Rheumatoid Arthritis In-Depth

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 ones.

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 age of onset peaking between 20 and 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 Sjögrens 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 in England found that approximately one third of individuals 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.
• 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. One small study found a very high prevalence of lung disease in newly diagnosed RA patients. The association between a history of smoking and a higher risk for RA, however, may at least partially account for this finding. (Cigarette smoking, in any case, may increase the severity of the disease.)
• 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 confirmed 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. Changes in the immune system associated with RA and certain RA treatments may play a role in the higher risk for lymphoma observed in patients. Some reviews report that patients with RA have a four times higher risk than healthy patients for developing non-Hodgkin’s lymphoma. A higher risk for lymphoma and blood cancers may also occur in patients who were given total lymphoid irradiation, an RA therapy used mainly in the 1980's when other therapies failed. Other cancers that may occur with increased frequency in RA patients include prostate and lung cancers..
• 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, morality rates are 0.29% (33 deaths in 11,287 patients).

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 may be difficult to diagnose. Many other conditions can 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.

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, it is now beginning to be used somewhat more commonly in the US. US 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 (between two and 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 identified 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 no none can completely cure the disease. Some experts believe that no single drug will ever cure rheumatoid arthritis because of the different immune systems and many other factors that affect the disease at various times. The goals of drug treatment for rheumatoid arthritis are the following:

• 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 are generally defines as follows:

• The least potent drugs used for RA are nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs relieve pain by reducing inflammation, but do not contain steroids, powerful anti-inflammatory hormones.
• The drugs traditionally used as second-line therapy are categorized as disease-modifying antirheumatic drugs (DMARDs). They 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. Such drugs are more effective than NSAIDs but also have more side effects.
• Corticosteroids, or steroids, are powerful anti-inflammatory drugs. They are often put into a different category from the DMARDs, because these drugs may be used for different aspects of the disease.
• Certain immunosuppressants are used as third-line drugs for disease that recurs or does not respond to second-line drugs. They inhibit the immune system and have potentially very serious side effects.
• New drugs that modify or block destructive immune factors are also now available. Tumor-necrosis factor (TNF) modifiers are major breakthroughs in the treatment of RA. The current drugs include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). An interleukin-1 antagonist, anakinra (Kineret), has also been approved.

All of these drugs have potentially toxic side effects.

Treatment Approaches

The question of how early and how aggressively to treat RA is currently the subject of great debate. Studies have found less joint damage in patients with early, aggressive treatment, particularly with the use of DMARDs and TNF modifiers. 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.

Inverted Pyramidal Approach.Some experts recommend a so-called "inverted pyramid"approach for patients with moderate to severe RA that uses the most aggressive drugs first. The method uses one of two approaches, depending on severity:

• Some patients start out immediately with DMARDs, with or without NSAIDs.
• Others start DMARDs after 3 months if NSAIDs have not relieved symptoms.

A TNF-modifier may be added if patients do not show 70 - 80% improvement after full-dose methotrexate therapy.

Pyramidal Approach. A pyramidal approach may be very useful for some RA patients, particularly those with benign, or type 1, rheumatoid arthritis:

• The least powerful drugs (usually NSAIDs) are used first to avoid toxic effects.
• If NSAIDs are still not effective after about 4 to 6 weeks, more potent drugs are added to the regimen.
• Gradually, stronger and stronger drugs are used until the disease is under control.
• Working through the pyramid, drug by drug, generally takes 5 to 8 years.

This pyramidal approach, while effective for type 1 RA, is not generally recommended for type 2 RA for the following reasons:

• It fails to prevent the progression to joint destruction and debility in people with severe type 2 RA.
• Much of the damage in type 2 RA occurs within the first 2 years. In the pyramidal approach, NSAIDs are used during this time period. NSAIDs have no effect against joint damage and, over time, the side effects of NSAIDs can even be as severe as those of some DMARDs.
• In one study, only 18% of RA patients using the pyramidal approach achieved an initial remission, and less than 2% had remissions that lasted more than 3 years.
• The association between lymphoma and immune system abnormalities in RA is also a possible argument for early aggressive treatment that inhibits immune factors.

On a cautionary note, overtreating a benign case can be almost as damaging as undertreating a serious case. Certain factors that might warrant against the aggressive approach include:

• Male gender
• Older age
• Lack of genetic markers
• An acute onset of the disease

Medications

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Two-thirds of people with RA ranked pain as their primary reason for seeking professional help. The most common pain relievers for RA are the 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. The most common pain relievers are the following:

• 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 have indicated that optimal 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 cardiovascular benefits, aspirin was excluded from these labeling revisions.

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:

• Increased blood pressure
• Dizziness
• Tinnitus (ringing in the ear)
• Headache
• Skin rash
• Depression
• Confusion or bizarre sensation (in some higher-potency NSAIDs, such as indomethacin)
• Increased risk of kidney failure (associated with high dose aspirin and other NSAIDs; risk low in those with healthy kidney function; tell your doctor about sudden weight gain or swelling; people with kidney disease should avoid these drugs)

Diabetics taking oral hypoglycemics may need to adjust the dosage if they also need to take NSAIDs because of possible harmful interactions between the drugs.

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 with less gastrointestinal distress. However, following numerous reports of cardiovascular events, skin rashes, and other adverse effects, the FDA is currently re-evaluating the risks and benefits of this drug class. At the time of this report, rofecoxib (Vioxx) and vadecoxib (Bextra) have been withdrawn 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.

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 is more effective when used in combination with other DMARDs or drugs. Studies indicating effective combinations suggest:

• Using it with cyclosporine and a corticosteroid may be effective and allow lower doses of methotrexate, thereby minimizing side effects. (Methotrexate has a wide range of actions against the immune system, while cyclosporine is fairly specific; it prevents T cells from proliferating.)
• The combination of methotrexate and leflunomide (which has different effects on the immune system) is very effective compared to methotrexate alone. (This combination poses a risk for liver toxicity and requires monitoring.)
• Methotrexate may reduce the risk for vascular disease among patients with RA. A retrospective study found that that this protective effect was stronger when methotraxate was administered along with folic acid.
• Combinations with the newer drugs, the tumor-necrosis factor (TNF) modifiers (such as infliximab) and the interleukin-1 antagonist anakinra, are considered the best therapy.

About 20% of patients withdraw because of 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. (Nevertheless, over the long term, it may be among the least toxic.) 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.

Immunosuppressants

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

• 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.

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.

Tumor-Necrosis Factor Modifiers

Tumor-necrosis factor (TNF) modifiers are major breakthroughs in the treatment of RA. The current drugs (known generally as biologic response modifiers) include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are genetically engineered to interfere with specific components of TNF, a powerful immune factor that is important in the disease process. Although they all block TNF, these drugs have some differences:

• Etanercept (Enbrel) is a protein made from the fusion of two TNF receptors. The end product mimics their effects, which neutralize TNF. A 2002 study suggested it is superior to methotrexate in slowing RA disease progression and has fewer side effects. It has been approved for RA, juvenile RA, and psoriatic arthritis.
• Inflixamab (Remicade) and adalimumab (Humira) are both monoclonal antibodies (MAbs), which are specially designed antibodies that target TNF. In one study, infliximab was superior to methotrexate, gold, corticosteroids, and a interleukin-1 receptor antagonist. Humira, the latest TNF modifier is the first fully human anti-TNF MAb, which may reduce some of the problems of infliximab. Humira is used alone or in combination with methotrexate or other DMARDs.

Studies have reported that all these drugs work rapidly and produce significant and sustained improvements. Combinations with methotrexate increase their effectiveness. The combinations may have fewer side effects than using methotrexate alone at higher doses. As with other drugs, they do not cure the disease, although some evidence suggests they may slow or even halt joint erosion.

The combination of adalimumab and the interleukin-1 antagonist anakinra (Kineret) has produced cases of serious infection. The FDA advises against this drug combination and the use of anakinra with other TNF modifiers.

Because TNF modifiers are very expensive, insurers will pay for them only if patients first fail to respond to full-dose weekly methotrexate.

By neutralizing TNF-A, these drugs may increase the risk of certain fungal and mycobacterial infections, including tuberculosis. These conditions are serious but respond to prompt, aggressive anti-infection therapy.

Side Effects and Complications of Tumor-Necrosis Factor Modifiers. Because TNF modifiers target precise molecular targets, they have fewer widespread effects on the body than general immunosuppressants. Nevertheless, there are concerns and some evidence that suppressing TNF can create long-term problems, including infections and nerve injury. The most common side effects are reactions 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. TNF modifiers have warnings regarding serious adverse events:

• Sepsis and pneumonia
• Tuberculosis
• Lymphomas and other malignancies
• Lupus and lupus-like syndrome
• Heart failure
• Blood disorders (including aplastic anemia)
• Liver damage

According to recent studies, TNF modifiers may increase the risk of non-melanoma skin cancer.

Interleukin-1 Antagonists

Drugs that inhibit the interleukin cytokines are also in development. Anakinra (Kineret) is the first of these. It is an intravenous drug that blocks interleukin-1, an important immune factor. It is showing good results when used in combination with DMARDs, such as methotrexate. A 2002 study suggested that it is similar in effectiveness to tumor necrosis factor modifiers. Primary side effects of Kineret include pain at the injection site and leukopenia--a reduction in white blood cell counts that increases the risk for infections.

Investigative Treatments

Biologic Drugs. Despite their initial promise, many patients fail to respond to TNF-modifiers. Researchers are developing novel drugs that target different aspects of the disease process. 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 investigative drugs are monoclonal antibodies (MAbs), biologic drugs that are designed to target specific receptors. Promising candidates in late-stage research include:

• Rituximab (Rituxan/MabThera) targets and depletes CD20 positive B cells. In Phase III trials, a single treatment (two infusions) of rituximab, combined with methotrexate, produced symptom improvement in patients with moderate to severe RA who had failed to respond to anti-TNF therapies.
• CTLA4-Ig (Abatacept) is the first drug in a new class known as selective T-cell co-stimulation modulators. The drug blocks T-cell activation. Phase III trials of patients who have failed to response to methotrexate have yielded positive results.
• Tocilizumab (Actemra) targets the IL-6 receptor. In Phase III trials, the drug worked better than DMARDs in slowing joint destruction.
• 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. 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. Interesting research is suggesting that compounds derived from statins, the highly regarded cholesterol-lowering drugs, may suppress inflammation responsible for RA damage.

Chinese herbal medicine. The NIH is 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.

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.

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.

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 the following:

• To maintain a wide range of motion
• To increase strength, endurance, and mobility
• Improve general health
• Promote well-being

In general, some patients 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, for example, walking, dancing, or swimming, particularly in heated pools. Avoid heavy impact exercises such as running, downhill skiing, and jumping.
• T'ai 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 two 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 exacerbate 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 interesting study in England 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. (Although not included in the Mediterranean diet, soy may have specific benefits for RA.) Some evidence also suggests that fish oil supplements might be helpful.
• Carbohydrate choices emphasize fresh fruits, vegetables, nuts, legumes, beans, and whole grains.
• Foods 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 beneficial 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 interesting 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 one small 2001 British study, acupuncture reduced pain by a third in 73% of patients, and more than half reported at least a 50% improvement in pain. Patients reduced their use of pain medications from 17 to 6  tablets per week on average.
• 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.

A number of herbal remedies have been used traditionally in treating RA, including boswellia, equisetum arvense (horsetail), devil's claw, borage seed oil, and many others. Herbal or other remedies can be of some concern, however, as the ingredients in over-the-counter herbal or natural remedies are not regulated or controlled.

Lots More Information

Resources

• www.nih.gov/niams -- 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

Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32(11):2130-2135.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52(11):3381-3390.

Khanna D, Park GS, Paulus HE, Simpson KM, Elashoff D, Cohen SB, et al. Reduction of the efficacy of methotrexate by the use of folic acid: post hoc analysis from two randomized controlled studies. Arthritis Rheum. 2005;52(10):3030-3038.

Sany J, Kaiser MJ, Jorgensen C, Trape G. Study of the tolerance of infliximab infusions with or without betamethasone premedication in patients with active rheumatoid arthritis. Ann Rheum Dis. 2005;64(11):1647-1649.

Welsing PM, Fransen J, van Riel PL. Is the disease course of rheumatoid arthritis becoming milder? Time trends since 1985 in an inception cohort of early rheumatoid arthritis. Arthritis Rheum. 2005;52(9):2616-2624.

Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165(20):2337-2344.