What Is Triple Therapy for Rheumatoid Arthritis?

An Effective Treatment Option for Some People

Three medications on table in front of patient.
asiseeit/E+/Getty Images

Different combinations of DMARDs (disease-modifying anti-rheumatic drugs) can be prescribed to treat rheumatoid arthritis as opposed to a single DMARD. Triple therapy, which is among the treatment options, refers to the use of three different DMARDs; sometimes it may refer to two different DMARDs and one low dose glucocorticoid.

What Is Triple Therapy?

The usual combination of DMARDs used as triple therapy for rheumatoid arthritis includes methotrexate, sulfasalazine (brand name Azulfidine), and hydroxychloroquine (Plaquenil).

Typically, a single DMARD (monotherapy) would be tried first, but if the response is inadequate, the doctor and patient would then consider other treatment options.

Who Should Consider Triple Therapy?

In 2012, treatment guidelines from the American College of Rheumatology, as well as the Canadian Rheumatology Association, recommended the use of combination therapy with DMARDs—including triple therapy—for people with early rheumatoid arthritis, with moderate to severe disease activity, and a poor prognosis. Triple therapy may also be appropriately considered for those who have had an inadequate response to one DMARD.

The European League Against Rheumatism (EULAR) recommendations for rheumatoid arthritis treatment in 2013 were less definitive and simply stated that for patients who have never been prescribed a DMARD, monotherapy or combination therapy may be appropriate. If the first DMARD strategy fails, switching to a different DMARD may be considered.

The updated 2015 American College of Rheumatology guidelines for rheumatoid arthritis treatment state that in early rheumatoid arthritis, if disease activity remains moderate to high with DMARD monotherapy (with or without a glucocorticoid), combination DMARDs or a TNF inhibitor or a biologic other than a TNF inhibitor (without preference to the order, and with or without methotrexate) should be considered rather than continuing with monotherapy.

(Note: The order of preference is lacking because head-to-head studies of the drugs are lacking. Future guidelines may address that aspect.)

What Have Studies Shown About Triple Therapy?

The first studies that revealed the benefit of triple therapy compared to monotherapy appeared in scientific literature in the 1990s. A 1999 study evaluated the effectiveness and tolerability of triple therapy (methotrexate, sulfasalazine, and plaquenil) and low-dose prednisone compared to monotherapy with or without oral prednisone in people with early or active rheumatoid arthritis. It was determined that triple therapy was more effective without being less safe than monotherapy when considering its ability to induce remission.

A study published in 2002 concluded that in people with rheumatoid arthritis, triple therapy with methotrexate, sulfasalazine, and plaquenil was well-tolerated and more effective than combination therapy with methotrexate and sulfasalazine. Triple therapy was "marginally superior" to methotrexate and hydroxychloroquine.

In 2010, a Cochrane systematic review and meta-analysis, which considered methotrexate monotherapy versus combination therapy, concluded that there was little difference between the strategies.

Overall, 9 out of 100 people stopped taking methotrexate because of side effects, while 14 out of 100 stopped taking methotrexate in combination with another DMARD.

Results presented at the 2013 annual scientific meeting of the American College of Rheumatology revealed that a high percentage of people with rheumatoid arthritis discontinue triple therapy after one or two years. Sorting out why there is a high rate of discontinuation is not easy, but one reason may be that people prefer fewer pills to take, not more pills.

Is Triple Therapy Often Prescribed?

Despite its safety and effectiveness, triple therapy is not often the go-to treatment in clinical practice when methotrexate alone is inadequate.

Reportedly (Sparks JA et al.), from 2009 to 2014, 0.7 percent of about 25,000 rheumatoid arthritis patients moved up to triple therapy from their original DMARD regimen. By comparison, 11.1 percent of the patients added a biologic drug in addition to their DMARD. That is the case, even though study results have indicated that triple therapy is as effective as biologics for rheumatoid arthritis—and certainly more cost effective.

Triple therapy (methotrexate, sulfasalazine, plaquenil) is significantly less costly than the combination of methotrexate and Enbrel (etanercept)—reportedly thousands less per patient per year. It has been suggested that triple therapy should be tried before a biologic, such as Enbrel, due to cost-effectiveness. The step up to Enbrel can be made later, in patients who have an inadequate response to triple therapy.

Despite the cost effectiveness of triple therapy, in clinical practice, a TNF inhibitor is the preferred choice of treatment if methotrexate alone is inadequate. Interestingly, with an entirely new drug category being developed, known as biosimilars, that may change yet again. A biosimilar is a biological product that is highly similar to its US-licensed biological reference drug. Supposedly, this should make treatments available that are as effective as biologic drugs at a cheaper price. Perhaps biosimilars may become the preferred path if methotrexate alone fails.


Katchamart, W et al. Cochrane Review. Methotrexate alone versus methotrexate in combination with other medications for rheumatoid arthritis. April 14, 2010.

Mottonen, T.T. et al. Combination DMARD Therapy Including Corticosteroids in Early Rheumatoid Arthritis. Clinical and Experimental Rheumatology. 1999.

O'Dell, JR, et al. Therapies for Active Rheumatoid Arthritis After Methotrexate Failure. New England Journal of Medicine. July 25, 2013.

O'Dell, JR, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications. Results of a two-year, randomised, double-blind, placebo-controlled trial. Arthritis & Rheumatology 46: 1164–1170. 2002.

Sparks, JA, et al. Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014. Arthritis and Rheumatology. June 24, 2016.