Rheumatoid Arthritis

Description

Alternative Names

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 agents 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). One study suggested that ibuprofen or naproxen is more effective than aspirin or acetaminophen for acute tension-type headache.
• Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil).

Studies have indicated that the optimal times for taking an NSAID might be after the evening meal and then again on awakening. The reason for this is 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.

Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been associated with the following side effects:

• Ulcers and gastrointestinal bleeding. This is the major danger with long-term use of NSAIDs.
• Increased blood pressure. Most NSAIDs appear to pose this risk, with higher risks observed with piroxicam (Feldene), naproxen (Aleve), and indomethacin (Indocin). (Sulindac has the smallest effect and aspirin as no risk.) People with hypertension, severe vascular disease, kidney, or liver problems and those taking diuretics must be closely monitored if they need to take NSAIDs.
• May delay the emptying of the stomach, which could interfere with the actions of other drugs. The elderly are at special risk.
• Dizziness.
• Tinnitus (ringing in the ear)
• Headache.
• Skin rash.
• Depression.
• Confusion or bizarre sensation (in some higher-potency NSAIDs, such as indomethacin).
• As with acetaminophen, high daily doses of aspirin have been associated with an increased risk of kidney failure, although the risk remains low in those with healthy kidney function. Kidney abnormalities have been reported in people taking other NSAIDs as well, which resolve when the drugs are withdrawn. Any sudden weight gain or swelling should be reported to a physician. Anyone 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.

Some studies have reported that ibuprofen (but not other NSAIDs) may blunt the heart-protective effects of low-dose aspirin. Additional research is needed to confirm these findings.

COX-2 Inhibitors (Coxibs). Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) are known as COX-2 (cyclooxygenase-2) inhibitors, or coxibs. They inhibit an inflammation-promoting enzyme called COX-2. Meloxicam (Mobicox) is a related drug known as a COX-2 preferential.

Most studies have found coxibs to be about equally effective to each other (and to NSAIDs) for allaying arthritic pain of osteoarthritis. Furthermore, evidence is increasing that the coxibs are somewhat less harmful to the GI tract than the common NSAID naproxen. Celebrex may be superior to Vioxx in this regard, although more studies are needed to confirm this. Some early evidence also suggests that, like NSAIDs, they may be partially protective against colon cancer and possibly even Alzheimer's disease.

In spite of their potential promise, some researchers theorize that inhibiting COX-2 may have some negative side effects over the long term. The effects of these drugs on the heart particularly require clarification. The following are possible adverse effects or complications:

• Some studies have reported twice the incidence of heart attacks in patients taking Vioxx compared to those taking standard NSAIDs. There were limitations to these studies, however, and 2003 study found no higher risk. Some (but not all evidence) suggests that the COX-2 inhibitors may increase the risk for blood clots. On the other hand, some studies have suggested that the anti-inflammatory effects, at least in Celebrex and meloxicam (Movicox) may have beneficial effects on blood vessels, which would be heart protective.
• In one study, people who took Celebrex or Vioxx experienced an increase in blood pressure, with Vioxx having the greater effect.
• A few cases of psychiatric side effects (hallucinations) have been observed with higher doses of Celebrex or Vioxx.
• Coxibs may have some adverse effects on kidney function, particularly in elderly people, which is similar to the effects of standard NSAIDs. Liver abnormalities, which are side effects of many drugs, have also been reported with coxibs and need further follow-up.
• They may have negative effects on pregnancy and fertility.
• No one who has allergic reactions, hives, or asthma from sulfa drugs, aspirin, or other NSAIDs should take a coxib. For example, life-threatening and wide spread reactions have been reported in patients taking valdecoxib (Bextra). Anyone who develops a rash after taking these agents should stop taking them immediately.
• Coxibs can interfere with other drugs taken concurrently. Patients taking anticoagulant drugs such as warfarin may experience a higher risk for bleeding with the use of these agents. The use of coxibs can interfere with many other drugs taken concurrently, including lithium, methotrexate, and many others taken for heart disease, high blood pressure, or epilepsy. Patients should discuss all other medications with their physician. Patients should discuss all other medications with their physician.

COX-2 inhibitors are also currently more expensive than traditional NSAIDs, however, costing about $80 per month, compared to about $15 for an NSAID like naproxen, and some insurers do not pay for them. More research is needed to confirm or refute any possible hazards from taking coxibs and also to determine whether their benefits are worth the higher cost.

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 five-year 2001 study published in 2001 that compared RA progression rates in patients from different countries. The slowest disease progression rates were observed in patients from Finland, who were given the most effective DMARDs immediately upon diagnosis. The worst and most rapid progression occurred in patients from Sweden, who tended to be given less potent DMARDs and whose treatment was delayed by three months. This group also tended to stay on treatment for shorter duration (two years) compared to the Finnish group (the majority was treated for five years).

There is also some evidence that early use of DMARDs may help protect against heart problems, which are major complications 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. They include the following:

• Methotrexate (considered to be the current standard of care. Newer agents 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, they all tend to lose effectiveness over time, even methotrexate. Patients rarely use one for more than two years. It is now apparent that 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) acts as an anti-inflammatory agent 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%s compared to other DMARDs. (Death rates from other causes were also lower, although less significantly.)

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

• 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.)
• Combinations with the newer agents, the tumor-necrosis factor (TNF) modifiers 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 has fewer serious toxic effects than many DMARDs, although rare, they can include the following:

• 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. (Taking folate supplements may be very helpful in reducing liver toxicity as well as relieving less serious side effects, although folate may interfere slightly with the effectiveness of methotrexate.)
• Possibly osteoporosis 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 report 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 agent.

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 six 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 agent 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.

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 beneficial for both adult and juvenile RA. (It is most effective when the disease is confined to the joints.)

Symptomatic relief can occur in four weeks. A 1999 study suggested that sulfasalazine was more effective than hydroxychloroquine and had fewer side effects than gold therapy (although also possibly fewer benefits).

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 three to six months to achieve full benefit. It also does not appear to slow disease progression. One study concluded that joint erosion after two 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 six 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 agent when used in combinations or as a sole agent 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, physicians are now prescribing third-line drugs that suppress the body's immune system. These agents include the following:

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

All 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 agents, 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.

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 physician first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their physician 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 agents (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 two-year 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.

Studies have reported that all these agents 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 agents, they do not cure the disease, although some evidence suggests they may slow or even halt joint erosion. For example, in a 1999 study on children with RA taking etanercept, 30% returned to fully normal activities.

Because TNF modifiers are very expensive (for example, $14,000 per year), 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 side effects of the three agents are similar, but there are some differences between etanercept and the two monoclonal antibodies:

• The most common adverse effects of all three are minor reactions at the injection site, but there are few other immediate side effects.
• Because these agents affect immune factors, there is some risk for severe infections particularly in susceptible individuals, such as those with uncontrolled diabetes, people taking other immunosuppressants, or anyone with a current active infection. For example, cases of tuberculosis and histoplasmosis (a fungal infection in the lungs) have been reported in patients taking TNF-modifiers. (While millions of healthy people unknowingly carry the TB organism, it rarely becomes active in those with healthy immune systems.) RA patients should be tested for TB before initiating treatment. It is not yet known if adalimumab poses as high a risk as infliximab.
• There have been a few reports of aplastic anemia.
• In rare cases, both etanercept and infliximab have been associated with nerve damage that resembles the disease process in multiple sclerosis. This involves demyelination (the loss of myelin, the insulation coat over nerve fibers) and can result in confusion, numbness, changes in vision, and difficulty walking. According to some experts, patients with multiple sclerosis should avoid these agents until further research is complete. (The effects of adalimumab are not known yet.)
• There have been reports of a lupus-like symptoms in a few patients taking etanercept, which resolved when the drug was stopped.
• Many patients develop an immune reaction to infliximab itself, which makes the drug less effective overtime. Nevertheless, in one study, benefits persisted for at least two years after stopping the drug. Although adalimumab is a similar agent, it is a fully human molecule and, therefore, may not provoke the immune response that infliximab does. Long-term studies are needed to confirm this.
• Infliximab has been linked to a few deaths in patients with pre-existing congestive heart failure.
• There is some suggestion that anti-TNF drugs increase the risk for lymphomas.

Interleukin-1 Antagonists

Drugs that inhibit the interleukin cytokines are also in development. Anakinra (Kineret) is the first of these. It is an intravenous agent 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 Remicade and Enbrel--the tumor-necrosis factor modifiers. The decisions to use it will depend on cost and individual side effects. 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

Investigative Biologic Response Modifiers. A number of other agents that inhibit part of the immune response are being investigated:

• Other tumor necrosis factor blockers.
• Agents that block specific chemical pathways involved with RA. For example, eculizumab (Alexion) is a monoclonal antibody that blocks an immune factor called human complement component C5, which plays a pro-inflammatory role.
• Vaccines that use anti-inflammatory factors to boost the immune systems response against the aberrant immune factors.

Tetracyclines. Tetracycline antibiotics are of interest because they have anti-inflammatory actions and because some cases of RA may be triggered initially by an infection. Minocycline, one of the tetracyclines being studied, has achieved mixed results. In a favorable 2001 study, 60% of patients taking the agent reported improvement compared with 33% taking the DMARD hydroxychloroquine. An earlier study even suggested that many patients may achieve long-term remission if the medication is administered early in the disease. (Studies on doxycycline, another tetracycline, have reported no benefits.)

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.

Oral Collagen Therapy. Oral type II collagen therapy is based on the theory that by consuming a foreign substance orally, the body will slowly become tolerant to it and will not launch an immune attack against it. Oral collagen (which is consumed in tablet form) appeared to slow the autoimmune process in small 2001 studies on adults and young people with juvenile RA. In one of the studies, 90% of recipients reported improvements in symptoms.

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

Hormonal Treatments. Some research is investigating the use of dehydroepiandrosterone (DHEA), a mild male hormone, which has anti-inflammatory effects and which is reduced in RA.

Although estrogen is commonly associated with heightened immune factors, some autoimmune diseases, including RA, improve during pregnancy when levels of estriol, a form of estrogen, are high. (Estriol levels are low at other times.) Investigators are testing estriol on patients with autoimmune diseases. Long-term use may have adverse effects, however, and further research is needed.

NO-NSAIDS. Experimental agents are being developed that combine nitric oxide with NSAIDs (NO-NSAIDs). Combining nitric oxide with NSAIDs may prevent gastrointestinal problems and provide benefits similar to the COX-2 inhibitors.

Licofelone. Licofelone is drug that inhibits both the COX enzyme plus an inflammatory substance called Lipoxygenase 5. Early trials indicate they may be effective and safer than either NSAIDs or COX-2 inhibitors, though further study is needed

Kappa Opioids. Opioids are powerful pain relievers but are not regularly used in RA because of their side effects and risk for dependency. Of some interest, however, are specific agents known as kappa opioids, such as asimadoline, that work in the peripheral nervous system (which affects the limbs in the body not the brain). Some evidence now suggests that they are powerful anti-inflammatory agents and in one study a kappa opioid reduced arthritic pain by 80%. More research is warranted.