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DISEASE-MODIFYING ANTIRHEUMATIC DRUG OVERVIEW — Disease-modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in people with rheumatoid arthritis. Some of these drugs are also used in treating other conditions such as ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus. They work to decrease pain and inflammation, to reduce or prevent joint damage, and to preserve the structure and function of the joints. (See "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)".)
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 (NSAIDs; 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.
CHOOSING BETWEEN DMARDS — The choice of disease-modifying antirheumatic drug (DMARD) depends on a number of factors, including the stage and severity of the person's condition, the balance between possible side effects and expected benefits, other medical conditions, and personal preference. Before treatment begins, the patient and clinician should discuss the benefits and risks of each type of therapy, including possible side effects and toxicities, dosing schedule, monitoring frequency, and expected results. Certain screening tests, including blood tests for past exposure to certain infections, may be needed before starting some of these medications.
In some cases, one DMARD is used. In others, combinations may be recommended. Sometimes a person must try different medicines or combinations to find one that works best and that has the fewest side effects. A person who does not respond completely to a single DMARD may be given a combination of DMARDs, such as methotrexate plus another medication.
CONVENTIONAL DMARDS — The most common conventional DMARDs are methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Azathioprine and other drugs are used much less frequently. Other names for this group of drugs are conventional synthetic DMARDs or traditional DMARDs.
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 joint damage. These lower doses are much less toxic and are better tolerated than the doses used for cancer. It is taken weekly (on the same day each week) as a pill, liquid, or injection. It may require four to six weeks of treatment to begin to see an improvement in symptoms. Methotrexate may be combined with other conventional DMARDs or with a biologic agent or other targeted synthetic DMARD if methotrexate alone does not adequately control disease. (See 'Biologic and targeted synthetic DMARDs' below.)
Common side effects include upset stomach and mouth sores. Methotrexate can rarely interfere with the bone marrow's production of blood cells. Low blood cell counts can cause fever, infections, swollen lymph nodes, easy bruising, and bleeding. Liver function problems can occur, even with low doses, and therefore regular blood tests are necessary for anyone taking methotrexate. People using methotrexate should also limit alcohol use because of the increased risk of liver injury with this combination. Rare injury to the lungs can occur, and methotrexate should be stopped if the person develops a new cough and shortness of breath. Women should not become pregnant or breastfeed while taking methotrexate. Women and men should stop methotrexate one to three months prior to attempting to conceive a child.
Proper monitoring is critical to identify drug toxicity in people taking methotrexate. Testing is performed prior to starting treatment to evaluate baseline blood counts and check kidney and liver function. These tests are repeated every 4 to 6 weeks for the first few months then every 8 to 12 weeks thereafter. The dose of methotrexate can be modified if problems are noted. Anyone taking methotrexate should take folic acid (1 to 3 mg daily) or folinic acid (5 mg weekly) to reduce the risk of certain side effects, such as upset stomach, mouth sores, low blood cell counts, and abnormal liver function.
Sulfasalazine — Sulfasalazine is used in the treatment of rheumatoid arthritis and of arthritis associated with ankylosing spondylitis and inflammatory bowel disease (ulcerative colitis and Crohn disease). Sulfasalazine may exert its effects through the gastrointestinal immune system. It may be combined with other DMARDs if a person does not respond adequately to one medication. It is typically taken as one to three pills two times per day, and it is usually started at a low dose and is increased slowly to minimize side effects. It may take one to two months of treatment before symptoms improve.
Side effects of sulfasalazine include changes in blood counts, nausea or vomiting, sensitivity to sunlight, skin rash, and headaches. People who are allergic to sulfonamide medications, such as sulfamethoxazole-trimethoprim (sample brand names: Bactrim, Septra), 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; people who take it may notice that their urine, tears, and sweat develop an orange tinge, which can stain clothing and contact lenses. It's important to drink plenty of fluids while taking sulfasalazine and to 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 very frequently 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, and can take two to three months or longer to improve symptoms.
The main toxicity of hydroxychloroquine is the risk of damage to the retina of the eye. Current screening tests allow early detection of this toxicity and drug discontinuation prior to clinically apparent visual loss.
Leflunomide — Leflunomide inhibits production of inflammatory cells to reduce inflammation. It may be used alone or in combination with methotrexate for people who have not responded adequately to methotrexate alone. It may also be used with a biologic agent. It is taken by mouth once daily.
Side effects include rash, temporary hair loss, abnormal liver function tests, nausea, diarrhea, weight loss, abdominal pain, and neuropathy (nerve damage). High blood pressure can occur in up to 10 percent of people. Testing for prior exposure to hepatitis and regular blood testing while on therapy are needed to monitor for liver damage and other toxicities. Women should not become pregnant while taking leflunomide or while it is still detectable in the body.
Azathioprine — Azathioprine has been used in the treatment of cancer, rheumatoid arthritis, lupus, 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. Its use for rheumatoid arthritis is now much less frequent than in the past.
The most common side effects of azathioprine include nausea, vomiting, decreased appetite, liver function abnormalities, low white blood cell counts, and infection. It is usually taken by mouth once daily. Regular blood testing is recommended during treatment with azathioprine.
BIOLOGIC AND TARGETED SYNTHETIC DMARDS — Biologic disease-modifying antirheumatic drugs (DMARDs), also known as "targeted biologic agents," "biologic agents," or simply "biologics," are DMARDs that are produced using molecular biology (recombinant DNA) techniques. These agents were designed to prevent or reduce the inflammation that damages joints. Biologics target molecules on cells of the immune system, joints, and the products that are secreted in the joints, all of which can promote inflammation and joint destruction. There are several types of biologics, each of which targets a specific type of molecule involved in this process:
All of these agents are given by injection or infusion.
Another group of DMARDs, called kinase inhibitors, includes tofacitinib, baricitinib, upadacitinib, and filgotinib. These drugs are produced by traditional drug-manufacturing techniques; they are similarly effective to biologics and are taken as pills. A biologic DMARD or a kinase inhibitor is often combined with methotrexate or other conventional DMARDs to improve efficacy. These drugs are sometimes referred to as "targeted synthetic DMARDs."
Unlike conventional DMARDs, which can take a month or more to begin working, biologics and kinase inhibitors tend to work more rapidly, within two weeks for some medications and within four to six weeks for others.
Side effects — Biologic agents and kinase inhibitors interfere with the immune system's ability to fight infection and should not be used in people with serious infections. To help reduce the risk of certain infections, it is also important to make sure you have received all recommended vaccines before starting DMARD therapies, and to continue to get the influenza (flu) vaccine each year. The risk of herpes zoster (shingles) is higher with the kinase inhibitors than other medications, but this risk can be lowered with recombinant zoster vaccination prior to treatment. (See "Patient education: Shingles (Beyond the Basics)".)
Testing for tuberculosis (TB) is necessary before starting biologic DMARDs, particularly anti-TNF therapy, and before starting kinase inhibitors. People who have evidence of prior TB infection should be treated because there is an increased risk of developing active TB while receiving anti-TNF therapy. (See "Patient education: Tuberculosis (Beyond the Basics)".)
Anti-TNF agents are not recommended for people who have certain health conditions such as multiple sclerosis or lymphoma (or who have been treated for lymphoma in the past); people with rheumatoid arthritis, especially those with severe disease, have an increased risk of lymphoma regardless of what treatment is used. Anti-TNF agents have been associated with a further increase in the risk of lymphoma in some studies but not others; more research is needed to define this risk.
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 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 — UpToDate offers two types of patient education materials.
The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Patient education: Rheumatoid arthritis (The Basics)
Patient education: Juvenile idiopathic arthritis (The Basics)
Patient education: Ankylosing spondylitis (The Basics)
Patient education: Vasculitis (The Basics)
Patient education: Disease-modifying antirheumatic drugs (DMARDs) (The Basics)
Patient education: Behçet syndrome (The Basics)
Patient education: Psoriatic arthritis in children (The Basics)
Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.
Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)
Patient education: Rheumatoid arthritis treatment (Beyond the Basics)
Patient education: Rheumatoid arthritis and pregnancy (Beyond the Basics)
Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.
General principles and overview of management of rheumatoid arthritis in adults
Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults
Initial treatment of rheumatoid arthritis in adults
Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy
Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy
Immunizations in autoimmune inflammatory rheumatic disease 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
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Peter H Schur, MD, who contributed to an earlier version of this topic review.
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