Rheumatoid arthritis

 | April 1, 2008

Rheumatoid arthritis

The treatment of rheumatoid arthritis has changed dramatically since the 1990s, owing to a better understanding of how to slow the progression of joint damage in this disease. Advances in treatment, discussed below, followed decades of research into how the immune system functions.

Until the mid-1960s, physicians lumped together most forms of arthritis that affected four or more joints as rheumatoid arthritis. Then researchers identified rheumatoid factor, an antibody present in the blood of 70%–80% of people with rheumatoid arthritis. The presence or absence of rheumatoid factor helped physicians distinguish rheumatoid arthritis from other types of inflammatory arthritis that may occur in people who have psoriasis, inflammatory bowel disease, or infectious diseases. Rheumatoid factor may also help distinguish between rheumatoid arthritis and osteoarthritis, because people with osteoarthritis are no more likely to have rheumatoid factor than the general population.

Rheumatoid arthritis is a chronic autoimmune disease in which the body's immune system attacks healthy tissue lining the joints. It affects about three million Americans, and strikes two to three times more women than men. Although the disease usually first appears during middle age, it may occur in the 20s and 30s. Some children develop a similar disease, called juvenile chronic arthritis, but this is considered a separate disorder.

The chronic inflammation of rheumatoid arthritis begins in the synovium, where an unknown event triggers an inflammatory reaction. As a result, synovial and other cells produce cytokines, other chemical mediators, and proteolytic enzymes, which together can destroy all the components of the joint. The synovial tissue also begins to proliferate, causing the normally smooth synovium to form pannus, a rough, grainy tissue that grows into the joint cavity and erodes cartilage (see Figure 7). If the tendons become inflamed, they may shorten and immobilize the joint, which can cause bone fusion and loss of mobility. If the tendons rupture, the joint may become loose or floppy.

Rheumatoid arthritis can affect connective tissue in other parts of the body. Inflammatory skin nodules at pressure points, such as the elbow, can appear gradually or suddenly, and may be tender and sometimes inflamed. Occasionally, surgery is needed if these nodules become infected or are bothersome during activity. At times, they may also disappear spontaneously.

Vasculitis (inflammation of blood vessels) can compromise circulation to the hands, feet, and nerves. People with rheumatoid arthritis often develop eye conditions, including keratoconjunctivitis sicca, or dry eye, which causes redness, burning, itching, reduced tearing, and sensitivity to light. Other complications include respiratory, heart, and neurologic disorders. In rare cases, the ligaments that tether the uppermost vertebrae (which support the skull) are damaged, allowing the vertebrae to slip out of alignment and pinch the spinal cord.

At advanced stages, rheumatoid arthritis can limit a person's ability to carry out normal daily activities such as dressing, bathing, and walking. Those affected often experience feelings of depression and helplessness as the disease progresses. However, medications are now helping to slow the progression of rheumatoid arthritis and make a dramatic difference in the lives of many of those affected.

One of the most important steps you can take if you are diagnosed with the disease is to become an active participant in your own care. This includes working with your doctor so that you can learn to recognize flare-ups and drug side effects, take medication as prescribed, and engage in activities to maintain joint function in order to prevent disability. Balancing rest with activity, dealing with the emotional impact of rheumatoid arthritis, and using splints or assistive devices to protect your joints against overuse are among the most helpful coping strategies (see "Physical and complementary therapies"). The ultimate goals in managing rheumatoid arthritis are to prevent or control joint damage, prevent loss of function, and decrease pain.

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Possible causes of rheumatoid arthritis

Scientists don't know what causes rheumatoid arthritis, but they are investigating many hypotheses. The disorder runs in families, is more common among women, and may initially resemble some forms of infectious diseases, such as viral arthritis.

Genetic factors. Rheumatologists have long theorized that some insult (perhaps a microbe or an environmental toxin) triggers rheumatoid arthritis in genetically susceptible people. Now geneticists believe that HLA genes may provide the link. HLA-DR genes — of which several dozen have now been identified — are instrumental in identifying and disposing of foreign antigens. Scientists reported in 1978 that 70% of people with rheumatoid arthritis had molecules of certain DR4 subsets on their lymphocytes, while only 28% of healthy subjects had such molecules. Subsequently, several other genes in the HLA family have been implicated as well.

Infectious agents. Scientists have searched — without success — for evidence that individuals with rheumatoid arthritis might harbor certain bacteria known to cause other types of arthritis, such as Mycoplasma (which causes pneumonia or genital infections) or Chlamydia (one of several sexually transmitted organisms that can cause Reactive Arthritis). A more likely role for bacteria would be through an immune system error: Lymphocytes might produce antibodies against a bacterial product that also react against a connective tissue protein. Other researchers believe that a virus is the most likely culprit.

This form of arthritis attacks multiple joints and is usually symmetrical — it affects joints similarly on both sides of the body, particularly the finger joints, base of the thumbs, wrists, elbows, knees, ankles, or feet. It nearly always involves the wrists and the middle and large knuckles, but seldom the joints nearest the fingertips (see Figure 8). At times, joint pain may be constant, even without movement. Morning stiffness that lasts for an hour or longer is a hallmark of the disease and one of the main ways doctors gauge the severity of inflammation.

The course of rheumatoid arthritis is unpredictable. Early on, the symptoms frequently abate or even disappear, only to flare up weeks or months later. Occasionally complete remission occurs, usually within the first year. But for some people the process is destructive, ending in severe disability within a few years.

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Diagnosing rheumatoid arthritis

People who have symptoms of arthritis should have a complete medical evaluation (see "Diagnosing arthritis"). The symptoms and physical examination are the most important parts of the diagnostic process. The early joint symptoms of other conditions, such as lupus, are sometimes indistinguishable from those of rheumatoid arthritis, making a definitive diagnosis difficult soon after symptoms start. Blood and imaging tests are often ordered to help with diagnosis.

It's important to understand that it may take several weeks (and several visits) before you receive a definite diagnosis. People often find it frustrating to wait, and they worry that they are not receiving prompt treatment. But you may find it reassuring to know that a few weeks' delay will not jeopardize your health, whereas undergoing the wrong therapy could.

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Blood tests for rheumatoid arthritis

Your doctor may order several types of blood tests, because no one test is sufficient to confirm a diagnosis.

Rheumatoid factor. The majority (70%–80%) of people with rheumatoid arthritis have an abnormal antibody called the rheumatoid factor in their blood, so you will probably undergo a simple blood test for this antibody. Just be aware that if rheumatoid factor is detected in your blood (meaning the test is positive), it doesn't necessarily mean that you have rheumatoid arthritis. About 10% of people who do not have rheumatoid arthritis will test positive for rheumatoid factor. Such people may either be perfectly healthy or suffering from another disorder such as systemic lupus erythematosus (see "Related disorders"). At the same time, some people with rheumatoid arthritis will test negative for rheumatoid factor. Thus your doctor is likely to order additional blood tests to look for causes of joint pain.

Anti-CCP. The anticitrullinated cyclic protein (anti-CCP) test measures the presence of an antibody associated with rheumatoid arthritis. Testing for antibodies to CCP is gradually becoming more common. (Indeed, some rheumatologists now order it routinely whenever they order a rheumatoid factor test.) Some small early studies have shown that the anti-CCP test can reliably help to diagnose rheumatoid arthritis in three types of people: those with early-stage disease for whom uncertainty remains about diagnosis, those with mild symptoms who test negative for rheumatoid factor, and those who test positive for rheumatoid factor but may suffer from some other condition. Researchers do not yet know whether the anti-CCP test is useful in other circumstances, or whether the anti-CCP test offers much benefit beyond standard clinical tests.

ESR. The erythrocyte sedimentation rate (ESR) provides a measure of body-wide inflammation: The higher the rate, the greater the likelihood that you are suffering from inflammation, which could be caused by rheumatoid arthritis. This test can also help determine how active your condition is..

CRP. The C-reactive protein (CRP) test also measures inflammation, but tends to change more rapidly than the ESR; minor elevations have also been associated with an increased risk of cardiovascular disease. In assessing inflammation due to rheumatoid arthritis, this test offers no clear advantages over the ESR.

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Imaging tests for rheumatoid arthritis

Since rheumatoid arthritis often involves the hands and feet, your doctor may also order x-rays and possibly magnetic resonance imaging (MRI) of these joints and others to check for bone erosions. Initial studies of MRI show that it is better at detecting bone erosions than x-rays, but its use is controversial because it may detect cysts or other bone changes that resemble erosions, and thus could lead to unnecessary treatment. The issue is important, because rheumatoid arthritis is a disease that varies greatly in its progression and impact: Treatment should be directed by symptoms, findings on physical examination, the results of joint imaging, and preferences of the patient, not just by the results of a single imaging test. In addition, MRI is expensive, and routine use could drive up the cost of caring for people with rheumatoid arthritis dramatically.

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Medications for rheumatoid arthritis

In the 1990s, the treatment of rheumatoid arthritis changed significantly, as researchers developed new medications to treat this disease. Prior to this, doctors treated rheumatoid arthritis conservatively. But evidence that joint damage starts early in the course of the disease has prompted physicians to treat it more aggressively from the beginning.

Given the complex nature of rheumatoid arthritis, and the fact that its progression varies from person to person, there are no easy answers when it comes to deciding on a treatment plan. In general, it is best to wait six to eight weeks to allow for a definitive diagnosis and to see how you respond to initial treatment before committing to long-term aggressive medical therapy. It is also important to remember that treatment should be tailored to the individual: Although some people with rheumatoid arthritis begin aggressive therapy within weeks of diagnosis, others may not need it right away.

Drugs for rheumatoid arthritis fall into several classes (see Appendix), and may be given in combination or sequentially. Although newly approved drugs tend to generate a lot of excitement, it's best to be cautious when using any new drug. The withdrawal of two COX-2 inhibitors from the market because of safety concerns shows dramatically that the true benefits and risks of any medication may not be known for years. Studies conducted to gain FDA approval for a drug may enroll no more than a few hundred or a few thousand people, who may be healthier than those who take the drug after it is approved. What's more, pre-approval studies are often limited in duration, while people taking the drugs for a disease like rheumatoid arthritis may take them for years. Uncommon side effects, interactions with other drugs, and long-term side effects only emerge in the general population in the years following approval. Unfortunately, there is no system in place to reliably identify these problems sooner. For all these reasons, make sure you understand and carefully weigh the risks and benefits before deciding to try a novel therapy.

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NSAIDs and COX-2 inhibitors

To alleviate the pain and inflammation of rheumatoid arthritis, most doctors prescribe a nonsteroidal anti-inflammatory drug (NSAID), such as ibuprofen, or a COX-2 inhibitor, such as celecoxib (Celebrex).

Although anti-inflammatories can provide considerable benefit, they may also have a variety of side effects. If you are considering long-term use of any NSAID (including a COX-2 inhibitor), it is important to talk with your doctor about your personal health risks, particularly any gastrointestinal problems you may have. (For more on these medications, see "NSAIDs" and "COX-2 inhibitors.")

Although NSAIDs and COX-2 inhibitors can reduce pain and swelling, they have little if any effect on the disease process involved in rheumatoid arthritis. As a result, most people with rheumatoid arthritis need disease-modifying antirheumatic drugs (DMARDs) to control disease activity.

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DMARDs

Disease-modifying antirheumatic drugs usually are used as first-line therapy in rheumatoid arthritis. They have the potential to slow the progression of rheumatoid arthritis by altering the function of the immune system. Because these medications can reduce or prevent joint damage and preserve joint function, they have become the standard of care for people with ongoing symptoms or joint damage.

DMARDs may be prescribed alone or in combination with drugs from other categories. Methotrexate (Folex, Rheumatrex, Trexall), when carefully prescribed, has an excellent safety profile, is highly effective, and is usually the first choice of therapy. It's also the drug against which all newer agents are judged. For example, leflunomide (Arava), a newer DMARD known as an immunomodulator, may prove to be as effective as methotrexate, and it has a different, but acceptable, safety profile. Like methotrexate, leflunomide can lead to liver toxicity. And it should be taken cautiously by anyone with compromised kidney function.

Other commonly prescribed DMARDs include hydroxychloroquine (Plaquenil) and sulfasalazine (Azulfidine), although often these are chosen for mild disease, in combination with methotrexate or when methotrexate is not tolerated. Additional options include gold salts (Myochrysine), cyclosporine (Neoral), and penicillamine (Cuprimine, Depen), but these are used much less often because they appear to be less effective or less safe, or both.

Although DMARDs are often highly effective, their toxicity may extend to frequently proliferating cells that are vital to the body's renewal processes. For example, they may have damaging effects on the bone marrow, bladder, lung, liver, intestine, and reproductive organs. Some also carry the risk of birth defects if taken by pregnant women. Anyone taking a DMARD is regularly monitored and may need to have frequent, complete blood cell counts, liver function tests, and urinalyses. The specific monitoring tests and frequency of testing vary depending on the drug taken.

One thing to keep in mind is that DMARDs are slow-acting drugs. Do not become discouraged and stop taking a DMARD before it has had a chance to work. Your doctor will probably advise you to take an NSAID or a corticosteroid during the early weeks or months of treatment until the DMARD begins to take effect. Failure to respond to one DMARD does not mean you will also fail to respond to a different DMARD.

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Biologic response modifiers

Biological response modifiers are a type of DMARD designed to alter the function of cytokines, signaling molecules that help mount an inflammatory reaction. These drugs may be able to do what other drugs have failed to do so far: stop the rate of joint deterioration.

Anti-TNF agents. These drugs block the action of tumor necrosis factor (TNF), which appears to be a primary instigator of joint inflammation (see Figure 9). Three anti-TNF agents are now available: adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade). About 60%–70% of people with rheumatoid arthritis respond well to anti-TNF agents.

In a number of people with rheumatoid arthritis, these drugs have induced something close to remission. However, like anti-cancer chemotherapy, these drugs are potent and expensive. In addition, infliximab requires frequent visits to the hospital for infusions. As such, anti-TNF agents may be too aggressive for people with a mild or benign form of rheumatoid arthritis. And not everyone with rheumatoid arthritis responds to anti-TNF therapy. Even those who do may find their disease flares up again once therapy is stopped. For these reasons, most experts recommend that anti-TNFs be used only when first-line treatment with methotrexate or some other DMARD fails.

Anti-TNF agents are often used in combination with methotrexate to benefit people with active rheumatoid arthritis whose symptoms don't respond to methotrexate alone. Currently, infliximab, which received its initial FDA approval for treating Crohn's disease, is recommended for use only in combination with methotrexate. It is given intravenously at intervals of four to eight weeks. Adalimumab and etanercept are self-injected, like insulin. Etanercept must be injected once or twice a week, while adalimumab is injected every other week.

Anti-TNF therapy has been associated, though rarely, with long-term neurological side effects, including flare-ups in people with multiple sclerosis. Anti-TNF therapy also should not be taken by people who may have a latent tuberculosis infection or other bacterial infections. Infliximab should not be taken by anyone with congestive heart failure.

Other immune system modulators. In 2005, abatacept (Orencia) was approved for the treatment of rheumatoid arthritis. A co-stimulation modulator, abatacept keeps the immune system from attacking healthy tissues by interfering with T-cell activation. It appears to reduce the signs and symptoms of rheumatoid arthritis, slow structural damage, and improve physical function in people with moderate-to-severe disease who have not responded well to one or more DMARD or anti-TNF therapies. Abatacept is used alone or with DMARDs, but it should not be used with anti-TNF medications because the combination may lead to infections. It is given as an intravenous infusion every four weeks.

The more common side effects with abatacept include headache, upper respiratory tract infection, sore throat, and nausea. Abatacept can also make you more vulnerable to infections (including pneumonia) or make an existing infection or lung disease worse. It may also cause an allergic reaction in some people.

In 2006, the FDA approved the use of rituximab (Rituxan), a drug originally developed to treat non-Hodgkin's lymphoma, as a new treatment for rheumatoid arthritis. Rituximab, which is given as an intravenous infusion up to twice yearly, targets and helps to destroy B cells thought to become overactive when the immune system malfunctions in rheumatoid arthritis. Rituximab is supposed to be used in combination with methotrexate, and only in people with moderate or severe rheumatoid arthritis whose disease has not responded to one or more anti-TNF therapies.

The most common serious adverse event caused by rituximab is a condition known as lymphopenia (a reduction in the number of lymphocytes, a type of white blood cell). In rare cases, an initial infusion has caused severe skin reaction or death from kidney failure. Other serious reactions have included shortness of breath, lung congestion, abnormal heart rhythm, and low blood pressure. More common side effects during the first infusion include fever, shaking, chills, weakness, nausea, and headache.

A third drug, anakinra (Kineret), inhibits the actions of interleukin-1 (IL-1), an inflammatory chemical. The FDA approved anakinra in November 2001 for the treatment of moderate to severe rheumatoid arthritis in people who were treated with one or more DMARDs without success. Unfortunately, this drug has not lived up to its promise and is used infrequently.

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Other medications

In some cases, corticosteroids or a device that filters the blood may provide further options for someone with rheumatoid arthritis.

Corticosteroids. Corticosteroids, such as prednisone, reduce the body's ability to generate an inflammatory reaction. But long-term use can actually damage the joints and cause other health problems such as osteoporosis, diabetes, increased susceptibility to infections, cataracts, and hypertension.

Today, corticosteroids are used very cautiously. They may be injected directly into a very inflamed joint or taken orally in low doses if other drugs fail to control inflammation. High doses are reserved for rare, life-threatening crises.

Prosorba column. This blood filtration device has been used since the 1990s to treat a rare blood disease; in 1999 it received FDA approval for use in treating rheumatoid arthritis. This device provides an option for people with moderate to severe rheumatoid arthritis who haven't seen improvement with drug therapy. In a process similar to kidney dialysis, blood is removed through an intravenous catheter attached to one of your arms and circulated through a machine that separates blood cells from plasma. The plasma passes through a column holding a protein that binds to and removes substances thought to cause joint pain and swelling (although these substances remain unidentified). The purified plasma is recombined with the blood cells and returned to the circulation through the other arm. It's effective only temporarily and is usually given once a week for 12 weeks.

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Surgery for rheumatoid arthritis

Some people with rheumatoid arthritis require surgery to reconstruct or replace a damaged joint. Surgery is usually recommended when drug treatment alone can no longer improve the situation, although the timing of such surgery — and whether to go ahead with it — is up to you and your physician. Surgery is usually viewed as a last resort to reduce pain and improve function. One possible exception is hand surgery, as many hand surgeons advocate early surgical intervention to remove inflamed tissue and to help protect the joints and nearby tendons.

Many of the surgical procedures used to repair joints damaged by osteoarthritis are also used in rheumatoid arthritis. The most common surgical procedures for rheumatoid arthritis are arthroscopy, synovectomy (removal of the inflamed tissue that lines the joint), and arthroplasty (joint repair, including joint replacement). The choice depends, in part, on which joints are involved and whether you have any other medical problems. Total joint replacement, most commonly for severe hip or knee arthritis, is a major operation and carries the associated risks (see "Joint reconstruction or replacement").

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Slowing the progression of rheumatoid arthritis

Rheumatoid arthritis is a chronic condition, without a cure. For that reason, most people find that it's necessary to combine the drug therapies and surgical options already described with lifestyle changes and supportive services. It's also a good idea to periodically review your balance of drug, surgery, and other management strategies to make sure they still meet your individual needs.

Physical and occupational therapy. When you have rheumatoid arthritis, it's important to pay special attention to the way you move and the way you function in general. Joint pain and generalized symptoms such as fatigue and stiffness can make ordinary activities — known as activities of daily living — more challenging, especially during flares. An occupational therapist or physical therapist can offer many suggestions about how to optimize your capacity to manage everyday tasks at home and at work.

These therapists can also provide you with special devices to help conserve your energy and protect your joints. For example, during times when your joints are particularly tender, you can use a splint, brace, sling, elastic bandage, or cane to reduce the pressure on your joints and protect them from further injury. A podiatrist may provide shoe inserts (orthotics), recommend special shoes, or suggest other treatments to reduce pain in your feet and improve your ability to function.

Exercise. To prevent disability and preserve joint function, it's important to develop an exercise routine. It may help to have your health care provider or a physical therapist evaluate the motion of your joints and suggest specific exercises to help maintain your present level of functioning. If you don't actively use a diseased joint because of pain, you may develop muscle atrophy, which can result in loss of muscle strength and endurance.

Isometric exercises, which do not require joint motion, can be especially effective during flares. It is crucial to work with your health care provider to arrive at the right balance between exercise and rest. Never exercise to the point of increased or severe pain.

Diet. Although unscrupulous vendors may claim otherwise, there is no diet known to improve the symptoms of rheumatoid arthritis, and there are no proven dietary supplements that are clearly effective over a long period of time.

Complementary and alternative therapies. A number of alternative therapies have been advocated for rheumatoid arthritis, although most have not been rigorously studied. Researchers are sorting out which complementary approaches work best for people with rheumatoid arthritis (see "Physical and complementary therapies").

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Review Date: 2008-04-01

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