Rheumatoid arthritis

Definition

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints, most often in the hands and feet. It results in swelling, stiffness, pain, and sometimes joint, bone, and cartilage destruction.

Description

Although the exact cause of RA is unknown, the disease belongs to a group of diseases called autoimmune disorders. In these disorders, the immune system, the function of which is to protect the body, produces antibodies that attack the soft tissues lining the joints and may also attack connective tissue in many other parts of the body, including the blood vessels and lungs. Eventually, the cartilage, bone, and ligaments of the joint deteriorate, causing deformity, instability, and scarring within the joint. The rate at which the joints deteriorate varies with the individual. A number of risk factors, including genetic predisposition, gender, and unspecified environmental factors, may put a person at risk for developing the disease as well as influence the pattern of the disease.

As with other forms of arthritis, RA involves inflammation of the joints. A membrane called the synovium lines each of the body's movable joints. In RA, white blood cells, which usually attack foreign invaders such as bacteria and viruses, move from the bloodstream into the synovium. There, these blood cells appear to play an important role in causing inflammation to the synovial membrane, a condition called synovitis. This inflammation results in the release of proteins that, over months or years, causes thickening of the synovium. These proteins

can also damage cartilage, bone, tendons, and ligaments. Gradually, the joint loses its shape and alignment, and eventually may be destroyed.

Genetic profile

Rheumatoid arthritis is a genetically complex disease. Studies in monozygotic (identical) and dizygotic (fraternal) twins indicate that genetic factors are involved in acquiring the susceptibility or tendency to RA rather than the disease itself. People with certain human leukocyte antigen (HLA) genes—specifically, the genetic marker called HLA-DR4 (the DR4 refers to the specific antigen)—are more likely to develop the disease than those without the genes. However, people without this antigen can develop the disease as well.

The HLA-DR4 marker is found in white blood cells and plays a role in helping the body distinguish between its own cells and foreign invaders. In addition, these genes also help predict the severity of the disease and how effectively the disease responds to treatment. The mechanism by which HLA alleles (HLA genetic variations) affect disease risk is still under investigation.

In one study, French scientists found 63 genes that appeared to be linked to the development of rheumatoid arthritis. The group studied and compared the expression of 5,200 genes in the synovial (joint) fluid of a group of patients with RA and another group with osteoarthritis. The researchers found 48 known and 15 unknown genes that were either overexpressed or underexpressed in RA patients compared with osteoarthritis patients. Two of the novel genes were located on chromosome 6, at the p21 region, which is an area already linked to inflammatory disease. Four other genes were located on the X chromosome. The French scientists hope their findings will lead to the identification of new pathways related to RA, as well as to new diagnostic and treatment options.

However, not all the genes associated with RA have been discovered, and more research is needed.

Demographics

Rheumatoid arthritis affects approximately 1% of the United States population. Although some people have a mild form of RA, 70% eventually develop chronic problems, and 15% have a severe crippling form of the disease.

The disease occurs in all races and countries. Although RA affects women two to three times more often than men, men tend to be affected more severely by it. The onset of RA most commonly occurs between the ages of 25 and 50, but children and adolescents as well as the elderly may be affected as well. When the disease occurs in children, it is referred to as juvenile RA.

Signs and symptoms

The course of RA varies with each individual. Some people may have mild symptoms, occasional flare-ups, and long periods without disease (remission), or disease that progresses steadily, either slowly or rapidly. The disease may begin suddenly, with many joints becoming inflamed simultaneously. Most often, however, RA begins subtly, gradually affecting different joints. Usually the inflammation is symmetric, with joints on both sides of the body affected. Typically, the small joints in the fingers, toes, hands, feet, wrists, elbows, and ankles become inflamed first. The inflamed joints are usually painful and often stiff, especially just after awakening (such stiffness generally lasts for at least 30 minutes and often much longer) or after prolonged inactivity. Some people feel tired and weak, especially in the early afternoon. In addition, RA may produce a low-grade fever.

Affected joints enlarge because of swelling of the soft tissue and can quickly become deformed. Joints may freeze in one position so that they cannot bend or open fully. The fingers may tend to dislocate from their normal position toward the little finger on each hand, causing tendons in the fingers to slip out of place.

Swollen wrists can pinch a nerve and result in numbness or tingling due to carpal tunnel syndrome. Cysts, which may develop behind affected knees, can rupture and cause pain and swelling in the lower legs. Up to 30% of people with RA have hard bumps (called rheumatoid nodules) just under the skin, usually near sites of pressure (such as the back of the forearm near the elbow).

In rare cases, RA causes an inflammation of blood vessels called vasculitis; this condition reduces the blood supply to tissues and may cause nerve damage or leg sores (ulcers) that may become infected. Inflammation of the membranes covering the lungs (pleura) or of the sac surrounding the heart (pericardium), or inflammation and scarring of the lungs can lead to chest pain and shortness of breath. Some people develop swollen lymph nodes, dry eyes or mouth, or red, painful eyes as a result of inflammation.

Diagnosis

In addition to the important characteristic pattern of symptoms, many tests may be used to support the diagnosis.

Laboratory tests may include rheumatoid factor, white blood cell count, a blood test for anemia, erythrocyte sedimentation rate (ESR, or sed rate), and C-reactive protein, which detects inflammation.

Many people with RA have certain characteristic antibodies in their blood, such as rheumatoid factor, which is present in 70% of people with RA. In addition to RA, rheumatoid factor occurs in several other diseases, such as hepatitis and other infections. Some people even have rheumatoid factor in their blood without any evidence of disease. A higher level of rheumatoid factor in the blood usually results in a more severe RA and a poorer prognosis. The rheumatoid factor level may decrease when joints are less inflamed.

Most people have mild anemia (an insufficient number of red blood cells). Rarely, the white blood cell count becomes abnormally low. When a person with RA has a low white blood cell count and an enlarged spleen, the disorder is called Felty's syndrome.

Nine out of 10 people with RA have an elevated sed rate, a test that measures the rate at which blood cells settle to the bottom of a test tube containing blood; an elevated sed rate suggests that active inflammation is present. The rate depends on certain proteins in the blood. However, this test alone cannot identify the cause of the inflammation. Doctors may monitor the sed rate when symptoms are mild to help determine whether the disease is still active.

A needle biopsy may be recommended. A needle biopsy is an examination of a joint fluid sample or of a tissue sample from rheumatoid nodules, both obtained by a needle.

Characteristic changes in the joints may be seen on x rays.

Treatment and management

Treatments for RA have improved in recent years. Although most treatments involve medications, in some cases, surgical procedures may be necessary.

Medications for rheumatoid arthritis can relieve its symptoms and slow or halt its progression. Nonsteroidal anti-inflammatory drugs (NSAIDs) help to alleviate both pain and inflammation, if taken on a regular basis. These drugs, which are available without a prescription, include aspirin, ibuprofen (Motrin, Advil), and naproxen (Aleve). These medications are available at higher dosages by prescription. Other NSAIDs available in prescription strength include ketoprofen (Oruvail), tolmetin (Tolectin), diclofenac (Arthrotec, Voltaren), nabumetone (Relafen), and indomethacin (Indocin).

Taking NSAIDs on a regular basis, however, can lead to adverse side effects, such as indigestion and stomach bleeding. Other potential harmful side effects may include damage to the liver and kidneys, ringing in the ears (tinnitus), fluid retention, and hypertension (high blood pressure).

Initially, it was thought that COX-2 inhibitors, another class of NSAIDS, was less damaging to the stomach than the traditional NSAIDS. Like other NSAIDs, COX-2 inhibitors, such as celecoxib (Celebrex), which is one of the few COX-2 inhibitors still on the market in the United States, suppress an enzyme called cyclooxygenase (COX) that is active in joint inflammation. It was believed that NSAIDs work against two versions of the COX enzyme present in the body: COX-1 and COX-2. However, there is increasing evidence to suggest that by suppressing COX-1, the enzyme responsible for protecting the stomach lining, NSAIDs may cause stomach and other problems. Unlike other NSAIDs, COX-2 inhibitors suppress only COX-2, the enzyme involved in inflammation.

Side effects of COX-2 inhibitors may include fluid retention and causing or exacerbating high blood pressure. Furthermore, this class of drugs has been linked to an increased risk of heart attack and stroke. These are reasons why Merck Pharmaceuticals chose to remove its COX-2 inhibitor rofecoxib (Vioxx) from the worldwide market in September 2004. About 1.3 million people in the United States and about 700,000 abroad were using the drug. In April 2005, the COX-2 inhibitor valdecoxib (Bextra) was voluntarily removed from the market by its manufacturer, Pfizer, at the request of the FDA, which stated that the potential risks of heart attack, stroke, and potentially life-threatening skin reactions were greater than its benefits. The FDA also announced new label requirements for both prescription and nonprescription NSAIDS. Prescription labels for COX-2 inhibitors like celecoxib were required to carry a "black box warning" stressing the life-threatening effects associated with the drug.

In December 2004, the FDA issued a Public Health Advisory recommending limited use of COX-2 inhibitors. The guidelines warn patients at high risk of gastrointestinal bleeding, those with a history of intolerance to certain NSAIDS. Individual patient risk for cardiovascular problems and other risks commonly associated with NSAIDS should be taken into account for each patient. Consumers are advised that all nonprescription pain relievers, including NSAIDS, should be used exactly as specified on the label. If NSAIDS are needed for more than 10 days, the FDA suggests that a doctor be consulted.

The FDA's actions differ from the recommendations of an FDA expert advisory panel, which, in February 2005, voted in favor of allowing COX-2 inhibitors celecoxib and valdecoxib to remain available. The panel also voted to allow rofecoxib back on the market, under strict conditions.

Corticosteroids, such as prednisone (Deltasone) and methylprednisolone (Medrol), reduce inflammation and pain and slow the progression of joint damage and destruction associated with RA. In the short term, corticosteroids alleviate pain significantly. When used for many months or years, however, these drugs tend to lose their efficacy and cause serious side effects that may include bruising, thinning of bones, cataracts, weight gain, and diabetes. Doctors often prescribe corticosteroids to alleviate acute symptoms, with the goal of gradually tapering off the medication when the patient's pain decreases.

Physicians prescribe disease-modifying antirheumatic drugs (DMARDs) to limit the amount of joint damage that occurs in RA. Taking these drugs during the early stages in the development of RA is especially important in an attempt to slow disease progression and save the joints and other tissues from permanent damage. Because many of these drugs act slowly, it may take weeks to months to detect any benefit. Typically, DMARDs are used in combination with an NSAID or a corticosteroid. Although the NSAID or corticosteroid alleviates any immediate symptoms and limits inflammation, the DMARD acts directly on the disease. Commonly used DMARDs include hydroxychloroquine (Plaquenil), the gold compound auranofin (Ridaura), sulfasalazine (Azulfidine), and minocycline (Dynacin, Minocin). Additional forms of DMARDs include immunosuppressants and tumor necrosis factor (TNF) blockers.

Immunosuppressants act to quiet the immune system, which is overactive in RA. In addition, some of these drugs attack and destroy cells associated with the disease. Some of the commonly used immunosuppressants include methotrexate (Rheumatrex), leflunomide (Arava), azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), and cyclophosphamide (Cytoxan). These medications may have potentially serious adverse side effects, such as increased susceptibility to infection.

The TNFs are a class of DMARDs known as biologic response modifiers. Tumor necrosis factor is a cell protein, or cytokine, that acts as an inflammatory agent in RA. Anti-TNF medications, or TNF blockers, target or block this cytokine and can help reduce pain, morning stiffness, and tender or swollen joints, typically within one or two weeks after initiating treatment. There is evidence that TNF blockers may halt the progression of disease. Often these medications are taken in combination with the immunosuppressant methotrexate. The TNF blockers approved for treatment of RA include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). These medications should not be taken if active infection is present.

Interleukin-1 receptor antagonist (IL-1Ra) is another type of biologic response modifier and is an artificially created (recombinant) form of the naturally occurring interleukin-1 receptor antagonist. Interleukin-1 (IL-1) is a cell protein that promotes inflammation and occurs in excessive amounts in people with RA or other types of inflammatory arthritis. If IL-1 is prevented from binding to its receptor, the inflammatory response is decreased.

The first IL-1Ra approved by the FDA for use in individuals with moderate to severe RA who have not responded adequately to conventional DMARD therapy is anakinra (Kineret). This drug may be used alone or in combination with methotrexate. Anakinra is administered as a daily self-injection. Some potential side effects include injection-site reactions, decreased white blood cell counts, headache, and increased upper respiratory tract infections, especially in people with asthma or chronic obstructive pulmonary disease. If active infection is present, anakinra should not be used.

Some people with RA also experience symptoms of depression. The most common antidepressants used for RA pain and for sleep that is not restful are amitriptyline (Elavil), nortriptyline (Aventyl, Pamelor), and trazodone (Desyrel).

Although a combination of medication and self-care is the first course of action for RA, other methods are available in severe cases of the disease. The Prosorba column is a blood-filtering technique used to remove certain antibodies that contribute to pain and inflammation in the joints and muscles and is usually performed once a week for 12 weeks on an outpatient basis. Some of the side effects of this procedure include fatigue and a temporary increase in joint pain and swelling for the first few days after the treatment. The Prosorba column treatment is not recommended in combination with angiotensin-converting enzyme (ACE) inhibitors or if heart problems, high blood pressure, or blood-clotting problems are present.

Joint replacement surgery is an option chosen by many people with RA when less invasive methods or medications are not able to alleviate pain and deter joint destruction. When joints are severely damaged, joint replacement surgery can often help restore joint function, reduce pain, or correct a deformity. In some cases, the entire joint may need to be replaced with a metal, ceramic, or plastic prosthesis. Surgery may also involve tightening or loosening tendons, fusing bones to reduce pain, or removing a portion of a diseased bone to improve mobility. The inflamed joint lining may also require removal (synovectomy).

Prognosis

In rare cases, RA resolves spontaneously. However, at least one out of 10 people with RA eventually becomes severely disabled.

Resources

BOOKS

Schlotzhauer, Tammi L., and James L. McGuire. Living with Rheumatoid Arthritis. Baltimore, MD: Johns Hopkins University Press, 2003.

Zashin, Scott J., and Laurette Hesser. Arthritis without Pain: The Miracle of TNF Blockers. Bangor, ME: Sarah Allison Publishing, 2004–2005.

PERIODICALS

Drazen, J. M. "Cox-2 Inhibitors: A Lesson in Unexpected Problems." New England Journal of Medicine 352 (March 17, 2005): 1131–32.

Silman, A. J., and Jacqueline E. Pearson. "Epidemiology and Genetics of Rheumatoid Arthritis." Arthritis Research & Therapy 4 (Supplement 3) (May 9, 2002): S265–S272. Available online: <http://arthritis-research.com/content/4/S3/S265>.

Smolen, J. S. "The Science of Rheumatoid Arthritis: A Prelude." Arthritis Research & Therapy 7 (Supplement 2) (March 16, 2005): S1–S3.

WEBSITES

Arthritis Research & Therapy. (April 22, 2005.) <http://arthritis-research.com/>.

ORGANIZATIONS

American Academy of Orthopaedic Surgeons. P.O. Box 2058, Des Plaines, IL 60017. (800) 824-2263. (April 22, 2005.) <http://www.aaos.org>.

American College of Rheumatology. 1800 Century Place, Suite 250, Atlanta, GA 30345. (404) 633-3777. (April 22, 2005.) <http://www.rheumatology.org/index.asp?>.

Arthritis Foundation. 1330 West Peachtree Street, Atlanta, GA 30309. (800) 283-7800. (April 22, 2005.) <http://www.arthritis.org>.

National Institute of Arthritis and Musculoskeletal and Skin Diseases. National Institutes of Health. 1 AMS Circle, Bethesda, MD 20892-3675 (877) 226-4267. (April 22, 2005.) <http://www.niams.nih.gov>.

Genevieve T. Slomski, PhD