Facts About DMARDs

Disease-Modifying Anti-Rheumatic Drugs

Drugs called disease-modifying antirheumatic drugs (DMARDs) are generally the first-line treatment for rheumatoid arthritis (RA) and other autoimmune/inflammatory conditions, including ankylosing spondylitis, psoriatic arthritis, and lupus. DMARDs are often referred to as immunosuppressants or immunomodulators because they appear to decrease inflammation by modifying the way your immune system works. It is this action that helps slow down the progression of such diseases and alleviate symptoms.

The earliest DMARDs have been around for decades, so doctors have a wealth of data to guide their treatment decisions. The medical community considers DMARDs to be highly effective long-term treatments. They are slow to work, however, so you may not notice any benefits for six to eight months after starting them.

DMARDs currently used for RA and similar conditions include:

  • Arava (leflunomide)
  • Azulfidine (sulfasalazine)
  • CellCept (mycophenolate mofetil)
  • Cuprimine (penicillamine)
  • Cytoxan (cyclophosphamide)
  • Imuran (azathioprine)
  • Neoral/Gengraf (cyclosporine)
  • Otezla (apremilast)
  • Plaquenil (hydroxychloroquine)
  • Rheumatrex/Trexall (methotrexate)

If DMARDs aren't effective enough, you may be prescribed two or more to take together. DMARDs are often prescribed with drugs from other classes as well.

While DMARDs do carry some risk of serious side effects, laboratory monitoring can help identify problems early.

This overview touches on some key information about each of these drugs. Speak to your doctor about all possible side effects. Be detailed when sharing your medical and treatment history, including what medications you are currently taking, what chronic conditions you are managing, and any drug allergies you have.

Arava (leflunomide)

Arava was first approved by the U.S. Food and Drug Administration (FDA) in 1998. It comes in tablet form and is taken orally.


Arava is only approved for active RA in adults. It's sometimes used off-label for psoriatic arthritis and psoriasis as well.

Special Considerations

  • This drug hasn't been evaluated for children under 12.
  • Arava is not safe for pregnant women. If you're breastfeeding, you should stop before you start taking Arava.
  • You shouldn't take this drug if you're currently taking the drug teriflunomide.
  • Arava has two black box warnings from the FDA: one related to embryo-fetal toxicity, the other related to severe liver injury or liver failure.

Azulfidine (sulfasalazine)

Usually called by its generic name, sulfasalazine is a combination of salicylate and an antibiotic. This oral medication has been around since the 1940s and is available in tablet form.


Sufasalazine is approved to treat mild-to-moderate ulcerative colitis (UC), as a first-line or combination treatment, and to prolong the period of remission between UC attacks. It can be used in adults as well as children age 6 and over.

It's sometimes used to treat RA but has become less popular over time due to the risk of side effects and the availability of other treatment options.

Special Considerations

  • This drug should be avoided by people with allergies to sulfa drugs and/or aspirin and other salicylates.
  • Some recommendations state that, during pregnancy, sulfasalazine is an acceptable alternative to methotrexate or leflunomide, which both are known to cause fetal harm. However, sulfasalazine is not well studied during pregnancy and the potential long-term effects on a child exposed in utero are unknown.
  • Nursing mothers are not advised to take this drug, as it is believed to pass into breastmilk and may have the potential to cause brain damage in the baby.

CellCept (mycophenolate mofetil)

CellCept, an oral medication, has been on the market since 1995. It's an especially potent immunosuppressant.


CellCept is sometimes used off-label to treat RA, people with lupus who also have kidney disease, and vasculitis.

However, it's FDA-approved to prevent organ rejection in kidney, heart, and liver transplants in adults, and kidney transplants in children. For its approved purposes, it's expected to be used alongside other immunosuppressants.

Special Considerations

  • CellCept comes with a black box warning because it can increase the risk of fetal malformations and pregnancy loss in the first trimester. Men may pass along the drug, and its risk of fetal toxicity, in their sperm. Birth control pills alone may not be adequate protection, as this drug may reduce its effectiveness.
  • A second black box warning relates to an increased risk of lymphoma and other malignancies, particularly skin cancer.
  • A third black box warning was issued because CellCept use can lead to serious bacterial, viral, fungal, and protozoal infections—including viral reactivation of hepatitis B and C—which can lead to hospitalizations and death.

Cuprimine/Depen (penicillamine)

Penicillamine is a distant relative of penicillin that became available in the 1970s. It's associated with a high incidence of severe side effects, including some that can be fatal. You'll need close monitoring by your doctor if you take this drug.


This drug is FDA approved for severe, active RA that hasn't responded to other therapies, a genetic liver disorder called Wilson's disease, and a genetic disorder that causes cystine stones in the urinary tract.

While many DMARDs are considered first-line treatment for RA, this one is not due to its risk of severe side effects. In fact, if you've been on 1,000 mg or more of penicillamine per day for a few months without improvement, it's assumed you won't benefit from the drug and your doctor will likely recommend discontinuing it.

Special Considerations

  • You should not take penicillamine if you are breastfeeding, have kidney disease, or you've had severe side effects from penicillamine in the past.
  • If you're allergic to penicillin, there's a possibility you could also be allergic to penicillimine.
  • This medication increases your risk of developing diseases of the immune system, including SLE, polymyositis, myasthenia gravis, and Goodpasture syndrome.
  • Some side effects can be signs of a serious health problem, including anemia, low blood platelets (thrombocytopenia), low white blood cells (neutropenia), or serious kidney disease.

Cytoxan (cyclophosphamide)

FDA approved since 1959, Cytoxan is one of the older DMARDs on the market. It is available in tablet and injectable forms. Like many of the older drugs, it has a risk of serious side effects.


This drug's approved uses are for the treatment of malignant diseases, including lymphoma, leukemia, and Hodgkin's disease, and for minimal change nephrotic syndrome in children.

Off-label, this drug is sometimes used for RA but, due to risks, only in people with severe disease that hasn't responded to other treatments. Often, Cytoxan is used short-term to get these cases into remission, after which a milder drug is prescribed for maintenance therapy.

Cytoxan is also used off-label for complications of lupus, myositis, scleroderma, or vasculitis.

Special Considerations

  • Your doctor will monitor your blood counts while you're on Cytoxan so problems can be spotted early and serious complications prevented. Examples include leukopenia, thrombocytopenia, and neutropenia.
  • Other serious side effects can include reactivation of latent infections, heart or respiratory problems, and liver disease.
  • You should not take Cytoxan while pregnant, as it is known to cause birth defects, impaired growth, miscarriage, and other toxic effects.
  • Fertility and reproductive function, including sterility, may be impaired in both men and women. In some cases, infertility may be permanent.

Cytoxan interacts negatively with numerous drugs, including ACE inhibitors (commonly used for high blood pressure). Some drugs may make severe side effects more likely. Be sure your doctor knows everything you're taking.

Imuran (azathioprine)

Imuran has been on the U.S. market since 1968. It is available in tablet form.


This drug is FDA approved for active RA and to prevent rejection in kidney transplants. It's sometimes used off-label to treat other autoimmune conditions, including dermatomyositis, SLE, inflammatory bowel disease, and vasculitis.

Special Considerations

  • Imuran has a black box warning because the drug may increase your risk of cancer, including lymphoma. Malignancies have primarily been observed in people who've had transplants or are being treated for inflammatory bowel disease.
  • This drug is known to cause fetal harm and should be avoided during pregnancy whenever possible.
  • Reliable contraception should be used anytime you're on Imuran, regardless of your sex. Imuran may temporarily lower sperm count and impair male fertility. Its impact on sperm may also cause birth defects.
  • If you stay on Imuran long-term, your doctor will need to monitor you for potential side effects and complications.

Neoral/Gengraf (cyclosporine)

Cyclosporine, under several brand names, has been on the market since 1983. Neoral and Gengraf are often used for RA and other autoimmune conditions.

Another brand, Sandimmune, has a different level of bioavailability and therefore cannot be used interchangeably with Neoral and Gengraf.

Neoral/Gengraf is available in soft gel capsule and liquid forms.


Cyclosporine was originally approved to combat post-transplant organ rejection. Later, the form of the drug in Neoral and Gengraf gained approval for:

Cyclosporine is used off-label for conjunctivitis, Langerhans cells histiocytosis, autoimmune hepatitis, Duchenne muscular dystrophy, ulcerative colitis, and other diseases.

Special Considerations

  • Cyclosporine comes with four black box warnings. The first is in regards to the different brands of the drug not being equivalent.
  • Second black warning: Due to its effects on the immune system, cyclosporine increases your risk of developing serious infections or cancer, especially lymphoma. This risk is increased if you're also taking other immunosuppressants such as azathioprine or methotrexate.
  • Third black box warning: Cyclosporine may cause high blood pressure and may damage your kidneys. The risk may be increased if you're taking other medications that may cause kidney damage, including Tagamet (cimetidine), Cipro (ciprofloxacin), Aleve (naproxyn), or Zantac (ranitidine).
  • Black box warning 4: If you have psoriasis, your risk of developing skin cancer while on cyclosporine is increased if you have ever been treated with psoralen and UVA (PUVA), coal tar, immunosuppressants, or certain other treatments.
  • When taken during pregnancy, cyclosporine may increase the risk of premature birth, low birth weight, and miscarriage.
  • This drug does pass into breast milk and breastfeeding is not recommended while taking it.

Otezla (apremilast)

Otezla is a newer DMARD approved in 2014. It's an oral medication in tablet form.


Otezla is FDA approved for:

  • Active psoriatic arthritis in adults
  • Moderate-to-severe plaque psoriasis in people who are candidates for phototherapy or systemic therapy

It's used off-label to treat mouth ulcers in Behçet's disease.

Special Considerations

  • Not much is known about Otezla's pregnancy risk in humans. In animal studies, the drug has been associated with miscarriage, especially in the first trimester.
  • Thus far, it's unknown whether Otezla passes into the breast milk.
  • In rare cases, depression/suicidal thoughts and unintended weight loss can occur while on Otezla.

Plaquenil (hydroxychloroquine)

Plaquenil has been available since 1955 and was originally used to treat malaria. For a short time in 2020, the FDA gave it an emergency use authorization to treat COVID-19, but that authorization was revoked after a large clinical trial found it wasn't beneficial.

This drug is available in tablet form.


Plaquenil is approved for:

  • Mild rheumatoid arthritis that hasn't responded to NSAIDs
  • Systemic lupus erythematosus in adults
  • Discoid lupus erythematosus in adults
  • Malaria

It's used off-label for pediatric forms of lupus, lupus nephritis, Sjögren's syndrome, other autoimmune diseases, and rash caused by sun sensitivity (polymorphous light eruption).

Special Considerations

  • Plaquenil is known to cause severe hypoglycemia (abnormally low blood sugar) which can cause a loss of consciousness and can be life-threatening. If you have diabetes, your medications may need to be adjusted.
  • In rare cases, Plaquenil is associated with retinal detachment, which is permanent and can cause blindness. Because of this risk, your vision will be monitored for changes that can occur prior to detachment as well as other vision changes associated with the drug.
  • Other serious side effects include hearing issues, muscle weakness, irregular heartbeat, and decreased/loss of consciousness.
  • Plaquenil isn't associated with fetal harm during pregnancy. However, it's not recommended while breastfeeding because the drug is passed on through the breast milk and can be toxic to the baby.

Rheumatrex/Trexall/RediTrex (methotrexate)

Known best by its generic name, methotrexate was FDA approved in 1953. Far from being outdated, though, this drug remains a common treatment for RA. It's also widely used for psoriasis and cancer. Proving its continued relevance, a new injectable version, called RediTrex, gained approval in late 2019.

This is despite numerous serious warnings that come with the drug.

Methotrexate is available in tablets and an injectable liquid form.


Methotrexate is approved to treat:

  • Severe, active rheumatoid arthritis in people who've failed on NSAIDs
  • Polyarticular juvenile idiopathic arthritis (pJIA) in children who've failed on NSAIDs
  • Severe, recalcitrant, disabling psoriasis that hasn't responded to other therapies, but only when the diagnosis has been confirmed by biopsy or dermatologic consultation
  • Multiple types of cancer

RediTrex is not approved to treat cancer but its indications are the same for RA, pJIA, and psoriasis.

Special Considerations

  • Medication adherence is imperative. People sometimes get confused and take methotrexate daily instead of weekly. This can lead to fatal side effects.
  • Methotrexate comes with 11 black box warnings from the FDA. They relate to: toxic reactions and death, embryo-fetal toxicity and death, bone marrow suppression, liver toxicity, lung disease, intestinal perforation, malignant lymphomas, tumor lysis syndrome, severe skin reactions, opportunistic infections, and tissue necrosis.
  • Routine monitoring of liver and kidney function is required while you're on this drug.
  • Methotrexate may impair fertility in both men and women. It's unknown whether this is temporary or permanent.

Biologics, Biosimilars, and JAK Inhibitors

Three newer types of DMARDs are now on the market. These may be tried after you've failed on an older DMARD or used as combination therapy with an older DMARD.


Biologics are drugs derived from living cells. They're also called TNFα inhibitors because they block the action of immune-system cells called tumor necrosis factor-alpha, which are associated with RA and other autoimmune disorders.

Common biologics:


Biosimilars are based on existing biologics. The FDA considers them to have no significant differences from their original reference drugs, but they can be less expensive. You can recognize them by the four-letter suffix after their generic name.

Common biosimilars include:

JAK Inhibitors

These drugs inhibit the activity of Janus kinase enzymes, which are involved in inflammation and autoimmunity. Common JAK inhibitors are:

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