Medications

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Two-thirds of people with RA ranked pain as their primary reason for seeking professional help. The most common pain relievers for RA are the nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs. The most common pain relievers are the following:

• Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
• Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil). In 2004, a new NSAID, meloxicam (Mobic) was approved in the U.S. for the management and treatment of rheumatoid arthritis.

Studies have indicated that optimal 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 down the pain-relieving effect.

In April 2005, the FDA asked drug manufacturers of prescription NSAIDs to include with their products the same warning label used for the COX-2 inhibitor celecoxib (Celebrex). This "black box" warning, the FDA's strongest warning, emphasizes the increased risks for cardiovascular events and gastrointestinal bleeding associated with these drugs’ use. The FDA also requested manufacturers of OTC NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and gastrointestinal risks. Due to its proven cardiovascular benefits, aspirin was excluded from these labeling revisions.

Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been associated many side effects. Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers and gastrointestinal bleeding. See Box: NSAID-Induced Ulcers and Gastrointestinal Bleeding.)

Other possible side effects of NSAIDs include:

• Increased blood pressure
• Dizziness
• Tinnitus (ringing in the ear)
• Headache
• Skin rash
• Depression
• Confusion or bizarre sensation (in some higher-potency NSAIDs, such as indomethacin)
• Increased risk of kidney failure (associated with high dose aspirin and other NSAIDs; risk low in those with healthy kidney function; tell your doctor about sudden weight gain or swelling; people with kidney disease should avoid these drugs)

Diabetics taking oral hypoglycemics may need to adjust the dosage if they also need to take NSAIDs because of possible harmful interactions between the drugs.

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 with less gastrointestinal distress. However, following numerous reports of cardiovascular events, skin rashes, and other adverse effects, the FDA is currently re-evaluating the risks and benefits of this drug class. At the time of this report, rofecoxib (Vioxx) and vadecoxib (Bextra) have been withdrawn from the United States market. Celecoxib (Celebrex) is still available, but patients should ask their doctor whether the drug is appropriate and safe for them.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Disease-modifying anti-rheumatic drugs (DMARDs) are the standard second line drugs. Early treatment with DMARDs improves patients' long-term outcome and quality of life and may also help slow down progression of the disease. Evidence supporting early use was reflected in a 5-year study that compared RA progression rates in patients from different countries. The slowest disease progression rates were observed in patients who were given the most effective DMARDs immediately upon diagnosis. The worst and most rapid progression occurred in patients who were given less potent DMARDs and whose treatment was delayed by 3 months.

There is also some evidence that early use of DMARDs may help protect against heart problems, a major complication of RA.

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 (considered to be the current standard of care. Newer drugs called biologic modifiers, however, are proving to be as effective with fewer side effects when used alone, and even more effective when used in combination with methotrexate.)
• Hydroxychloroquine
• Sulfasalazine
• Gold
• D-penicillamine
• Cyclosporine
• Leflunomide

Unfortunately, all DMARDs tend to lose effectiveness over time, even methotrexate. Patients rarely use one drug for more than 2 years. Combining DMARDs with each other or with drugs in other categories offers the best approach for many patients. The addition of a corticosteroid to any combination may be important.

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. Methotrexate (Rheumatrex, Trexall) acts as an anti-inflammatory drug and is now the most frequently used DMARD, particularly for severe disease. It has the following advantages over other DMARDs:

• A faster mode of action than other DMARDs (starts working within a few weeks).
• The best record to date for long-term use.
• A 2002 study suggested that it reduced mortality rates from heart disease by 70% compared to other DMARDs. (Death rates from other causes were also lower, although less significantly.)
• A 2005 study indicated that methotrexate may be more effective than leflunomide for treatment of juvenile rheumatoid arthritis.

Even this drug loses effectiveness, however, when used alone. It is more effective when used in combination with other DMARDs or drugs. Studies indicating effective combinations suggest:

• Using it with cyclosporine and a corticosteroid may be effective and allow lower doses of methotrexate, thereby minimizing side effects. (Methotrexate has a wide range of actions against the immune system, while cyclosporine is fairly specific; it prevents T cells from proliferating.)
• The combination of methotrexate and leflunomide (which has different effects on the immune system) is very effective compared to methotrexate alone. (This combination poses a risk for liver toxicity and requires monitoring.)
• Methotrexate may reduce the risk for vascular disease among patients with RA. A retrospective study found that that this protective effect was stronger when methotraxate was administered along with folic acid.
• Combinations with the newer drugs, the tumor-necrosis factor (TNF) modifiers (such as infliximab) and the interleukin-1 antagonist anakinra, are considered the best therapy.

About 20% of patients withdraw because of 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 has fewer serious toxic effects than many DMARDs. Although these severe reactions are rare, they may include:

• Kidney and liver damage. People at particular risk for liver damage from methotrexate include diabetics with existing liver or kidney problems, alcoholics, those who are obese, the elderly, and (at very high risk) those with psoriasis.
• Osteoporosis may possibly develop at high doses. (A 2001 study reported no higher risk for bone loss at low doses.)
• Increased risk for infections, particularly herpes zoster and pneumonia.
• Lung disease occurs in up to 5% of people who take methotrexate and deserves special mention. There are five key risk factors for methotrexate-induced lung diseases: Age, diabetes, existing rheumatoid involvement in the lung, protein in the urine, and previous use of other DMARDs, (particularly sulfasalazine, oral gold and d-penicillamine). Patients with multiple risk factors should notify their doctor about any symptoms, such as coughing, that might indicate lung injury.
• The drug increases the risk for birth defects when taken by pregnant women.
• There have been a few reports of lymphomas in some patients taking methotrexate. In such cases, the disease appears to go into remission when the drug is stopped. Most studies have found no significant risk for cancer in patients taking this drug.

Leflunomide. Leflunomide (Arava) blocks autoimmune antibodies and reduces inflammation. It also may inhibit metalloproteinases (MMP), which are involved in cartilage destruction. It has the following benefits:

• It is the first oral treatment approved for RA.
• It slows disease progression as early as 6 months into treatment.
• Comparison studies with methotrexate report a better quality of life with leflunomide, including more energy, greater vitality, and fewer emotional side effects. (Studies comparing their risk for serious adverse effects are mixed. One, for example, showed fewer problems with leflunomide, while another reported identical rates.)

The combination of methotrexate and leflunomide (which has different effects on the immune system) is very effective compared to either drug alone. (This combination poses a risk for liver toxicity and requires monitoring.)

Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects infections and liver injury. Everyone taking leflunomide should be monitored regularly, and anyone with liver problems should avoid this drug until further research has determined its full effects. A 2005 study found that monitoring serum concentrations of A77 1726, the active metabolite of leflunomide, could help predict treatment response.

Sulfasalazine. Sulfasalazine (Azulfidine) was developed in the 1930s for treating rheumatoid arthritis, but fell into disfavor when gold treatment emerged. It has regained popularity, however, and is now used for both adult and juvenile RA. It works best when the disease is confined to the joints. Symptom relief can occur in 4 weeks.

Side effects are common, particularly stomach and intestinal distress. A coated-tablet form may help reduce them. Other side effects include skin rash, sensitivity to sunlight, and, in rare cases, lung problems. People with intestinal or urinary obstructions or who have allergies to sulfa drugs or salicylates should not take sulfasalazine.

Hydroxychloroquine. Hydroxychloroquine (Plaquenil) was originally used for preventing malaria and is now also used for mild, slowly progressive arthritis. It has the following benefits:

• Relieves pain
• Improve mobility
• Has one of least toxic profiles of the DMARDs

The downside is that it takes 3 - 6 months to achieve full benefit. It also does not appear to slow disease progression. One study concluded that joint erosion after 2 years was worse than with no DMARD at all.

As with all DMARDs, gastrointestinal complaints are fairly common. Mild headaches and eye problems may be more common with this drug than with others. The most serious side effect is damage to the retina, although this is very uncommon when low doses are used and can be reversed if treated in time. Some experts recommend eye examinations every 6 months in people over 60 who take hydroxychloroquine. It may aggravate psoriasis, and it poses a slight risk for birth defects.

Gold. Gold has been a long-standing DMARD for rheumatoid arthritis. Rather than suppressing immune factors that cause inflammation, research in 2002 suggests that it may stimulate specific protective factors.

It can be administered in one of two ways:

• Orally as auranofin (Ridaura). The oral form has fewer side effects but is less effective than the injected form.
• Injected (known as chrysotherapy). This form uses either gold sodium thiomalate (Myochrysine) or aurothioglucose (Solganal). Although injected gold used to be the favorite second-line drug, it is generally used for mild, slowly progressive cases.

Side effects differ according to the method of administration:

• Oral gold can cause skin rash and mouth sores as well as stomach irritation. About 50% of people taking oral gold experience diarrhea, which can be offset by reducing the dosage or taking bulk formers, such as Metamucil.

Injected gold is the most toxic of all the DMARDs during early stages of treatment, and in one study 43% of the patients stopped taking it. (Nevertheless, over the long term, it may be among the least toxic.) The injected form can cause skin problems and sores in the mucous membranes in about 20% of people. The most serious side effects of gold injections are kidney damage and decreased white blood cell count. Women who are pregnant or people with major medical conditions of the heart, kidney, liver, skin, and blood should be very cautious about using this therapy.

Penicillamine. It may take up to a year for penicillamine (Cuprimine, Depen) to be effective in reducing the effects of RA, and its use is declining. More than half the patients who take it withdraw because of side effects. It causes stomach and intestinal side effects similar to those of gold. In addition, it may leave the patient with a metallic taste in the mouth or, even, no taste at all. Other side effects include inflamed muscles, skin blisters, and fever. Serious side effects include liver and kidney damage and problems in the lungs.

Cyclosporine. Cyclosporine (Sandimmune, Neoral) is actually an immunosuppressant that started out as a third-line drug. It has proven to be an effective and safe drug when used in combinations or as a sole drug for RA, however, so it is now often listed as one of the DMARDs. It is particularly effective when used in combination with methotrexate.

Side effects include gum disease, hair growth, and flare-ups in the joints, but they are usually manageable. There has been some concern over reports associating cyclosporine with an increased risk for cancer, but one controlled study found no such danger.

Immunosuppressants

For treatment of very severe active rheumatoid arthritis, doctors are now prescribing third-line drugs that suppress the body's immune system. These drugs include the following:

• Azathioprine (Imuran)
• Cyclophosphamide (Cytoxan)
• Chlorambucil (Leukeran)

Azathioprine is the most commonly used of these drugs, with the most usual side effects being stomach and intestinal distress, skin rash, mouth sores, and anemia. All three, however, are potentially very toxic and should not be used unless other drugs are ineffective. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants. Blood counts should be taken frequently to check for anemia and more serious blood problems. Some increase in certain cancers has been associated with the use of some of these drugs, such as lymphoma with azathioprine and bladder cancer with cyclophosphamide, although the benefits of these therapies in patients with severe disease may outweigh any risk.

Corticosteroids (Steroids)

Corticosteroids work rapidly to control inflammation and pain and are about as effective as aspirin for RA. Long-time use, however, can have severe adverse effects. Still, they are often used under the following conditions:

• Oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone), are most often used in combination with DMARDs, which significantly enhances the benefits of DMARDs.
• Oral corticosteroids are sometimes used in early stage-RA for patients who cannot tolerate NSAIDs. Studies, in fact, suggest that low-dose corticosteroids may significantly slow joint when it is the first drug administered and then used for two years. (Even low-dose oral steroids have adverse effects on bone density, blood sugar, and weight.)
• Corticosteroids are sometimes injected directly into joints for relief of flare-ups when only one or a few joints are affected. Experts suggest no more than three or four injections a year. Steroid injections in the joints may be a safe and effective treatment for juvenile rheumatoid arthritis and reduce the need for oral medications.
• Corticosteroid pulse therapy (intravenous administration) may be as beneficial as DMARDs.

Side Effects of Oral Corticosteroids. Serious side effects are associated with long-term use of oral steroids. (Low doses may reduce these risks but they do not eliminate them.) Osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, or bisphosphonates (alendronate etidronate, risedronate). Other adverse effects include cataracts, glaucoma, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and, rarely, psychosis. Recent research suggests that prednisone can increase the risk of developing non-melanoma skin cancer.

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 so-called 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. There have been a few cases of severe adrenal insufficiency that occurred when switching from oral to inhaled steroids, which, in rare cases, has resulted in death.

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.

Tumor-Necrosis Factor Modifiers

Tumor-necrosis factor (TNF) modifiers are major breakthroughs in the treatment of RA. The current drugs (known generally as biologic response modifiers) include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are genetically engineered to interfere with specific components of TNF, a powerful immune factor that is important in the disease process. Although they all block TNF, these drugs have some differences:

• Etanercept (Enbrel) is a protein made from the fusion of two TNF receptors. The end product mimics their effects, which neutralize TNF. A 2002 study suggested it is superior to methotrexate in slowing RA disease progression and has fewer side effects. It has been approved for RA, juvenile RA, and psoriatic arthritis.
• Inflixamab (Remicade) and adalimumab (Humira) are both monoclonal antibodies (MAbs), which are specially designed antibodies that target TNF. In one study, infliximab was superior to methotrexate, gold, corticosteroids, and a interleukin-1 receptor antagonist. Humira, the latest TNF modifier is the first fully human anti-TNF MAb, which may reduce some of the problems of infliximab. Humira is used alone or in combination with methotrexate or other DMARDs.

Studies have reported that all these drugs work rapidly and produce significant and sustained improvements. Combinations with methotrexate increase their effectiveness. The combinations may have fewer side effects than using methotrexate alone at higher doses. As with other drugs, they do not cure the disease, although some evidence suggests they may slow or even halt joint erosion.

The combination of adalimumab and the interleukin-1 antagonist anakinra (Kineret) has produced cases of serious infection. The FDA advises against this drug combination and the use of anakinra with other TNF modifiers.

Because TNF modifiers are very expensive, insurers will pay for them only if patients first fail to respond to full-dose weekly methotrexate.

By neutralizing TNF-A, these drugs may increase the risk of certain fungal and mycobacterial infections, including tuberculosis. These conditions are serious but respond to prompt, aggressive anti-infection therapy.

Side Effects and Complications of Tumor-Necrosis Factor Modifiers. Because TNF modifiers target precise molecular targets, they have fewer widespread effects on the body than general immunosuppressants. Nevertheless, there are concerns and some evidence that suppressing TNF can create long-term problems, including infections and nerve injury. The most common side effects are reactions at the injection site. To prevent injection reactions, patients are sometimes pretreated with betamethasone, a corticosteroid drug, but some research suggests that the steroid does little good. TNF modifiers have warnings regarding serious adverse events:

• Sepsis and pneumonia
• Tuberculosis
• Lymphomas and other malignancies
• Lupus and lupus-like syndrome
• Heart failure
• Blood disorders (including aplastic anemia)
• Liver damage

According to recent studies, TNF modifiers may increase the risk of non-melanoma skin cancer.

Interleukin-1 Antagonists

Drugs that inhibit the interleukin cytokines are also in development. Anakinra (Kineret) is the first of these. It is an intravenous drug that blocks interleukin-1, an important immune factor. It is showing good results when used in combination with DMARDs, such as methotrexate. A 2002 study suggested that it is similar in effectiveness to tumor necrosis factor modifiers. Primary side effects of Kineret include pain at the injection site and leukopenia--a reduction in white blood cell counts that increases the risk for infections.

Investigative Treatments

Biologic Drugs. Despite their initial promise, many patients fail to respond to TNF-modifiers. Researchers are developing novel drugs that target different aspects of the disease process. For many years, therapeutic treatment of rheumatoid arthritis focused on T cell mediation. New research is now examining the role of B cells, which become overactive in autoimmune disease, and how B-cell depletion may help to reduce disease activity. Other areas of intense research include interleukin receptor antagonists which target cytokines involved in the inflammatory process. Many of the current investigative drugs are monoclonal antibodies (MAbs), biologic drugs that are designed to target specific receptors. Promising candidates in late-stage research include:

• Rituximab (Rituxan/MabThera) targets and depletes CD20 positive B cells. In Phase III trials, a single treatment (two infusions) of rituximab, combined with methotrexate, produced symptom improvement in patients with moderate to severe RA who had failed to respond to anti-TNF therapies.
• CTLA4-Ig (Abatacept) is the first drug in a new class known as selective T-cell co-stimulation modulators. The drug blocks T-cell activation. Phase III trials of patients who have failed to response to methotrexate have yielded positive results.
• Tocilizumab (Actemra) targets the IL-6 receptor. In Phase III trials, the drug worked better than DMARDs in slowing joint destruction.
• AMG-714 is a monoclonal antibody that targets the IL-15 receptor. In a Phase II/III trial of patients who had not responded to DMARD treatment, AMG-714 reduced disease symptoms.
• HuMax-CD20, like rituximab, regulates CD20 B-cell activity. It is currently in Phase II trials.
• Belimumab (Lymphostat-B) also focuses on B-cell depletion. The drug is in Phase II trials and is also being investigated for treatment of lupus.
• Golimumab (CNTO 148) targets tumor necrosis factor alpha. In a Phase II trial, 62% of patients treated with golimumab and methotrexate experienced at least 20% improvement in RA symptoms, and 27% achieved remission.

Thalidomide. Thalidomide inhibits tumor necrosis factors and other cytokines. It also reduces the formation of new blood vessels that allow the disease to progress. Although it was notorious in the past for causing birth defects, it is now being investigated for many diseases, including rheumatoid arthritis. Severe adverse effects, however, may outweigh any benefits.

Statins. Interesting research is suggesting that compounds derived from statins, the highly regarded cholesterol-lowering drugs, may suppress inflammation responsible for RA damage.

Chinese herbal medicine. The NIH is conducting a clinical trial to compare the clinical effects of the Chinese herb Tripterygium wilfordi Hook F (TwHF) with the pharmaceutical drug sulfasalazine. TwHF is traditionally used in Chinese medicine for its anti-inflammatory properties.