In rheumatoid arthritis (RA), the immune system attacks and destroys joints. As inflammation occurs in the joint linings, the affected joints swell painfully. Therefore, drugs that prevent immune responses in the body and also decrease inflammation are used to treat RA. Generally called disease modifying antirheumatic drugs (DMARDs), drugs from several different classes decrease, delay, or stop joint damage from RA.

DMARDs include:

Auranofin (Ridaura) Auranofin is an oral gold compound (also called a gold salt). Thought to interfere with the body's production of certain proteins, auranofin and other gold compounds interrupt the actions of white blood cells that are involved in inflammation. Once a mainstay of RA treatment, gold compounds currently are not used much due to their potentially severe side effects such as kidney damage.

Hydroxychloroquine (Plaquenil, Quineprox) An anti-malaria drug, hydroxychloroquine also lessens the pain and inflammation of RA by suppressing the immune system.

Immunosuppressants Primarily given to prevent rejection of organ transplants, drugs that suppress the immune system may also limit the progression of RA. The two immunosuppressants most commonly used for RA are:

• Azathioprine (Imuran, Azasan) - Azathioprine is an oral immune-system suppressant that also reduces inflammation.
• Cyclosporine (Gengraf, Neoral, Sandimmune) - Cyclosporine is believed to affect a type of T-lymphocytes (specialized white blood cells) involved in attacking joint tissue.

Leflunomide (Arava) A relatively recent oral drug, leflunomide belongs to a new class known as pyrimidine synthesis inhibitor immunomodulators. Approved for RA in 1998, it treats RA by interfering with an enzyme that helps to activate T-cells. Leflunomide relieves symptoms, lessens joint damage, and increases the ability to move for many individuals with RA.

Methotrexate (Rheumatrex, Trexall) The most common DMARD, methotrexate affects the body's use of a substance known as folate to interfere with DNA synthesis. By preventing cell replication and limiting immune reactions in the body, methotrexate helps to decrease inflammation.

Minocycline (Minocin) An oral antibiotic, minocycline also has anti-inflammatory effects. It is not FDA-approved for treating RA, but taking it for three months or longer has resulted in pain relief and better joint mobility for many RA patients.

Penicillamine (Cuprimine, Depen) How penicillamine (sometimes called D-penicillamine) works to relieve RA symptoms is not known. Presently, it is not used often for RA patients due to its potentially serious side effects.

Sulfasalazine (Azulfidine, Azulfidine EN-tabs, Sulfazine, Sulfazine EC) is an oral combination of a sulfa antibiotic and a salicylate pain reliever similar to aspirin. Also known as salicylazosulfapyridine, salazopyrine, or SASP, it is used primarily for its anti-inflammatory effects. In addition to relieving pain and swelling, sulfasalazine may also prevent, lessen, or delay joint damage by RA.

DMARDs used to be second-line RA treatment after NSAIDs and other drugs were tried. In the past few years, however, early and aggressive treatment has shown benefit in preventing RA progression. Currently, treatment for RA is recommended to start for most patients within three months of the RA diagnosis. Frequently, treatment begins with an NSAID. But, depending on the severity of the RA and the patient's response to any previous RA therapy, a DMARD may be combined with an NSAID, more than one DMARD may be used at a time, or the DMARD may be changed after a period of use. Many of the DMARDs are teratogenic, meaning they can be harmful to a developing fetus. Women who are pregnant or trying to become pregnant should be sure their physicians know they are taking a DMARD.

Many DMARDs take several weeks or months to become effective and their effectiveness often decreases when they are used for a long time. However, because RA symptoms frequently come back after DMARDs are stopped, patients whose RA is not progressing may still be kept on DMARD therapy. Prescribing and monitoring DMARDs may be quite complicated. Because many family physicians have little experience with using DMARDs for RA, patients who need them are often referred to a rheumatologist (a specialist in arthritis).

DMARDs relieve pain, swelling, and inflammation. They may also stop damage to cartilage and bones.

Drugs in this Class
Azathioprine (Azasan, Imuran)
Leflunomide (Arava)
Azathioprine Injection (Imuran Injection)
Hydroxychloroquine (Plaquenil)
Auranofin (Ridaura)

Summarizing the Evidence

In the many studies that have compared the effectiveness of DMARDs with placebo (inactive sugar pills), all DMARDs showed more effectiveness than placebo in treating RA. However, because they act in significantly different ways, comparing one DMARD to another is difficult.

Although no one DMARD is the drug of choice for all RA patients, many rheumatologists start RA patients on methotrexate because of its favorable safety and effectiveness. Hydroxychloroquine and sulfasalazine are also common first-line DMARDs due to their safety, low cost, and convenient dosing. Some study results suggest that combination therapy with two DMARDs may increase the relief of RA symptoms. However, using two or more DMARDs at the same time also increases the risk of side effects. The use of DMARDs is probably best managed by a rheumatologist, a doctor who specializes in treating arthritis and other joint conditions.

Dosing and Administration

Treating RA with DMARDs must be individualized according to factors such as the severity of the arthritis and other medical conditions that may be present. Several different doses and combinations of drugs may need to be tried to find the best treatment for each individual. Some DMARDs are started at low doses that can be increased, if needed. Others are started at high doses and then are reduced to lower doses for maintenance therapy. Lower doses may also work for children and older adults.

General dose ranges and schedules for DMARDs include:

• Auranofin - 6 mg to 9 mg daily in one dose or two doses
• Azathioprine - 50 mg to 150 mg daily in one dose to three doses
• Cyclosporine - 100 mg to 400 mg daily in two doses based on weight.
• Hydroxychloroquine - 200 mg to 600 mg daily in one dose or two doses
• Leflunomide - 10 mg or 20 mg daily
• Methotrexate - 7.5 mg to 20 mg per week
• Minocycline - 200 mg daily in two doses to four doses
• Penicillamine - 125 mg to 250 mg daily in one dose to start, increased to a maximum of 1500 mg (1.5 grams) daily in three doses
• Sulfasalazine - 500 mg to 3,000 mg (3 grams) daily in two doses to four doses

Cautions

Auranofin causes the skin to be more sensitive to sunburn so individuals using it should avoid exposure to sunlight and artificial light such as in tanning booths.

Azathioprine should be taken with food.

Cyclosporine should be taken at the same time every day. Regular blood tests will be needed to measure blood levels of cyclosporine. Individuals who use cyclosporine may be more likely to get infections and some types of cancer.

Hydroxychloroquine causes the skin to be more sensitive to sunburn so individuals using it should avoid exposure to sunlight and artificial light such as in tanning booths. Taken for very long periods or in high doses, hydroxychloroquine may affect vision. Therefore, individuals taking hydroxychloroquine should have an eye examination before they start to take it and at least once a year during therapy. Any visual problems should be reported to a doctor immediately.

Leflunomide increases the risk of birth defects. Women who are pregnant or trying to become pregnant and men who are trying to father a child should not take it. Reliable birth control must be used during treatment with leflunomide and for several months after leflunomide is stopped.

Methotrexate increases the risk of birth defects. Women who are pregnant or trying to become pregnant and men who are trying to father a child should not take it. Reliable birth control must be used during treatment with methotrexate and for several weeks after methotrexate is stopped. Individuals with alcoholism or blood, kidney, liver, or lung conditions should not take methotrexate. Blood, kidney and liver testing and chest x-rays will be needed before methotrexate is started and frequently while it is being taken.

Minocycline causes the skin to be more sensitive to sunburn so individuals using it should avoid exposure to sunlight and artificial light such as in tanning booths. It should be taken on an empty stomach, at least one hour before or two hours after eating. Minocycline should not be given to children because it may cause their teeth to darken.

Penicillamine should be taken on an empty stomach at least one hour before or two hours after eating. Penicillamine should not be taken with auranofin due to an increased risk of kidney damage. Because penicillamine reduces the amount of pyridoxine (vitamin B6) in the body, individuals taking it may need a vitamin supplement.

Sulfasalazine should be taken with at least 8 ounces of water to prevent the formation of residue in the urine. Occasionally, sulfasalazine may cause skin, sweat, or urine to have a yellow or orange color, which may stain clothing and contact lenses. It may cause temporary infertility in men because it can decrease sperm counts.

Generic Availability

Generics are available for:
Azathioprine tablets and injection
Cyclosporine capsules, injection, and oral solution
Hydroxychloroquine tablets and injection
Methotrexate tablets
Minocycline capsules and tablets
Sulfasalazine tablets

Generics are not yet available for auranofin, leflunomide, or penicillamine.

Drug Interactions

Some interactions between medications can be more severe than others. The best way for you to avoid harmful interactions is to tell your doctor and/or pharmacist what medications you are currently taking, including any over-the-counter products, vitamins, and herbals. For specific information on how the drugs interact and the severity of the interaction, please use our Drug Interactions Checker.

Side Effects

To view specific side effect information, please use our Side Effect Checker.

Additional Information

References

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Last Updated: August 2008

Note: The above information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist, or other healthcare professional. It should not be construed to indicate that the use of the product is safe, appropriate, or effective for you. Consult your healthcare professional before taking any medication.

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