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Treating Rheumatoid Arthritis: The Facts About Triple Therapy

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  • Treatment options for RA

    Treatment options for RA

    If you’re diagnosed with rheumatoid arthritis (RA), your doctor and rheumatologist will work with you to reduce painful symptoms and slow the progression of the disease.

    Medication is often the first line of treatment for RA. Drugs include:

    • nonsteroidal anti-inflammatory drugs (NSAIDs)
    • corticosteroids
    • disease-modifying antirheumatic drugs (DMARDS)
    • biologic agents

    Some doctors will administer a combination of drug therapies. This depends on your symptoms and the stage of the disease.

    Discuss your medication options with your doctor to determine the best course of treatment for you.

  • Types of DMARDs

    Types of DMARDs

    People recently diagnosed with RA will likely receive a prescription for a DMARD such as:

    In the past, doctors typically started people off with aspirin or NSAIDs to reduce pain and inflammation. Now, many doctors treat people more aggressively and earlier with DMARDS in an effort to prevent joint damage.

    Two other categories of DMARDs used to treat RA are biologic response modifiers and JAK inhibitors. Biologics such as etanercept block tumor necrosis factor (TNF), which triggers inflammation.

    A new category of drugs called Janus kinase (JAK) inhibitors fight inflammation within the cells. Tofacitinib is an example of one of these.

  • The TEAR study

    The TEAR study

    With so many drug options, doctors will work with you to determine the best combination of therapy to treat your RA.

    In 2012, researchers led by Larry W. Moreland, M.D., studied oral triple therapy. The study looked at treatment of early aggressive RA over two years. The study became known by the acronym TEAR: treatment of early aggressive rheumatoid arthritis.

  • TEAR study goals and results

    TEAR study goals and results

    The people with RA in the study received one of four treatments:

    • initial treatment with MTX, plus etanercept
    • initial treatment with oral triple therapy: MTX, sulfasalazine, and hydroxychloroquine
    • a step up from initial MTX monotherapy to one of the above combination therapies
    • placebos

    The TEAR study reported that both of the first two treatments were more effective than MTX monotherapy.

  • The O’Dell study

    The O’Dell study

    James R. O’Dell, M.D., at the University of Nebraska Medical Center in Omaha, has authored many studies of RA over the decades. He was a coauthor on the TEAR study.

    In July 2013, O’Dell led a 48-week study of 353 people with RA. Numerous coauthors joined O’Dell in this multinational effort.

  • O’Dell results

    O’Dell results

    All participants in the O’Dell study had active RA, despite earlier treatment with MTX. Investigators assigned treatment randomly, either:

    • triple therapy with MTX, sulfasalazine, and hydroxychloroquine
    • etanercept plus MTX

    People who didn’t show improvement at 24 weeks were switched to the other group.

    Both groups in the O’Dell study recorded significant improvement. Patients who didn’t respond to initial triple therapy were changed to etanercept and methotrexate. Doing so didn’t adversely affect their clinical outcomes. It also allowed them to be treated in a more cost-effective way. 

  • Cost considerations

    Cost considerations

    MTX, sulfasalazine, and hydroxychloroquine are all older drugs. They provide a relatively inexpensive treatment option. Combining MTX with etanercept, a biologic that combines Enbrel and Immunex, is more expensive.

    O’Dell told the European League Against Rheumatism Congress 2013 that while the two strategies provide comparable benefits, triple therapy is $10,200 cheaper per person per year.

    O’Dell concluded that starting people off with triple therapy makes economic sense. He suggested that people with an unsatisfactory response switch to MTX and etanercept.

  • Work time results

    Work time results

    Dutch researchers also give a thumbs-up to triple therapy for lowering both direct and indirect costs in this study. They reported on 281 people newly diagnosed with RA in October 2013. The Rotterdam study is called tREACH.

    Those on triple therapy needed less costly treatment. This is in part because they didn’t need costly biologicals to augment MTX. They also didn’t miss as much time from work because they were sick less.


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  • de Jong, P. H., Quax, R. A., Huisman, M., Gerards, A. H., Feelders, R. A., de Sonnaville, P. B., … Hazes, J. M. (2013, October). Response to glucocorticoids at 2 weeks predicts the effectiveness of DMARD induction therapy at 3 months: post hoc analyses from the tREACH study. Annals of Rheumatic Diseases, 72(10), 1659-1663. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23117243
  • Handout on health: Rheumatoid arthritis. (2016, February). Retrieved from http://www.niams.nih.gov/Health_Info/Rheumatic_Disease/
  • Moreland, L. W., O’Dell, J. R., Paulus, H. E., Curtis, J. R., Bathon, J. M., St. Clair, E.W., …TEAR Investigators. (2012, September). 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 & Rheumatology, 64(9), 2824-2835. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/22508468 
  • O’Dell, J. R., Mikuls, T. R., Taylor, T. H., Ahluwalia, V., Brophy, M., Warren, S. R., … Keystone, E. (2013, July 25). Therapies for Active Rheumatoid Arthritis after Methotrexate Failure. The New England Journal of Medicine, 369, 307-318. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa1303006