Disease-Modifying Anti-Rheumatic Drugs (DMARDs)
Disease-modifying anti-rheumatic drugs (DMARDs) are the standard treatments for rheumatoid arthritis (RA). They are used either alone or in combination with newer biologic DMARDs.
DMARDs do not have any common properties other than their ability to slow down the progression of rheumatoid arthritis. Many were used for other diseases and were found accidentally to help RA. DMARDs include:
- Methotrexate, leflunomide, hydroxychloroquine, minocycline, and sulfasalazine are the DMARDs most commonly prescribed for RA.
- Gold, azathioprine, and cyclosporine are older DMARDs. Cyclosporine and azathioprine are used in specific clinical scenarios and gold is no longer used for rheumatoid arthritis.
Unfortunately, many patients experience a decrease in efficacy of a DMARD after extended periods of therapy. Combining DMARDs with each other or with other types of drugs offers the best approach for many patients.
All DMARDs may produce stomach and intestinal side effects, and, over the long term, each poses some risk for rare but serious reactions. (In some cases, however, they may be less harmful than long-term NSAID treatment.)
Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo, generic) acts as an anti-inflammatory drug and is generally the most frequently used DMARD, particularly for severe disease. Methotrexate starts working within 3 to 6 weeks, but its full effect may not occur until after 12 weeks of treatment.
Even this drug loses effectiveness, however, when used alone. For this reason, it is often used in combination with other DMARDs such as hydroxychloroquine, sulfasalazine (Triple Therapy). It may also be combined with various biological response modifier drugs, especially for treatment of patients with early aggressive arthritis. The combination appears to work better than single drug therapy.
Some patients have to stop taking methotrexate because of its side effects. They include nausea and vomiting, rash, mild hair loss, headache, mouth sores, and muscle aches. Methotrexate reduces levels of folic acid (folate) in the body, which can lead to some of these side effects. Doctors may prescribe folic acid supplements to prevent side effects. However, some research suggests that folic acid may interfere with methotrexate's effectiveness.
Methotrexate is usually given as pills. Patients who need higher doses can take it as an injection. Methotrexate has fewer serious toxic effects than many DMARDs. Although these severe reactions are rare, they may include:
- Bone marrow toxicity. Methotrexate can induce severe and sometimes fatal bone marrow suppression. This effect results in problems with blood cell formation and can lead to anemia or abnormally low levels of white blood cells or platelets.
- Kidney and liver damage. People at particular risk for liver damage from methotrexate include those with diabetes, obesity, and alcoholism. Patients should abstain from alcohol consumption while taking this drug.
- Increased risk for infections. Methotrexate should not be given to patients with active bacterial infections, active herpes-zoster viral infection, active or latent tuberculosis, or acute or chronic hepatitis B or C.
- Lung disease occurs in some people. People who have poor lung function are most at risk.
- The drug increases the risk for birth defects and should not be taken by pregnant women. However, methotrexate will not harm a woman's chance for future healthy pregnancies after she stops taking the drug.
Leflunomide (Arava, generic) blocks autoimmune antibodies and reduces inflammation. It also may inhibit metalloproteinases (MMP), which are involved in cartilage destruction. Leflunomide takes several weeks before improving joint pain or swelling. Full benefits may not occur until 6 to 12 weeks of treatment.
Leflunomide may be given alone or in combination with other DMARDs such as methotrexate. (This combination poses a risk for liver toxicity and requires monitoring.)
Side effects are similar to those of methotrexate, including nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and severe liver injury. Everyone taking leflunomide should be monitored regularly, including blood tests for liver function, and anyone with liver problems should not take this drug. Leflunomide should not be taken by patients with active bacterial infections, active herpes-zoster viral infection, active or latent tuberculosis, or acute or chronic hepatitis B or C. As with methotrexate, the drug increases the risk for birth defects and should not be taken by pregnant women. Patients should not drink alcohol while using leflunomide.
Hydroxychloroquine (Plaquenil, generic) was originally used for preventing malaria and is now also used for mild, slowly progressive rheumatoid arthritis. Hydroxychloroquine starts to improve symptoms within 1 to 2 months, but it may take up to 6 months to achieve full benefit. Hydroxychloroquine usually causes fewer side effects than other DMARDs but it does not appear to slow disease progression. The most common side effects are nausea and diarrhea, which typically improve over time or when the drug is taken with food. Less common side effects include skin rash or bleaching or thinning of hair.
This drug used to be associated with eye and vision problems, but with current lower doses this side effect is rare. If vision problems occur, it is usually with people taking very high doses, those with kidney disease, or those over 60 years of age. Still, patients should have an eye exam (including retinal examination) within the first year of treatment. Patients on Plaquenil should have frequent eye exams. Patients should notify their doctors if they experience any sudden changes in vision.
Sulfasalazine (Azulfidine, generic) works best when the disease is confined to the joints. Symptom relief occurs within 1 to 3 months.
Side effects are common, particularly stomach and intestinal distress, which usually occur early in the course of treatment. (However, serious gastrointestinal side effects, such as stomach ulcers, occur less frequently with sulfasalazine than with NSAIDs.) A coated-tablet form may help reduce side effects. Other side effects include skin rash and headache. Sulfasalazine increases sensitivity to sunlight. Be sure to wear sunscreen (SPF 15 or higher) while taking this drug. People with intestinal or urinary obstructions or who have allergies to sulfa drugs or salicylates should not take sulfasalazine.
Minocycline (Minocin, generic) is a tetracycline antibiotic that is generally reserved for patients with mild RA. It can take 2 to 3 months before symptoms begin to improve and up to a year for full benefit. Side effects include upset stomach, dizziness, and skin rash. Long-term use of minocycline can cause changes in skin color, but this side effect usually disappears once the medication is stopped. Minocycline can cause yeast infections in women. It should not be used by women who are pregnant or planning on becoming pregnant. Minocycline increases sensitivity to sunlight and patients should be sure to wear sunscreen. In rare cases, minocycline can affect the kidneys and liver.
Gold used to be a time-honored DMARD for RA but its use has decreased with the development of newer DMARDs and biologic drugs. Gold is usually administered in an injected form because the oral form, auranofin (Ridaura, generic), is much less effective. There are two injectable forms of gold: gold sodium thiomalate (Myochrysine, generic) and aurothioglucose (Solganal, generic). It can take 3 to 6 months before injections have an effect on RA symptoms. Gold injections can cause a number of side effects including mouth sores and skin rash and in rare cases more serious problems such as kidney damage.
Azathioprine (Imuran, generic) suppresses immune system activity. It takes 6 to 8 weeks for early symptom improvement and up to 12 weeks for full benefit. Azathioprine can cause serious problems with the gastrointestinal tract including nausea and vomiting, often accompanied by stomach pain and diarrhea. Azathioprine can also cause problems with liver function and pancreas gland inflammation and can reduce white blood cell count.
Like azathioprine, cyclosporine (Sandimmune, Neoral, generic) is an immunosuppressant. It is used for people with RA who have not responded to other drugs. It can take a week before symptoms improve and up to 3 months for full benefit. The most serious and common side effects of cyclosporine are high blood pressure and kidney function problems. While kidney function usually improves once the drug is stopped, mild-to-moderate high blood pressure may continue. Swelling of the gums is also common. Patients should practice good dental hygiene, including regular brushing and flossing.
Small Molecule DMARDs
Janus Kinase (JAK) Inhibitors
Janus kinase (JAK) inhibitors are a newer type of DMARD. Tofacitinib (Xeljanz) was the first in this new class of drugs. It works by blocking "Janus kinase" molecules involved in joint inflammation. Small molecule DMARDs might be an alternative to biologic DMARDs, and a new option for patients with moderate-to-severe RA who have not been helped by methotrexate. Three JAK inhibitors are currently approved and these are tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq). Several newer investigational drugs that work in a similar same way are being studied. These include Decernotinib, Fostamatinib, and Filgotinib.
Biologic Response Modifiers (Biologic DMARDs)
Biologic response modifiers are drugs made from living cells. These drugs target specific components of the immune system that contribute to the joint inflammation and damage that are part of the RA disease process.
Biologic DMARDs are generally used to treat moderate-to-severe RA. Some of these drugs are used as first-line treatments for RA. Others are used for patients who have not responded to DMARDs or other types of treatment. Depending on the specific drug, they may be used alone or in combination with the DMARD methotrexate. However, biologic response modifiers are not used in combination with each other, as this can lead to serious infections.
As with other RA drugs, these drugs do not cure the disease but can help slow progression and joint damage.
Most biologic DMARDs are anti-tumor necrosis factor (anti-TNF) drugs. They block TNF, which is a cytokine involved in the inflammatory process. Anti-TNF drugs approved for treatment of RA are:
- Etanercept (Enbrel)
- Infliximab (Remicade)
- Adalimumab (Humira)
- Golimumab (Simponi)
- Certolizumab (Cimzia)
Other Biologic DMARDs
Other biologic DMARDs approved for RA treatment are:
- Tocilizumab (Actemra) blocks interleukin-6 (IL-6), another type of immune factor.
- Abatacept (Orencia) is a T cell co-stimulation modulator, which blocks T cell activation.
- Rituximab (Rituxan) targets CD20-positive B cells and blocks their activation.
- Anakinra (Kineret) targets interleukin-1 (IL-1), but is not as used as often as the other biologic DMARDs.
- Sarilumab (Kevzara) targets the interleukin 6 (IL-6) receptor.
Side Effects and Complications
Etanercept, adalimumab, anakinra, golimumab, certolizumab, and abatacept come in pre-filled syringes and are given by injection under the skin (subcutaneous injection). This may cause pain at the injection site.
Infliximab, tocilizumab, abatacept, and rituximab are given by intravenous infusion in a doctor's office. Common infusion reactions include headache, nausea, and flu-like symptoms. Because biologic response modifiers affect the immune system, patients who take these drugs have an increased risk for infections.
Biologic DMARDs should not be taken by patients with active bacterial infections, active herpes-zoster (shingles) viral infection, active or latent tuberculosis, or active or chronic hepatitis B. Anti TNF drugs should be avoided in patients with acute hepatitis C infection or with chronic hepatitis C infection (treated or untreated) with significant liver injury. In addition, anti-TNF drugs should not be given to patients with a history of heart failure, a history of lymphoma, or who have multiple sclerosis or other demyelinating disorders.
Other risks associated with these drugs include:
- Anti-TNF drugs (etanercept, infliximab, adalimumab, golimumab, certolizumab) have been associated with sepsis (blood infections), pneumonia, tuberculosis, and other opportunistic and invasive fungal, bacterial, and viral infections. Other risks include non-melanoma skin cancer, lymphoma (Hodgkin disease and non-Hodgkin lymphoma), and other malignancies; lupus; heart failure; blood disorders (including aplastic anemia and leukemia); psoriasis; lung disease; and liver damage.
- Abatacept should be used cautiously in patients with chronic obstructive pulmonary disorder (COPD) as it may increase the risk for respiratory complications.
- Rituximab has been associated with cases of a rare and deadly brain disease called progressive multifocal leukoencephalopathy (PML). It also may cause hepatitis B reactivation, viral infections, heart rhythm disturbances, and other heart problems.
Corticosteroids, also called glucocorticoids or steroids, are powerful drugs that work rapidly to reduce inflammation. Steroids mimic the action of cortisol, a hormone produced naturally in the adrenal gland. For treatment of rheumatoid arthritis, corticosteroids may be given orally by mouth or by injection into a joint.
Oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone, generic) are often used in combination with DMARDs. Corticosteroids are often used early in the treatment of active RA since they act rapidly. As the DMARDS begin to reduce activity of RA, the corticosteroids are tapered off and stopped. They may also be used during an acute flare-up.
Side Effects of Oral Corticosteroids
Serious side effects are associated with long-term use of oral steroids. Doctors recommend taking as low a dose as possible. (However, side effects can still occur with daily use of low doses.)
Osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Other adverse effects include weight gain, fat deposits, fluid retention and swelling, increased appetite and weight gain, bruising, acne, high blood pressure, cataracts, glaucoma, diabetes, susceptibility to infections, muscle wasting, menstrual irregularities, and mood swings.
Withdrawal from Long-Term Use of Oral Corticosteroids
Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again.
No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctor measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Two-thirds of people with RA rank pain as their primary reason for seeking professional help. The most common pain relievers for RA are nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs block prostaglandins, the substances that widen blood vessels and cause inflammation and pain. There are dozens of NSAIDs:
- Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin, Advil, generic), naproxen (Aleve, generic), ketoprofen (Actron, Orudis KT, generic).
- Prescription NSAIDs include prescription forms of ibuprofen, naproxen, and ketoprofen, flurbiprofen (Ansaid, generic), diclofenac (Voltaren, generic), and tolmetin (Tolectin, generic). Meloxicam (Mobic, generic) is approved specifically for the management and treatment of rheumatoid arthritis. Duexis is a pill that combines ibuprofen and the H2 blocker famotidine (Pepcid, generic) that is also approved specifically for rheumatoid arthritis, and osteoarthritis.
Studies suggest that the best times for taking an NSAID may be after the evening meal and then again on awakening. RA symptoms increase gradually during the night, reaching their greatest severity at the time of awakening. Taking NSAIDs with food can reduce stomach discomfort, although it may slow the pain-relieving effect.
Long-term, regular use of NSAIDs (with the exception of aspirin) can increase the risk for heart attack, especially for people who have a heart condition. Long-term use of NSAIDs also increases the risk for ulcers and gastrointestinal bleeding. This risk can be reduced by taking antacid medication such as omeprazole (Prilosec, generic) along with the NSAID. To reduce the risks associated with NSAIDs, take the lowest dose possible for pain relief.
Other possible side effects of NSAIDs may include:
- Upset stomach
- Diarrhea or constipation
- Skin bruising
- High blood pressure
- Fluid retention
- Reduced kidney function
COX-2 Inhibitors (Coxibs)
Coxibs inhibit an inflammation-promoting enzyme called COX-2. This drug class was initially thought to provide benefits equal to NSAIDs but cause less gastrointestinal distress. However, following numerous reports of heart problems, skin rashes, and other adverse effects, the FDA re-evaluated the risks and benefits of COX-2 inhibitors. Several coxib drugs were removed from the United States market. Celecoxib (Celebrex) is still available, but patients should ask their doctors whether the drug is appropriate and safe for them. Like all NSAIDs, celecoxib has a "black box" warning on its prescribing label that it may increase the risk for heart attack, stroke, and serious stomach problems.