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Rheumatoid Arthritis

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 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.

WHAT CAUSES RHEUMATOID ARTHRITIS?

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 self-attack. One prevalent theory is that a combination of factors trigger 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 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 B-cell 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 destructive process of rheumatoid arthritis are those known as interleukins (ILs) and tumor necrosis factor (TNF). Researchers are specifically interested in interleukins 1,6, 9, 10, 11, 12, 15, and 17. (Some of these, such as interleukin-10, may be protective.) Some cytokines play a role in releasing enzymes, such as those known as collagenase and cathepsin L, which destroy collagen.

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 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.

Nitric Oxide. 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.

Genetic Factors

Genetic factors play some role in RA, but most experts believe that more than one gene collaborates in the process and that the disease still requires other factors to set it off.

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. However, these genetic factors do not cause RA, though they may make the disease more severe once it has developed.

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 the inflammation does not completely prevent further joint destruction. Research has suggested that a mutation of gene known as p53 may perpetuate the process. This defect would not be inherited but would occur overtime as the disease progressed:

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.

Environmental or Biologic Triggers

Infectious Agents. 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.

Hormones. 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:

Heavy Smoking. Heavy long-term smoking is a very strong risk factor for RA, particularly in patients without a family history of the disease.
Shorter reproductive life. Women who have a shorter fertility time (and so lower levels of reproductive hormones) may be at higher risk.
History of blood transfusions.
Obesity.
Coffee. A 2000 Finnish study reported a direct association between coffee consumption and an increased risk for RA. The study did not account for other factors, however, such as other behaviors or habits, or the way coffee is prepared in Finland (typically without filters). Further investigation in other countries is needed.
Interferon. Interferon-alpha, an agent used for hepatitis, autoimmune diseases, and others has triggered rheumatoid arthritis in rare cases.
Of note, most studies are not finding any association between silicone breast implants and rheumatoid arthritis or other autoimmune disease (except possibly Sjögren'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 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 could result in corneal damage.
Infections. RA patients have a higher risk for infections, particularly from some of the immune-suppressing 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. 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% to 50% more likely to suffer heart vessel blockages and 60% to 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. Alterations in the immune system associated with RA and certain treatments may play a role in the higher risk for lymphoma observed in RA patients. 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. Aggressive treatments for RA that suppress the immune system may help prevent such cancers, 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.
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.

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 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 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 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.

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. Some investigative 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. [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.
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.

Diseases with Similar Symptoms to Rheumatoid Arthritis

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

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 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 agents. They are often put into a different category from the DMARDs, 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. Two new agents, infliximab and etanercept, 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 three 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:

High levels of rheumatoid factor plus indication of disease progression from diagnostic tests.
Involvement in parts of the body other than joints.

Studies are finding less joint damage in patients with early, aggressive treatment, particularly with the use of drug combinations. There is also some evidence that early use of DMARDs may help protect against heart problems, which can be major complications of RA.

However, some studies have not found significant reductions in joint damage or mortality rates from long-term treatment. Also, on a cautionary note, over-treating a benign case 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 anti-inflammatory 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 times 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 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.
May delay the emptying of the stomach, which could interfere with the actions of other drugs. The elderly are at special risk.
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).
NSAIDs may pose a higher risk for kidney injury, which would be of concern in patients with kidney problems. 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.

Ulcers and Gastrointestinal Bleeding. Long-term use of nonsteroidal anti–inflammatory drugs (NSAIDs) is the second most common cause of ulcers. Up to 20 million people take prescription NSAIDs regularly and about 26 billion tablets of over-the-counter brands are sold each year in America. The most common NSAIDs are the following:

Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT). One study suggested that ibuprofen or naproxen is more effective than aspirin or acetaminophen for acute tension-type headache.
Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox, diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), indomethacin (Indocin).

Many others are available. [ See Box . Ulcer Risk by Specific NSAIDs]

Ulcers form when the rate of damage inflicted by the NSAID exceeds the rate of repair conducted by the stomach. Their damaging effects may be two-fold:

Mild Acids. NSAIDs are mild acids and can cause some injury by direct exposure to the lining of the stomach. Their primary damaging effects, however, are from actions that block protective factors in the intestines.
COX-1 Enzymes Inhibitors. NSAIDs reduce pain and inflammation by blocking an enzyme called cyclooxygenase (COX), which is involved in the production of prostaglandins. The COX enzyme has two functions: the COX-1 form protects the mucus lining while the COX-2 form causes intestinal contractions and inflammation. Because most NSAIDs reduce both COX-1 and COX-2, they relieve pain, but they also impair an important defense system in the intestine. Blocking prostaglandins can damage the mucous layer, lower bicarbonate levels, and reduce blood flow in the intestine. Each of these actions can increase the risk for ulcers and gastrointestinal bleeding. Even if an NSAID is injected intravenously, the drug will still inhibit prostaglandins in the stomach and duodenum. (Newer NSAIDs are now available that block only COX-2.)

No NSAIDs, even over-the-counter brands, should be used for long-term pain relief except under physician direction. For example, an analysis of controlled trials reported that about 1% of patients taking aspirin over a 28 month period will experience gastrointestinal bleeding. A significant risk existed even at low doses or with the use of modified-release formulations. Of further concern was a 1998 study indicating that taking NSAIDs for only six months posed a risk for symptomatic ulcers that was greater than 1%. The risk for bleeding is continuous for as long as a patient is on these drugs and may even persist for about a year after taking them. Taking short courses of NSAIDs for temporary pain relief should not cause major problems because the stomach has time to recover and repair any damage that has occurred.

Ulcer Risk by Specific NSAIDs
Lowest Risk	Medium Risk (see note)	Highest Risk
Nabumetone (Relafen) Etodolac (Lodine) Salsalate Sulindac (Clinoril)	Aspirin Ibuprofen (Motrin, Advil, Nuprin, Rufen) Naproxen (Aleve, Naprosyn, Naprelan, Anaprox) Diclofenac (Voltaren) Tolmetin (Tolectin) NOTE: Drugs within the medium risk group vary in risk. For example, studies show that use of naproxen is twice as likely as ibuprofen to be associated with hospitalization from GI bleeding.	Flurbiprofen (Ansaid) Piroxicam (Feldene) Fenoprofen Indomethacin (Indocin) Meclofenamate (Meclomen) Oxaprozin Ketoprofen (Actron, Orudis KT) NOTE: Ketoprofen is often considered a medium-risk drug, but one study reported that taking the drug even one week at low doses causes significant GI injury.

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 a 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 drugs 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 valdecoxib (Bextra) are known as COX-2 (cyclooxygenase-2) inhibitors. They may prove to be beneficial for chronic tension-type headache without incurring as high risk for ulcers and bleeding. Meloxicam (Mobic) is a new drug known as a COX-2 preferential; i.e., it inhibits COX-2 more than COX-1. It is not known yet if its actions differ significantly from standard NSAIDs.

Benefits. These agents may prove to be as effective and less harmful to the GI tract than NSAIDs. Importantly, studies are reporting 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.

Theoretically, they may even have properties that produce less adverse effects on cartilage than NSAIDs may have.

Some early evidence also suggests they may be protective against colon cancer and possibly even Alzheimer's disease.

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:

Although COX-2 inhibitors are very likely to have a lower risk for ulcers and GI bleeding than standard NSAIDs, studies have been mixed on whether patients taking COX-2 inhibitors have the same gastrointestinal symptoms (e.g., diarrhea, abdominal discomfort) as standard NSAIDs. Vioxx may pose a higher risk for symptoms than Celebrex. (Other side effects found with short-term use include headache, and dizziness.)
COX-2 inhibitors may have adverse effects on kidney function, particularly in elderly people, that were similar to the effects of standard NSAIDs. This effect can also trigger fluid build up and high blood pressure. (Celebrex may have fewer of these effects than Vioxx.)
Studies are reporting a higher incidence of heart attacks in patients taking Vioxx and Celebrex than in those taking standard NSAIDs. Some (but not all) evidence suggests that COX-2 inhibitors may increase the risk for blood clots. Supporters of the drugs argue, however, that the higher heart attack rates observed with the COX-2 inhibitors were simply due to the fact that the NSAIDs they were compared to were known to be heart- protective. It should be noted, moreover, that RA patients are at higher risk in any case for heart disease and anyone taking low-dose aspirin for heart protection should continue it even while they are taking COX-2 inhibitors.
Other possible but uncommon adverse effects include psychiatric side effects (hallucinations) and liver toxicity. A laboratory study reported slower ligament healing in rats that were given COX-2 inhibitors. It is not known if this observation applies to people.
Their effect on pregnancy and fertility are unknown and women who are pregnant or wish to conceive should avoid them.
More research is needed to confirm or refute any other possible hazards.

Drug Interactions. The use of COX-2 inhibitors can interact with many other drugs taken concurrently, including many taken for epilepsy, heart disease and high blood pressure. Patients taking anticoagulant drugs may experience a higher risk for bleeding with the use of these agents. Anyone who has experienced allergic reactions, hives, or asthma from sulfa drugs, aspirin, or other NSAIDs, should also not take a COX-2 inhibitor. Patients should discuss all other medications with their physician.

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) 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 five-year 2001 study published in 2001 that compared RA progression rates in patients from different countries. The slowest disease progression rates were observed in patients from Finland, who were given the most effective DMARDs immediately upon diagnosis. The worst and most rapid progression occurred in patients from Sweden, who tended to be given less potent DMARDs and whose treatment was delayed by three months. This group also tended to stay on treatment for shorter durations (two years) compared to the Finnish group (the majority were treated for five years).

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

One 10-year study published in 2001 suggests that long term use does not prevent deterioration or reduce mortality rates, but the study was small and it isn't evident from the report how early in the disease process the patients had started taking DMARDs.

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. 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 other DMARDs (starts working within a few weeks).
The best record to date 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 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.)
In a 2000 study the combination of methotrexate and leflunomide (which has different effects on the immune system) was effective for 46% of patients, compared to only 20% who benefited from methotrexate alone. It should be noted that this combination poses a higher risk for liver toxicity than either alone.
Combinations with biologic response modifiers, such as Infliximab, are also promising.

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 has fewer serious toxic effects than many DMARDs, but some, although rare, they can 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. (Taking folate supplements may be very helpful in reducing liver toxicity as well as relieving less serious side effects, although folate may interfere slightly with the effectiveness of methotrexate.)
Possibly osteoporosis 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 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 regained popularity, however, and is now beneficial for both adult and juvenile RA. (It is most effective when the disease is confined to the joints.)

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. Rather than suppressing immune factors that cause inflammation, research in 2002 suggests that it may stimulate specific protective factors (interleukins 6 and 10).

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.

Leflunomide. Leflunomide (Arava) blocks autoimmune antibodies and reduces inflammation. It has the following advantages:

It is the first oral treatment approved for RA.
It appears to slow disease progression as early as six 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.)

Research has suggested that a combination of leflunomide and methotrexate would be very effective, since each have different effects on the immune system. Of concern, however, were 2001 reports of liver damage, including a few deaths, in people taking leflunomide,. The risk increased when the drug was used in combination with methotrexate or other liver-toxic agents. Everyone taking the drug should be monitored regularly, and anyone with liver problems should avoid this drug until further research has determined its full effects. A major consumer group has been urging its withdrawal at the date of this report.

A 2001 study reported that to date it was generally safe and effective, and appeared to have minimal side effects compared to methotrexate. Common ones include nausea, diarrhea, hair loss, and rash. Animal studies also indicate a risk for birth defects, so pregnant women should not take it.

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 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 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 about as effective as aspirin for RA, but still might be useful under the following conditions:

Some physicians use oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone) as an alternative treatment in patients who have severe problems with 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.
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.
Corticosteroid pulse therapy (intravenous administration) may be as beneficial as DMARDs.

Side Effects of Oral Corticosteroids. Serious side effects, however, are associated with long-term use of oral steroids although using low doses appears to reduce the risk for these complications. 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, bisphosphonates (alendronate etidronate, risedronate), or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts.

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. 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.

Tumor-Necrosis Factor Modifiers

The drugs infliximab (Remicade) and etanercept (Enbrel) have actions against tumor necrosis factor (TNF), a powerful immune factor called a cytokine, that is important in the disease process. These agents and other so-called 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.

Both infliximab and etanercept have been approved by the FDA for treating moderate-to-severe cases, even in patients who have not yet been treated with DMARDs. 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. In addition, there are concerns and some evidence that suppressing TNF can create long-term problems, including infections and nerve injury. Of note, etanercept (Enbrel) has induced systemic erythmatosus lupus in some arthritis patients.

Etanercept. Etanercept (Enbrel) neutralizes TNF. It needs to be injected twice a week, and is showing the following benefits:

Pain and swelling reduction. In one 2001 study, at 30 months 73% of patients had reported improvement, with 17% to 28% reporting 100% improvement in some symptom categories.
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.

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 in many patients.
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.

Side Effects and Complications of Tumor-Necrosis Factor Modifiers.

The side effects of the two agents are similar. The most common adverse effects are minor reactions at the injection site, but there are few other immediate side effects. Although a two-year study reported no unusual adverse effects during that time, investigators are concerned about long term problems due to suppression of immune factors. Some include the following:

The areas of specific concern are possible 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. Of note are 2001 studies reporting that patients who take infliximab and who harbor the tuberculosis organism are at high risk for developing an active infection. (While millions of healthy people unknowingly carry the TB organism, it rarely becomes active in those with healthy immune systems.) RA patients should be tested for TB before initiating treatment. Etanercept does not appear to increase this risk, although more research is needed to confirm this.
There have also been a few reports of aplastic anemia.
In rare cases, both etanercept and infliximab have been associated with nerve damage that resembles the disease process in multiple sclerosis. This involves demyelination (the loss of myelin, the insulation coat over nerve fibers) and can result in confusion, numbness, changes in vision, and difficulty walking. According to some experts, patients with multiple sclerosis should avoid these agents until further research is complete.

Other Biologic Response Modifiers.

Anakinra. Drugs that inhibit the interleukin cytokines are also in development. One of these, anakinra (Kineret) has been approved for RA by the FDA. Anakinra (Kineret) is an intravenous agent that blocks interleukin-1, an important immune factor. While anakinra has shown a 20% greater effect than placebo in alleviating symptoms, it reduces white blood cell counts in over 10% of patients, which increases their risk for infections. Experts are still cautious about its use.

Investigative Agents. A number of other agents that inhibit part of the immune response are being investigated:

Other tumor necrosis factor blockers.
Agents that inhibit other cytokines, such as interleukin-1.
Monoclonal antibodies (genetically derived antibodies) used to target receptors on T-cells that promote inflammation. A promising example is HuMax, which inhibits a receptor call CD4.
Agents that block specific chemical pathways involved with RA.
Vaccines that use anti-inflammatory factors to boost the immune system's own response against the aberrant immune factors.

Immunosuppressants (Third-Line Drugs)

For treatment of very severe active rheumatoid arthritis, physicians are now prescribing third-line 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. Tetracycline antibiotics are of interest because they have anti-inflammatory actions and because some cases of RA may be triggered initially by an infection. Minocycline, one of the tetracyclines being studied, has achieved mixed results. In a favorable 2001 study, 60% of patients taking the agent reported improvement compared with 33% taking the DMARD hydroxychloroquine. An earlier study even suggested that many patients may achieve long-term remission if the medication is administered early in the disease. (Studies on doxycycline, another tetracycline, have reported no benefits.)

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.

Oral Collagen Therapy. Oral type II collagen therapy is based on the theory that by consuming a foreign substance orally, the body will slowly become tolerant to it and will not launch an immune attack against it. Oral collagen (which is consumed in tablet