Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. Autoimmune diseases are illnesses that occur when the body's tissues are mistakenly attacked by their own immune system. The immune system contains a complex organization of cells and antibodies designed normally to "seek and destroy" invaders of the body, particularly infections. Patients with autoimmune diseases have antibodies and immune cells in their blood that target their own body tissues, where they can be associated with inflammation. While inflammation of the tissue around the joints and inflammatory arthritis are characteristic features of rheumatoid arthritis, the disease can also cause inflammation and injury in other organs in the body. Because it can affect multiple other organs of the body, rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid disease. Rheumatoid arthritis is a classic rheumatic disease. Rheumatoid arthritis that begins in people under 16 years of age is referred to as juvenile idiopathic arthritis or JIA (formerly juvenile rheumatoid arthritis or JRA).
RA symptoms come and go, depending on the degree of tissue inflammation. When body tissues are inflamed, the disease is active. When tissue inflammation subsides, the disease is inactive (in remission). Remissions can occur spontaneously or with treatment and can last weeks, months, or years. During remissions, symptoms of the disease disappear, and people generally feel well. When the disease becomes active again (relapse), symptoms return. The return of disease activity and symptoms is called a flare. The course of rheumatoid arthritis varies among affected individuals, and periods of flares and remissions are typical.
The cause of rheumatoid arthritis is unknown. Even though infectious agents such as viruses, bacteria, and fungi have long been suspected, none has been proven as the cause. The cause of rheumatoid arthritis is a very active area of worldwide research. It is believed that the tendency to develop rheumatoid arthritis may be genetically inherited (hereditary). Certain genes have been identified that increase the risk for rheumatoid arthritis. It is also suspected that certain infections or factors in the environment might trigger the activation of the immune system in susceptible individuals. This misdirected immune system then attacks the body's own tissues. This leads to inflammation in the joints and sometimes in various organs of the body, such as the lungs or eyes.
It is not known what triggers the onset of rheumatoid arthritis. Regardless of the exact trigger, the result is an immune system that is geared up to promote inflammation in the joints and occasionally other tissues of the body. Immune cells, called lymphocytes, are activated and chemical messengers (cytokines, such as tumor necrosis factor/TNF, interleukin-1/IL-1, and interleukin-6/IL-6) are expressed in the inflamed areas.Environmental factors also seem to play some role in causing rheumatoid arthritis. For example, scientists have reported that smoking tobacco, exposure to silica mineral, and chronic periodontal disease all increase the risk of developing rheumatoid arthritis. There are theories about different gut bacteria (the microbiome of gut microbes that naturally inhabit the lining of the bowels) that might trigger the onset of rheumatoid arthritis in genetically susceptible individuals. No specific microbes have been identified as definite causes.
There is no known cure for rheumatoid arthritis. To date, the goal of treatment in rheumatoid arthritis is to reduce joint inflammation and pain, maximize joint function, and prevent joint destruction and deformity. Earlymedical intervention has been shown to be important in improving outcomes. Aggressive management can improve function, stop damage to joints as monitored on X-rays, and prevent work disability. Optimal RA treatment involves a combination of medications, rest, joint-strengthening exercises, joint protection, and patient (and family) education. Treatment is customized according to many factors such as disease activity, types of joints involved, general health, age, and patient occupation. RA treatment is most successful when there is close cooperation between the health care professional, patient, and family members.
Two classes of medications are used in treating rheumatoid arthritis: fast-acting "first-line drugs" and slow-acting "second-line drugs" (also referred to as disease-modifying antirheumatic drugs or DMARDs). The first-line drugs, such as aspirin and cortisone (corticosteroids [Rayos, Celestone, Depo-Medrol, Kenalog]), are used to reduce pain and inflammation. The slow-acting second-line drugs, such as methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo) and hydroxychloroquine (Plaquenil), promote disease remission and prevent progressive joint destruction.
The degree of destructiveness of rheumatoid arthritis varies among affected individuals. Those with uncommon, less destructive forms of the disease or disease that has quieted after many years of activity ("burned out" rheumatoid arthritis) can be managed with rest plus pain control and anti-inflammatory medications alone. In general, however, function is improved and disability and joint destruction are minimized when the condition is treated earlier with second-line drugs (disease-modifying antirheumatic drugs), even within months of the diagnosis. Most people require more aggressive second-line drugs, such as methotrexate, in addition to anti-inflammatory agents. Sometimes these second-line drugs are used in combination.
The areas of the body other than the joints that are affected by rheumatoid inflammation are treated individually. Sjögren's syndrome can be helped by artificial tears and humidifying rooms in the home or office. Medicated eyedrops, cyclosporine ophthalmic drops (Restasis), are also available to help the dry eyes in those affected. Regular eye checkups and early antibiotic treatment for infection of the eyes are important. Inflammation of the tendons (tendinitis), bursae (bursitis), and rheumatoid nodules can be injected with cortisone. Inflammation of the lining of the heart and/or lungs may require high doses of oral cortisone.
In some cases with severe joint deformity, surgery may be recommended to restore joint mobility or repair damaged joints. Doctors who specialize in joint surgery are orthopedic surgeons. The types of joint surgery range from arthroscopy to partial and complete replacement of the joint. Arthroscopy is a surgical technique whereby a doctor inserts a tube-like instrument into the joint to see and repair abnormal tissues.
Total joint replacement is a surgical procedure whereby a destroyed joint is replaced with artificial materials. For example, the small joints of the hand can be replaced with plastic material. Large joints, such as the hips or knees, are replaced with metals.
Acetylsalicylate(aspirin), naproxen (Naprosyn), ibuprofen (Advil, Medipren, Motrin), etodolac (Lodine), and diclofenac (Voltaren) are examples of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are medications that can reduce tissue inflammation, pain, and swelling. NSAIDs are not cortisone. Aspirin, in doses higher than those used in treating headaches and fever, is an effective anti-inflammatory medication for rheumatoid arthritis. Aspirin has been used for joint problems since the ancient Egyptian era. The newer NSAIDs are just as effective as aspirin in reducing inflammation and pain and require fewer dosages per day. Patients' responses to different NSAID medications vary. Therefore, it is not unusual for a medical professional to try several NSAID drugs in order to identify the most effective agent with the fewest side effects. The most common side effects of aspirin and other NSAIDs include stomach upset, abdominal pain, ulcers, and even gastrointestinal bleeding. In order to reduce gastrointestinal side effects, NSAIDs are usually taken with food. Additional medications are frequently recommended to protect the stomach from the ulcer effects of NSAIDs. These medications include antacids, sucralfate (Carafate), proton-pump inhibitors (Prevacid and others), and misoprostol (Cytotec). Newer NSAIDs include selective Cox-2 inhibitors, such as celecoxib (Celebrex), which offer anti-inflammatory effects with less risk of stomach irritation and bleeding risk.
Corticosteroid medications can be given orally or injected directly into tissues and joints. They are more potent than NSAIDs in reducing inflammation and in restoring joint mobility and function. Corticosteroids are useful for short periods during severe flares of disease activity or when the disease is not responding to NSAIDs. However, corticosteroids can have serious side effects, especially when given in high doses for long periods of time. These side effects include weight gain , facial puffiness, thinning of the skin and bone, easy bruising, cataracts , risk of infection, muscle wasting, and destruction of large joints, such as the hips. Corticosteroids also carry some increased risk of contracting infections. These side effects can be partially avoided by gradually tapering the doses of corticosteroids as the individual achieves improvement in symptoms. Abruptly discontinuing corticosteroids can lead to flares of the disease or other symptoms of corticosteroid withdrawal and is discouraged. Thinning of the bones due to osteoporosis may be prevented by calcium and vitamin D supplements .
While "first-line" medications (NSAIDs and corticosteroids) can relieve joint inflammation and pain, they do not necessarily prevent joint destruction or deformity. Rheumatoid arthritis requires medications other than NSAIDs and corticosteroids to stop progressive damage to cartilage, bone, and adjacent soft tissues. The RA medications needed for ideal management of the disease are also referred to as disease-modifying antirheumatic drugs or DMARDs. They come in a variety of forms and are listed below. These "second-line" or "slow-acting" medicines may take weeks to months to become effective. They are used for long periods of time, even years, at varying doses. If maximally effective, DMARDs can promote remission, thereby retarding the progression of joint destruction and deformity. Sometimes a number of DMARD second-line medications are used together as combination therapy. As with the first-line medications, the doctor may need to try different second-line medications before treatment is optimal.
Research suggests that patients who respond to a DMARD with control of the rheumatoid disease may actually decrease the known risk (small but real) of lymphoma (cancer of lymph nodes ) that exists from simply having rheumatoid arthritis. The various available DMARDs are reviewed next.
Hydroxychloroquine (Plaquenil) is related to quinine and has also been used in the treatment of malaria . It is used over long periods for the treatment of rheumatoid arthritis. Possible side effects include upset stomach , skin rashes, muscle weakness, and vision changes. Even though vision changes are rare, people taking Plaquenil should be monitored by an eye doctor (ophthalmologist).
Sulfasalazine (Azulfidine) is an oral medication traditionally used in the treatment of mild to moderately severe inflammatory bowel diseases, such as ulcerative colitis and Crohn's colitis . Azulfidine is used to treat rheumatoid arthritis in combination with anti-inflammatory medications. Azulfidine is generally well tolerated. Common side effects include rash and upset stomach . Because Azulfidine is made up of sulfa and salicylate compounds, it should be avoided by people with known sulfa allergies .
Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo) has gained popularity among health care professionals as an initial second-line drug because of both its effectiveness and relatively infrequent side effects. It also has an advantage in dose flexibility (dosages can be adjusted according to needs). Methotrexate is an immunosuppressive drug. It can affect the bone marrow and the liver , even rarely causing cirrhosis . All people taking methotrexate require regular blood tests to monitor blood counts and liver function . Taking folic acid as a supplement can reduce the risk of methotrexate side effects.
Gold salts have been used to treat rheumatoid arthritis throughout most of the past century. Gold thioglucose (Solganal) and gold thiomalate (Myochrysine ) are given by injection, initially on a weekly basis, for months to years. Oral gold, auranofin (Ridaura ), was introduced in the 1980s. Side effects of gold (oral and injectable) include skin rash , mouth sores , kidney damage with leakage of protein in the urine , and bone marrow damage with anemia and low white cell count. Those receiving gold treatment are regularly monitored with blood and urine tests. Oral gold can cause diarrhea . These gold drugs have lost favor in the treatment of RA because of the availability of more effective treatments, particularly methotrexate.
D-penicillamine (Depen , Cuprimine ) can be helpful in selected cases of progressive forms of rheumatoid arthritis. Side effects are similar to those of gold. They include fever, chills , mouth sores , a metallic taste in the mouth , skin rash, kidney and bone marrow damage, stomach upset, and easy bruising. People taking this medication require routine blood and urine tests. D-penicillamine can rarely cause symptoms of other autoimmune diseases and is no longer commonly used for the treatment of rheumatoid arthritis.
Immunosuppressive medicines are powerful medications that suppress the body's immune system. A number of immunosuppressive drugs are used to treat rheumatoid arthritis. They include methotrexate as described above, azathioprine (Imuran), cyclophosphamide (Cytoxan ), chlorambucil (Leukeran ), and cyclosporine (Sandimmune ). Because of potentially serious side effects, immunosuppressive medicines (other than methotrexate) are generally reserved for those who have very aggressive disease or those with serious complications of rheumatoid inflammation, such as blood vessel inflammation (vasculitis). The exception is methotrexate, which is not frequently associated with serious side effects and can be carefully monitored with blood testing. Methotrexate has become a preferred second-line medication as a result.
Immunosuppressive medications can depress bone-marrow function and cause anemia, a low white cell count, and low platelet counts. A low white count can increase the risk of infections, while a low platelet count can increase the risk of bleeding. Methotrexate rarely can lead to liver cirrhosis, as described above, and allergic reactions in the lung. Cyclosporine can cause kidney damage and high blood pressure (hypertension). Because of potentially serious side effects, immunosuppressive medications are used in low doses, usually in combination with anti-inflammatory agents.
Combinations of traditional DMARDs, including sulfasalazine, methotrexate, and hydroxychloroquine, have been shown by researchers to be another potent method of stopping disease progression of rheumatoid arthritis.
Newer "second-line" drugs (DMARDs) for the treatment of rheumatoid arthritis include leflunomide (Arava) and the "biologic" medications etanercept (Enbrel), infliximab (Remicade), anakinra (Kineret), adalimumab(Humira), rituximab (Rituxan), abatacept (Orencia), golimumab (Simponi), certolizumab pegol (Cimzia), tocilizumab (Actemra), and JAK inhibitors represented by tofacitinib (Xeljanz). Each of these medications can increase the risk for infections, and the development of any infections should be reported to the health-care professional when taking these newer second-line drugs.
Leflunomide (Arava) is available to relieve the symptoms and halt the progression of the disease. It seems to work by blocking the action of an important enzyme that has a role in immune activation. Leflunomide can cause liver disease, diarrhea, hair loss, and/or rash in some people. It should not be taken just before or during pregnancy because of possible birth defects and is generally avoided in women who might become pregnant.
Biologic DMARDs represent a novel approach to the treatment of rheumatoid arthritis and are products of modern biotechnology. These are referred to as the biologic medications or biological response modifiers. In comparison with traditional DMARDs, the biologic medications have a much more rapid onset of action and can have powerful effects on stopping progressive joint damage. In general, their methods of action are also more directed, defined, and targeted.
Etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol are biologic medications that intercept a messenger protein in the joints (tumor necrosis factor or TNF) that promotes inflammation of the joints in rheumatoid arthritis. These TNF-blockers intercept TNF before it can act on its natural receptor to "switch on" the process of inflammation. This effectively blocks the TNF inflammation messenger from recruiting the cells of inflammation. Symptoms can be significantly, and often rapidly, improved in those using these drugs. Etanercept must be injected subcutaneously once or twice a week. Infliximab is given by infusion directly into a vein (intravenously). Adalimumab is injected subcutaneously either every other week or weekly. Golimumab is injected subcutaneously on a monthly basis. Certolizumab pegol is injected subcutaneously every two to four weeks. Each of these medications is being evaluated by health care professionals in practice to determine what role they may have in treating patients in various stages of rheumatoid arthritis. Research has shown that biological response modifiers also prevent the progressive joint destruction of rheumatoid arthritis. They are currently recommended for use after other second-line medications have not been effective. The biological response modifiers (TNF-inhibitors) are expensive treatments. They are also frequently used in combination with methotrexate and other DMARDs. Furthermore, it should be noted that the TNF-blocking biologics all are more effective when combined with methotrexate. These medications should be avoided by people with significant congestive heart failure or demyelinating diseases (such as multiple sclerosis) because they can worsen these medical conditions.
Anakinra (Kineret) is another biologic DMARD treatment that is used to treat moderate to severe rheumatoid arthritis. Anakinra works by binding to a cell messenger protein (IL-1, a pro-inflammatory cytokine). Anakinra is injected under the skin daily. Anakinra can be used alone or with other DMARDs. The response rate of anakinra does not seem to be as high as with other biologic medications. Rituximab (Rituxan) is an antibody that was first used to treat lymphoma, a cancer of the lymph nodes. Rituximab can be effective in treating autoimmune diseases like rheumatoid arthritis because it depletes B-cells, which are important cells of inflammation and in the production of abnormal antibodies that are common in these medical conditions. Rituximab is used to treat moderate to severely active rheumatoid arthritis in patients who have failed treatment with the TNF-blocking biologics. Preliminary studies have shown that Rituximab was also found to be beneficial in treating severe rheumatoid arthritis complicated by blood vessel inflammation (vasculitis) and cryoglobulinemia. Rituximab is an intravenous infusion given in two doses, two weeks apart, approximately every six months.
Abatacept (Orencia) is a biologic medication that blocks T-cell activation. Abatacept is used to treat adult patients who have failed treatment with a traditional DMARD medication. Abatacept is an intravenous infusion given monthly or a weekly subcutaneous injection.
Tocilizumab (Actemra) is approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Tocilizumab is the first approved biologic medication that blocks interleukin-6 (IL-6), which is a chemical messenger of the inflammation of rheumatoid arthritis. Tocilizumab is an intravenous infusion given monthly or a weekly subcutaneous injection.
Tofacitinib (Xeljanz) is the first in a new class of medications used to treat rheumatoid arthritis called JAK inhibitors. Tofacitinib is used to treat adults with moderately to severely active rheumatoid arthritis in which methotrexate did not work well. Tofacitinib can be used with or without methotrexate. This prescription medicine is taken by mouth twice daily. Tofacitinib is considered a "targeted" medication that specifically blocks special enzymes of inflammation in joints (called Janus kinase) within cells. Tofacitinib is, therefore, referred to as a JAK inhibitor.
While biologic medications are often combined with traditional DMARDs in the treatment of rheumatoid arthritis, they are generally not used with other biologic medications because of the unacceptable risk for serious infections. Similarly, JAK inhibitor medication is not used with traditional biologic medications.
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