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•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Symptoms
•	Complications
•	Diagnosis
•	Treatment
•	Medications
•	Surgery
•	Lifestyle Changes
•	Resources
•	References

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Rheumatoid arthritis

Highlights

Drug Approvals

• Celecoxib (Celebrex) was approved in December 2006 for treatment of juvenile rheumatoid arthritis (JRA). It is not recommended for patients with systemic onset JRA, a more serious form of the disease.
• Rituximab (Rituxan) was approved in April 2006 for treatment of adult patients with rheumatoid arthritis who have failed to respond to anti-tumor necrosis factor (anti-TNF) drugs. In December 2006, the FDA warned that rituximab has been associated with cases of progressive multifocal leukoencephalopathy, a rare and deadly brain infection.
• Abatacept (Orencia) was approved in December 2005 for treatment of rheumatoid arthritis in adults with moderate-to-severe RA who have not responded to disease modifying anti-rheumatism drugs (DMARDs) or anti-TNF drugs.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

In December 2006, the FDA proposed adding stronger warnings to the labels of NSAIDs. The new warnings will emphasize these drugs’ risk for stomach bleeding and potentially fatal liver damage. The risks are highest when these drugs are taken in combination with each other or with alcohol. NSAIDs should also never be combined with steroids or blood thinner drugs.

Early Treatment of Rheumatoid Arthritis

Several 2006 studies suggest that aggressive treatment of rheumatoid arthritis in its early stages may help lead to remission. Among these findings:

• A combination of methotrexate (Rheumatrex, Trexall) and adalimumab (Humira) works better in improving symptoms and achieving remission than either drug alone.
• A combination of methotrexate and infliximab (Remicade) works better than single drug therapies.
• Intensive dosing with methotrexate produces a higher remission rate than standard dosing.

Rheumatoid Arthritis and Lymphoma

People with severe arthritis have a much higher risk of developing lymphoma than people with milder forms of the disease, according to a 2006 study. The researchers suggest that the chronic inflammatory process of arthritis plays a major role in heightening lymphoma risk. However, this study, combined with other recent research, indicates that drug treatments for arthritis, including biologic response modifiers, do not increase lymphoma risk.

Introduction

Rheumatoid arthritis (RA) is a chronic disease in which various joints in the body are inflamed, leading to swelling, pain, stiffness, and the possible loss of function. Some experts classify rheumatoid arthritis as type 1 or type 2.

• Type 1, the less common form, lasts a few months at most and leaves no permanent disability.
• Type 2 is chronic and lasts for years, sometimes for life.

Rheumatoid arthritis is an autoimmune disease in which the body's immune system attacks itself. The pattern of joints affected is usually symmetrical, involves the hands and other joints, and is worse in the morning. Rheumatoid arthritis is a systemic (body-wide) disease, involving other body organs, whereas osteoarthritis is limited to the joints. Both forms of arthritis can be crippling.

The process probably develops in the following way:

• The disease process leading to rheumatoid arthritis begins in the synovium, the membrane that surrounds a joint and creates a protective sac.
• This sac is filled with lubricating liquid called the synovial fluid. In addition to cushioning joints, this fluid supplies nutrients and oxygen to cartilage, a slippery tissue that coats the ends of bones.
• Cartilage is composed primarily of collagen, the structural protein in the body, which forms a mesh to give support and flexibility to joints.
• In rheumatoid arthritis, an abnormal immune system produces destructive molecules that cause continuous inflammation of the synovium. Collagen is gradually destroyed, narrowing the joint space and eventually damaging bone.
• If the disease develops into a form called progressive rheumatoid arthritis, destruction to the cartilage accelerates. Fluid and immune system cells accumulate in the synovium to produce a pannus, a growth composed of thickened synovial tissue.
• The pannus produces more enzymes that destroy nearby cartilage, aggravating the area and attracting more inflammatory white cells, thereby perpetuating the process.

This inflammatory process not only affects cartilage and bones but can also harm organs in other parts of the body.

Click the icon to see an image of rheumatoid arthritis.

Causes

Although much has been learned about the process leading to rheumatoid arthritis, researchers have yet to uncover all the factors that lead to this devastating disease. One prevalent theory is that a combination of factors triggers rheumatoid arthritis, including an abnormal autoimmune response, genetic susceptibility, and some environmental or biologic trigger, such as a viral infection or hormonal changes.

The Immune Response and Inflammatory Process

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

• When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
• The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight any infections.
• In the process the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting off any bleeding blood vessel and initiating fiber-like patches to the tissue.
• Under normal conditions, the immune system has other special factors that control and limit this inflammatory process.

The Infection Fighters. Two important components of the immune system that play a role in the inflammation associated with rheumatoid arthritis are B cells and T cells, both of which belong to a family of immune cells called lymphocytes.

When macrophages recognize foreign particles entering the bloodstream, they are programmed to ingest them, split them into pieces, and bring specific sections of them (antigens) into contact with the surface of the T cell. These antigens are placed within specialized proteins on the surface of the T cell that signal to a T cell and begin a process of immune system inspection. This process involves the interaction of several proteins on B cells and T cells, which seem to signal back and forth.

If the T cell recognizes an antigen as "non-self," then it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion. T cells can be further categorized as killer T cells or helper T cells. Killer T cells directly attack antigens, such as viruses and tumor cells. Helper T cells recognize antigens that are presented to them by macrophages (or other specialized cells), and can stimulate B cells to mount various kinds of attacks on the antigen. They also produce chemicals (cytokines) that can have a more direct role in the inflammatory process.

For reasons that are still not completely understood, both the T cells and the B cells become overactive in patients with RA. In an immune response it is normal for the antibody response to change over time, particularly if the first antibodies that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes in an attempt to achieve better recognition and a stronger inflammatory response against a recalcitrant invader. In RA, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal repertoire of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, infections, injuries, tissue repair, blood clotting, clearing of debris from inflamed blood vessels, and other aspects of healing. If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury.

Cytokines are very important in the destructive process of rheumatoid arthritis, particularly those known as interleukins (ILs) -- notably IL1 and IL6 -- and tumor necrosis factor (TNF). TNF is now known to be the major cause of joint damage and various systemic manifestations of RA, including weight loss.

Leukocytes. The leukocytes, the other major white blood cells in the body, are also spurred into action by the over-zealous T cells. Leukocytes stimulate the production of key players in the inflammatory process:

• Leukotrienes attract white blood cells to the area.
• Prostaglandins open blood vessels and increase blood flow.
• Nitric Oxide is a gas that is important in blood vessel flexibility and dilation. In excessive amounts, however, it becomes a damaging substance that may play a major destructive role in RA.

The Hypothalamic-Pituitary-Adrenal Axis and Stress Hormones. Some research suggests that abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) may contribute to RA. The HPA system includes two parts of the brain (the hypothalamus and the pituitary) and the adrenal gland.

Click the icon to see an image of the adrenal glands.

The HPA axis regulates a person's response to stress, which includes the release of cortisol (an important stress hormones) and DHEA (a weak male hormone). The cytokines interleukin-6 and TNF-alpha normally stimulate a surge in these hormones, which then block further release of the cytokines. Research suggests, however, that in RA, a defective HPA axis responds to the cytokines with a lower-than-normal release of cortisol and DHEA. Without a strong stress response, the cytokine levels remain high and become destructive, causing inflammation.

Genetic Factors

Genetic factors play some role in RA, but some twin studies suggest that it is not very important in most cases. The presence of certain genetic mutations, however, may worsen the disease process. It should be pointed out that defective genes not only can be inherited but they may be changed and mutated by environmental or other factors. More research is needed to determine the specific genetic contributions to this disease.

HLA. HLA (human leukocyte antigen) is a genetically regulated molecule that traps part of antigens and presents them on the surface of cells for destruction by antibodies and T cells. It is designed to recognize self- from non-self cells. Researchers have identified a number of HLA genetic forms called HLA-DRB1 alleles, which are referred to as the RA-shared epitope because of their association with rheumatoid arthritis. These genetic factors do not cause RA, though they may make the disease more severe once it has developed. A 2004 study suggested that genetic variations in the HLA region may also predict drug treatment response. In this study, researchers found that genetics determined how well a patient responded to treatment with the anti-TNF blocker etanercept. Similarly, particular HLA genes determined response to the disease-modifying anti-rheumatic drug methotrexate.

Lack of Corticotropin-Releasing Hormone. Some people with RA may have a genetic deficiency of a hormone known as corticotropin-releasing hormone (CRH), which produces corticosteroids, hormones that suppress the inflammatory process.

Mutation of P53 Gene. Even successful treatment of inflammation in RA does not completely prevent further joint destruction. Research has suggested that a mutation of the gene known as p53 may prolong the process. This defect is inherited but occurs over time as the disease progresses. In its normal state, the p53 gene is known as a tumor suppressor gene and causes apoptosis, a natural process by which cells self-destruct. When the p53 gene is defective, cells do not die but continue to reproduce. The actions of a defective p53 gene may help explain several processes associated with RA:

• The development of a pannus, the growth composed of thickened synovial tissue.
• The progressive destruction of cartilage and bone that occurs even after the inflammation has been treated.
• A higher than normal risk for certain cancers. A p53 mutation is found in many cancers. Although the defective p53 gene behaves differently in RA than in cancer, researchers are investigating whether it may play some role in this higher risk.

Environmental Triggers

Infections. Although many bacteria and viruses have been studied, no single organism has been proven to be the primary trigger for the autoimmune response and subsequent damaging inflammation. Higher than average levels of antibodies that react with the common intestinal bacteria E. coli have appeared in the synovial fluid of people with RA. Some experts think they may stimulate the immune system to prolong RA once the disease has been triggered by some other initial infection.

Chemicals. A number of chemicals are being investigated as triggers of rheumatoid arthritis. For example, exposure to silica was associated with RA in a 2003 study. A number of other chemicals are under investigation but it is very difficult to determine causal effects of any specific one.

Risk Factors

Rheumatoid arthritis (RA) is an ancient disease. The condition has been identified in skeletons thousands of years old. According to the Arthritis Foundation, RA affects an estimated 2.1 million Americans.

Age

Although the disease can occur at any age from childhood to old age, it usually starts in young adulthood, with onset peaking between the ages of 20 - 45. Still, about 50,000 children may be afflicted with juvenile rheumatoid arthritis.

Gender

Women are more likely to have RA than men. (The risk for women is slightly lower if they have been pregnant.) Women are also at higher risk for the severe type 2 rheumatoid arthritis.

Family History

Some people may inherit genes that make them susceptible to RA, but a family history of RA does not appear to increase an individual's risk.

Other Risk Factors

Other factors may place certain susceptible individuals at higher risk for developing RA:

• Heavy long-term smoking is a very strong risk factor for RA, particularly in patients without a family history of the disease.
• Women who have a shorter fertility time (and so lower levels of reproductive hormones) may be at higher risk.
• History of blood transfusions.

Most studies have not found any association between silicone breast implants and rheumatoid arthritis or other autoimmune disease (except possibly Sjögren syndrome).

The Role of Allergies

Reports from a Dutch study suggest that hay fever sufferers have a reduced risk of developing rheumatoid arthritis, and, conversely, arthritis patients are less likely to have hay fever.

Symptoms

The hallmark symptom of rheumatoid arthritis is morning stiffness that lasts for at least an hour. (Stiffness from osteoarthritis, for instance, usually clears up within half an hour.) Even after remaining motionless for a few moments, the body can stiffen. Movement becomes easier again after loosening up.

Swelling and Pain

Swelling and pain in the joints must occur for at least 6 weeks before a diagnosis of rheumatoid arthritis is considered. The inflamed joints are usually swollen and often feel warm and "boggy" when touched. The pain often occurs symmetrically but may be more severe on one side of the body, depending on which hand the person uses more often.

Specific Joints Affected

Although rheumatoid arthritis almost always develops in the wrists and knuckles, the knees and joints of the ball of the foot are often affected as well. Indeed, many joints may be involved, even causing the spine to become misaligned. It does not usually show up in the fingertips, where osteoarthritis is common, but joints at the base of the fingers are often painful.

Nodules

In about 20% of people with RA, inflammation of small blood vessels can cause nodules, or lumps, under the skin. They are about the size of a pea or slightly larger, and are often located near the elbow, although they can show up anywhere. Nodules can occur throughout the course of the disease. Rarely, nodules may become sore and infected, particularly if they are in locations where stress occurs, such as the ankles. On rare occasions, nodules can reflect the presence of rheumatoid vasculitis, a condition that can affect blood vessels in the lungs, kidneys, or other organs.

Fluid Buildup

Fluid may accumulate, particularly in the ankles. In rare cases, the joint sac behind the knee accumulates fluid and forms what is known as a Baker cyst. This cyst feels like a tumor and sometimes extends down the back of the calf causing pain.

Flu-Like Symptoms

Symptoms such as fatigue, weight loss, and fever may accompany early rheumatoid arthritis. Some people describe them as being similar to those of a cold or flu except, of course, RA symptoms can last for years.

Symptoms in Children

In children, juvenile rheumatoid arthritis, also known as Still's disease, is usually preceded by high fever and shaking chills along with pain and swelling in many joints. A pink skin rash may be present.

Complications

Rheumatoid arthritis is not fatal, but complications of the disease may shorten survival by a few years in some individuals. Although type 2 rheumatoid arthritis is progressive and there is no cure, over time the disease becomes less aggressive, and symptoms may even improve.

Treatments for RA are increasingly effective in slowing this debilitating disease, and some may even prevent initial destruction by aggressively reducing inflammation. If bone and ligament destruction and any deformities have occurred, however, the effects are permanent. It is essential, therefore, to seek a doctor's help as soon as symptoms develop. Side effects of the treatments often contribute to the severity of the disease.

Effect of Joint Disability and Pain on Daily Life

Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible. According to one survey, 70% of patients with rheumatoid arthritis feel the disease prevents them from living a fully productive life. A 2000 study found that approximately one-third of people with RA stop working within 5 years of onset of the disease.

Complications in Other Areas of the Body

Rheumatoid arthritis can affect other parts of the body as well as the joints. Some patients with severe disease may then be at higher risk for complications such as the following:

• Peripheral Neuropathy. This condition affects the nerves, most often those in the hands and feet. It can result in tingling, numbness, or burning.
• Anemia. People with RA may develop anemia, which involves a decrease in the production of red blood cells.
• Scleritis. This is an inflammation of the blood vessels in the eye that can result in corneal damage.
• Infections. RA patients have a higher risk for infections, particularly from some of the immune-suppressing drugs that they take.
• Skin Problems. Skin problems are common, particularly on the fingers and under the nails. Some patients develop severe skin complications that include rash, ulcers, blisters (which may bleed in some cases), lumps under the skin, and other problems. Severe skin disease can reflects a more serious case of RA in general.
• Gastrointestinal Problems. Although patients may experience stomach and intestinal distress, one 2000 study reported lower rates of stomach and colorectal cancers among RA patients.
• Osteoporosis. Osteoporosis, a disorder in which bone density decreases, is more common than average in postmenopausal women with RA. The hipbone is particularly affected. The risk for osteoporosis also appears to be higher than average in men with RA who are over 60 years old.
• Lung Disease. Patients with RA are susceptible to chronic lung diseases.
• Heart Disease. Mounting evidence suggests that RA can increase the risk for heart disease, possibly because of the inflammatory response in RA, which may also injure arteries and heart muscle tissue. Some studies have reported that people with RA are 30 - 50% more likely to suffer heart vessel blockages and 60 - 70% more likely to die as result than people without RA. A smaller British study indicated that about half of RA patients are likely to have silent symptoms of heart disease, and that it tends to develop about 10 years earlier than in people without RA.
• Lymphoma and Other Cancers. Research suggests that patients with RA are four times more likely than healthy patients to develop non-Hodgkin’s lymphoma. There has also been concern that some RA treatments may increase the risk for lymphoma. Studies from 2006 indicate that RA’s chronic inflammatory process may play a role in the development of lymphoma. Researchers found that patients with very severe and long-term RA had a substantially increased risk of developing lymphoma. Other 2006 research suggests that RA drugs, such as biologic response modifiers, do not increase lymphoma risk, although they do increase skin cancer risk.
• Periodontal Disease. People with RA may be twice as likely as non-arthritic individuals to have periodontal disease. Chronic inflammation and immune dysfunction are central to both diseases.
• Pregnancy. Women with RA have an increased risk for premature delivery. They are also three times more likely than healthy women to develop hypertension during the last trimester of pregnancy.

Severity of Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis often resolves before adulthood. Patients who experience arthritis in only a few joints do better than those with more widespread (systemic) disease, which is very difficult to treat. Although it can be very serious, very few people die from this condition.

MAS. Macrophage activation syndrome (MAS) is a life-threatening complication of this disorder and requires immediate treatment with high-dose steroids and cyclosporin A. Parents should be aware of symptoms, which include persistent fever, weakness, drowsiness, and lethargy.

Diagnosis

Rheumatoid arthritis can be difficult to diagnose. Many other conditions resemble it and its symptoms can develop insidiously. Blood tests and x-rays may show normal results for months after the onset of joint pain. Even after rheumatoid arthritis has been diagnosed, it is extremely important to determine whether the course of the disease is benign (type 1) or aggressive (type 2) in order to treat the problem appropriately.

Blood Tests

Various blood tests may be used to help diagnose RA, determine its severity, and detect complications of the disease.

Rheumatoid Factor. In RA, antibodies that collect in the synovium of the joint are known as rheumatoid factor. In about 80% of cases of RA, blood tests reveal rheumatoid factor. It can also show up in blood tests of people with other diseases. However, when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of type 2 RA. The presence of rheumatoid factor plus evidence of bone damage on x-rays also suggests a significant chance for progressive joint damage.

Erythrocyte Sedimentation Rate Test. An erythrocyte sedimentation rate (ESR or sed rate) measures how fast red blood cells (erythrocytes) fall to the bottom of a fine glass tube that is filled with the patient's blood. The higher the sed rate the greater the inflammation. In addition to rheumatoid arthritis, the sed rate can be high in many conditions ranging from infection to inflammation to tumors. The test is used, then, not for diagnosis, but to help determine how serious the condition is.

C-Reactive Protein. High levels of C-reactive protein (CRP) are also indicators of active inflammation. However, because obesity also increases CRP levels, the doctor should consider a patient’s body mass index when evaluating CRP levels during RA diagnosis.

Anti-CCP Antibody Test. The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop. In combination with the test for rheumatoid factor, the CCP antibody test is the best predictor of which patients will go on to develop severe RA. Used in Europe, the test is now beginning to be used somewhat more commonly in the U.S. U.S. laboratories have not yet developed consistent standards for interpreting the test, however.

Tests for Anemia. Anemia is a common complication and blood tests should be taken that determine the amount of red blood cells (hemoglobin and hematocrit) and iron (soluble transferrin receptor and serum ferritin) in the blood.

Possible RA Markers in Synovial Fluid

Analyzing the synovial fluid might prove to be helpful in detecting markers of joint destruction, but this is not commonly performed. Some investigational examples include the following:

• An enzyme called MMP-3 (matrix metalloproteinase 3) is involved with the degradation of cartilage. Its presence in synovial fluid is strongly associated with progressive joint destruction in patients with chronic RA.
• High levels urocortin, a member of the peptide family involved in the stress response, may also be a major player in the RA inflammation.

Imaging Techniques

X-Rays. X-rays generally have not been helpful to detect the presence of early rheumatoid arthritis because they cannot show images of soft tissue. The use of a technique known as dual energy x-ray absorptiometry, however, may be useful in detecting early bone loss in rheumatoid arthritis (2 - 27 months after onset). Evidence of damage on x-rays along with elevated rheumatoid factor is a significant predictor for progressive joint destruction.

Ultrasound. Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. PDUS may be reliable for monitoring inflammatory activity in the joint. QUS, which is used for osteoporosis, has been used to detect bone loss in fingers, which may prove to be a good indicator of early RA.

Magnetic Resonance Imaging. Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays cannot. Further evaluation is necessary.

Ruling Out Other Disorders

Symptoms of rheumatoid arthritis can be mimicked by things as benign as a bad mattress or as serious as cancer. A number of rare genetic diseases attack the joints. Physical injuries, infections, and poor circulation are among the many problems that can cause aches and pains. It would be impossible to discuss in this report the dozens of other conditions that present themselves with symptoms of joint aches and pains.

Osteoarthritis. Osteoarthritis requires some special mention because it is the most common form of arthritis. It differs from RA in several important respects.

• Osteoarthritis usually occurs in older people.
• It is located in only one or a few joints. (In fact, osteoarthritis is probably most often confused with rheumatoid arthritis if it affects multiple joints in the body.)
• The joints are less inflamed.
• Progression of pain is almost always gradual.

Gout. Gout also causes swelling and severe pain in a joint, although most commonly starting in one joint. It is particularly difficult to distinguish chronic gout in older people from rheumatoid arthritis, however, since gout in this population can occur in a number of joints. A proper diagnosis can be made with a detailed medical history, laboratory tests, and detection in the affected joint of a salt called monosodium urate (MSU), which identifies gout.

Treatment

The treatment of rheumatoid arthritis involves medications and lifestyle changes.

General Guidelines for Drug Treatments

Many drugs are used for managing the pain and slowing the progression of rheumatoid arthritis, but none completely cure the disease. Some experts believe that no single drug will ever cure rheumatoid arthritis because of the many factors that affect the disease at various times. The goals of drug treatment for rheumatoid arthritis include:

• Reduce inflammation
• Prevent damage to the bones and ligaments of the joint
• Preserve movement
• To be as inexpensive and as free from side effects as possible over the long-term

Drug Categories Used for Rheumatoid Arthritis

The drug categories used for RA include:

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are the least potent drugs used for RA. These drugs relieve pain by reducing inflammation, but do not contain steroids.
• Disease-Modifying Anti-Rheumatic Drugs (DMARDs) are the main drugs used for treating rheumatoid arthritis. They slow the progression of the disease. They are much more effective than NSAIDs but also have more side effects. Methotrexate (Rheumatrex, Trexall) is the most widely used of these drugs.
• Biologic Response Modifiers (also known as Biologic DMARDs) are often prescribed to patients who have failed to respond to DMARDs. They may be used alone or in combination with DMARDs such as methotrexate. They modify or block destructive immune factors such as tumor-necrosis factor (TNF). Current anti-TNF drugs include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). Other biologic response modifiers include the interleukin-1 antagonist anakinra (Kineret), the T-cell co-stimulation modulator abatacept (Orencia), and rituximab (Rituxan), which targets CD20-positive B cells.
• Corticosteroids, or steroids, are powerful anti-inflammatory drugs that are used to quickly reduce inflammation. These drugs include prednisone and prednisolone.
• Immunosuppressant drugs are used for disease that recurs or does not respond to other drugs. They inhibit the immune system and have potentially very serious side effects. These drugs include azathioprine (Imuran) and cyclophosphamide (Cytoxan)

Treatment Approaches

The question of how early and how aggressively to treat RA has been the subject of great debate. Current practice has moved towards treating the disease aggressively while it is in its early stages to help prevent it from reaching a more severe and chronic state.

Studies have found less joint damage in patients with early, aggressive treatment, particularly with the use of DMARDs and TNF modifiers. Research from 2006 showed promising results from early treatment with methotrexate in combination with either infliximab (Remicade) or adaliumumab (Humira). Other studies indicate that intensive early dosing of methotrexate may help slow progression of rheumatoid arthritis. Early combination therapy with DMARDs and corticosteroids is also showing good results. Some experts believe that with early aggressive therapy, remissions may be so successful that RA might even be considered potentially curable. There is also evidence that early use of DMARDs may help protect against heart problems, which can be major complications of RA.

It is not fully clear, however, which patients should receive such early aggressive treatment. Of all patients with RA, some will go into remission and remain in remission for the length of their lives even in the absence of treatment, while others will go on to develop active, sometimes severe RA. European researchers found that if the disease subsides within 3 months after diagnosis, patients tend to stay in remission. If disease persists beyond 3 months, it is likely to persist long-term. At this time, the evidence suggests that people who are most likely to develop severe disease have the following characteristics:

• Positive rheumatoid factor
• Antibodies to CCP
• Early erosive damage to joints
• Persistent inflammation despite steroids or NSAIDs

These indicators are not absolute, and further study is underway to better determine who is at greatest risk of disease progression, and how beneficial early aggressive therapy is among different patient populations. Nevertheless, new "early arthritis centers" are encouraging people with the earliest symptoms to seek help from arthritis specialists, with the hope of detecting and treating the disease before symptoms progress.

Layered or Step Approach

Given the recent evidence and the important questions still outstanding, a layered, "step-up" or "step-down" approach probably describes the manner in which therapies are administered in the majority of cases today. One or more drugs may be given for a period of time; depending on symptoms one or more may be added or dropped as needed.

Because there are so many potential combinations, it is not possible to list a typical regimen. Numerous variables affects which drugs may be prescribed at a given time, including the severity of disease, how well a particular drug has worked for an individual, patient preferences regarding pills or injections, side effects, and other factors.

Overall, however, doctors are increasingly using stronger medications first, based on studies showing that joint damage can be slowed or stopped with the early use of such drugs. Combinations of DMARDs (especially methotrexate) and biological drugs (TNF modifiers) are considered by far the most effective therapies. DMARDs combined with a corticosteroid such as prednisone are also showing good results.

Medications

Nonsteroidal Anti-Inflammatory Drugs (NSAIDS)

Two-thirds of people with RA rank pain as their primary reason for seeking professional help. The most common pain relievers for RA are nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs. They include:

• Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
• Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil). In 2004, a new NSAID, meloxicam (Mobic) was approved in the U.S. for the management and treatment of rheumatoid arthritis.

Studies suggest that the best times for taking an NSAID may be after the evening meal and then again on awakening. RA symptoms increase gradually during the night, reaching their greatest severity at the time of awakening. Taking NSAIDs with food can reduce stomach discomfort, although it may slow down the pain-relieving effect.

In April 2005, the FDA asked drug manufacturers of prescription NSAIDs to include with their products the same warning label used for the COX-2 inhibitor celecoxib (Celebrex). This "black box" warning, the FDA's strongest warning, emphasizes the increased risks for cardiovascular events and gastrointestinal bleeding associated with these drugs’ use. The FDA also requested manufacturers of OTC NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and gastrointestinal risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions. In December 2006, the FDA proposed even stronger labeling changes to highlight these drugs’ risk for liver damage as well as alcohol and drug interactions.

Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been associated many side effects. Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers and gastrointestinal bleeding. (See Box: "NSAID-Induced Ulcers and Gastrointestinal Bleeding.")

Other possible side effects of NSAIDs include:

• Upset stomach
• Dyspepsia (burning, bloated feeling in pit of stomach)
• Drowsiness
• Skin bruising
• High blood pressure
• Fluid retention
• Headache
• Rash
• Reduced kidney function

COX-2 Inhibitors (Coxibs). Coxibs inhibit an inflammation-promoting enzyme called COX-2. This drug class was initially thought to provide benefits equal to NSAIDs but cause less gastrointestinal distress. However, following numerous reports of heart problems, skin rashes, and other adverse effects, the FDA re-evaluated the risks and benefits of this drug class. This lead to the removal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the United States market. Celecoxib (Celebrex) is still available, but patients should ask their doctor whether the drug is appropriate and safe for them. In December 2006, the FDA approved celecoxib for the relief of symptoms of juvenile rheumatoid arthritis in patients ages 2 years and older.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Disease-modifying anti-rheumatic drugs (DMARDs) are the standard second-line drugs. Early treatment with DMARDs improves patients' long-term outcome and quality of life and may also help slow down progression of the disease. Evidence supporting early use was reflected in a 5-year study that compared RA progression rates in patients from different countries. The slowest disease progression rates were observed in patients who were given the most effective DMARDs immediately upon diagnosis. The worst and most rapid progression occurred in patients who were given less potent DMARDs and whose treatment was delayed by 3 months.

There is also some evidence that early use of DMARDs may help protect against heart problems, a major complication of RA.

DMARDs do not have any common properties other than their ability to slow down the progression of rheumatoid arthritis. Many were used for other diseases and were found accidentally to help RA. DMARDs include:

• Methotrexate (considered to be the current standard of care. Newer drugs called biologic modifiers, however, are proving to be as effective with fewer side effects when used alone, and even more effective when used in combination with methotrexate.)
• Hydroxychloroquine
• Sulfasalazine
• Gold
• D-penicillamine
• Cyclosporine
• Leflunomide

Unfortunately, all DMARDs tend to lose effectiveness over time, even methotrexate. Patients rarely use one drug for more than 2 years. Combining DMARDs with each other or with drugs in other categories offers the best approach for many patients. The addition of a corticosteroid to any combination may be important.

All DMARDs may produce stomach and intestinal side effects, and, over the long-term, each poses some risk for rare but serious reactions. (In some cases, however, they may be less harmful than long-term NSAID treatment.)

Methotrexate. Methotrexate (Rheumatrex, Trexall) acts as an anti-inflammatory drug and is now the most frequently used DMARD, particularly for severe disease. It has the following advantages over other DMARDs:

• A faster mode of action than other DMARDs (starts working within a few weeks).
• The best record to date for long-term use.
• A 2002 study suggested that it reduced mortality rates from heart disease by 70% compared to other DMARDs. (Death rates from other causes were also lower, although less significantly.)
• A 2005 study indicated that methotrexate may be more effective than leflunomide for treatment of juvenile rheumatoid arthritis.

Even this drug loses effectiveness, however, when used alone. It may be more effective when used in combination with other DMARDs or drugs. Recent studies have focused on combining methotrexate with various biological response modifier drugs, especially for treatment of patients with early aggressive arthritis. Study results from 2006 suggested that combining methotrexate with either adalimumab or infliximab could help lead to remission in these patients. The combination appears to work better than single drug therapy.

About 20% of patients withdraw from methotrexate because of its side effects. They include nausea and vomiting, rash, mild hair loss, headache, mouth sores, and muscle aches. Methotrexate reduces levels of folic acid (folate) in the body, which can lead to some of these side effects. Doctors may prescribe folic acid supplements to prevent side effects. However, some research suggests that folic acid may interfere with methotrexate’s effectiveness.

Methotrexate has fewer serious toxic effects than many DMARDs. Although these severe reactions are rare, they may include:

• Kidney and liver damage. People at particular risk for liver damage from methotrexate include diabetics with existing liver or kidney problems, alcoholics, those who are obese, the elderly, and (at very high risk) those with psoriasis.
• Osteoporosis may possibly develop at high doses. (A 2001 study reported no higher risk for bone loss at low doses.)
• Increased risk for infections, particularly herpes zoster and pneumonia.
• Lung disease occurs in up to 5% of people who take methotrexate and deserves special mention. There are five key risk factors for methotrexate-induced lung diseases: Age, diabetes, existing rheumatoid involvement in the lung, protein in the urine, and previous use of other DMARDs, (particularly sulfasalazine, oral gold and d-penicillamine). Patients with multiple risk factors should notify their doctor about any symptoms, such as coughing, that might indicate lung injury.
• The drug increases the risk for birth defects when taken by pregnant women.
• There have been a few reports of lymphomas in some patients taking methotrexate. In such cases, the disease appears to go into remission when the drug is stopped. Most studies have found no significant risk for cancer in patients taking this drug.

Leflunomide. Leflunomide (Arava) blocks autoimmune antibodies and reduces inflammation. It also may inhibit metalloproteinases (MMP), which are involved in cartilage destruction. It has the following benefits:

• It is the first oral treatment approved for RA.
• It slows disease progression as early as 6 months into treatment.
• Comparison studies with methotrexate report a better quality of life with leflunomide, including more energy, greater vitality, and fewer emotional side effects. (Studies comparing their risk for serious adverse effects are mixed. One, for example, showed fewer problems with leflunomide, while another reported identical rates.)

The combination of methotrexate and leflunomide (which has different effects on the immune system) is very effective compared to either drug alone. (This combination poses a risk for liver toxicity and requires monitoring.)

Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects infections and liver injury. Everyone taking leflunomide should be monitored regularly, and anyone with liver problems should avoid this drug until further research has determined its full effects. A 2005 study found that monitoring serum concentrations of A77 1726, the active metabolite of leflunomide, could help predict treatment response.

Sulfasalazine. Sulfasalazine (Azulfidine) was developed in the 1930s for treating rheumatoid arthritis, but fell into disfavor when gold treatment emerged. It has regained popularity, however, and is now used for both adult and juvenile RA. It works best when the disease is confined to the joints. Symptom relief can occur in 4 weeks.

Side effects are common, particularly stomach and intestinal distress. A coated-tablet form may help reduce them. Other side effects include skin rash, sensitivity to sunlight, and, in rare cases, lung problems. People with intestinal or urinary obstructions or who have allergies to sulfa drugs or salicylates should not take sulfasalazine.

Hydroxychloroquine. Hydroxychloroquine (Plaquenil) was originally used for preventing malaria and is now also used for mild, slowly progressive arthritis. It has the following benefits:

• Relieves pain
• Improve mobility
• Has one of least toxic profiles of the DMARDs

The downside is that it takes 3 - 6 months to achieve full benefit. It also does not appear to slow disease progression. One study concluded that joint erosion after 2 years was worse than with no DMARD at all.

As with all DMARDs, gastrointestinal complaints are fairly common. Mild headaches and eye problems may be more common with this drug than with others. The most serious side effect is damage to the retina, although this is very uncommon when low doses are used and can be reversed if treated in time. Some experts recommend eye examinations every 6 months in people over 60 who take hydroxychloroquine. It may aggravate psoriasis, and it poses a slight risk for birth defects.

Gold. Gold has been a long-standing DMARD for rheumatoid arthritis. Rather than suppressing immune factors that cause inflammation, research in 2002 suggests that it may stimulate specific protective factors.

It can be administered in one of two ways:

• Orally as auranofin (Ridaura). The oral form has fewer side effects but is less effective than the injected form.
• Injected (known as chrysotherapy). This form uses either gold sodium thiomalate (Myochrysine) or aurothioglucose (Solganal). Although injected gold used to be the favorite second-line drug, it is generally used for mild, slowly progressive cases.

Side effects differ according to the method of administration:

• Oral gold can cause skin rash and mouth sores as well as stomach irritation. About 50% of people taking oral gold experience diarrhea, which can be offset by reducing the dosage or taking bulk formers, such as Metamucil.

Injected gold is the most toxic of all the DMARDs during early stages of treatment, and in one study 43% of the patients stopped taking it. The injected form can cause skin problems and sores in the mucous membranes in about 20% of people. The most serious side effects of gold injections are kidney damage and decreased white blood cell count. Women who are pregnant or people with major medical conditions of the heart, kidney, liver, skin, and blood should be very cautious about using this therapy.

Penicillamine. It may take up to a year for penicillamine (Cuprimine, Depen) to be effective in reducing the effects of RA, and its use is declining. More than half the patients who take it withdraw because of side effects. It causes stomach and intestinal side effects similar to those of gold. In addition, it may leave the patient with a metallic taste in the mouth or, even, no taste at all. Other side effects include inflamed muscles, skin blisters, and fever. Serious side effects include liver and kidney damage and problems in the lungs.

Cyclosporine. Cyclosporine (Sandimmune, Neoral) is actually an immunosuppressant that started out as a third-line drug. It has proven to be an effective and safe drug when used in combinations or as a sole drug for RA, however, so it is now often listed as one of the DMARDs. It is particularly effective when used in combination with methotrexate.

Side effects include gum disease, hair growth, and flare-ups in the joints, but they are usually manageable. There has been some concern over reports associating cyclosporine with an increased risk for cancer, but one controlled study found no such danger.

Biologic Response Modifiers (Biologic DMARDs)

Biologic response modifiers are drugs made from living cells. These drugs target specific components of the immune system that contribute to the joint inflammation and damage that are part of the rheumatoid arthritis disease process.

Currently approved biologic response modifiers include:

• Etanercept (Enbrel). Etanercept is an anti-tumor necrosis factor (anti-TNF) drug. Approved in 1998, etanercept was the first biologic response modifier drug for treatment of rheumatoid arthritis. It is also approved for juvenile RA and psoriatic arthritis.
• Infliximab (Remicade). Approved in 1999, infliximab is also an anti-TNF drug. It is used in combination with methotrexate.
• Adalimumab (Humira). Adalimumab is another anti-TNF drug. First approved in 2002 as a second-line treatment for RA, adalimumab received additional approvals in 2005 as a first-line treatment for RA and psoriatic arthritis. It is used alone or in combination with methotrexate or other DMARDs. It is also showing promising results in clinical trials for juvenile rheumatoid arthritis.
• Anakinra (Kineret). Approved in 2001, anakinra targets interleukin-1 (IL-1), another type of immune factor.
• Abatacept (Orencia). Approved in 2005 for adults with moderate-to-severe RA who have not responded to DMARD or anti-TNF drugs. Abatacept is known as a T cell co-stimulation modulator. It blocks T cell activation. It is used alone or in combination with other DMARDs aside from anti-TNF drugs.
• Rituximab (Rituxan). Approved in 2006, rituximab targets CD20-positive B cells and blocks their activation. It is used in combination with methotrexate for patients with moderate-to-severe RA who have not responded to anti-TNF therapies.

Some of these drugs are used as first-line treatments for RA. Others are used for patients who have not responded to DMARDs or other types of treatment. Depending on the specific drug, they may be used alone or in combination with the DMARD methotrexate. However, biologic response modifiers are not used in combination with each other, as they can lead to serious infections.

As with other rheumatoid arthritis drugs, these drugs do not cure the disease but can help slow progression and joint damage. In recent clinical trials, some patients have achieved remission using methotrexate in combination with infliximab, adalimumab, or rituximab.

Side Effects and Complications. Etanercept, infliximab, adalimumab, and anakinra are given by injection and may cause pain at the injection site. To prevent injection reactions, patients are sometimes pretreated with betamethasone, a corticosteroid drug, but some research suggests that the steroid does little good. Abatacept and rituximab are given by intravenous infusion. Common infusion reactions include headache, nausea, and flu-like symptoms. Because biologic response modifiers affect the immune system, patients who take these drugs have an increased risk for infections.

Other risks associated with these drugs include:

• Anti-TNF drugs (etanercept, infliximab, adalimumab) have been associated with sepsis, pneumonia, and tuberculosis; non-melanoma skin cancer, possibly lymphoma, and other malignancies; lupus; heart failure; blood disorders (including aplastic anemia); palmoplantar psoriasis; and liver damage.
• Anakinra may cause a sudden drop in white blood cells (leukopenia) that increases the risk for infections.
• Abatacept should be used cautiously in patients with chronic obstructive pulmonary disorder (COPD) as it may increase the risk for respiratory complications.
• Rituximab has been associated with cases of a rare and deadly brain infection called progressive multifocal leukoencephalopathy (PML). It also may cause hepatitis B reactivation, viral infections, and heart rhythm disturbances and other heart problems.

Corticosteroids (Steroids)

Corticosteroids work rapidly to control inflammation and pain and are about as effective as aspirin for RA. Long-time use, however, can have severe adverse effects. Still, they are often used under the following conditions:

• Oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone), are most often used in combination with DMARDs, which significantly enhances the benefits of DMARDs.
• Oral corticosteroids are sometimes used in early stage-RA for patients who cannot tolerate NSAIDs. Studies, in fact, suggest that low-dose corticosteroids may significantly slow joint when it is the first drug administered and then used for two years. (Even low-dose oral steroids have adverse effects on bone density, blood sugar, and weight.)
• Corticosteroids are sometimes injected directly into joints for relief of flare-ups when only one or a few joints are affected. Experts suggest no more than three or four injections a year. Steroid injections in the joints may be a safe and effective treatment for juvenile rheumatoid arthritis and reduce the need for oral medications.
• Corticosteroid pulse therapy (intravenous administration) may be as beneficial as DMARDs.

Side Effects of Oral Corticosteroids. Serious side effects are associated with long-term use of oral steroids. (Low doses may reduce these risks but they do not eliminate them.) Osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, or bisphosphonates (alendronate etidronate, risedronate). Other adverse effects include cataracts, glaucoma, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and, rarely, psychosis. Recent research suggests that prednisone can increase the risk of developing non-melanoma skin cancer.

Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. There have been a few cases of severe adrenal insufficiency that occurred when switching from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctor measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.

Immunosuppressants

For treatment of very severe active rheumatoid arthritis, doctors may prescribe third-line drugs that suppress the body's immune system. These drugs include:

• Azathioprine (Imuran)
• Cyclophosphamide (Cytoxan)
• Chlorambucil (Leukeran)

Azathioprine is the most commonly used of these drugs, with the most usual side effects being stomach and intestinal distress, skin rash, mouth sores, and anemia. All three, however, are potentially very toxic and should not be used unless other drugs are ineffective. Grapefruit juice has an enzyme that may enhance the effects of some immunosuppressants. Blood counts should be taken frequently to check for anemia and more serious blood problems. Some increase in certain cancers has been associated with the use of some of these drugs, such as lymphoma with azathioprine and bladder cancer with cyclophosphamide, although the benefits of these therapies in patients with severe disease may outweigh any risk.

Investigational Treatments

Biologic Drugs. For many years, therapeutic treatment of rheumatoid arthritis focused on T cell mediation. New research is now examining the role of B cells, which become overactive in autoimmune disease, and how B cell depletion may help to reduce disease activity. Other areas of intense research include interleukin receptor antagonists, which target cytokines involved in the inflammatory process. Many of the current investigational drugs are monoclonal antibodies (MAbs), biologic drugs that are designed to target specific receptors. Promising candidates in late-stage research include:

• Tocilizumab (Actemra) targets the IL-6 receptor. In Phase III trials, the drug worked better than DMARDs in slowing joint destruction. It has also shown promise in Phase III trials for systemic juvenile arthritis.
• AMG-714 is a monoclonal antibody that targets the IL-15 receptor. In a Phase II/III trial of patients who had not responded to DMARD treatment, AMG-714 reduced disease symptoms.
• HuMax-CD20, like rituximab, regulates CD20 B cell activity. It is currently in Phase II trials.
• Belimumab (Lymphostat-B) also focuses on B cell depletion. The drug is in Phase II trials and is also being investigated for treatment of lupus.
• Golimumab (CNTO 148) targets tumor necrosis factor alpha. It is currently in Phase III trials. In a Phase II trial, 62% of patients treated with golimumab and methotrexate experienced at least 20% improvement in RA symptoms, and 27% achieved remission.

Thalidomide. Thalidomide inhibits tumor necrosis factors and other cytokines. It also reduces the formation of new blood vessels that allow the disease to progress. Although it was notorious in the past for causing birth defects, it is now being investigated for many diseases, including rheumatoid arthritis. Severe adverse effects, however, may outweigh any benefits.

Statins. Some research suggests that compounds derived from statins, the highly regarded cholesterol-lowering drugs, may suppress the inflammation responsible for RA damage.

Stem cell transplantation. Stem cells are the early versions of mature, specialized blood cells. Investigators are reporting that transplantation of donated hemopoietic stem cells, which mature into various blood cells, has induced remission in a few children with severe juvenile rheumatoid arthritis. The procedure is promising in select cases, but it can be dangerous. More studies are needed to determine risks and benefits for RA patients.

Surgery

A device called the Prosorba column removes inflammatory antibodies from the patient's blood. It works in the following way:

• The blood is first removed from the body through a catheter (a process called apheresis).
• The blood is passed through a column about the size of a coffee mug.
• The column is coated with a substance called protein A, which binds to the antibodies.
• The blood is then returned to the patient.
• The procedure lasts for about 2.5 hours. It is performed once a week for 12 weeks.

Studies are reporting that the therapy can slow or even halt the progression of the disease in a third to a half of patients.

Side effects from the Prosorba column may include anemia, fatigue, itching, fever, a drop in blood pressure, and nausea. Nearly all patients experience an immediate flare-up of joint pain that lasts a few days. Some patients develop infection from the catheter used to remove blood.

Joint Surgeries

Certain surgical techniques may be helpful for people with severe deformities or disabilities.

Arthroscopy. Arthroscopy is performed to clean out bone and cartilage fragments that cause pain and inflammation. It is usually performed on the knee, but it also may be done on the hip:

• The surgeon makes a small incision and injects a sterile solution to make the joint swell for easier viewing.
• A lighted tube, called an arthroscope (which enables the surgeon to view the joint), is then inserted through another small incision.
• Through a third incision, the surgeon trims, shaves, or stitches the damaged tissue. (Arthroscopy is most successful when the removal of cartilage only, and not bone, is involved.)

In many cases, the procedure can be done using local anesthetic, and the patient can go home within a day. In the case of knee operations, patients can resume mild activity in a couple of days, but full recovery can take up to 3 months.

Osteotomy. If only a certain section (the medial compartment) of the knee is damaged and deformed, the surgeon may choose to perform osteotomy:

• The knee is opened.
• A debridement (removal of damaged tissue) is performed in the joint to eliminate the loose or torn fragments that are causing pain and inflammation.
• The bone is then reshaped to remove the deformity.

The procedure is best used in heavier adults who are under 60 years old.

Unicompartmental Knee Arthroplasty. Unicompartmental knee arthroplasty (also called unicondylar knee arthroplasty) may be a useful procedure in some cases of limited damage in the knee. It is intended to relieve pain and preserve function as long as possible before a total knee replacement is necessary. The procedure involves a small incision and insertion of small implants. It retains important knee ligaments, which should preserve more movement than a total knee replacement. The procedure is not widely available and is somewhat controversial, since the implants may not be as reliable as those in total knee replacement.

Synovectomy. Synovectomy is a procedure whereby the diseased joint lining is removed. It is used when more conservative measures fail, particularly in the wrist. Studies are suggesting, however, that with the use of lasers for the procedure, eventually synovectomy may prove to be an alternative to DMARD treatments in reducing symptoms and achieving long-term remission.

Joint Replacement Surgery. Eventually, even after these procedures, rheumatoid arthritis may progress to the point that normal functioning is impossible. In such cases, artificial (prosthetic) replacement joint implants may be considered for knees, hips, or other joints. The prosthesis is usually made of a chromium alloy and plastic and may be attached to the adjoining bones using a cement, polymethyl methacrylate, or the prosthesis may be composed of a porous material that allows bone to grow into and eventually adhere to the device.

Although this procedure has usually been performed in people over 60, implants are now lasting 20 years and more and younger patients with severe disability are finding them useful. Uncemented arthroplasty using porous material is showing particularly good results. Studies on hip replacement, for example, now report that after 10 years, 5% of patients require reoperation and 12% of patients report some pain.

Low-Level Laser Therapy

Low-level laser therapy employs pure light with a single wavelength. It does not heat the body, but it produces certain chemical responses. It is being investigated for rheumatoid arthritis, and, according to a major analysis of the evidence, it appears to reduce pain and morning stiffness. However, the technique has not yet been standardized, and it is not clear which factors produce benefits.

Lifestyle Changes

It is important to maintain a balance between rest (which will reduce inflammation) and exercise (which will relieve stiffness and weakness). Studies have suggested that even as little as 3 hours of physical therapy over 6 weeks will help people with RA, and that these benefits are sustained.

The goal of exercise is to:

• Maintain a wide range of motion
• Increase strength, endurance, and mobility
• Improve general health
• Promote well-being

In general, doctors recommend the following approaches:

• Start with the easiest exercises, stretching and tensing of the joints without movement.
• Next attempt mild strength training. (One study found that people with RA who exercised with machines that use compressed air for gentle resistance experienced less pain and increased muscle tone.)
• Aerobic exercises may then be tried. These include walking, dancing, or swimming, particularly in heated pools. Avoid heavy impact exercises such as running, downhill skiing, and jumping.
• Tai chi, which uses graceful slow sweeping movements, is an excellent method for combining stretching and range-of-motion exercises with relaxation techniques. It is of particularly value for elderly RA patients who report significantly less pain after practicing this technique.

While traditional guidelines have restricted RA patients to only gentle exercise, recent research suggests that more intense exercise may not only be safe, but may actually produce greater muscle strength and overall functioning. Common sense is the best guide:

• If exercise is causing sharp pain, stop immediately.
• If lesser aches and pains continue for more than 2 hours afterwards, then a lighter exercise program should be tried for a while.
• Using large joints instead of small ones for ordinary tasks can help relieve pressure, for instance, closing a door with the hip or pushing buttons with the palm of the hand.

Diet

Fad diets for RA are common:

• Some people claim that foods from the nightshade family (tomatoes, potatoes, green peppers, and eggplant) can worsen arthritis.
• The Dong Diet eliminates all additives, preservatives, fruits, red meat, herbs, alcohol, and dairy.
• A few studies have reported that vegetarian diets may be helpful for some patients. In one study, 40% of patients who were on a vegetarian diet and avoided foods containing gluten (found in wheat, barley, and rye) reported improved scores.
• In another study high total caloric intake correlated with worse symptoms.

Little scientific evidence of benefits for RA exists for any of these diets, and some may result in deficiencies of important nutrients. On the other hand, one study found that 10 out of 17 people benefited from any diet recommended by their doctor.

Mediterranean Diet. Perhaps the best recommendation is for the Mediterranean Diet. A 2003 study reported that RA patients who followed it experienced reduced inflammatory activity, improved physical function and improved vitality compared to those on a standard Western diet. The Mediterranean diet is also rich in heart-healthy fiber and nutrients, omega-3 fatty acids, and antioxidants. The diet recommends:

• A relatively high fat intake (about 35 - 45% of daily calories), but mostly from monounsaturated and polyunsaturated oils. The Mediterranean diet is known specifically for its use of olive oil. Some evidence suggests that high intake of olive oil and cooked vegetables reduces the risk of RA.
• Daily glass or two of wine
• Protein source with this diet is primarily fish, which might be specifically helpful for RA patients. Fish (particularly -- but not only -- oily fish) has anti-inflammatory effects. Protein is lost during the inflammatory process, and high amounts of protein may be protective. Either fish or soy should be the primary sources of protein. Some evidence also suggests that fish oil supplements might be helpful.
• Carbohydrate choices emphasize fresh fruits, vegetables, nuts, legumes, beans, and whole grains.
• Foods are seasoned with garlic, onions, and herbs.

Coffee and Tea. A 2002 study reported an association between RA and decaffeinated coffee but not regular coffee. Furthermore, drinking tea was associated with a lower risk.

Vitamins. Certain vitamin supplements may be beneficial. For example, certain drugs used for RA deplete folic acid, a critical vitamin B. Some patients take antioxidant supplements, such as vitamins C and E and selenium, although there is no strong evidence supporting their benefits. (Some studies have reported some possible benefits with vitamin E or other antioxidant combinations when used with standard medications.) Patients should check with their doctors about the need for supplements.

Miscellaneous Supportive Treatments

Various ointments, including Ben Gay and capsaicin (a cream that use the active ingredient in chilies) may help soothe painful joints.

Orthotic devices are specialized braces and splints that support and help align joints. Many such devices made from a variety of light materials are available and can be very helpful when worn properly.

A number of specially designed appliances and devices are available to ease daily activities.

Managing Psychological and Emotional Conditions

Although the influence of stress or emotions on the progression of RA is not fully known, having a history of major depression that persists or reoccurs seems to increase the pain, disability, and fatigue. Stress management alone cannot reduce pain, but it may be very helpful in helping people deal with their condition.

One study found that people with RA reported significant clinical improvement after writing about their pain, stress, or other traumatic experiences. Writing for 20 minutes, just a few days a week, resulted in improvement that lasted for months. A 2001 study found that spirituality (defined as "a belief in a power outside oneself and one's own existence," as opposed to the practice of any specific religion) is associated with better health, happiness and well-being among RA patients. (Spiritual healing does not appear to offer any advantages.)

Alternative and Integrative Medicine

People often turn to alternative therapies or nontraditional remedies to relieve the pain of rheumatoid arthritis. Some alternative procedures, such as acupuncture, massage, relaxation techniques, biofeedback, and hypnosis, are not harmful and may be a useful adjunct to standard treatments.

• In a small 2001 study, acupuncture reduced pain by a third in 73% of patients, and more than half reported at least a 50% improvement in pain. Patients also reduced their use of pain medications. Research presented at the 2006 American College of Rheumatology annual meeting suggested that both electroacupuncture and traditional acupuncture may help reduce joint tenderness.
• Balneotherapy, also known as hydrotherapy or spa therapy, is an ancient form of therapy that involves mineral baths to soothe pain, and some patients have reported relief using such baths.
• The NIH is conducting clinical trials to examine whether relaxation response, tai chi, stress management, and cognitive-behavioral therapy can help patients with RA feel better.

Herbal Remedies

Herbal remedies used for RA include boswellia, equisetum arvense (horsetail), devil's claw, borage seed oil, and many others. To date, no evidence supports their efficacy.

Researchers are currently conducting studies in animals to determine if supplements extracted from the turmeric spice can help prevent joint inflammation. The U.S. National Institutes of Health is also conducting a clinical trial to compare the clinical effects of the Chinese herb Tripterygium wilfordi Hook F (TwHF) with the pharmaceutical drug sulfasalazine. TwHF is traditionally used in Chinese medicine for its anti-inflammatory properties.

Resources

• www.niams.nih.gov -- The National Institute of Arthritis and Musculoskeletal and Skin Diseases
• www.rheumatology.org -- American College of Rheumatology
• www.arthritis.org -- The Arthritis Foundation
• www.fda.gov/cder/drug/infopage/cox2 -- FDA information on COX-2 inhibitors and NSAIDs
• www.clinicaltrials.gov -- Find a clinical trial

References

Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006 Mar;54(3):692-701.

Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. The PREMIER study. Arthritis Rheum. 2006 Jan;54(1):26-37.

Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006 May;54(5):1390-400.

Funk JL, Frye JB, Oyarzo JN, Kuscuoglu N, Wilson J, McCaffrey G, et al. Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis. Arthritis Rheum. 2006 Nov;54(11):3452-64.

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