Traditional Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Disease-modifying anti-rheumatic drugs (DMARDs) are effective at reducing inflammation associated with rheumatoid arthritis (RA) and slowing or preventing damage to joints. This enables a person with RA to maintain function and quality of life. These drugs are called “disease-modifying” because they can interrupt the processes that cause damage in rheumatic diseases. The introduction of DMARDs for the treatment of RA significantly changed and improved the prospects for patients with RA. Before the availability of drugs like methotrexate, damage to joints and related structures from chronic inflammation associated with RA was inevitable for many patients.1

The most widely used traditional or conventional DMARDs include methotrexate, sulfasalazine (Azulfidine®), leflunomide (Arava®), and hydroxychloroquine (Plaquenil®). (Newer biologics are also considered DMARDs, so the words “traditional” and “conventional” refer to non-biologics.) Other conventional DMARDs that are less widely used and for which there is limited recent data on efficacy and safety include gold salts, azathioprine (Imuran), and cyclosporine (Neoral).2,3 The side effects listed are not all the possible side effects of the specified traditional DMARD. Patients should talk to their doctor about what to expect with treatment with a specific traditional DMARD.


Methotrexate is called an antimetabolite and an antifolate. It inhibits the metabolism of folic acid, which is necessary in the production of key immune system cells. Therefore, it results in a dampening of immune processes at work in RA. It has become the cornerstone of RA treatment since it was first introduced over five decades ago as an anti-cancer drug. In RA, methotrexate is given at a low dose and has been shown to be effective in controlling inflammation and related symptoms, while slowing or preventing damage to joints and related structures. Additionally, with experience in over half a million patients with RA, methotrexate has a strong safety record when monitored appropriately.4


Leflunomide (Arava®) is an immunodulatory drug that inhibits the production of immune system cells. It is considered a second choice to methotrexate. It provides efficacy similar to methotrexate, including similar disease control, slowing of disease progression (as shown by x-ray), and improvement of physical functioning. Additionally, it is associated with greater improvements in quality of life compared with methotrexate.5,6


Sulfasalazine (Azulfidine®) is made up of two components, aspirin (5-aminosalicyclic acid) and sulfapyridine. It is unclear how these work together to provide benefit in RA, but scientists think sulfasalazine may act in a way similar to methotrexate, as an antimetabolite, interfering with the production of key immune system cells. It also appears to inhibit tumor necrosis factor (TNF), which plays an important role in the immune response. In terms of disease activity and disease progression (as shown by x-ray), it has similar efficacy to both leflunomide and methotrexate. However, it appears to be less effective than leflunomide in improving functional capacity.5,7


Hydroxychloroquine (Plaquenil®)is an antimalarial drug that changes or modulates the immune system response. The exact mechanism of action for hydroxychloroquine and another antimalarial drug chloroquine in RA is not known, but scientists think that these drugs decrease production of a number of different chemicals that are important to the immune response. Hydroxychloroquine has been shown to reduce RA symptoms, including pain, swelling, and tenderness, and improve physical functioning in many patients (up to 80% in clinical trials). Antimalarials are generally well tolerated, with gastrointestinal side effects occurring in about 10% of patients. Serious adverse effects, such as toxicity affecting the eyes, are rare, occurring in less than 2% of patients.5,7

Auranofin and sodium aurothiomalate

Auranofin (Ridaura) and sodium aurothiomalate are gold salts. Auranofin is still available in the United States; however, sodium aurothiomalate has been discontinued. Auranofin is formulated for oral administration. Sodium aurothiomalate was available in different formulations for parenteral administration, typically for intramuscular injection. Up until 1990, intramuscular gold was a cornerstone treatment for RA, although it is rarely used now. The mechanism of action of gold salts is not known. It is thought that gold may act on macrophages and cytokines in the joint space to interfere with the immune response. Auranofin has limited efficacy, and the potential for toxicity (side effects) is a major limitation with gold salts. Adverse effects occur in 30% to 40% of patients and include pruritis (itching), stomatitis, and dermatitis. Because of the potential for side effects and toxicity, close monitoring is important during treatment with gold salts.7


Azathioprine (Imuran) is an immunosuppressant. It works on the level of cell DNA to inhibit proliferation of cells or cause cell death. Results from comparative studies suggest that azathioprine is equal in potency in controlling disease activity to gold salts (parenteral) and less potent than methotrexate. However, it is less effective than both in slowing or stopping joint erosion.7

Adverse effects cause discontinuation in up to 30% of patients who receive azathioprine. The most common side effects include GI effects (nausea, vomiting, and diarrhea). Myelosuppression (suppression of the ability of bone marrow to produce blood cells and platelets) occurs commonly with azathioprine. Regular monitoring, including weekly complete blood counts and monthly liver function testing is necessary until a stable dose has been established, after which monitoring can occur less frequently.7,8


Cyclosporine (Neoral) is a medication derived from fungus. It is an immunosuppressant that inhibits production of T-cells. When prescribed for RA treatment, Cyclosporine helps decrease pain and swelling, preventing joint damage. Results from a limited number of trials have shown that cyclosporine is significantly more effective than placebo in providing RA disease control. Common side effects with cyclosporine include nausea, hair growth on the body, tremor, paresthesias (abnormal sensations), and overgrowth of the gum tissue. Some patients are affected by significant bone pain requiring dose reduction or discontinuation. Serious side effects that can occur early in treatment include hypertension and decreased kidney function.7,9

Is it important to begin DMARD treatment immediately after diagnosis?

There is a growing body of evidence supporting the benefits of early aggressive treatment of RA using DMARDs and other drug treatment to achieve early control of RA disease activity. In fact, much of the joint damage that happens with RA which results in disability begins early in the course of the disease. So, early detection, diagnosis, and treatment are important. Many doctors recommend that patients with RA begin treatment with a DMARD as soon as possible after diagnosis. Choice of drug treatment and the intensity of treatment will depend on the level of disease activity.1

Based on 2015 American College of Rheumatology guidelines, in patients with mild disease, initial treatment with an non-steroidal anti-inflammatory drug (NSAID) for relief of symptoms and control of minor inflammation, while simultaneously starting a DMARD, preferably methotrexate (DMARDs typically take 4 to 6 weeks to achieve full effect), may result in control of disease activity.1,2

With moderate to severe disease activity, initial anti-inflammatory treatment with an NSAID or glucocorticoid as a “bridge” therapy while starting methotrexate may result in control of disease activity.1

If a patient is resistant to initial DMARD treatment of only methotrexate, combination DMARD treatment may be used by adding one or more conventional DMARDs (leflunomide, hydroxychloroquine, sulfasalazine) or biologic to methotrexate. Recent research suggests that combinations of conventional DMARDs may be effective as an early treatment approach to RA, as well as following inadequate response to methothrexate. Additionally, anti-inflammatory treatment (with an NSAID or glucocorticoid) can be used to control active inflammation.1

How will I select a conventional DMARD treatment?

Your doctor will work closely with you to select the right DMARD treatment based on several different factors, including:

  • Your level of disease activity
  • Your previous treatment history
  • Your preferences, including how a drug is taken, cost considerations, and monitoring requirements
  • Your other diagnoses or comorbidities

Since DMARDs are associated with side effects and safety concerns (many of these safety concerns only affect a minority of patients), your doctor will screen you carefully to minimize risk for side effects when selecting a DMARD. Before choosing a DMARD, your doctor will give you several screening tests. Some of these tests apply to specific DMARDs. They include7:

  • General laboratory tests, including complete blood count, serum creatinine, liver function tests
  • Hepatitis test (for methotrexate, leflunomide, and newer biologic treatments)
  • Ophthalmologic screening (for hydroxychloroquine)
  • Tuberculosis screening (for methotrexate and newer biologic treatments)

Your doctor may also test your blood for immune responses to common childhood vaccinations, and then suggest that you receive recommended vaccinations prior to starting a DMARD.

What are the monitoring requirements with conventional DMARDs?

Your monitoring requirements will vary according to the specific drug treatment or treatments that you receive. In general, your doctor will want to see you on a regular basis to check for drug toxicities, as well as to monitor disease activity and how well your treatment is keeping RA under control. Regular monitoring for treatment response may include:

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Written by: Jonathan Simmons and Emily Downward | Last reviewed: April 2021.