Combinations of DMARDs and Biologics

Written by: Jonathan Simmons and Emily Downward | Last reviewed: March 2022 | Last updated: April 2022

Rheumatoid arthritis (RA) is a varied disease, and not everyone with RA responds to every medication. Presently, there isn't a way to determine which patients will respond to which therapy, although research is ongoing in this area. While, 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 (only using this one medication), others need a combination 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.The 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

Benefits of DMARD combinations after inadequate response to methotrexate

Results from a 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.3

At 24 weeks, both treatment regimens resulted in a similar significant improvement in disease activity scores for 28-joint counts compared with measurements at the start of the study (baseline). 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.3

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 (TNF). TNF inhibitors Enbrel® (etanercept), Remicade® (infliximab), Humira® (adalimumab), Simponi® (golimumab), and Cimzia® (certolizumab) may be 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 inhibitors with methotrexate are significantly more effective in providing disease control and slowing joint damage than either agent given as monotherapy.1

Triple traditional DMARD therapy compared to biologic DMARDs

A study published in 2017 analyzed data from 5 trials including 515 patients who received the triple therapy of methotrexate, sulfasalazine, and hydroxychloroquine and 710 patients who received biologic DMARDs. The analysis determined that biological treatment seems to be more efficient than triple combination in terms of slowing radiological progression in RA in those who had an inadequate response to methotrexate. The rate of side effects (adverse events) were similar in the two groups, although they differed in type: those receiving triple therapy had more gastrointestinal issues, compared to more infections in those receiving biologic DMARDs.4

Methotrexate in combination with JAK inhibitors

Tofacitinib (brand name Xeljanz®) is a Janus kinase (JAK) inhibitor used in the treatment of RA. JAK inhibitors are also known as target-specific DMARDs. A 2017 study evaluated three different treatment arms: tofacitinib as monotherapy, tofacitinib in combination with methotrexate, and Humira (adalimumab) in combination with methotrexate. A total of 1,146 patients were included in the study who had experienced an inadequate response to methotrexate alone to control their RA. The two combination groups (those who received methotrexate in addition to either tofacitinib or adalimumab) had similar response rates. Tofacitinib alone was not as effective as the combination of tofacitinib and methotrexate.5

Another study evaluated the JAK inhibitor Olumiant® (baricitinib) alone or in combination with methotrexate. A total of 588 patients were randomly assigned to receive either baricitinib alone, methotrexate alone, or a combination of the two medications. Baricitinib monotherapy was superior to methotrexate monotherapy, with a higher ACR20 response rate (77% versus 62%) at week 24. The combination of baricitinib and methotrexate was also more effective than methotrexate alone, but the rate of side effects was increased in the combination group.6

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