DMARDs: Combination Therapy

Multiple medications are often more effective than individual ones for controlling inflammatory arthritis.


Sometimes a single medication is all that’s needed to control inflammatory arthritis. But more commonly the simultaneous use of two or more medications – combination therapy – is required to relieve symptoms and prevent long-term joint damage and disability of these diseases.

Almost two decades ago research helped confirm that, for rheumatoid arthritis, combination therapy is usually more effective than a single drug alone (monotherapy). 

Research since then has continued to show benefits of disease-modifying antirheumatic drugs (DMARDs) in combination with other DMARDs or with drugs from other classes. As doctors strive to control inflammation before it can cause damage, drug combinations are becoming even more important in arthritis treatment. The American College of Rheumatology recommends combination therapy in early RA for people with moderate to high disease activity and features that would indicate a poor prognosis. 

The development of new drugs and increased experience with others now means that more combinations are available. Research is also examining the benefits of combination therapy for other forms of arthritis, including psoriatic arthritis and ankylosing spondylitis. 

Here are some common combination types that your doctor may recommend.

Double Therapy

One of the most commonly used DMARDs, methotrexate, is also the one most commonly used in combination with other DMARDs. Traditional DMARDs that have been paired with methotrexate include sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide and azathioprine. While studies of these combinations have shown differing levels of benefit, the combinations of methotrexate and leflunomide and methotrexate and sulfasalazine are among the most effective. 

DMARD Plus a Biologic

The development of biologic agents has made it possible for increasing number of people with RA and other forms of inflammatory arthritis to avoid permanent joint damage and achieve remission. Yet research shows that in many cases the effectiveness of biologics is improved by adding a DMARD, most commonly methotrexate.

In fact, golimumab, a biologic that blocks tumor necrosis factor (TNF) is FDA approved only in combination with methotrexate for RA. It is also used in combination with methotrexate for psoriatic arthritis.

Adalimumab, another TNF blocker, is approved for rheumatoid arthritis with or without methotrexate or other DMARDs. However, weekly – instead of every-other week – dosing may be required for those not taking methotrexate along with it.

For people with psoriasis or psoriatic arthritis, research shows that adding methotrexate to a biologic can prolong the biologic’s effectiveness. Studies have shown that infliximab, adalimumab and etanercept are all more effective for psoriasis or psoriatic arthritis when combined with methotrexate.

Researchers propose several reasons why adding methotrexate may improve the effectiveness of a biologic, including its ability to help keep the biologic in the body longer. Another theory is that people sometimes develop anti-drug antibodies to the biologic, which makes it less effective; methotrexate can prevent those antibodies from forming. 

Triple Therapy

If one or two medications are not enough, doctors can turn to triple therapy. The most common combination is methotrexate, sulfasalazine and hydroxychloroquine. Research shows that in some cases, using three traditional DMARDs together is just as effective as using a DMARD in combination with a biologic drug.

DMARDs and Anti-inflammatories

Often DMARDs are prescribed with other medications, such as corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) for quick relief of inflammation and pain. This is particularly important during the time it takes DMARDs to take effect, which can be several weeks or months.

While waiting for DMARDs to produce their full effect, corticosteroids may be used to keep inflammation at bay. But the goal is to use DMARDs instead of – not in addition to – corticosteroids. In cases where a corticosteroid is needed long term, prescribing it with a DMARD allows a doctor to use the lowest dose possible.

Other drugs commonly prescribed along with DMARDs include NSAIDs such as ibuprofen, naproxen and meloxicam. Most NSAIDs can be taken two or more times daily to relieve inflammation and pain. Because they work differently, NSAIDs and DMARDs are often prescribed together for their complementary effects.

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