DMARDs (Disease-Modifying Antirheumatic Drugs)


DMARD stands for disease-modifying antirheumatic drug. Other than glucocorticoids (steroids), DMARDs have been on the market the longest and have the most evidence to support their use. The most commonly used DMARD is methotrexate (Trexall®, Rheumatrex®, Otrexup®, Resuvo®).

Other DMARDs include sulfasalazine (Azulfidine®), leflunomide (Arava®), hydroxychloroquine (Plaquenil®), Cyclosporine (Neoral®, Sandimmune®)Azathioprine (Imuran®), and Apremilast (Otezla®).

Methotrexate (Trexall®, Rheumatrex®, Otrexup®, Resuvo®)

Methotrexate works by blocking enzymes that help DNA (genetic material in the cells of your body) form or repair. This prevents some cells in your body from reproducing themselves. Experts believe that methotrexate also interacts with your immune system. It’s been proven to be effective in reducing swelling, pain, and long-term damage to joints.

Methotrexate is given once a week as either a pill or shot. Some people have better results with methotrexate shots. You absorb the drug differently this way. If you get an upset stomach from the pill form of the drugs, you may be able to tolerate shots more easily. That’s because the drug goes into your bloodstream without going through your stomach first.

Do not get pregnant or conceive a child while taking methotrexate. Methotrexate can cause serious birth defects in unborn babies. So you should not conceive a child while you are on methotrexate. This risk includes both women and men. Talk to your rheumatologist if you plan to start a family or think you may be pregnant before you start methotrexate.

It’s a common myth that patients taking methotrexate can never have children. You can work with your rheumatologist to go off methotrexate for a period of time to clear it from your system. For women, recommendations vary from 1 month to 3 months as to how long you should be off methotrexate before getting pregnant. The package insert recommends male patients be off methotrexate for 3 months.

Side Effects of Methotrexate

It’s important to remember that most patients do not experience serious side effects from methotrexate, and for those who do have them, they may improve with time. Side effects are more likely to occur at higher doses and you should always consult your doctor if you think you’re experiencing any of these side effects.

Certain antibiotics such as “sulfa” drugs (i.e. Bactrim®) should not be taken with methotrexate. Check with your physician before taking an antibiotic with your methotrexate.

Talk to your doctor if you think you’re experiencing any of these side effects.

  • Gastrointestinal problems, such as nausea, stomach upset, and loose stool
  • Mouth ulcers
  • Hair loss
  • Abnormal liver function blood tests
  • Abnormal blood counts

Rare side effects include liver cirrhosis or scarring. If you take methotrexate, you should limit or cut out your alcohol use. Drinking alcohol puts a strain on your liver. Liver cirrhosis or scarring usually happens with patients who already have liver problems or are taking more drugs that impact the liver. Lung problems also occur rarely, and typically only with patients who already have lung issues. Report any difficulty breathing or a cough that won’t go away to your doctor. Take these side effects very seriously.

People with liver disease may not be able to take methotrexate or require closer monitoring or lower dosing.

Increased skin sensitivity to the sun can also occur, but may stop when the medication is stopped. Supplements like folic acid may help you manage these side effects. If regular folic acid doesn’t help, you may try another type called methylated folic acid. Talk to your doctor about getting methylated folic acid if you still get mouth ulcers, hair loss, or just a “yucky feeling” from your methotrexate. Vitamin A and dextromethorphan (the DM in Robitussin DM®) can also be used to help with those side effects.

Sulfasalazine (Azulfidine®)

Sulfasalazine (Azulfidine®) is used to treat ulcerative colitis, rheumatoid arthritis, and Crohn’s disease.

Sulfasalazine (Azulfidine®) is part of a class of medicines called sulfa drugs. It’s a mix of salicylate, which is the main ingredient in aspirin, and an antibiotic. Some people are allergic to all sulfa drugs, so they can’t take sulfasalazine (Azulfidine®).

Most people take two 500 mg tablets of sulfasalazine (Azulfidine) twice per day. Some people may start with a lower dose, such as one or two tablets per day, then build up to the normal dose. Some people may need six 500 mg tablets per day.

You should take your sulfasalazine (Azulfidine®) with food and a full glass of water to help ease stomach side effects. You shouldn’t crush or chew up your sulfasalazine (Azulfidine®) tablets.

Sulfasalazine (Azulfidine®) should be safe to take during pregnancy but, as always, you should check with your physician if you are planning a pregnancy. It may be necessary to take extra folic acid if you continue on sulfasalazine during pregnancy. However, using it during breastfeeding may cause a serious type of jaundice in babies.

If you have an infection, your doctor may have you stop taking sulfasalazine (Azulfidine®).

Side Effects of Sulfasalazine (Azulfidine®)

Most people have few side effects with sulfasalazine (Azulfidine®). The most common ones are nausea, stomach upset, and headache. Usually, this gets better over time. You can take a coated sulfasalazine (Azulfidine®) pill that may be easier to digest.

Rarer side effects include headache, skin rashes, itching, mouth sores, or liver or lung problems. If you get a severe rash, tell your doctor.

Sulfasalazine (Azulfidine®) may make your skin more sensitive to sunburns, so wear a high SPF sunblock lotion or avoid getting too much sun. Some people who take sulfasalazine (Azulfidine®) have orange-colored urine or skin. While this seems alarming, it’s actually harmless. It will go away when you stop taking this drug. Sulfasalazine (Azulfidine®) can make it harder for you to fight off infections because it can lower the amount of white blood cells your body makes. Your doctor can test your blood to make sure your blood cell levels are healthy.

Leflunomide (Arava®)

Leflunomide (Arava®) is a DMARD approved to treat moderate to severe rheumatoid arthritis, but is sometimes prescribed “off label” to treat PsA.

It can lower joint damage and disability. It can also help ease some symptoms, but isn’t effective for skin psoriasis. It may be used alone or in combination with other DMARDs.

Leflunomide (Arava®) blocks the development of certain cells in your immune system. By doing this, leflunomide (Arava®) works to suppress your immune system and reduce inflammation that causes pain, swelling, and other symptoms.

The typical dose of leflunomide (Arava®) is one 20 mg pill a day. Some people may take 10 mg a day, especially if the higher dose causes side effects. You should take your leflunomide (Arava®) with food.

Your doctor may prescribe a “loading dose” of leflunomide (Arava®) for you, which means you’ll be prescribed extra drug in the beginning to give the medication a chance to build up in your body and become effective. Because of the possibility of increased side effects with a loading dose, most rheumatologists do not use loading doses of leflunomide (Arava®). Without the loading dose it may take a little longer (six to twelve weeks) to notice a benefit from leflunomide (Arava®).

One of the side effects of leflunomide (Arava), like methotrexate, is the potential for liver toxicity. So you shouldn’t drink alcohol or take certain medications while you take leflunomide (Arava®). If you’ve had significant liver disease in the past, leflunomide (Arava®) may not be right for you. You’ll need regular liver function blood tests to make sure your liver is healthy.

Leflunomide (Arava®) can also be harmful to an unborn fetus. It can cause serious birth defects, so you should take extra precautions not to get pregnant while taking this drug. Because leflunomide (Arava®) can stay in your system anywhere from 10 weeks to 2 years, it is important to get a blood test to see if the drug is still in your blood before even trying to get pregnant. Breastfeeding should be avoided as well, unless leflunomide (Arava®) is completely out of your system. Men who take leflunomide (Arava®) should also use birth control to avoid getting their partner pregnant because of the birth defect risk.

Side Effects of Leflunomide (Arava®)

The most common side effect of leflunomide (Arava®) is diarrhea. It often gets better over time. You can take anti- diarrheal medicines to ease this side effect, or even lower your leflunomide (Arava®) dose.

Other side effects include nausea, indigestion, hair loss, stomach pain, liver toxicity, or skin rashes. More rarely, this drug may lower your amount of blood cells or platelets, or cause lung problems like cough or shortness of breath.

Leflunomide (Arava®) may also raise your risk of getting infections. Let your doctor know if you have signs of an infection, like fever or chills.

Hydroxychloroquine (Plaquenil®)

Hydroxychloroquine (Plaquenil®) is used for rheumatoid arthritis and systemic lupus erythematosus. 

Hydroxychloroquine (Plaquenil®) is an antibiotic used to treat malaria, but it also works to treat symptoms of RA, lupus, and other rheumatic diseases. It can reduce your joint pain and swelling. In the long term, it may help prevent joint damage or lower your risk of joint disability. We don’t really know why this drug works to control RA symptoms or complications. One theory is that hydroxychloroquine (Plaquenil®) interferes with communications between the cells of your immune system. Your hydroxychloroquine (Plaquenil®) dose will be based on your weight. Usually, adults with RA will take either 200 or 400 mg of hydroxychloroquine (Plaquenil®) per day in pill form.

Side Effects of Hydroxychloroquine (Plaquenil®)

Most people tolerate hydroxychloroquine (Plaquenil®) well. Some side effects include nausea and diarrhea, but they may lessen over time or if you take your pills with food. Less common side effects are rashes, changes in your skin’s pigment (like dark spots), changes to your hair (like thinning), or muscle weakness.

Although rare, hydroxychloroquine (Plaquenil®) use could lead to damage of the cells in the back of your eye that detect light and color. You’ll receive a specialized baseline eye exam when you start the drug. Later, you’ll follow up with your ophthalmologist as directed. The most recent recommendations say you don’t need a follow-up eye exam for five years, but you may need one sooner depending on your other medical conditions or if you have changes in your vision while taking hydroxychloroquine.

Hydroxychloroquine seems to be safe during pregnancy, but any time you are considering pregnancy you should discuss all medications with your doctor.

Other rare side effects of hydroxychloroquine (Plaquenil) are:

  • Anemia, especially in people with porphyria
  • Muscle weakness

Cyclosporine (Neoral®, Sandimmune®)

Cyclosporine is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. It may be used for psoriatic arthritis treatment in some cases, such as people with severe skin psoriasis or joint inflammation. 

Cyclosporine is usually a short-term option, not a drug you would take regularly over time.

Cyclosporine suppresses your immune system and slows down the growth of certain cells in your immune system that may play a role in inflammation. It may be used to treat severe psoriasis in some people. It can rapidly relieve symptoms. You may see symptoms improve after just two weeks of taking cyclosporine, but you may need up to four months to see the full effect of the drug.

Cyclosporine is taken by mouth in capsule form twice a day. The starting dose is based on your weight. Your doctor can increase the dose if needed. You’ll need regular blood tests to monitor any adverse effects of taking cyclosporine.

Side Effects of Cyclosporine (Neoral®, Sandimmune®)

High blood pressure and renal (kidney) problems are the most serious and common side effects of cyclosporine. Drink plenty of water when you take your capsules. Make sure you are well hydrated at other times too. Older people may be more at risk for these side effects.

Cyclosporine could raise your risk of infections and fevers. Let your doctor know if you have any signs of infection or a fever.

Other side effects that are possible with cyclosporine include: headaches, nausea, indigestion, vomiting, swollen hands or feet, tremors (shaking), swollen gums, increased hair growth, cramps, and numb or tingling hands or feet.

Azathioprine (Imuran®)

Azathioprine (Imuran®) is indicated for rheumatoid arthritis. It is used very rarely to treat psoriatic arthritis.

It can suppress your immune system which can help reduce joint pain and swelling. It may also curb joint damage and disability. It may only offer mild relief for skin psoriasis.

Azathioprine (Imuran®) works in your body to block your immune system’s overactive responses. It interferes with how DNA, the building block of all your cells, works, so it stops certain cells from dividing, multiplying, and causing problems in your joints.

Your azathioprine (Imuran®) dose is based on your body weight. People with arthritis may get 1 milligram (mg) per each kilogram (kg) of their weight. Your dose may go up every one to two months if needed up to 2.5 mg/kg of weight. You may have lower levels of white blood cells. If you take the drug for a long time in combination with other drugs that lower your immune system, you may be at slightly higher risk for some cancers, like lymphoma.

If you take azathioprine (Imuran®), your rheumatologist will check your blood often to make sure you don’t have toxic levels of the drug in your system. Blood tests can also check for signs of infection. You may also get a test called thiopurine methyltransferase enzyme activity level (TPMT). This will test how well your body processes azathioprine.

Azathioprine (Imuran®) can have some interactions with other drugs, including allopurinol (Alorprim®, Zyloprim®), used for gout; warfarin; some blood pressure medicines; olsalazine (Diptenum®); mesalamine (Asacol®, Pentasa®); and sulfasalazine (Azulfidine®).

Apremilast (Otezla®)

Apremilast (Otezla®) is used to treat psoriatic arthritis and psoriasis.

Apremilast (Otezla®) stops inflammation in your cells and helps control your psoriatic arthritis symptoms like tender or swollen joints, as well as skin symptoms. It works by blocking an enzyme called phosphodieasterase-4 that may play a role in psoriatic inflammation. You may take apremilast (Otezla®) with methotrexate or other drugs.

If you take a CYP450 inducer drug such as rifampin at the same time, this may reduce the effectiveness of apremilast (Otezla®). Only adults with PsA can take apremilast (Otezla®). It is not used by children with the disease. Nursing mothers may need to use caution if they take this drug.

The usual dose is a 30 mg tablet taken twice daily. For the first five days of treatment, you will build up the amount you take slowly until you reach that dose. People with severe renal (kidney) impairment may need to take a reduced dose.

Side Effects of Apremilast (Otezla®)

The most common side effects of apremilast (Otezla®) are diarrhea, nausea, and headache, but they were mild in most people. These side effects mainly occur in the first two weeks and then lessen afterward.


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