other treatment group.6

At 24 weeks, both treatment regimens resulted in a similar significant improvement in disease activity scores for 28-joint counts (DAS28) compared with measurements at the start of the study (baseline) (P=0.001). Twenty-seven percent (27%) of subjects in each group switched to the other treatment group at the 24-week point in the study and a similar proportion of switching patients derived significant benefit from the new treatment. Overall, the triple therapy regimen was found to be similar in efficacy to etanercept (Enbrel) and methotrexate, with no significant differences between treatment groups in outcomes, including radiographic progression, pain, quality of life, or major side effects or adverse events.6


Methotrexate in combination with biologic DMARDs

Since their introduction in the late 1990s, biologic targeted treatments have marked an important advance in the treatment of RA. These agents have expanded the treatment options for patients with RA and added treatment approaches that are more specifically targeted to the immune system cytokines and cell-surface molecules that drive the RA disease process. The main group of biologics now approved for treatment of RA in the US target the key immune system cytokine tumor necrosis factor-alpha (TNF-α). TNF-α inhibitors (etanercept, infliximab, adalimumab, golimumab, and certoizumab) are typically given in combination with the conventional DMARD methotrexate. These agents have also been shown to be effective as monotherapy. However, results from a number of studies demonstrate that combinations of single TNF-α inhibitors with methotrexate are significantly more effective in providing disease control and slowing joint damage than either agent given as monotherapy.1

Written by: Jonathan Simmons | Last reviewed: September 2013.
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