Rheumatoid Arthritis

March 2001

What Is Rheumatoid Arthritis?

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. 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, 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.

What Causes Rheumatoid Arthritis?

Rheumatoid arthritis is unlikely to be due to a single cause, but rather a combination of genetic and environmental factors that trigger an abnormal immune response. The Inflammatory Process and Rheumatoid Arthritis The Normal Immune System Response. The inflammatory process is a byproduct 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 infective agents. In the process the surrounding area becomes inflamed and some healthy tissue is injured. Under normal conditions, the immune system has other factors that control and limit this inflammatory process.

The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes. Lymphocytes include two subtypes known as T-cell s and B-cells. Both types of cells are designed to recognize foreign invaders (antigens) and to launch an offensive or defensive action against them: B-cells produce antibodies, which are separate agents that can either ride along with a Bcell or travel on their own to attack the antigen. T-cells have special receptors attached to their surface that recognize the specific antigen. T-cells are further categorized as killer T-cells or helper T-cells (TH cells). Killer T-cells directly attack antigens that occur in any cells that contain a nucleus. Helper T-cells also recognize antigens, but their role is two fold. They stimulate B-cells and other white cells to attack the antigen. They also produce cytokines , powerful immune factors that have an important role in the inflammatory process . Helper T-Cells and Rheumatoid Arthritis. The actions of the helper T-cells are of special interest in rheumatoid arthritis. For some unknown reason, the T-cells become overactive in rheumatoid arthritis and mistake the body's own collagen as an antigen and trigger a series of immune responses to destroy the false enemy: TH-cells stimulate B-cells to produce antibodies. In this case, however, they appear to direct the B-cells to produce autoantibodies , which are directed against the body's own cells. Antibodies come in five types: IgM, IgG, IgA, IgD or IgE. The autoantibody in rheumatoid arthritis appears to be derived from IgG. TH-cells also secrete or stimulate the production of powerful immune factors called cytokines . In small amounts, cytokines are indispensable for healing. If overproduced, however, they can cause serious damage, including inflammation and injury in the joints during the rheumatoid arthritis process. They may even be responsible for inflammation that occurs in parts of the body beyond the joints, including fever, shock, and even damage to organs, such as the liver. Cytokines. Important cytokines in the process of rheumatoid arthritis are those known as interleukins (ILs) and tumor necrosis factor (TNF). (Levels of TNF soar in the synovial fluid during arthritic flare-ups.) Some cytokines play a role in releasing enzymes, such as those known as collagenase and cathepsin L, which destroy collagen. Other cytokines under study are interferon, GM-CSF, and interleukins 1,6, 9, 10, 11, 15, and 17. Leukocytes. The leukocytes are the other major white blood cells. They are also spurred into action by the over-zealous T-cells. Leukocytes stimulate the production of two key players in the inflammatory process: Leukotrienes , which attract even more white blood cells to the area. Prostaglandins , which open blood vessels and increase blood flow. Other Factors. Excessive amounts of nitric oxide, a substance important in blood vessel flexibility and dilation, may also play a major destructive role in RA.

Genetic Factors Although much has been learned about the inflammatory process leading to rheumatoid arthritis, researchers have yet to uncover the factors that lead to this devastating self-attack. One prevalent theory is that a combination of factors trigger rheumatoid arthritis, including genetic susceptibility, an abnormal autoimmune response, and a viral infection. HLA-DR4. 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 molecule called HLA-DR4, which is present in many patients with autoimmune conditions. This HLA molecule may be responsible for the confusion between collagen and an actual foreign antigen in people with rheumatoid arthritis. HLA-DR4, however, is also present in many people who do not contract RA, and many experts believe that more than one gene must be involved in order for the disease to develop. Lack of Corticotropin-Releasing Hormone. Some people 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 the inflammation does not completely prevent further joint destruction. Research has found the presence of a mutated gene known as p53 in synovial tissue obtained from a group of patients. This mutation does not appear to be inherited but to develop as part of the disease process: 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, however, 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. Infectious Triggers 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, which some experts think may stimulate the immune system to perpetuate RA once the disease has been triggered by some other initial infection. Hormonal Triggers Hormonal imbalances may contribute to the processes leading to RA. People with RA appear to have lower than normal levels of certain hormones secreted by the adrenal gland, including the following: Cortical, a stress hormone. In women, dehydroepiandrosterone (DHEA), a weak androgen (male hormone).

Who Gets Rheumatoid Arthritis?

Rheumatoid arthritis (RA) is an ancient disease. Bone changes indicating the condition have been identified in skeletons thousands of years old. RA affects an estimated 2.1 million Americans, or 1% of the US population. 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 the juvenile rheumatoid arthritis. Gender Up to three quarters of rheumatoid arthritis sufferers are women. (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 The risk increases in those with relatives who have rheumatoid arthritis. Other Risk Factors Other factors may place certain susceptible individuals at higher risk for developing RA: Long-Term Smoking. History of Blood Transfusions. Obesity. Coffee Consumption. A 2000 Finnish study reported a direct association between coffee consumption and an increased risk for RA, possibly because coffee's effect on rheumatoid factor. The study did not account for other factors, however, such as other behaviors or habits, or the way coffee is prepared (typically without filters in Finland). Further investigation is needed. Silicone Implants. Most studies are not finding any association between silicone breast implants and rheumatoid arthritis or other autoimmune disease (except possibly Sjgren's 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.

What Are the Symptoms of Rheumatoid Arthritis?

Morning Stiffness in the Joints 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 six 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 Build-up 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.

How Serious Is Rheumatoid Arthritis?

Long-Term Outlook 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. If bone and ligament destruction and any deformities have occurred, however, the effects are permanent. 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 five years of onset of the disease. Complications in Other Areas of the Body Rheumatoid arthritis can effect 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 nerve, 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 could result in corneal damage. Infections. RA patients have a higher risk for infections, particularly from some of the immune-suppress drugs that they take. 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 rheumatoid arthritis. 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. RA can affect the blood vessels in the body and possibly increase the risk for heart disease. Lymphoma and Other Cancers. Alterations in the immune system associated with RA may play a role in the higher risk for lymphoma observed in RA patients. Aggressive treatments for RA that suppress the immune system may help prevent this cancer, but more research will be needed to evaluate this possibility. Other cancers that may occur with increased frequency in RA patients include prostate and lung cancers.

Effect of Treatments Treatments for RA are increasingly effective in slowing down this debilitating disease, and some may even prevent initial destruction by aggressively reducing inflammation. It is essential, therefore, to seek a physician's help as soon as symptoms develop. It should be noted that side effects of the treatments themselves often contribute to the severity of the disease. 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.

How Is Rheumatoid Arthritis Diagnosed?

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 it's 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 rheumatoid arthritis, 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 also suggests a 70% chance that joint damage will occur within two years of onset of the disease. 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. Hemoglobin and Hematocrit Tests. Tests that determine the amount of red blood cells are known as hemoglobin and hematocrit tests. Such tests can determine if RA patients have anemia, a fairly common complication. Analysis of Synovial Fluid Analyzing the synovial fluid might prove to be helpful in detecting markers of joint destruction. For example, 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 and it may possibly serve as a target in future therapeutic strategies.

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 xray absorptiometry, however, may be useful in detecting early bone loss in rheumatoid arthritis (between two and 27 months after onset). 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. [For a list see Table, below. ] 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.

Diseases with Similar Symptoms to Rheumatoid Disease Osteoarthritis Infectious Arthritis Postinfectious or Reactive Arthritis Crystal Induced Arthritis Other rheumatic Autoimmune Diseases Fibromyalgia Other Diseases Chronic fatigue syndrome, fibromyalgia, hepatitis C, familial Mediterranean fever, cancers, AIDS, leukemia, bunions, Whipples disease, dermatomyositis, Henoch-Schonlein purpura, Kawasakis disease, erythema nodosum, erythema multiforme, pyoderma gangrenosum, pustular psoriasis Lyme disease, septic arthritis, bacterial endocarditis, mycobacterial and fungal arthritis, viral arthritis Reiters syndrome (a disorder characterized by arthritis and inflammation in the eye and urinary tract), rheumatic fever, inflammatory bowel disease Gout and pseudogout Systemic vasculitis, systemic lupus erythematosus, scleroderma, Stills Disease (also called juvenile rheumatoid arthritis) Behcets disease Specific Subtypes

What Are the General Guidelines for Treating Rheumatoid Arthritis?

The treatment of rheumatoid arthritis involves medications and life-style changes. General Guidelines for Drug Treatments Many drugs are used for managing the pain and slowing the progression of rheumatoid arthritis, but no medical program has been found to 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: To 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 antiinflammatory hormones. The drugs traditionally used as second-line therapy are categorized as disease-modifying antirheumatic drugs (DMARDs). Such drugs are more effective than NSAIDs and may even improve long-term function and slow down progression of joint damage. Corticosteroids, or steroids, are often put into a different category, because these drugs may be used for different aspects of the disease. Biologic response modifiers are newer agents that block specific immune factors leading to RA and may have fewer side effects than immunosuppressants [below]. Two new agents have now been approved as second-line drugs. Agents known as immunosuppressants are used as third-line drugs for disease that recurs or does not respond to second-line agents. They inhibit the immune system and have potentially very serious side effects. All of these drugs have potentially toxic side effects. [For discussions of individual drugs see What Are the Specific Drugs Used in Treating Rheumatoid Arthritis?] Treatment Approaches 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 four to six 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 five to eight years. This pyramidal approach, while effective for type 1 RA, is not generally recommended now 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 two years, when under the pyramidal approach, NSAIDs are being used, which 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 rheumatoid arthritis is also a possible argument for early aggressive treatment that inhibits immune factors. Inverted Pyramidal Approach. Many experts are now recommending a so-called inverted pyramidal approach for patients with moderate to severe RA that uses the most aggressive agents 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 three months if NSAIDs have not relieved symptoms. Indicators for the need for prompt and aggressive treatment with DMARDs include the following: Evidence of progression. Involvement in parts of the body other than joints. High levels of rheumatoid factor. Genetic markers. Studies are finding less joint damage in patients with early, aggressive treatment, particularly with the use of drug combinations. In spite of increasing evidence in the value for RA, their use, according to a 1999 study, has not increased by physicians other than rheumatologists since 1980. And fewer than 44% of RA patients are using them. There is some danger that broadening the use of immediate aggressive therapy will result in over-treating a benign case, which can be almost as damaging as undertreating a serious case. Certain factors that might warrant against the aggressive approach include the following: Male gender. Older age. Lack of genetic markers. An acute onset of the disease.

What Are the Specific Drugs Used in Treating Rheumatoid Arthritis?

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Common 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 antiinflammatory drugs (NSAIDs). These agents block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs. Some of the most common are aspirin, ibuprofen, naproxen, and ketoprofen, but many others are now available. Timing of Administration. Studies have indicated that the optimal time for taking an NSAID might be after the evening meal and then again on awakening. The reason for this is 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.

Side Effects and Complications. Regular use of even over-the-counter NSAIDs may be hazardous for anyone and has been are associated with the following side effects: Ulcers and gastrointestinal bleeding. This is the major danger with long-term use of NSAIDs. [See Box Ulcers and Gastrointestinal Bleeding.] Increased blood pressure. This is a particular problem in those on medications to reduce hypertension. Piroxicam (Feldene), naproxen (Aleve), and indomethacin (Indocin) appear to pose the greatest risks for high blood pressure. (Sulindac has the smallest effect.) People with hypertension, severe vascular disease, kidney, or liver problems, and those taking diuretics must be closely monitored if they need to take NSAIDs. Dizziness, ringing in the ear. Headache. Skin rash. Depression has also been noted. Confusion or bizarre sensation (in some higher-potency NSAIDs, such as indomethacin). Kidney abnormalities have been reported in people taking NSAIDs, which resolves when the drugs are withdrawn. Any sudden weight gain or swelling should be reported to a physician. 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. Note. Pain-killers that do not reduce inflammation, such as acetaminophen (eg, Tylenol) or opioids (such as codeine), may actually produce additional damage. If pain is suppressed but inflammation is not, joint use can exacerbate the inflammation and release more destructive enzymes.

Ulcers and Gastrointestinal Bleeding NSAIDs are a major cause of ulcers and gastrointestinal (GI) bleeding. Gastrointestinal complications from the use of NSAIDs account for almost 100,000 hospitalizations and at least 16,000 deaths a year in the United States. Bleeding and ulcers can occur at any time, with or without symptoms. One study indicated that taking NSAIDs for only six months posed a risk for symptomatic ulcers that was greater than 1%. The risk for bleeding is continuous as long as a patient is on these drugs and may even persist as long as a year after the drug is discontinued. Alcohol abuse may increase the risks for GI bleeding when taking NSAIDs. Because NSAIDs reduce the clotting of the blood, anyone undergoing surgery should stop taking the medication a week before the operation. Ulcer Risk for Specific NSAIDs. One study ranked the sixteen most commonly used NSAIDs according to risk for ulcers and bleeding. Lowest Risk: nabumetone (Relafen), etodolac (Lodine), salsalate, and sulindac (Clinoril). Medium risk: diclofenac (Voltaren), ibuprofen (Motrin, Advil, Nuprin, Rufen), aspirin, naproxen (Aleve, Naprosyn, Naprelan, Anaprox), and tolmetin (Tolectin). (Drugs within this group vary in risk. Studies show, for example, that short-term use of naproxen is twice as likely as ibuprofen to be associated with hospitalization from GI bleeding. Although ketoprofen (Actron, Orudis KT) was considered a medium-risk drug, another study reported that even one week of taking the drug at low doses causes significant GI injury. Highest risk: flurbiprofen (Ansaid), piroxicam (Feldene), fenoprofen, indomethacin (Indocin), meclofenamate (Meclomen), and oxaprozin. Drugs for Prevention of NSAID-Induced Ulcers. For people who need to take NSAIDs regularly, some agents are available that may protect against bleeding and ulcers. Proton-pump inhibitors include omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), and pantoprozole. Proton pump inhibitors are possibly the most protective agents and can actually heal existing ulcers. Their use has been demonstrated to reduce NSAID-ulcer rates by as much as 80% compared with no treatment. Misoprostol. Misoprostol is a prostaglandin, the protective substance blocked by NSAID use. It protects against the major intestinal toxicity of NSAIDs. It is used to prevent NSAID-induced ulcers, both duodenal and gastric, but is not useful in healing existing ulcers. H2 Blockers. Some H2 blockers may help prevent NSAID-induced ulcers. These drug are available over the counter and include famotidine (Pepcid AC), ranitidine (Zantac), cimetidine (Tagamet), and nizatidine (Axid). In one 2000 study, ranitidine and famotidine were associated with a lower risk for bleeding in patients taking NSAIDs, but another study found no protection from cimetidine.

COX-2 Inhibitors Celecoxib (Celebrex), rofecoxib (Vioxx), and meloxicam (Mobic) are known as COX-2 (cyclooxygenase-2) inhibitors, the so-called super-aspirins. These agents may prove to be as effective and less harmful to the GI tract than NSAIDs. Theoretically, they may even have properties that produce less adverse effects on cartilage than NSAIDs may have. They may be effective for gout, although there is no data on the use of these agents for gout patients as yet. Some studies have found that patients taking COX-2 inhibitors have the same gastrointestinal symptoms (eg, diarrhea, abdominal discomfort) as standard NSAIDs. (Other side effects found with short-term use include headache, and dizziness.) Importantly, however two 2000 studies reported a lower incidence of ulcers and other toxic side effects in patients taking the COX-2 inhibitors than in those taking NSAIDs. The drugs were all equally effective in relieving pain. (One study compared celecoxib with the NSAIDs ibuprofen or diclofenac and the other compared rofecoxib with the NSAID naproxen). One 1999 study even found the rate of GI problems with celecoxib was equal to that in people who do not take NSAIDs at all. COX-2 inhibitors are currently more expensive than traditional NSAIDs, however, and some insurers do not pay for them. Possible Negative Effects. In spite of their promise, some researchers theorize that inhibiting COX-2 may have some negative side effects over the long term: One 2000 study observed that the COX-2 inhibitors had some adverse effects on kidney function, particularly in elderly people, that were similar to the effects of standard NSAIDs. Patients taking anticoagulant drugs may experience a higher risk for bleeding with the use of these agents. A few cases of psychiatric side effects (hallucinations), fluid build up, high blood pressure, and excess potassium in the blood has been observed with higher doses of celecoxib or rofecoxib. They may have negative effects on pregnancy and fertility. The use of COX-2 inhibitors can also increase the blood levels of many other drugs taken concurrently, including warfarin, ACE inhibitors, and methotrexate. More research is needed to confirm or refute any possible hazard. Other Investigative Alternatives to NSAIDs NO-NSAIDS. Experimental agents are being developed that combine nitric oxide with NSAIDs (NO-NSAIDs). Nitric oxide increases blood flow in the mucous lining and secretions of mucus and bicarbonate. Combining nitric oxide with NSAIDs may provide benefits similar to the COX-2 inhibitors. Disease-Modifying Anti-Rheumatic Drugs (DMARDs) Disease-modifying anti-rheumatic drugs (DMARDs), also known as slow-acting antirheumatic drugs (SAARDs), do not have any common properties other than their ability to slow down the progression rheumatoid arthritis. Many were used for other diseases and were found accidentally to help RA. They include the following: Methotrexate (considered to be the current second-line standard of care. Newer agents called biologic modifiers, however, may prove to be as effective with fewer side effects.) Hydroxychloroquine. Sulfasalazine. Gold. D-penicillamine. Cyclosporine. Leflunomide.

Unfortunately, they all tend to lose effectiveness over time, even methotrexate. Patients rarely use one for more than two years. It is now apparent that 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) acts as an anti-inflammatory agent 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 others (starts working within a few weeks). The best record for long term use. Even this drug loses effectiveness, however, when used alone. It is more effective when used in combination with other DMARDs or agents. Studies indicating effective combinations are as follows: Using it with cyclosporine and a corticosteroid may be effective and allow lower doses of methotrexate, thereby not incurring additional side effects. (Methotrexate has a wide range of actions against the immune system, while cyclosporine is fairly specific; it prevents Tcells from proliferating.) One 2000 study found that the combination of methotrexate and leflunomide (a recent DMARD) was effective for 46% of patients, compared to only 20% who benefited from methotrexate alone. Leflunomide has complementary actions on the immune system. (In some cases this drug may prove to be more beneficial than methotrexate.) Combinations with biologic response modifiers, such as Infliximab, are also promising. Methotrexate has fewer toxic effects than many DMARDs, but some, although rare, can still be serious. Common side effects of methotrexate are nausea and vomiting, rash, mild hair loss, headache, and mouth sores. It may also cause muscle aches. (Many of these symptoms are due to folic acid deficiency. Patients should ask their physician about supplements to offset these symptoms.) More serious complications include the following: 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. 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 report 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 agent.

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 the least toxic side effects of the DMARDs. The downside is that it takes three to six months to achieve full benefit. It also does not appear to slow disease progression. One study concluded that joint erosion after two 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 six months in people over 60 who take hydroxychloroquine. It may aggravate psoriasis, and it poses a slight risk for birth defects. Sulfasalazine. Sulfasalazine (Azulfidine) was developed in the 1930s for treating rheumatoid arthritis, but fell into disfavor when gold treatment emerged. It has since been used for treating colitis. Recently, however, it has regained popularity and is now approved for both adult and juvenile RA. Symptomatic relief can occur in four weeks. A 1999 study suggested that sulfasalazine was more effective than hydroxychloroquine and had fewer side effects than gold therapy (although also possibly fewer benefits). 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. Gold. Gold has been a long-standing DMARD for rheumatoid arthritis. 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. (A small study conducted in England suggests that wearing gold rings may slow the progression of rheumatoid arthritis in finger joints.) 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 over the short term. It may be among the least toxic, however, over long duration. 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.

Leflunomide. Leflunomide (Arava) is the newest DMARD and blocks autoimmune antibodies and reduces inflammation. It has the following advantages: It is the first oral treatment approved for RA. It may slow disease progression. Studies indicate that it reduces symptoms, as well as or possibly even better than methotrexate. In one 1999 study, patients taking leflunomide reported more energy, greater vitality, and fewer emotional side effects than those taking methotrexate. Its cellular mechanisms appear to complement those of methotrexate, with each drug blocking out different destructive immune factors. Combinations of the two drugs, then, are proving to be very promising. Common side effects of leflunomide include nausea, diarrhea, hair loss, rash, and possible liver injury. Long term side effects, however, particularly the effect on the liver, remain unknown and require further study. Animal studies indicate a risk for birth defects, so pregnant women should not take it. Cyclosporine. Cyclosporine (Sandimmune, Neoral) is actually an immunosuppressant and, started out as a third-line drug. It has proven to be an effective and safe agent when used in combinations or as a sole agent 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 recent controlled study found no such danger. 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. Corticosteroids (Steroids) Corticosteroids work rapidly to control inflammation and pain. They are used in the following ways for RA: Some physicians use oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone) as an alternative treatment in patients who have severe problems with NSAIDs. Joint destruction may be slowed significantly when a corticosteroid is the first drug administered and then used for two years. Several 1999 studies found that combining oral corticosteroids with DMARDs significantly enhances the benefits of DMARDs. 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. Studies also suggest that corticosteroid pulse therapy (intravenous administration) may be as beneficial as DMARDs. The possibility for serious side effects associated with long-term steroid use of oral steroids, however, does raise some concern [see below]. Some studies have even reported twice the mortality rates in people taking long-term steroids compared to other RA patients. This may be due to the fact that patients using steroids generally have a more severe form of the disease, but more research is warranted. Of some encouragement is a 1998 study reporting that long-term low dose steroids were still effective with none of the severe side effects of higher doses.

Side Effects of Oral Corticosteroids. Adverse effects of prolonged use of oral steroids include cataracts, glaucoma, osteoporosis, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and psychosis. 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, alendronate etidronate, risedronate, or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts. W i t h d r a w a l 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. It should be noted that 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 physician first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their physician measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases. Biologic Response Modifiers Biologic response modifiers are genetically engineered drugs that interfere with specific components of the autoimmune response in RA. Because of their precise targets, these drugs do not damage the entire immune system the way that general immunosuppressants do. They are the first agents to produce the dramatic effects originally seen with corticosteroids. Of special interest are the following agents: Infliximab and etanercept have actions against tumor necrosis factor (TNF), an cytokine that is important in the disease process. Both have been approved by the FDA for treating moderate-to-severe cases, even in patients who have not yet been treated with DMARDs. These drugs are proving to be as effective as methotrexate. As with other agents, infliximab and etanercept do not cure the disease and are effective only during treatment. At this time these agents are also very expensive, approximately $10,000 to $12,000 per year per patient. Many insurers do not cover them. Other drugs are being investigated that inhibit other cytokines called interleukins, specific helper T-cells, and B cells. Etanercept. Etanercept (Enbrel) neutralizes TNF. It needs to be injected twice a week, and is showing the following benefits: Pain and swelling reduction. According to a 2000 study, these effects may last for at least four years. In some studies, slowing and even halting joint erosion, even more effectively than methotrexate. In one study 72% of patients had no joint erosion. Fewer severe side effects than most DMARDs. In a 1999 study on children with RA taking etanercept, 30% returned to fully normal activities. Combinations with methotrexate may prove to be even more effective than either drug alone, and the combination may have fewer side effects than using methotrexate alone at higher doses. Further long-term research is needed to determine if benefits persist after discontinuing the drug, and, if so, for how long.

About a third of patients experience minor reactions at the injection site, but there are few other immediate side effects. The most serious potential complications are severe infections, particularly in people who may be susceptible to them, such as those with poorly managed or uncontrolled diabetes or anyone with an active infection. There have also been a few reports of aplastic anemia. The drug may have also severe effects on patients with multiple sclerosis. Infliximab. Infliximab (Remicade) is made from a specially developed antibody (termed a monoclonal antibody ) called cA2, which acts against TNF. It requires intermittent intravenous infusions. Used alone or in combination with methotrexate, it appears to safely reduce symptoms of rheumatoid arthritis. The combination also appears to halt progression of joint damage more effectively than methotrexate alone. Many patients, however, develop antibodies to infliximab itself, and some studies indicate that the benefits dissipate when the drug is discontinued. Nevertheless, in one study, benefits persisted for at least two years after stopping the drug. And, a 1999 study reported that progression of joint damage was halted. In another group of patients with severe RA, it may have controlled the disease process better than any other therapies to date. Side effects are similar to those of etanercept. Investigative Biologic Response Modifiers. A number of other agents that inhibit part of the immune response are being investigated: Monoclonal antibodies (genetically derived antibodies), such as rituximab, used to destroy the B-cells that produce the autoimmune response. The body responds by making new, healthy B-cells. Preliminary results in 2000 are encouraging and warrant further study. Other agents that block tumor necrosis factor. Agents that inhibit different cytokines, such as interleukin-1. Vaccines that use anti-inflammatory factors to boost the immune systems own response against the aberrant immune factors. Immunosuppressants (Third-Line Drugs) For treatment of very severe active rheumatoid arthritis, physicians are now prescribing thirdline drugs that suppress the body's immune system. These agents include the following: Azathioprine (Imuran). 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. Cyclophosphamide (Cytoxan). Chlorambucil (Leukeran). All 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 agents, 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. Other Investigative Treatments Tetracyclines. Tetracyclines, antibiotics that also have anti-inflammatory actions, are being studied. Because some cases of RA may be triggered initially by an infection, these agents are of interest. Minocycline is a tetracycline antibiotic that is currently being studied. Results are mixed. Some are reporting that the drug has a small but significant effect on disease activity; one suggested that many patients may achieve long-term remission if the medication is administered early in the disease. Side effects include gastrointestinal distress, dizziness, rash, and headache. More serious and less common effects are increased pressure in the skull, inflammation in the lungs, lupus-like symptoms, liver injury, and skin color changes.

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. Metalloproteinase Inhibitors. Some research is focusing on drugs that block the enzyme metalloproteinase, which is involved with the breakdown of collagen. Estrogen and other Hormone Replacement Therapy Female Hormone-Replacement Therapy. Female hormone-replacement therapy should be considered by women with RA after menopause. It helps protect against osteoporosis and might be helpful for RA as well. It has certain risks, however, which a patient should discuss with her physician. [See the Well-Connected Report Menopause, Estrogen Loss, and Their Treatments.] DHEA. Some research is investigating the use of dehydroepiandrosterone (DHEA), a mild male hormone that is reduced in rheumatoid arthritis. (Reductions in this hormone may be due to medications used to treat RA, however. Androgen Replacement. Some work is also being conducted on male-hormone replacement therapy in men. As with DHEA, however, reduced hormone levels may be due to RA treatments.

What Are the Procedures Used to Treat Rheumatoid Arthritis?

Prosorba Column 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 two and a half 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. Then a lighted tube, called an arthroscope (which enables the surgeon to view the joint), is 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 three 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. One 2000 study reported, however, that it was superior, in some cases, 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. 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.

What Lifestyle Changes Can Help Manage Rheumatoid Arthritis?

Exercise and Joint Protection Recommendations It is important to maintain a balance between rest (which will reduce inflammation) and exercise (which will relieve stiffness and weakness). One study showed that even as little as three hours of physical therapy over six weeks will help people with RA. The goal of exercise is the following: To maintain a wide range of motion. To increase strength, endurance, and mobility. Improve general health. Pomote 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. 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. There are claims, for example, 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. 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. Of the studies that have been done, a few recommendations follow: One study found that high total calorie intake appeared to aggravate RA. A few studies have shown that some people who reduce their fat intake, especially vegetarians who eat no dairy or animal products, have less pain than those with high meat consumption. (About 5% of people with RA experience worse symptoms after drinking milk.) It should be noted, however, that protein is lost during the inflammatory process, and one study indicated that high amounts of protein might be protective. If people choose to eliminate meat and dairy products, they should eat fish or be sure their diets are rich in vegetable proteins, such as soy products. In fact, a recent animal study suggests that a soy rich diet may actually bring pain relief.

 Note that certain fats may be important. Studies have found improvement in RA symptoms using black currant or primrose seed oils and cold-water fish oils. These oils contain a polyunsaturated fatty acid known as gamma linolenic acid, which seems to block the release of cytokines and prostaglandins, substances thought to play major destructive roles in RA. Olive oil may even have some benefits. One 1999 study found some evidence that high intake of olive oil and cooked vegetables reduced the risk of RA. Certain vitamin supplements may be beneficial. For example, certain drugs used for RA deplete folic acid, a critical vitamin B. Some patients take antioxidant vitamins C and E, although there is no evidence supporting their benefits. Patients should check with their physicians 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. Psychological and Emotional Conditions The influence of stress on the progression of RA is currently under study. Having a history of major depression that persists or reoccurs seems to increase the pain, disability, and fatigue experienced by patients with arthritis. One interesting 1999 study found that people with RA or asthma 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. Although longer term studies are needed, this report indicates that management of emotional stress can play a very important role along with drug therapy. 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, therapeutic touch, massage, relaxation techniques, biofeedback, and hypnosis, are nearly always harmless as long as they are not used as substitutes for proven treatments. 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. A number of herbal remedies have been used traditionally in treating RA, including boswellia, equisetum arvense (horsetail), devils claw, 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. [See Box.]

Warnings on Alternative and So-Called Natural Remedies It should be strongly noted that alternative or natural remedies are not regulated and their quality is not publicly controlled. In addition, any substance that can affect the body's chemistry can, like any drug, produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. In addition, some so-called natural remedies were found to contain standard prescription medication. Most problems reported occur in herbal remedies imported from Asia. Even if studies report positive benefits, most, to date, are very small. In addition, the substances used in such studies are, in most cases, not what are being marketed to the public. The following website is building a database of natural remedy brands that it tests and rates. Not all are available yet. http://www.ConsumerLab.com/ The Food and Drug Administration has a program called MEDWATCH for people to report adverse reactions to untested substances, such as herbal remedies and vitamins (call 800-3321088).

Where Else Can Help Be Found For Rheumatoid Arthritis?

The Arthritis Foundation, 1330 West Peachtree St., Atlanta GA 30309. Call(800-283-7800) or (404-872-7100) or on the Internet (http://www.arthritis.org/) This is an excellent source for many types of services. The foundation funds research and provide brochures, video tapes, exercise programs, physician referrals, and local chapters. Chapters of the organization across the country provide different services, some offer support groups, others emphasize clinical testing, others focus on equipment to help osteoarthritis sufferers. Offers a 12-hour self-help class to help people manage RA. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), One AMS Circle, Bethesda MD 20892-3675. Call (301-495-4484) or (877-22-NIAMS), or on the Internet (http://www.nih.gov/niams/). The institute provides an information packet and two bibliographies of resources, one for health professionals and one for osteoarthritis patients. American Academy of Orthopedic Surgeons, PO Box 2058, Des Plaines, IL 60017. This organization will send information on arthritis by sending a self-addressed stamped business envelope. Be sure to designate Arthritis on the outside envelope. Aids for Arthritis, Inc., (Call 609-654-6918) or on the Internet (www.aidsforarthritis.com). Enrichments. Call (800-323-5547) or on the Internet (www.sammonspreston.com) Both companies offer supportive devices and products for people with arthritis. Call for catalogs. American Orthotic and Prosthetic Association, Orthotic Patient Education, 1650 King St., Suite 500, Alexandria, VA 22314 . American College of Rheumatology, 60 Executive Park South, Suite 150, Atlanta, GA 30329. Call (404-633-3777) or on the Internet (http://www.rheumatology.org/) American Autoimmune Related Diseases Association, Inc., 15475 Gratiot Ave., Detroit, MI 48205. On the Internet (http://www.aarda.org/) ConsumerLab, on the internet (http://www.consumerlab.com) provides the results of quality testing of herbal products, as well as other health information.

Recent Literature A b o u t Well-Co n n ect ed

Well-Connected reports are written and updated by experienced medical writers and reviewed and edited by the in-house editors and a board of physicians, including faculty at Harvard Medical School and Massachusetts General Hospital. The reports are distinguished from other information sources available to patients and health care consumers by their quality, detail of information, and currency. These reports are not intended as a substitute for medical professional help or advice but are to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. The reports may not be copied without the express permission of the publisher. Board of Editors Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School; Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center Masha J. Etkin, MD, PhD, Gynecology, Harvard Medical School; Physician, Massachusetts General Hospital John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts General Hospital Daniel Heller, MD, Pediatrics, Harvard Medical School; Massachusetts General Hospital; Active Staff, Children's Hospital Associate Pediatrician,

Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital Carol Peckham, Editorial Director Cynthia Chevins, Publisher Sherry Knecht Update Editor 2001 Nidus Information Services, Inc., 41 East 11th Street, 11th Floor, New York, NY 10003 or email webmaster@well-connected.com or on the Internet at www.well-connected.com.