Peter H Schur, MD
Daniel E Furst, MD
Paul L Romain, MD
DISEASE MODIFYING ANTIRHEUMATIC DRUG OVERVIEW — Disease modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in patients with rheumatoid arthritis. They work to decrease pain and inflammation, reduce or prevent joint damage, and preserve the structure and function of the joints. Some of these drugs are also used in treating other conditions such as ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus. (See “Patient information: Rheumatoid arthritis symptoms and diagnosis” and “Patient information: Rheumatoid arthritis treatment” and “Patient information: Complementary therapies for rheumatoid arthritis”.)
WHAT ARE DISEASE MODIFYING ANTIRHEUMATIC DRUGS? — DMARDs work to suppress the body’s overactive immune and/or inflammatory systems. They take effect over weeks or months and are not designed to provide immediate relief of symptoms.
Other medicines, such as pain relievers, nonsteroidal antiinflammatory drugs (eg, ibuprofen or naproxen), and sometimes prednisone, are given to provide faster relief of ongoing symptoms. DMARDs are often used in combination with these medications to reduce the total amount of medication needed and to prevent damage to joints.
DISEASE MODIFYING ANTIRHEUMATIC DRUGS — The choice of DMARD depends on a number of factors, including the stage and severity of the joint condition, the balance between possible side effects and expected benefits, and patient preference. Before treatment begins, the patient and clinician should discuss the benefits and risks of each type of therapy, including side effects and potential toxicities, dosing schedule, how frequently monitoring should occur, and what results are expected.
In some cases, one DMARD is used. In others, more than one medication may be recommended. Sometimes a patient must try different medicines or combinations to find one that works best and has the fewest side effects. A patient who does not respond completely to a single DMARD may be given a combination of DMARDs, such as methotrexate plus another medication.
The most common DMARDs are: methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Less frequently used medications include gold salts, azathioprine, and cyclosporine.
Methotrexate — Methotrexate was originally used as a chemotherapy treatment for cancer. When used in much lower doses for rheumatoid arthritis and other rheumatic diseases, methotrexate works to reduce inflammation and decrease bone damage. It is usually taken once per week as a pill, liquid, or injection. Methotrexate may be combined with other DMARDs or with a biologic agent if methotrexate alone does not adequately control a patient’s disease (see ‘Biologic agents’ below).
Common side-effects include upset stomach and a sore mouth. Methotrexate can interfere with the bone marrow’s production of blood cells. Low blood cell counts can cause fever, infections, swollen lymph nodes, and easy bruisability and bleeding. Liver or lung damage can occur, even with low doses, and therefore requires monitoring. People using methotrexate are strongly discouraged from drinking alcoholic beverages because of the increased risk of liver damage with this combination.
Monitoring reduces the risk of long-term damage from methotrexate. A chest x-ray is recommended before beginning treatment, and regular blood testing is recommended. While taking methotrexate, many patients take folic acid 1 mg daily or folinic acid 5 mg weekly to reduce the risk of certain side effects, such as upset stomach, sore mouth, and abnormal liver function.
Sulfasalazine — Sulfasalazine is used in the treatment of rheumatoid arthritis and for arthritis associated with ankylosing spondylitis and inflammatory bowel disease (ulcerative colitis and Crohn’s disease). It is not clear how sulfasalazine works. It may be combined with other DMARDs if a person does not respond adequately to one medication. It is taken as a pill twice per day, and is usually started at a low dose and increased slowly to minimize side effects.
Side effects of sulfasalazine include changes in blood counts, nausea or vomiting, sensitivity to sunlight, skin rash, and headaches. People who are allergic to sulfa drugs may have a cross reaction to sulfasalazine and should therefore not take it. Periodic blood tests are recommended to monitor the blood count on a regular basis.
Sulfasalazine is a yellow/orange color; patients who take it may notice that their urine, tears, and sweat develop an orange tinge, which can stain clothing and contact lenses. Patients should drink plenty of fluids while taking sulfasalazine and avoid taking it on an empty stomach or with antacids.
Hydroxychloroquine — Hydroxychloroquine, originally developed as a treatment for malaria, was later found to improve symptoms of arthritis. It can be used early in the course of rheumatoid arthritis and is often used in combination with other DMARDs. It is also often used for treatment of systemic lupus erythematosus. It can be combined with steroid medications to reduce the amount of steroid needed. It is usually taken in pill form once or twice per day.
Taking a high dose of hydroxychloroquine for prolonged periods of time may increase the risk of damage to the retina of the eye, although high doses are not usually required for treatment of rheumatoid conditions. An eye examination is recommended before starting treatment and periodically thereafter. It is common to have an eye check-up done once each year.
Leflunomide — Leflunomide inhibits production of inflammatory cells to reduce inflammation. It is often used alone but may be used in combination with methotrexate for people who have not responded adequately to methotrexate alone or together with a biologic agent. It is taken by mouth once daily.
Side effects include rash, temporary hair loss, liver damage, nausea, diarrhea, weight loss, and abdominal pain. Regular testing to monitor for liver damage is required.
Azathioprine — Azathioprine (AZA) has been used in the treatment of cancer, rheumatoid arthritis, and a variety of other inflammatory illnesses since the 1950s. It has also been used in organ transplantation to prevent rejection of the transplanted organ. AZA is generally reserved for patients who have not responded to other treatments.
The most common side effects of AZA include nausea, vomiting, decreased appetite, liver function abnormalities, low white blood cell counts, and infection. It is usually taken by mouth once daily. Blood testing is recommended during treatment with AZA.
Cyclosporine — Cyclosporine was originally developed to prevent rejection after organ transplant. It works in patients with rheumatoid arthritis to inhibit T lymphocytes, a cell that contributes to the inflammation associated with rheumatoid arthritis. There is concern about the long-term safety of cyclosporine and its association with kidney disease and high blood pressure, so it is generally reserved for patients who have not responded to other treatments. It is usually taken by mouth in pill or liquid form twice per day; an injectable form is also available.
Side effects include high blood pressure, swelling, kidney damage, increased hair growth, nausea, diarrhea, and heartburn. Patients should have blood pressure and kidney function monitoring on a regular basis.
BIOLOGIC AGENTS — Another class of medications used in persons with rheumatoid arthritis is biologic agents, sometimes called biologic DMARDs, including etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab, which are all part of a class of drugs called tumor necrosis factor (TNF) inhibitors; and a variety of other agents with different targets, including anakinra, abatacept , rituximab, and tocilizumab. These medications are often combined with methotrexate or other DMARDs to improve efficacy. (See “Patient information: Rheumatoid arthritis treatment”, section on ‘Biologic agents’.)
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem.
This article will be updated as needed every four months on our web site (www.uptodate.com/patients).
Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.
Patient Level Information:
Patient information: Rheumatoid arthritis symptoms and diagnosis
Patient information: Rheumatoid arthritis treatment
Patient information: Complementary therapies for rheumatoid arthritis
Patient information: Rheumatoid arthritis and pregnancy
Professional Level Information:
General principles of management of rheumatoid arthritis
Overview of the use of immunosuppressive and disease modifying drugs in the rheumatic diseases
Randomized clinical trials of DMARDs in rheumatoid arthritis
Treatment of early, mildly active rheumatoid arthritis in adults
Treatment of early, moderately active rheumatoid arthritis in adults
Treatment of early, severely active rheumatoid arthritis in adults
Treatment of persistently active rheumatoid arthritis in adults
The following organizations also provide reliable health information.
- National Library of Medicine
- The Arthritis Foundation
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- American College of Rheumatology
- American Academy of Family Physicians
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002; 46:328.
- O’Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46:1164.
- Weinblatt ME, Reda D, Henderson W, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999; 26:2123.
- Cohen SB, Iqbal I. Leflunomide. Int J Clin Pract 2003; 57:115.
- Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990; 33:1449.
- Chambers CD, Tutuncu ZN, Johnson D, Jones KL. Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strategies for developing post-marketing data. Arthritis Res Ther 2006; 8:215.