Few people with arthritis would be willing to stop taking a medication that works, especially when nothing else has. But what if joint pain and stiffness are inevitable if you don't take the medication, yet heart problems could occur if you do? Health officials say that, as with any drug, only you and your doctor can determine the level of risk that is acceptable with medications currently available to treat arthritis.

The unsettling news in late 2004 that the popular anti-inflammatory arthritis drugs Vioxx (rofecoxib), Celebrex (celecoxib), and Bextra (valdecoxib) could cause a heart attack or stroke or aggravate high blood pressure has left some patients wondering whether they should keep taking them.

Data from clinical trials showed that cyclooxygenase-2 selective agents, better known as COX-2 inhibitors, may be associated with an increased risk of serious cardiovascular problems, especially when used in high doses or for long periods in patients with existing cardiovascular disease, or in very high-risk situations, such as immediately after heart surgery. COX-2 inhibitors are the newest subset of non-steroidal anti-inflammatory drugs (NSAIDs). COX-2 inhibitors were developed specifically to decrease the well-recognized gastric side effects and intolerance associated with the use of some NSAIDs.

Traditional NSAIDs, such as aspirin or ibuprofen, act by blocking the production of a family of chemicals known as prostaglandins, which are not only important in the development of inflammation, but also play an important role in maintaining the integrity of the stomach lining. At least two enzymes are involved in this inflammation, namely cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Traditional NSAIDs inhibit both COX-1 and COX-2. Unfortunately, this non-selective inhibition of both COX enzymes also inhibits those prostaglandins involved in some of the important "housekeeping" functions of the body, such as helping blood to clot and protecting the stomach from ulceration.

It is this non-selective inhibition of both enzymes by aspirin and other non-selective NSAIDs that increases the risk of stomach ulcers and consequent bleeding. In theory, the newer COX-2 selective inhibitors only inhibit the enzyme involved in inflammation, leaving the other functions alone.

But Sandra Kweder, M.D., deputy director of the Food and Drug Administration's Office of New Drugs, says that new studies have had a surprising twist. "The downside of the COX-2 selective inhibitors is that they appear to be associated--particularly when used for many consecutive months to years--with an increased risk of cardiovascular problems," she says. Moreover, COX-2 inhibitors, like other NSAIDs, don't influence the course of the disease--which doctors say is a common misconception among patients--because these drugs only provide for symptom relief.

Coincidentally, preliminary results from a three-year trial on the non-selective NSAID Aleve (naproxen) also suggested that long-term use may be associated with an increased risk for cardiovascular problems.

Since the results of studies on both non-selective and selective NSAIDs are preliminary and conflict with data from earlier studies of the same drugs, the FDA issued a public health advisory in December 2004 concerning use of all NSAIDs, pending further review of data that continue to be collected. The agency has recommended, among other things, that physicians limit the use of COX-2 inhibitors until further review.

"Monitoring the drug safety of marketed products requires close collaboration between our clinical reviewers and drug safety staff to evaluate and respond to adverse events identified in ongoing clinical trials or reported to us by physicians and their patients," says Kweder. "The most recent actions concerning [NSAIDs] illustrate the vital importance of the ongoing assessment of the safety of a product once it is in widespread use."

Others Weigh In

The concerns with the safety of so many pain relievers used to treat arthritis underscores the importance of arthritis as a major health care issue in the United States. Arthritis experts, patient advocacy groups, and other health organizations also are weighing in on the uncertainty of NSAIDs, and are recognizing the need for developing new and safer medications.

The American College of Rheumatology is advising physicians to follow current treatment guidelines and manufacturers' dosage recommendations for NSAIDs. Treatment guidelines exist to help doctors choose the best options for their patients, based on current scientific studies.

The Arthritis Foundation said in a statement that the findings about the drugs should not have any immediate impact on the clinical use of them.

"Non-steroidal anti-inflammatory drugs continue to play an important role in the management of arthritis pain," says John H. Klippel, M.D., president and CEO of the Arthritis Foundation. "Patients who derive benefit from these drugs should remain on their treatment regimen, and discuss concerns with their physicians," he says.

But Charles A. Birbara, M.D., a rheumatologist and associate professor of medicine at the University of Massachusetts Medical School in Worcester, Mass., says that he has prescribed COX inhibitors cautiously in older people or those with cardiovascular or renal disease ever since early clinical studies discovered a possible risk in this patient population.

"I'm not always willing to take a risk with my patients, because we clearly don't have a complete understanding of all the potential clinical issues associated with use of these drugs," he says. Even before the controversy, Birbara notes that the long-term effects of COX-2 agents were unknown. Besides, he says, there are other treatment options available that are equally effective.

"There are so many wonderful things happening with respect to current therapies of arthritis," he says. "Clearly, we are so much better able to control inflammatory arthritis with new biologic agents." Birbara adds that so many people whose lives were diminished by joint disease can now look forward to an unrestricted lifestyle, which was "not even imaginable just a few short years ago."

Richard Shirley, 64, an avid birdwatcher from Wrentham, Mass., battled rheumatoid arthritis in nearly every joint in his body for more than 25 years before he saw Birbara. He couldn't button his shirt cuffs, walk frontward down a flight of stairs, or get in and out of a car without a struggle. At times, his hands were so swollen he couldn't grasp small objects or make a closed fist. Shirley had his wedding ring resized so it would fit.

"Richard had seen a number of physicians and had been on many medications to treat his disease," Birbara says. "However, the aggressive nature of his arthritis was not very responsive to standard medications." According to Birbara, X-rays of Shirley also showed evidence of joint destruction.

"Doctor Birbara has a zero tolerance for hot and inflamed joints," Shirley says, "because that's when the damage is done." Shirley also believes, from his own experience, that each person needs to work with his or her physician to find the appropriate medicine. For him, a new biologic product made the difference.

Finding the right treatments for those at greatest risk for the potential complications of arthritis and other rheumatic conditions, Birbara says, hopefully will lessen the burden of this disease, not only in the United States, but for the entire world.

The Burden of Arthritis

Although the clinical term literally means joint inflammation, "arthritis" actually refers to a group of more than 100 rheumatic conditions. According to the Centers for Disease Control and Prevention (CDC), self-reported doctor-diagnosed arthritis collectively affects nearly 43 million Americans--or about 1 in 5 adults. Another 23 million have chronic musculoskeletal symptoms that suggest they, too, may have arthritis. This makes arthritis one of the most common illnesses in the United States and a leading cause of disability. As the population ages, the CDC says that the number of Americans affected will increase dramatically.

"People ignore arthritis both as public and personal health problems because it doesn't kill you," says Capt. Charles G. Helmick, M.D., a medical epidemiologist at the CDC. "But what they don't realize is that, as people work and live longer, arthritis can affect their quality of life and lead to limitations in activities and work and eventually disability."

Link to long descriptionArthritis limits everyday activities for 8 million Americans, according to statistics compiled by the CDC. Each year, arthritis results in 750,000 hospitalizations and 36 million outpatient visits. In 1997, medical care for arthritis cost over $51 billion. The disease affects people of all ages. Nearly two-thirds of those with arthritis are younger than 65. Arthritis may affect people of all racial and ethnic groups. It is more common among women and older Americans.

Arthritis symptoms include joint pain, stiffness, inflammation, and limited movement of joints. When a joint is inflamed, it may be swollen, tender, red, or warm to the touch. In a healthy joint, the ends of the bones are covered by cartilage, a spongy material that allows almost frictionless motion between bones. In fact, Birbara says the amount of heat produced when bones normally meet is less than when two pieces of ice are rubbed together. The joints are enclosed in a capsule and lined with tissue called the synovium. This lining releases a slippery, lubricating fluid that helps the joint move smoothly and easily. Muscles and tendons support the joint and help it move. With arthritis, the cartilage may be damaged or worn away by degenerative processes or by inflammation, making movement painful and difficult. If left undiagnosed and untreated, arthritis may progress to cause irreversible damage to the joints.

Some rheumatic diseases are systemic, meaning they can affect the whole body. Diseases such as systemic lupus erythematosus (SLE) can cause arthritis as well as damage to virtually any bodily organ or system, including the heart, lungs, kidneys, blood vessels, skin, and brain, and may result in debilitating, and often life-threatening, complications.

According to the Arthritis Foundation, the most common form of the disease--osteoarthritis (OA)--affects about 21 million people in the United States. Also called "degenerative joint disease," OA is caused by the breakdown of cartilage and bones from the wear and tear of life, resulting in pain and stiffness. OA usually affects weight-bearing joints such as the knees and hips, but an inherited form commonly affects the hands and spine. Pain and stiffness are the earliest symptoms in OA, which affects both men and women and usually occurs after age 45. Other risk factors include joint trauma, obesity, and repetitive joint use. In most cases, OA can be detected by X-rays. Treatments include medications, education, physical activity or exercise, heat or cold, joint protection, pacing activities, weight loss if overweight, self-care skills, and sometimes surgery.

Shirley has the second most common type--rheumatoid arthritis (RA)--an autoimmune disease that occurs when the body's immune system mistakenly attacks the synovium and can lead to damage of both cartilage and the adjacent bone. RA may affect any joint but most commonly starts with inflammation in the hands and feet.

While the cause remains elusive, doctors suspect that genetic factors are important in RA. Recent studies have begun to tease out those specific genetic characteristics that make a person susceptible to developing RA. However, the inherited trait alone does not appear to fully account for the development of the illness. Researchers think this trait, along with some other unknown factor--probably in the environment--triggers the disease.

But RA can be difficult to diagnose early because it may begin gradually with subtle symptoms that usually wax and wane. According to the Arthritis Foundation, this form of arthritis affects more than 2 million people in the United States and is more common in women than men. Ironically, even when the disease appears to be relatively inactive--as measured by the patient's pain, swelling, and stiffness--joint deterioration is likely to be progressing.

In early disease, most of the disability that patients experience is due to inflammation. In later disease, however, it is the loss of joint integrity that creates disability. This often necessitates surgical joint reconstruction or replacement procedures. Treatments for RA also include medications, exercise, rest, joint protection, and self-care skills.

Managing Arthritis and Rheumatic Conditions

For years, the pain and inflammation of arthritis have been treated using medications, local steroid injections, and joint replacement--all with varying success. Seldom did the therapies make the pain go away completely or for very long, nor did they affect the underlying joint damage.

Today's researchers are working to improve diagnostic tools and develop treatments to forestall joint erosion. Even people whose joints are already damaged by arthritis can benefit from the knowledge generated by today's research. Patients should consult with their doctors to determine which treatments are the most appropriate for their conditions.

Most arthritis medications fall into three categories: those that relieve pain; those that reduce inflammation or the body process that causes swelling, warmth, and redness; and those that slow the disease process and limit further damage to the joints--so-called disease-modifying agents.

Pain relievers such as Tylenol (acetaminophen) and NSAIDs such as Motrin (ibuprofen) are used to reduce the pain caused by many rheumatic conditions. NSAIDs have the added benefit of decreasing the inflammation associated with arthritis. But a common side effect of NSAIDs is stomach irritation, which can often be reduced by changing the dosage or medication. Even acetaminophen has risks when taken in large doses, Kweder says.

Before safety concerns about Vioxx, Celebrex, and Bextra emerged in December 2004, these newer COX-2 NSAIDs were used primarily to reduce gastrointestinal side effects and offered an additional option for treatment.

Depending on the type of arthritis, a person may use a disease-modifying anti-rheumatic drug (DMARD). This category includes several unrelated medications that are intended to slow or stop disease progress and prevent disability and discomfort. DMARDs include Rheumatrex (methotrexate), Azulfidine (sulfasalazine), and Arava (leflunomide).

Someone diagnosed with RA today is likely to be prescribed a DMARD fairly early in the course of the disease, as doctors have found that starting these drugs early can help prevent irreparable joint damage that might otherwise occur.

Corticosteroids, such as prednisone, cortisone, methylprednisolone, and hydrocortisone, are used to treat many rheumatic conditions because they decrease inflammation and suppress the immune system. The dosage of these medications will vary depending on the diagnosis and the patient. Corticosteroids can be given by mouth or by direct injection into a joint or tendon sheath.

For Shirley, any minor relief he experienced over the 25 years was due to injections of corticosteroid preparations into his joints. The injections would relieve his pain, stiffness, and swelling temporarily. Unfortunately, corticosteroids given orally and for prolonged periods and at higher doses may carry side effects such as brittle bones, cataracts, elevated blood sugar, and an increased susceptibility to infections throughout the body.

Biologic Treatments

Biological products are a relatively new class of drugs used for the treatment of RA. Biologics differ from conventional drugs in that they are derived from living sources, such as cell culture systems. Conventional drugs are chemically synthesized. Of the four currently licensed biologics, three help reduce inflammation and structural damage of the joints by blocking a substance called tumor necrosis factor (TNF), a protein involved in immune system responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid and some other arthritis patients.

The first biologic to receive FDA approval for patients with moderate-to-severe RA was Enbrel (etanercept). Initially, it was taken twice weekly by injection, but a once-weekly preparation is now available. Enbrel has been shown to decrease pain and morning stiffness and improve joint swelling and tenderness. In 2000, the drug's approved uses were expanded to include delaying structural damage. Besides RA, Enbrel now has been approved for two other common forms of arthritis: psoriatic arthritis and ankylosing spondylitis.

The two other TNF-blocking products approved to treat RA are Remicade (infliximab) and Humira (adalimumab), a drug that provided the long-awaited relief for Shirley through a 2002 clinical trial. All three TNF blockers have been demonstrated to improve physical function in studies of at least two years in duration.

"While all three inhibit the action of TNF," says Jeffrey N. Siegel, M.D., team leader for the FDA's Division of Therapeutic Biological Internal Medicine Products, "they do it in somewhat different ways." Remicade and Humira are monoclonal antibodies, laboratory-produced proteins similar to those made by a person's immune system that bind and remove TNF from the body before it can set off the immune reaction responsible for RA.

Enbrel, on the other hand, is a soluble cytokine receptor, which means it is similar in structure to protein molecules found attached to the surface of cells that bind TNF. Enbrel competes with these receptors to inhibit them from binding TNF, thus blocking them from setting off the immune process responsible for RA, psoriatic arthritis, and ankylosing spondylitis.

Siegel warns that caution is important when using these agents as treatments. "All TNF blockers are associated with infection," he says.

Kineret (anakinra), another biologic approved by the FDA for patients with RA, has been shown in clinical trials to improve pain and swelling and slow the progression of structural damage in patients.

Arthritis Treatment Devices

Two medical device products, Hyalgan and Synvisc, are preparations that mimic a naturally occurring body substance that lubricates the knee joint called hyaluronic acid. The products, which were approved by the FDA for the treatment of OA of the knee, are injected directly into the knee joint to help provide temporary relief of pain and flexible joint movement.

Another device used in arthritis treatment is transcutaneous electrical nerve stimulation (TENS), which has been found effective in modifying pain perception. TENS blocks pain messages to the brain by directing mild electric pulses to nerve endings that lie beneath the painful area of the skin.

A blood-filtering device called the Prosorba Column is used in some cases for filtering out harmful antibodies in people with severe rheumatoid arthritis.

Heat and cold can both be used to reduce the pain and inflammation of arthritis. Patients and their doctors can determine which one works best.

Thanks to the right treatment, Shirley says his pain level today is only about 10 percent of what it once was. "Looking back on those days," he says, "it's hard to believe all the things I can do now. I've regained mobility and strength." And once again, Shirley can mow the lawn, cook meals, fix things around his house, and even pursue his favorite hobby of bird watching.

"Rheumatoid arthritis is now an illness for which newer treatments offer the real likelihood of patients being able to pursue a lifestyle without the limitations imposed by joint pain and deformity," adds Birbara.

Importance of Diet and Exercise

Arthritis experts say there's value in physical activity, the right diet, and other non-medicinal interventions that can help prevent arthritis, reduce pain, and keep people moving, as emphasized in a 10-year initiative called Healthy People 2010. A comprehensive, nationwide health promotion and disease prevention program developed by the Department of Health and Human Services, Healthy People 2010 contains 467 objectives for improving the nation's health in conditions such as cancer, sexually transmitted diseases, and arthritis.

Research in 2004, for example, demonstrated that exercise and diet together significantly improve physical function and reduce knee pain in people older than 60 who are overweight or obese, according to both the Arthritis Foundation and the American College of Rheumatology. The results of the study are published in the May 2002 issue of Arthritis and Rheumatism. Similarly, pain and disability accompanying all types of arthritis can be minimized through early diagnosis and appropriate management, including self-management, physical and occupational therapy, joint replacement surgery, weight control, and physical activity.

According to the CDC, research shows that physical activity decreases joint pain, improves function and a person's mood and outlook, and delays disability. Exercise helps reduce the pain and fatigue of many different kinds of arthritis and helps people work and do daily activities and remain independent. Range-of-motion, strengthening, and endurance exercises, such as moving a joint as far as it will go, using muscles without moving joints, and aerobic exercises, respectively, are beneficial in decreasing fatigue, strengthening muscles and bones, increasing flexibility and stamina, and improving the general sense of well-being.

It's important that people stay at their recommended weight, especially as they get older, because being overweight makes them more at risk for OA. Extra weight increases the risk for getting OA in the knees and possibly in the hips. This is especially true for women. In men, extra weight increases the risk for getting another common form of arthritis, gout (excess uric acid in the blood), as well. Maintaining a healthy weight and avoiding joint injuries reduces the risk of developing arthritis and decreases disease progression.

Some people claim to have been cured by treatment with herbs, oils, chemicals, special diets, radiation, or other products. According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), however, there is no scientific evidence that such treatments cure arthritis. Moreover, some of these unproven treatments may lead to serious side effects. Patients should talk to their doctors before using any therapy that has not been prescribed or recommended by their health care team.

Juvenile Arthritis

Nearly 300,000 children in the United States have a form of juvenile arthritis or a rheumatic disease that occurs before age 16. The most common form in children is juvenile rheumatoid arthritis. The cause of most forms of juvenile arthritis remains unknown. Juvenile arthritis is not contagious, and there is no evidence that foods, toxins, allergies, or vitamin deficiencies play a role. Current research indicates that there may be a genetic predisposition to juvenile arthritis. In other words, the combination of genes a child inherits may contribute to the development of arthritis when combined with other undefined factors. Most of the symptoms of juvenile arthritis are due to inflammation as a result of imbalances in the immune system. Despite not knowing the exact cause or causes, there are many effective treatments available to help children and their parents manage juvenile arthritis. Experts say that most children with arthritis can expect to live normal lives.

The Future

Many government and private organizations are working together to carry out a plan to guide the use of the nation's resources to decrease the burden of arthritis for all Americans and increase the quality of life of those affected by arthritis. Called the "National Arthritis Action Plan: A Public Health Strategy," it provides a blueprint for reducing pain, activity limitations, and disability among people with arthritis, as well as for preventing certain types of arthritis.

As for the safety of future arthritis treatments, experience has shown that the full magnitude of some potential risks of all drugs has not always emerged during the mandatory safety and effectiveness studies conducted before the FDA can approve a drug. As always, the agency advises physicians to consider the evolving information on any medication in evaluating the risks and benefits of these drugs in individual patients.

"The outlook for people with arthritis has never been more hopeful," adds Birbara.