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Rheumatoid Arthritis (RA)
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 destruction of joints.
The immune system damages the joints and connective tissues.
Joints (typically the small joints of the limbs) become painful and have stiffness that persists for more than 60 minutes on awakening and after inactivity.
Fever, weakness, and damage to other organs may occur.
Diagnosis is based mainly on symptoms but also on blood tests for rheumatoid factor and on x-rays.
Treatment can include exercises and splinting, drugs (nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and immunosuppressive drugs), and sometimes surgery.
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 35 years and 50 years of age, but it may occur at any age. A disorder similar to rheumatoid arthritis can occur in children. The disease is then called juvenile idiopathic arthritis. However, the prognosis for juvenile idiopathic arthritis is often somewhat different.
The exact cause of rheumatoid arthritis is not known. It is considered an autoimmune disease. Components of the immune system attack the soft tissue that lines the joints (synovial tissue) 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 (wear away), causing deformity, instability, and scarring within the joint. The joints deteriorate at a variable rate. Many factors, including genetic predisposition, may influence the pattern of the disease. Unknown environmental factors (such as viral infections and cigarette smoking) are thought to play a role.
People with rheumatoid arthritis may have
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 about equally. Rheumatoid arthritis can affect any joint, but most often the first inflamed are the small joints in the
Other commonly affected joints include the
Rheumatoid arthritis can also affect the neck. The lower spine and the joints at the tips of the fingers are not affected.
The inflamed joints are usually painful and often stiff, especially just after awakening (such stiffness generally lasts for more than 60 minutes) or after prolonged inactivity. Some people feel tired and weak, especially in the early afternoon. Rheumatoid arthritis may cause a loss of appetite with weight loss and a low-grade fever.
Affected joints are often tender, warm, and enlarged because of swelling of the soft tissue lining the joint (synovitis) and sometimes fluid within the joint (synovial fluid). Joints can quickly become deformed. Joints may freeze in one position so that they cannot bend or open fully, which leads to a limited range of motion. 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, or may develop other deformities (see Figure: When the Fingers Are Abnormally Bent).
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, 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). Vasculitis 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 or heart can lead to chest pain or shortness of breath. Some people develop swollen lymph nodes (lymphadenopathy), Felty syndrome (a low white blood cell count and an enlarged spleen), Sjögren syndrome (dry mouth and eyes), thinning of the white of the eye (sclera), or red, irritated eyes caused by inflammation (episcleritis).
Rheumatoid arthritis can also affect the neck, making the bones unstable and increasing the risk of the bones putting pressure on (compressing) the spinal cord (see Compression of the Spinal Cord).
In addition to the important characteristic pattern of symptoms, doctors follow established criteria when evaluating a person for rheumatoid arthritis. Doctors suspect people have rheumatoid arthritis if they have more than one joint with definite swelling of the joint's lining that is not caused by another disorder. Doctors diagnose people with rheumatoid arthritis if they have certain combinations of the following criteria:
Involvement of the joints that are most typical of rheumatoid arthritis
High blood levels of rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) antibodies, or both
High blood levels of C-reactive protein, a high erythrocyte sedimentation rate (ESR), or both
Symptoms that have lasted at least 6 weeks
Doctors do blood tests to determine a person's blood levels of rheumatoid factor and anti-CCP antibodies and usually C-reactive protein, ESR, or both. They also frequently do x-rays of the hands, wrists, and affected joints. X-rays show characteristic changes in the joints caused by rheumatoid arthritis. Magnetic resonance imaging (MRI), another imaging test, detects joint abnormalities at an earlier stage but is not usually needed at first.
Doctors may also insert a needle into a joint to draw a sample of synovial fluid. The fluid is examined to determine whether it is consistent with features of rheumatoid arthritis and to rule out other disorders that cause symptoms similar to rheumatoid arthritis. Synovial fluid needs to be analyzed to establish that a person has rheumatoid arthritis but does not always need to be analyzed whenever an RA flare-up causes joints to become swollen.
Many people with rheumatoid arthritis have distinctive antibodies in their blood, such as rheumatoid factor and anti-CCP antibodies.
Rheumatoid factor is present in 70% of people with rheumatoid arthritis. (Rheumatoid factor also occurs in several other diseases, such as cancers, systemic lupus erythematosus, hepatitis, and some other infections. Some people without any disorder, particularly older adults, have rheumatoid factor in their blood.) 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.
Anti-CCP antibodies are present in over 75% of people who have rheumatoid arthritis and are almost always absent in people who do not have rheumatoid arthritis.
C-reactive protein levels are often high in people with rheumatoid arthritis. Levels of C-reactive protein (a protein that circulates in the blood) dramatically increase when there is inflammation. High C-reactive protein levels can mean the disease is active.
The ESR is increased in 90% of people who have active rheumatoid arthritis. The ESR is another test for inflammation and measures the rate at which red blood cells settle to the bottom of a test tube containing blood. However, similar increases in the ESR, C-reactive protein level, or both occur in many other disorders. Doctors may monitor the ESR or C-reactive protein to help determine whether the disease is active.
Most people with rheumatoid arthritis have mild anemia (an insufficient number of red blood cells). 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 syndrome.
The course of rheumatoid arthritis is unpredictable. The disorder progresses most rapidly during the first 6 years, particularly the first year, and 80% of untreated people develop permanent joint abnormalities within 10 years. Rheumatoid arthritis decreases life expectancy by 3 to 7 years. Heart disease (a risk with rheumatoid arthritis), infection, and gastrointestinal bleeding are the most common complications that cause death. Side effects of drug treatment, cancer, and the underlying disease also may be responsible. Rarely, rheumatoid arthritis resolves spontaneously.
Treatment relieves symptoms in 3 of 4 people. However, at least 10% of people with rheumatoid arthritis are eventually severely disabled despite full treatment. Factors that tend to predict a poorer prognosis include the following:
Treatments include simple, conservative measures in addition to drugs and surgical treatments. Simple measures are meant to help the person’s symptoms and include rest, adequate nutrition, and physical treatments. People should take measures that decrease their risk of heart disease, such as stopping smoking and getting treated, if necessary, for high blood pressure and high blood lipids or cholesterol.
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 nearby muscles from weakening and joints from freezing in place.
A regular, healthy diet is generally appropriate. A diet rich in fish (omega-3 fatty acids) and plant oils but low in red meat can partially relieve symptoms in some people. Some people may have flare-ups after eating certain foods, and if so, these foods should be avoided, but such flare-ups occur rarely. No specific foods have been proved to cause flare-ups. Many diets have been proposed but have not proved helpful. Fad diets should be avoided.
Along with drugs to reduce joint inflammation, a treatment plan for rheumatoid arthritis should include nondrug therapies, such as exercise, physical therapy (which includes massage, traction, and deep heat treatments), and occupational therapy (which includes self-help devices).
Inflamed joints should be gently stretched so they do not freeze in one position. Heat therapy can be helpful because heat improves muscle function by reducing stiffness and muscle spasm. As the inflammation subsides, regular, active exercises can help, although a person should not exercise to the point of excessive fatigue. For many people, exercise in warm water may be easier.
Treatment of tight joints consists of intensive exercises and occasionally the use of splints to gradually extend the joint. Cold may be applied to reduce pain caused by temporary worsening in one joint.
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 self-help devices such as grippers reduce the need to squeeze the hand forcefully.
If drugs have not helped, surgical treatment may be needed. Surgical repair must always be considered in terms of the total disease. For example, deformed hands and arms limit a person’s ability to use crutches during rehabilitation, and seriously affected knees and feet limit the benefits of hip surgery. Reasonable objectives for each person must be determined, and ability to function must be considered. Surgical repair may be performed while the disease is active.
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 pinch, and unstable vertebrae at the top of the neck can be fused to prevent them from compressing the spinal cord.
Joint repair with prosthetic joint replacement is indicated if damage severely limits function. Total hip replacements and knee replacements are most consistently successful.
Replacing All of a Hip (Total Hip Replacement)
Replacing a Knee
The main goal of drug treatment is to reduce inflammation and thereby prevent erosions, progressive deformity, and loss of joint function. The main categories of drugs used to treat rheumatoid arthritis are
Among the various DMARDs, methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine are frequently given, but the immunosuppressive drugs azathioprine and cyclosporine are not given as often because of their side effects. Other classes of immunosuppressive drugs are often collectively called biologic agents. A biologic agent is something made from a living organism. Many biologic agents used to treat rheumatoid arthritis are antibodies. Biologic agents used to treat rheumatoid arthritis include abatacept, rituximab, tumor necrosis factor (TNF)–inhibiting drugs (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab), an interleukin-1 receptor antagonist (anakinra), an interleukin-6 receptor antagonist (tocilizumab), and a Janus kinase inhibitor (tofacitinib). Many of these drugs are usually used in combination with DMARDs. However, biologic agents are not used in combination with other biologic agents because these combinations increase the frequency of infections.
Generally, stronger drugs have potentially serious side effects that must be looked for during treatment.
Drugs Used to Treat Rheumatoid Arthritis
NSAIDs are commonly used to treat the symptoms of rheumatoid arthritis. They do not prevent the damage caused by rheumatoid arthritis from progressing and thus should not be considered the primary treatment.
NSAIDs can reduce the swelling in affected joints and relieve pain. Rheumatoid arthritis, unlike osteoarthritis, causes considerable inflammation. Thus, drugs that decrease inflammation, including NSAIDs, have an important advantage over drugs such as acetaminophen that reduce pain but not inflammation. However, NSAIDs (except cyclooxygenase inhibitors) should not be taken by people who have active digestive tract (peptic) ulcers—including stomach ulcers or duodenal ulcers—because NSAIDs can upset the stomach. Drugs called proton pump inhibitors (such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) can reduce the risk of stomach or duodenal ulcers (see Table Drugs Used to Treat Peptic Ulcer Disease).
Other possible side effects of NSAIDs may include headache, confusion, increased blood pressure, worsening of high blood pressure, worsening of kidney function, swelling, and decreased platelet function. People who get hives, inflammation and swelling in the nose, or asthma after they take aspirin may have the same symptoms after taking other NSAIDs. NSAIDs may increase the risk of heart attacks and strokes. The risk appears to be higher if the drug is used at higher doses and for longer periods of time. The risk is higher with certain NSAIDs than others.
Aspirin is no longer used to treat rheumatoid arthritis because effective doses are often toxic.
The cyclooxygenase (COX-2) inhibitors (coxibs, such as celecoxib) are NSAIDs that act similarly to the other NSAIDs but are slightly less likely to damage the stomach. However, if a person also takes aspirin, stomach damage is almost as likely to occur as with other NSAIDs. Caution should be taken with use of coxibs and probably all NSAIDs for long periods or by people with risk factors for heart attack and stroke.
DMARDs, such as methotrexate, hydroxychloroquine, leflunomide, and sulfasalazine, slow the progression of rheumatoid arthritis and are given to nearly all people with rheumatoid arthritis. Doctors typically prescribe these drugs as soon as the diagnosis of rheumatoid arthritis is made. Many take weeks or months to have an effect. Even if pain is decreased with NSAIDs, a doctor will likely prescribe a DMARD because the disease progresses even if symptoms are absent or mild.
About two thirds of people improve overall, and complete remissions are becoming more common. The progression of arthritis usually slows, but pain may remain. People should be made fully aware of the risks of DMARDs and monitored carefully for evidence of toxicity.
Combinations of DMARDs may be more effective than single drugs. For example, hydroxychloroquine, sulfasalazine, and methotrexate together are more effective than methotrexate alone or the other two together. Also, combining biologic agents with a DMARD is often more effective than using a single drug or certain combinations of DMARDs. For example, methotrexate can be combined with a TNF inhibitor.
Methotrexate is taken by mouth once weekly. It is anti-inflammatory at the low doses used to treat rheumatoid arthritis. It is very effective and begins to work within 3 to 4 weeks, which is relatively rapid for a DMARD. If a person has liver dysfunction or diabetes and takes methotrexate, frequent doctor visits and blood tests may be warranted so that possible side effects can be detected early. The liver can scar, but this scarring most often can be detected and reversed before major damage develops. People must refrain from drinking alcohol to minimize the risk of liver damage. Bone marrow suppression (suppression of the production of red blood cells, white blood cells, and platelets) is possible. Blood counts should be tested about every 2 months in all people taking the drug. Inflammation of the lung is rare but potentially fatal. Inflammation in the mouth and nausea can also develop. Severe relapses of arthritis can occur after methotrexate is discontinued. Folate (folic acid) tablets may decrease some of the side effects, such as mouth ulcers. Rheumatoid nodules may enlarge with methotrexate therapy.
Hydroxychloroquine is given daily by mouth. 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 12 months during treatment. If the drug has not helped after 9 months, it is discontinued. Otherwise, hydroxychloroquine can be continued as long as necessary.
Leflunomide is taken daily by mouth and has benefits that are similar to those of methotrexate but it is less likely to cause suppression of blood cell production in the bone marrow, abnormal liver function, or inflammation of the lungs (pneumonitis). It can be given at the same time as methotrexate. The major side effects are rashes, liver dysfunction, hair loss, and diarrhea.
Sulfasalazine tablets are initially given nightly by mouth and can relieve symptoms and slow the development of joint damage. Sulfasalazine 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 is seen within 3 months. Because sulfasalazine may quickly cause a person's white blood cell count to become very low (neutropenia), blood tests are done after the first 2 weeks and then about every 12 weeks while the person is taking the drug. Like the other DMARDs, it can cause stomach upset, diarrhea, liver problems, blood cell disorders, and rashes.
Gold compounds are not used anymore.
Corticosteroids, such as prednisone, are the most dramatically effective drugs for reducing inflammation and symptoms of rheumatoid arthritis anywhere in the body. Although corticosteroids are effective for short-term use, they may not prevent joint destruction and may 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 short-term use in the following situations:
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. When corticosteroids are injected into a joint, the person does not get the same side effects as when taking a corticosteroid by mouth (orally) or vein (intravenously). Corticosteroids can be injected directly into affected joints for fast, short-term relief of pain and swelling.
Corticosteroids may worsen high blood pressure, diabetes, glaucoma, and other eye problems and increase the risk of certain infections.
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. However, by interfering with the immune system, immunosuppressive drugs may increase the risks of infection and certain cancers. Such drugs include azathioprine, cyclosporine, and biologic agents such as several tumor necrosis factor (TNF) inhibitors, an interleukin-1 receptor antagonist (anakinra), an interleukin-6 receptor antagonist (tocilizumab), rituximab, abatacept), and a Janus kinase inhibitor (tofacitinib).
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 toxic and serious side effects, including liver disease, an increased susceptibility to infection, and the suppression of blood cell production in the bone marrow. In addition, they may increase the risk of some cancers. In women who are considering pregnancy, immunosuppressive drugs should be used only after discussion with a doctor.
Etanercept, infliximab, golimumab, certolizumab pegol, and adalimumab are TNF inhibitors and can be dramatically effective for people who do not respond sufficiently to methotrexate alone.
Etanercept is given once a week by injection under the skin.
Infliximab is given by vein. After the first dose of infliximab is given, the next two doses are given at 2 and at 6 weeks. Then infliximab is given every 8 weeks.
Golimumab is given by injection under the skin once every 4 weeks.
Certolizumab pegol is given by injection under the skin. After the first dose, the next two doses are given at 2 and at 4 weeks. Then the drug is given at 2-week or 4-week intervals, depending on the dose.
Adalimumab is injected under the skin once every 1 to 2 weeks.
TNF is an important part of the body’s immune system, so inhibition of TNF can impair the body’s ability to fight infections, particularly a reactivated tuberculosis infection. These drugs should be avoided in people who have active infections and should be discontinued before major surgery. Etanercept, infliximab, and adalimumab can be, and are often, used with methotrexate. People who have severe heart failure should not take high doses of infliximab.
Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist, which means it interrupts one of the major chemical pathways involved in inflammation. Anakinra is given as a single daily injection under the skin. Pain and itching at the injection site are the most common side effects. IL-1 is part of the immune system, so inhibiting IL-1 can impair the ability to fight infections. Anakinra can also suppress production of white blood cells. It should not be used with TNF inhibitors. It is used less often because it must be given every day.
Rituximab is a biologic agent that decreases the number of B-cell lymphocytes, one of the white blood cells responsible for causing inflammation and for fighting infection. Because there is not as much evidence for the safety of rituximab as many other drugs, rituximab is usually reserved for people who do not improve enough after taking methotrexate and a TNF inhibitor. It is injected in a vein, as 2 doses, 2 weeks apart. Side effects, as with other immunosuppressive drugs, may include increased risk of infections. In addition, rituximab can cause effects while it is being given, such as rashes, nausea, back pain, itching, and high or low blood pressure.
Abatacept is another biologic agent that interferes with the communication between cells that coordinates inflammation. The first injection in the vein takes over 30 minutes to complete. After that, it is injected in a vein or under the skin at 2 weeks and at 4 weeks after the first dose and every 4 weeks thereafter.
Tocilizumab is a recombinant interleukin-6 receptor antagonist, which means it interrupts one of the major chemical pathways involved in inflammation. It is often used to treat people who are also taking methotrexate. It is given by vein every 4 weeks.
Tofacitinib is a Janus kinase (JAK) inhibitor that interferes with the communication between cells that coordinates inflammation by inhibiting an enzyme (Janus kinase, or JAK). This drug is used if a person has taken methotrexate and has not improved enough. Tofacitinib can be used at the same time as methotrexate. Tofacitinib is taken my mouth twice daily.