Triple Therapy / Combination Therapy for Rheumatoid Arthritis

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Treatments for Rheumatoid Arthritis

shadow of lizard in windowIn the past few decades, Rheumatoid Arthritis has been treated with therapies designed for other diseases. It was not always clear how these drugs treated Rheumatoid Arthritis / Rheumatoid Disease, but they were found to reduce immune activity in various ways. Because researchers recognized certain drugs could slow or modify progression of disease, they called them disease modifying anti-rheumatic drugs (DMARDs) – listed here. Sometimes, stronger immune suppressants, such as those used to reduce organ transplant rejection, are used in Rheumatoid patients.

Biologicals or biologic DMARDs used to treat Rheumatoid Disease (RD) were developed to specifically target certain aspects of immune function that are significant to Rheumatoid disease activity. As more is learned about immune function, it becomes possible to “interrupt” certain pathways or signals. For some people, these treatments reduce disease activity significantly.

Here’s a list of biologic DMARDs currently approved in the U.S. for treating RD.

Note that a new abbreviation for biologic DMARD is being used: bDMARD.

Combination therapy: Rheumatoid Arthritis treatments taken jointly 😉

Biologics like Enbrel, Humira, Actemra, Orencia and others are usually used in combination with a conventional DMARD like methotrexate. Combination treatments are more effective at reducing disease activity, and biologics were tested in clinical trials in conjunction with methotrexate. Methotrexate is believed to help reduce the tendency to produce antibodies against Biologics.

Triple therapy with DMARDs

In recent years, triple therapy has been investigated as an alternative to more expensive biologics. Triple therapy refers to a combination of three non-biologic DMARDs, most frequently sulfasalazine, hydroxychloroquine, and methotrexate. Other DMARDs can be used based on what medications patients can tolerate. Combining biologics is not approved by the FDA, or done in usual practice, but some investigation is being done. Of course any combination therapy including triple therapy reduces immune function, so people treated with these methods should make their doctors aware of every medication they use, and practice preventive first aid.

Does it work?

Triple therapy is not inferior to Biologic combination therapy

A study by O’Dell et al. published in June, Therapies for Active Rheumatoid Arthritis after Methotrexate Failure, compared triple therapy head to head with Enbrel (etanercept) and methotrexate.[1] They found the clinical benefit of triple therapy (sulfasalazine, hydroxychloroquine, and methotrexate) was “noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy.”

Clinical benefit was compared with various scores of symptom improvement and joint damage (see partial list below). Although the Enbrel combination scores were better in some cases, the investigators determined that as a whole, triple therapy was statistically noninferior and would be an option to use before more expensive bDMARDs are tried.

What do you think? Here’s my reaction

Studies have shown that biologic DMARDs, when effective, reduce damage and disease progression. They address systemic RD inflammation that causes changes in bone metabolism, evidenced by both localized erosions and generalized bone loss (osteoporosis).[2] By reducing systemic inflammation, biologics also reduce the risk of premature death in RD (by 25% in one study).[3]

Successful treatment of Rheumatoid Disease must involve both symptom improvement and reduction of long-term disease progression or damage of the musculoskeletal system. And, RD treatments should also address matters related to systemic disease that are not frequently measured at this point. That is the definition of successful treatment in my book.

I’m sure I’ll hear more at the ACR Annual Scientific Meeting about both the benefits of triple therapy and reasons newer treatments are better. I’ll let you know.

NOTE: Some scores reported in the study. TT is triple therapy. Enbrel was combined with mtx.

Health Assessment Questionnaire II score

At 24wk TT mean change −0.44±0.77 Enbrel mean change −0.51±0.84; P value 0.46
At 48wk TT mean change −0.46±0.82 Enbrel mean change −0.64±0.78; P value 0.06

Modified Sharp score

At 24wk TT mean change 0.42±1.91; Enbrel mean change 0.003±3.62; P value: 0.20
At 48wk TT mean change 0.54±1.93; Enbrel mean change 0.29±3.32; P value: 0.43


At 24wk TT mean change 0.23±1.32; Enbrel mean change −0.03±1.44; P value: 0.10
At 48wk TT mean change 0.29±1.35; Enbrel mean change 0.08±1.48; P value: 0.21

Joint-space narrowing

At 24wk TT mean change 0.19±1.25; Enbrel mean change 0.03±2.47; P value: 0.45
At 48wk TT mean change 0.25±1.18; Enbrel mean change 0.21±2.09; P value: 0.83

Recommended reading

1 O’Dell JR, Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, Lew RA, Cannella AC, Kunkel G, Phibbs CS, Anis AH, Leatherman S, Keystone E; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med [Internet]. 2013 Jul 25 [cited 2013 Oct 19];369(4):307-18. doi: 10.1056/NEJMoa1303006. Available from:
2 Corrado A, Neve A, Maruotti N, Cantatore FP. Bone effects of biologic drugs in rheumatoid arthritis. Clinical and Developmental Immunology [Internet].  2013 [cited 2013 Oct 19];2013, Article ID 945945, doi:10.1155/2013/945945. Available from:
3 American College of Rheumatology (ACR). Biologics may prevent premature death in people with rheumatoid arthritis, study suggests. ScienceDaily [Internet] 2012 Nov 11 [cited 2013 Oct 19]. Available from:

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Kelly Young. All rights reserved.

This entry was posted on Tuesday, October 29th, 2013 at 4:44 am and is filed under Treating RA. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.


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