What is the Role of Triple Therapy in Treating Rheumatoid Arthritis?

Patient Expert

Treatment options for rheumatoid arthritis is a complicated arena for RA patients and rheumatologists alike.   For years, conventional disease-modifying anti-rheumatic (DMARD) drugs (such as methotrexate, leflunomide, and sulfasalazine), low-dose steroids, and non-steroidal anti-inflammatory (NSAID) drugs were the primary treatment approaches used to treat RA, improve symptoms, and slow joint damage.   Additional DMARDs include immune-suppressing agents (such as cyclosporine and azathioprine) and the newest FDA approved therapy tofacitinib (Xeljanz) targeting Janus kinase molecules.

Since the FDA approval of the first tumor necrosis factor (TNF)-inhibitor drug etanercept (Enbrel) in 1998, expanded treatment options with the biologic response modifiers (often called biologics) have excited the RA community.   There are currently five anti-TNF drugs available (Enbrel, Remicade, Humira, Simponi, Cimzia), in addition to other biologic DMARDs which include Actemra, Orencia, Rituxan, and Kineret.

With so many treatment choices, how do we know where to begin?

Rheumatologists will often begin their newly diagnosed patients on conventional DMARDs such as methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), each alone or in any combination.   In fact, when combining the three drugs, it is commonly known as "triple therapy" and is often used as a step-up in treatment after trying MTX alone.

Triple therapy as a treatment approach to RA has received recent attention in the news due to a study published in the New England Journal of Medicine (NEJM) on June 11, 2013.   In this study, no significant difference in disease activity was demonstrated in patients who received triple therapy as compared to those who received treatment with etanercept + methotrexate. All the patients prior to enrolling in this study had experienced active disease despite methotrexate therapy alone (O'Dell, 2013).

In a similar study, the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study, patients were randomly assigned to MTX monotherapy (alone), triple therapy, or MTX + etanercept with no significant difference in primary outcome (based on Disease Activity Severity DAS28 scores) between the latter two groups. However, x-rays did show more disease progression in the triple therapy group.

The concept of triple therapy is not new. In fact, a quick pubmed.gov search reveals several research studies that have been published on the subject since 1996 when O'Dell et al. published "Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications" in NEJM.

When I was first diagnosed with RA in 2007, my rheumatologist discussed triple therapy with me and that's the treatment approach we took, specifically since I was not a good candidate for using an anti-TNF biologic drug due to having MS.   However, I wasn't able to tolerate HCQ, so I ended up only taking MTX and SSZ until I switched to a biologic + MTX in 2009.   If I had not been diagnosed with MS at the time, my rheumatologist may have suggested that we move directly to a biologic.

So what is the big fuss about the recent study?

A potential concern in the RA community is that information taken from studies such as this one might be used by insurance companies to require patients to use MTX alone or try triple therapy (and "fail" treatment or rather have it not work for them) before being approved for a more expensive biologic which may be more effective for the individual patient.

Each of the triple therapy drugs are available in generic form, but may require taking 2-6 pills every day in addition to once weekly MTX (1-10 pills).   The approximately annual cost of triple therapy is less than $1000/year.   None of the biologics are available in generic form and are given by self-injection or infusion.   The newest DMARD approved in November 2012, tofacitinib (Xeljanz), is a pill taken twice a day and costs about $25,000/year (approximately the same price as Enbrel).

In an accompanying editorial published in the June 11, 2013 edition of NEJM (and updated on July 3, 2013 at NEJM.org), Dr. Joan Bathon and Donald McMahon state, "We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as the study by O'Dell et al. In addition, future identification of biomarkers to identify the patients who are most likely to have a response to, or are least likely to have side effects with, specific therapies will be the next great leap in the treatment of rheumatoid arthritis."

Identifying biomarkers to determine which treatment approaches would be most effective for each individual patient".now THAT would be exciting news


Bathon JM, McMahon DJ. Making Rational Treatment Decisions in Rheumatoid Arthritis When Methotrexate Fails. N Engl J Med. Published online June 11, 2013, updated July 3, 2013. DOI:10.1056/NEJMe1306381.

Moreland LW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 2012 Sep; 64(9):2824-35. DOI:10.1002/art.34498.

O'Dell JR, et al. Therapies for Active Rheumatoid Arthritis after Methotrexate Failure. N Engl J Med. Published online June 11, 2013. DOI:10.1056/NEJMoa1303006.

O'Dell JR, et al. Treatment of Rheumatoid Arthritis with Methotrexate Alone, Sulfasalazine and Hydroxychloroquine, or a Combination of All Three Medications. N Engl J Med 1996 May; 334(20):1287-1291. DOI:10.1056/NEJM1996051633442002.

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, Randomized, Double-Blind, Placebo-Controlled Trial.   Arthritis & Rheumatism 2002 May; 46(5):1164-1170.   DOI:10.1002/art.10228.

Saunders SA, et al. Triple Therapy in Early Active Rheumatoid Arthritis: A Randomized, Single-Blind, Controlled Trial Comparing Step-Up and Parallel Treatment Strategies.   Arthritis & Rheumatism 2008 May; 58(5):1310-1317. DOI:10.1002/art.23449.

Combination Therapy for Rheumatoid Arthritis: Triple Therapy. Medscape Education. Access July 3, 2013.