Patient information: Disease modifying antirheumatic drugs (DMARDs)

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.

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 methotrexate plus another medication.

The most common DMARDs are: methotrexate (Rheumatrex®), sulfasalazine (Azulfidine®), hydroxychloroquine (Plaquenil®), leflunomide (Arava®) and cyclosporine (Sandimmune®, Neoral®). Less frequently used medications include gold salts (Solganal®) and azathioprine (Imuran®).

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. It is usually started at a low dose (less than 12.5 mg/week) and increased at monthly intervals until the maximum desired dose is achieved (usually 25 mg/week). Methotrexate may be combined with other DMARDs or with a biologic response modifier if methotrexate alone does not adequately control a patient's disease (see 'Biologic response modifiers' 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. Drinking alcoholic beverages while using methotrexate is discouraged because of the risk of liver damage.

Monitoring reduces the risk of long-term damage from methotrexate. A chest x-ray is recommended before beginning treatment, and blood testing is usually recommended every 4 to 8 weeks. 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.

Pregnancy risks — Methotrexate is not safe during pregnancy due to the risk of miscarriage and serious birth defects; women who take it must use a reliable method of birth control to prevent pregnancy. Women on methotrexate should discontinue this medication and allow one full menstrual cycle to pass before attempting to conceive. Men on methotrexate should discontinue this medication and wait at least three months before attempting to conceive. (See "Patient information: Rheumatoid arthritis and pregnancy".)

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 (500 mg per day) and increased slowly (to 2000 to 3000 mg per day) 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. Blood tests are recommended to monitor the blood count every two to four weeks initially, then every one to three months thereafter.

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.

Pregnancy risks — The risk of harm from taking sulfasalazine during pregnancy is likely to be very low; the drug is usually continued in women with active disease. However, in two studies, harm to the fetus was reported if mothers were exposed to folic acid antagonists (such as sulfasalazine) in early pregnancy. To address this concern, a folic acid supplement (1 mg = 1000 micrograms daily) has been recommended before and during pregnancy. Sulfasalazine is generally regarded as safe for use while breastfeeding. (See "Patient information: Rheumatoid arthritis and pregnancy".)

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 can also be used for patients with 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 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 every 6 to 12 months thereafter.

Pregnancy risks — The safety of hydroxychloroquine during pregnancy is controversial, although there is no evidence that it increases the risk of miscarriage or birth defects at normal doses. It is safe to use while breastfeeding. (See "Patient information: Rheumatoid arthritis and pregnancy".)

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. It is usually taken by mouth at a dose of 20 mg once daily.

Side effects include rash, temporary hair loss, liver damage, nausea, diarrhea, weight loss, and abdominal pain. Monthly testing to monitor for liver damage is recommended for the first 6 to 12 months of treatment, followed by testing at longer intervals.

Pregnancy risks — Leflunomide is not considered safe for use during pregnancy. Women who plan to become pregnant should discuss a treatment plan with their healthcare provider several months before trying to conceive. (See "Patient information: Rheumatoid arthritis and pregnancy".)

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 every two to four weeks when starting cyclosporine, and then monthly thereafter.

Pregnancy risks — There is insufficient information about the safety of cyclosporine during pregnancy, and most experts recommend that pregnant women take it only if the potential benefits outweigh the potential risks. (See "Patient information: Rheumatoid arthritis and pregnancy".)

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. This usually includes a complete blood count (including hemoglobin, white blood cell count, and platelet count) every two weeks as the dose is increased, and every four to six weeks when the dose is stabilized. Liver function testing is generally recommended every 4 to 8 weeks.

Pregnancy risks — Studies of the safety of azathioprine during pregnancy have shown conflicting results, with some studies showing an increased risk of lower birthweight, prematurity, jaundice, and respiratory distress syndrome. Other studies have shown no increased risks.

As a result, most experts recommend avoiding AZA during pregnancy, if the woman's disease permits. However, if an immunosuppressive drug is needed during pregnancy, AZA may be safer than many other immunosuppressive agents.

Although azathioprine has no observable effects on sperm or semen production, men who take AZA are advised to stop AZA three months before trying to conceive, if the man's disease permits.

WHEN TO START AND STOP DISEASE MODIFYING ANTIRHEUMATIC DRUGS

The goal of treatment with DMARDs is to suppress disease activity and prevent joint damage while reducing pain and stiffness and maintaining physical mobility. All but the mildest cases of RA are usually treated with a DMARD. The ideal time to begin the drug is within three months of the date that RA is diagnosed because joint damage, which ultimately may result in disability, begins early in the course of RA.

Complete remission of arthritis sometimes occurs during DMARD therapy, although RA often recurs if DMARDs are stopped, leading most clinicians to recommend DMARD treatment on an ongoing basis, even if remission occurs.

BIOLOGIC RESPONSE MODIFIERS

Another class of medications used in persons with rheumatoid arthritis is the biologic response modifiers, including Etanercept (Enbrel®), adalimumab (Humira®), and infliximab (Remicade®), anakinra (Kineret®), abatacept (Orencia®), and rituximab (Rituxan®). These medications are often combined with methotrexate or other DMARDs to improve efficacy. (See "Patient information: Rheumatoid arthritis treatment", section on 'Biologic response modifiers'.)

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two people are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

Some of the most pertinent include:

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

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

• National Library of Medicine

      (www.nlm.nih.gov/medlineplus/healthtopics.html)

• The Arthritis Foundation

      (www.arthritis.org)

• National Institute of Arthritis and Musculoskeletal and Skin Diseases

      (www.niams.nih.gov/hi/index.htm)

• American College of Rheumatology

      (www.rheumatology.org)

      phone: 404-633-3777
      fax: 404-633-1870

• American Academy of Family Physicians

      (www.aafp.org)

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