Rheumatoid Arthritis
Rheumatoid arthritis is an inflammatory arthritis in which joints, usually including those of the hands and feet, are inflamed, resulting in swelling, pain, and often the destruction of joints.
Worldwide, rheumatoid arthritis develops in about 1% of the population, regardless of race or country of origin, affecting women 2 to 3 times more often than men. Usually, rheumatoid arthritis first appears between 25 and 50 years of age, but it may occur at any age. Rheumatoid arthritis can occur in children--the disease is then called juvenile rheumatoid arthritis, and the symptoms and prognosis are somewhat different (see Section 23, Chapter 280).
The exact cause of rheumatoid arthritis is not known. It is considered an autoimmune disease (see Section 16, Chapter 186). Components of the immune system attack the soft tissue that lines the joints and can also attack connective tissue in many other parts of the body, such as the blood vessels and lungs. Eventually, the cartilage, bone, and ligaments of the joint erode, causing deformity, instability, and scarring within the joint. The joints deteriorate at a highly variable rate. Many factors, including genetic predisposition, may influence the pattern of the disease.
Symptoms
People with rheumatoid arthritis may have a mild course, occasional flare-ups with long periods of remission without disease, or a steadily progressive disease, which may be slow or rapid. Rheumatoid arthritis may start suddenly, with many joints becoming inflamed at the same time. More often, it starts 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. Rheumatoid arthritis 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 slightly 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 (see Section 5, Chapter 71). Cysts, which may develop behind affected knees, can rupture, causing pain and swelling in the lower legs. Up to 30% of people with rheumatoid arthritis 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).
Rarely, rheumatoid arthritis causes an inflammation of blood vessels (vasculitis (see Section 5, Chapter 69)); this condition reduces the blood supply to tissues and may cause nerve damage or leg sores (ulcers). Inflammation of the membranes that cover the lungs (pleura) or of the sac surrounding the heart (pericardium) or inflammation and scarring of the lungs can lead to chest pain or shortness of breath. Some people develop swollen lymph nodes; Sjögren's syndrome, which consists of dry eyes or mouth (see Section 5, Chapter 68); or red, painful eyes due to inflammation.
Diagnosis
In addition to the important characteristic pattern of symptoms, the doctor may use the following to support the diagnosis: laboratory tests, an examination of a joint fluid sample obtained with a needle, and even a biopsy (removal of a tissue sample for examination under a microscope) of rheumatoid nodules. Characteristic changes in the joints may be seen on x-rays.
In 9 of 10 people who have rheumatoid arthritis, the erythrocyte sedimentation rate (ESR--a test that measures the rate at which red blood cells settle to the bottom of a test tube containing blood) is increased, which suggests that active inflammation is present. However, this test alone cannot identify the cause of the inflammation. Doctors may monitor the ESR when symptoms are mild to help determine whether the disease is still active.
Many people with rheumatoid arthritis have distinctive antibodies in their blood, such as rheumatoid factor, which is present in 70% of people with rheumatoid arthritis. (Rheumatoid factor also occurs in several other diseases, such as hepatitis and some other infections; some people even have rheumatoid factor in their blood without any evidence of disease.) Usually, the higher the level of rheumatoid factor in the blood, the more severe the rheumatoid arthritis and the poorer the prognosis. The rheumatoid factor level may decrease when joints are less inflamed.
Most people have mild anemia (an insufficient number of red blood cells (see Section 14, Chapter 172)). Rarely, the white blood cell count becomes abnormally low. When a person with rheumatoid arthritis has a low white blood cell count and an enlarged spleen, the disorder is called Felty's syndrome.
Prognosis and Treatment
Rarely, rheumatoid arthritis resolves spontaneously. Treatment alleviates symptoms in 3 of 4 people. However, at least 1 of 10 people eventually becomes severely disabled.
Treatments range from simple, conservative measures to drugs and even surgery. Simple measures are meant to help the person's symptoms and include rest and adequate nutrition. Certain drugs--the slow-acting drugs--may actually improve the disease rather than just the symptoms. Treatment starts with the least aggressive measures; however, drugs that can slow disease progression should generally be added during the first several months.
Severely inflamed joints should be rested, because using them can aggravate the inflammation. Regular rest periods often help relieve pain, and sometimes a short period of bed rest helps relieve a severe flare-up in its most active, painful stage. Splints can be used to immobilize and rest one or several joints, but some systematic movement of the joints is needed to prevent adjacent muscles from weakening and joints from freezing in place.
A regular, healthy diet is generally appropriate. A diet rich in fish and plant oils but low in red meat can have small beneficial effects on the inflammation. Rarely, people have flare-ups after eating certain foods, and if so, these foods should be avoided.
The main categories of drugs used to treat rheumatoid arthritis are the nonsteroidal anti-inflammatory drugs (NSAIDs), slow-acting drugs, corticosteroids, and methotrexate or other immunosuppressive drugs, including the tumor necrosis factor (TNF) inhibitors. A newer biologic therapy, involving the use of interleukin-1 receptor antagonists, is available. Generally, the stronger drugs have important side effects that must be looked for during treatment.
 See the drug table Drugs Used to Treat Rheumatoid Arthritis.
Nonsteroidal Anti-Inflammatory Drugs: The nonsteroidal anti-inflammatory drugs (NSAIDs) (see Section 6, Chapter 78) are the most widely used drugs to treat the symptoms of rheumatoid arthritis. They can reduce the swelling in affected joints and relieve pain. However, all NSAIDs (including aspirin) can upset the stomach and cannot be taken by anyone who has active digestive tract (peptic) ulcers--including stomach ulcers or duodenal ulcers.
Symptoms of upset stomach may be reduced by eating food while taking an NSAID or taking antacids or other drugs such as the histamine-2 blockers (ranitidine, famotidine, or cimetidine) at the same time. Misoprostol or proton pump inhibitors are sometimes given in conjunction with an NSAID and can reduce the risk of stomach ulcers in people who need long-term treatment with an NSAID for rheumatoid arthritis. Misoprostol may cause diarrhea and does not prevent the nausea or abdominal pain that can result from taking aspirin or other NSAIDs.
Aspirin has been the traditional cornerstone of treatment for rheumatoid arthritis for many years. Ringing in the ears is a side effect that suggests the dose is too high. Other NSAIDs, including ibuprofen, naproxen, and diclofenac, are more often prescribed than is aspirin. Fewer pills are required (sometimes just 1 or 2 a day); these drugs may also have fewer side effects than high doses of aspirin.
A new type of NSAID, the cyclooxygenase (COX-2) inhibitors (coxibs), are similar in action to the other NSAIDs but are much less likely to cause damage to the stomach. These drugs do not inhibit the function of platelets, and thus are safer to use than the traditional NSAIDs for people who are at risk of bleeding. Two examples are celecoxib and rofecoxib.
Slow-Acting Drugs: Slow-acting drugs, such as gold compounds, penicillamine, hydroxychloroquine, and sulfasalazine, sometimes can improve the course of rheumatoid arthritis, although improvement may take several months. These drugs are usually added promptly if the disease persists (as it usually does) in people taking NSAIDs, including the coxibs. Even if pain is decreased, a doctor will likely prescribe a slow-acting drug within the first 2 months if joint swelling persists.
Gold compounds, which can slow the formation of bone deformities, may cause a temporary remission of the disease. Usually, a gold compound is given as a weekly injection. A preparation given by mouth is available but is not as effective. The weekly injections are continued until a total of 1 gram has been given or until side effects preclude their use or significant improvement occurs, whichever comes first. If the drug is effective, the frequency of the injections can be gradually decreased. Sometimes improvement is sustained for years on maintenance doses.
Gold compounds can adversely affect several organs, and people who have severe liver or kidney disease or certain blood disorders cannot take these drugs. Consequently, blood and urine samples are tested before treatment begins and frequently--up to once a week--during treatment. Side effects of these drugs include potentially dangerous rashes, itchy skin, and decreased numbers of blood cells. Less commonly, gold compounds can affect the liver and lungs, and rarely, they cause diarrhea. The gold compound is usually discontinued if any of these severe side effects occur, although the compound may be started again after a mild rash resolves.
Penicillamine is taken by mouth and has beneficial effects similar to those of gold compounds and may be used when gold compounds are not effective or when they cause intolerable side effects. The dose of penicillamine is gradually increased until a person shows some improvement. Side effects include suppression of blood cell production in the bone marrow, kidney problems, muscle disease, rash, and a bad taste in the mouth. Penicillamine can also cause disorders such as myasthenia gravis, Goodpasture's syndrome, and a lupus-like syndrome. If any of these side effects occur, the drug must be discontinued. Because of these side effects, penicillamine is not usually an early choice. Blood and urine samples are tested as often as every 2 to 4 weeks during treatment.
Hydroxychloroquine is given daily by mouth and is often used rather than gold compounds or penicillamine to treat less severe rheumatoid arthritis; it may be added to other slow-acting drugs or methotrexate and seems to provide an additive effect. Side effects, which are usually mild, include rashes, muscle aches, and eye problems. However, some eye problems can be permanent, so people taking hydroxychloroquine must have their eyes checked by an ophthalmologist before treatment begins and every 6 months during treatment. If the drug has not helped after 6 months, it is discontinued. Otherwise, hydroxychloroquine can be continued as long as necessary.
Sulfasalazine tablets can also be used in people who have less severe rheumatoid arthritis or added to other drugs to boost their effectiveness. The dose is increased gradually, and improvement usually occurs within 3 months. Like the other slow-acting drugs, it can cause stomach upset, liver problems, blood cell disorders, and rashes.
Corticosteroids: Corticosteroids, such as prednisone, are the most dramatically effective drugs for reducing inflammation anywhere in the body. Although corticosteroids are effective for short-term use, they tend to become less effective over time, and rheumatoid arthritis is usually active for years.
There is some controversy as to whether corticosteroids can slow the progression of rheumatoid arthritis. Furthermore, the long-term use of corticosteroids almost invariably leads to side effects, involving almost every organ in the body. Consequently, doctors usually reserve corticosteroids for the short-term use in severe flare-ups when many joints are affected or when all other drugs have been ineffective. They are also useful in treating inflammation outside of joints, for example, in the membranes covering the lungs (pleura) or in the sac surrounding the heart (pericardium). Because of the risk of side effects, the lowest effective dose is almost always used. Corticosteroids can be injected directly into the affected joints for fast, short-term relief. However, they can actually contribute to long-term damage, especially when a person who receives frequent injections overuses the temporarily pain-free joint, hastening its destruction.
 See the sidebar Corticosteroids: Uses and Side Effects.
Immunosuppressive Drugs: Although corticosteroids suppress the immune system, other drugs do so even more potently and are referred to as immunosuppressive drugs. Each of these drugs can slow the progression of disease and decrease the damage to bones adjacent to joints. Such drugs include methotrexate (which is often the first drug used after NSAIDs), leflunomide, azathioprine, cyclophosphamide, cyclosporine, and tumor necrosis factor (TNF) inhibitors.
Immunosuppressive drugs are effective in treating severe rheumatoid arthritis. They suppress the inflammation so that corticosteroids can be avoided or given in lower doses. But immunosuppressive drugs have their own potentially serious side effects, including liver disease, lung inflammation, an increased susceptibility to infection, the suppression of blood cell production in the bone marrow, and, with cyclophosphamide, bleeding from the bladder. In addition, azathioprine and cyclophosphamide may increase the risk of developing cancer. In women who are considering pregnancy, immunosuppressive drugs should be used only after discussion with a doctor.
Methotrexate, given by mouth once a week in gradually increasing doses, is the drug used increasingly to treat rheumatoid arthritis in its early stages. This drug can take effect quickly--sometimes after several weeks. Methotrexate may be given before slow-acting drugs when the joint inflammation is severe. Most people tolerate methotrexate well but must be closely monitored and their white blood cell counts tested about every 2 months. They must refrain from drinking alcohol to minimize the risk of liver damage. Folic acid tablets may decrease some of the side effects, such as mouth ulcers.
Leflunomide is a drug with benefits and risks that are similar to those of methotrexate. It is given daily by mouth, sometimes with the first three doses (loading doses) being higher to speed the onset of action.
Etanercept or infliximab, which are tumor necrosis factor (TNF) inhibitors, can be dramatically effective for people who do not respond sufficiently to methotrexate alone. Etanercept is given twice weekly by injection under the skin, and infliximab is given intravenously every 8 weeks after loading doses. These drugs should be avoided in people who have active infections or malignancies because TNF may make such conditions worse.
Other Treatments: Along with drugs to reduce joint inflammation, a treatment plan for rheumatoid arthritis should include nondrug therapies, such as exercise, physical or occupational therapy, and sometimes surgery. Inflamed joints should be exercised gently so they do not freeze in one position. As the inflammation subsides, regular, active exercises can help, although a person should not exercise to the point of fatigue. For many people, exercise in water may be easier.
Treatment of tight joints consists of intensive exercises and occasionally the use of splints to gradually extend the joint. If drugs have not helped, surgery may be needed. Surgically replacing knee or hip joints is the most effective way to restore mobility and function when the joint disease is advanced. Joints can also be removed or fused together, especially in the foot, to make walking less painful. The thumb can be fused to enable a person to grasp, and unstable vertebrae at the top of the neck can be fused to prevent them from compressing the spinal cord.
People who are disabled by rheumatoid arthritis can use several aids to accomplish daily tasks. For example, specially modified orthopedic or athletic shoes can make walking less painful, and devices such as grippers reduce the need to squeeze the hand forcefully.
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