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Rheumatoid arthritis is an systemic autoimmune disorder of unknown cause characterized by symmetric,erosive synovitis,and more often,mutisystem involvement. Most patients exibit a chronic changeing course of disease that if left untreated may result in progressive joint destruction, deformity, disability, and possible premature death. RA is one of the most common and serious type of arthritis.

It affects all ages and races. RA affects approximetly 1% of the population and this low prevelance may mean that many health care professionals may have little experience in treating the disease successfully.

Some Facts About RA:
a) RA affects more than 2 million Americans.
b) Direct and indirect costs of RA reached $65 billion in 1992.
c) More than 75% of RA patients are women.
d) Peak onset is between age 20 and 45.

e) Osteooporosis is common in patients with RA.

RA can be difficult to diagnose early because it may begin gradually with subtle symptoms. Blood tests and X-rays may be normal initially. The disease varies among individuals with respect to symptoms,joints affected and the nature of other organs involved,such as the eyes,lungs,and blood. Other types of arthritis may mimac RA. There are mild,moderate,and severe types of RA. Skill,often-patience,and experience are essential to reach a precise diagnosis and to arrive at the appropriate treatment

Although we do not know the cause of rheumatoid arthritis,joint damage is caused by inflammation in the synovial membrane. This normally thin memberane becomes inflamed and thick,filled with cells called fibroblasts, lymphocytes,polymorphs, and macrophages. This thick,inflamed synovial membrane is called the pannus. The cells within the pannus becomes activated, and releases enzymes,and chemicals that both permanetly damage the cartilage and the bone,and also attract more cells into the inflamed tissue. In RA,this inflammatory process is like a one-way highway, the inflammation continue indefinitely causing more and more damage,leading to possible joint deformity and destruction if not controlled.

This inflammatory process is part of the body's immune system. The immune system is a natural defense against invaders such as bacteria, viruses,and even cancer. The cells of the immune system recognize,and respond to invaders either by making antibodies to combat invaders or by attacking invaders directly. Although the immune system is normally activated by a foreign agent,it can be activated to attack normal cells. In RA,for unknown reasons,the immune system becomes over-activated and causes marked inflammation in the synovial membrane. Many of the drugs used to fight RA have antibacterial and/or anti-immune system activity.

The damage to the joints caused by RA is thought to be caused by the interaction of many inflammatory cells and chemicals. Cytokines,like tumour necrosis factor,IL-ra alpha etc., are secreated by synovial fibroblasts and other cells resulting in pain,and inflammation TNF may also be responsible for influencing other inflammatory compounds including interleukins (IL-1), collagenase,and prostaglandins

Tumor necrosis factor (TNF-a) converting enzyme contributes to production of TNF-a in the synovial tissue of patients with RA,who have a excess of TNF. Biologic drugs such as Etanercept (Enbrel) and Infliximab (Remicade) have developed to combat TNF. Due to the high cost these drugs have mostly been used on patients who do not respond to conventional therapy.

Leflunomide (Arava) is a new DMARD which suppresses cells that are rapidly dividing have also been recently developed. Recently another drug was approved by the (F.D.A.)Federal Drug Administration to combat another cytokine IL-1 also involved in the inflammatory process. There are currently many research projects going on to combat rheumatoid arthritis.

The major underlying feature of RA is inflammation. By controlling inflammation,not only can the symptoms of RA be alleviated,but permanent disability can be prevented or minimized.

The help of specifically trained health care workers in rheumatic diseases will help in the management and treatment of RA. The major aim of treating RA is to control the inflammation before erosive and destructive forcess come to play in the disease process.

If the ("fire") inflammation of RA is controlled,pain,and swelling will diminish, and damage and possible deformity will be limited. Limited from inflammation, the patient will be able to resume a more satisfying,and productive life-style.

The patient will have the greatest interest in getting the most effective treatment for RA disease control. To accomplish this goal,the arthritis must be diagnosed promptly,and its type determined. A knowledgeable,and compassionate physician who is able to select,modify,and recommend the most appropiate treatment is a essential component of the whole disease control process.

Patients must take resposibility for their own disease,and navigate through the health care system to ensure the disease gets the treatment it needs. The "window of opportunity" to control the disease,when the disease is more manageable (2 years-onset of disease)exists,but it is never to late,to initiate DMARD therapy.

Successful management of RA requires early diagnosis and aggressive treatment before functional impairement and irreversible joint damage has ocurred. Nonsteriodal anti-inflmmatory drugs such as ibuprofen may be used first,but all RA patients with persistentent swelling in the joints are candidates for treatment with disease-modifying drugs, These drugs include methotrexate, hydroxychloroquine, sulfasalzine, corticosteriods,and intramuscular and oral gold,d-penicillamine, minocycline, azathioprine,cyclosporine,leflunomide and etanercept.

Optimal treatment requires comprehensive coordinated care,patient education and the expertise of a number of providers.including rheumatoligists,primary care physicians,specialized nurses trained in rheumatic diseases,occupational, physical therapist,physiatrists,social workers, and orthopedic surgeons if required.

With the success of total joint replacement surgery (especially hip and knee) many patients with advanced disease have continued to be active and mobile.

RA has ben a primary focus of rheumatologic research. The chronic nature of RA and the diagnostic and treatment complexicity have made the specialized skills and training of a rheumatologist critically important in the care of people with RA. Expertise is needed to balance the risks and benefits of disease modifying drugs.

Complete remission is defined as the absence of:

1) symptoms of active inflammatory joint pain (in contrast to mechanical joint pain).

2) morning stiffness.

3) fatigue.

4) synovitis on joint examination.

5) progression of radiographic damage on sequential radiographs.

6) elevated erthrocyte sedimintation rate or (ESR),or C-reactive protein (CRP) level.

If complete remission is not achieved,the management goals are to control disease activity,alleviate pain,maintain function for essential activities of daily living,and work,maximize quality of life,and slow the rate of joint damage. Complete remission is rare,but in happens in some patients. Partial remission is the likely outlook.

Dismantling the treatment pyramid: those of you remember "Red Kelly" then coach of the Toronto Maple Leafs hockey club of the NHL who tried "pyramid power" to motivate his team.

It was a seventies fad based on vague interpretations of mysteries,such as using crystals to "realign your aura" The mix of specious reasoning and hokey data was enough to convince students and athletes to sit under pyramids as a way of increasing their prowess in studies and sport. The practise, fortunately, has gone the way of the "zoot suit",but the pyramid did have one serious application: as a symbol for rheumatoid arthrtis management

The "pyramid approach to treatment" is a visual for the administeration of sequentially more powerful interventions: The base of the pyramid is rest, physical therapy,ASA,and other NSAIDs. Next up are progressively stronger disease-modifying anti-rheumatic drugs (DMARDs-slow acting anti-rheumatic drugs-then referred to as SAARDs) capped,at the apex of the pyramid,by experimental drugs and procedures.

The pyramid approach has long been part of the fabric of rheumatology , certainly for as long as Dr. James F. Fries can remember. Fries is director of ARAMIS (Arthritis Rheumatism and Aging Medical Information System) based at Stanford University Medical Centre,where,for the past decades or so,he and his colleagues have been building databases on arthritis. their research has contributed to a new understanding of RA,and a recognition that the pyramid approach to treatment was based on some false notions about the disease.

The first was the view that RA is a relatively mild disease,followed a leisurely course,that doesn't amount to much in most people,and often goes into remission by itself. Then there was the belief,Fries says "that ASA and NSAIDs wer very benign drugs,and that disease modifying drugs-like intramuscular gold and,even worse,methtrexate or azathioprine-were too dangerous in a benign disease." Incorrect,and wrong again. On the basis of such false premises says Fries,"we accepted the pyramid strategy".

In recent years,a number of studies-many of them drawing on the remarkable ARAMIS database-have led to a very different conclusions. What they've learned has led to what Fries calls "a 180-degree change in the way we therapeutically approach RA",similar to the change in the way heart attack victimins are treated: Years ago,heart patients were prescribed six weeks of absolute bed rest,which seemed logical at the time. But outcomes took a leap foward when cardiologists started hauling their patients out of bed and up into treadmills and out running marathons. "Those of us who have seen both eras",Fries says,"realize we were flatly wrong in the way we approached coronary artery disease-and we were flatly wrong in RA. So,we're at a time when we made a 180-degree shift,in this case with the treatment pyramid".

"Initially,the pyramid approach was useful because at the base of the pyramid you had one drug,ASA " says Dr. Bill Benson a rheumatologist a St. Joseph's Hospital in Hamilton Ontario. "And then,of course,you went very quickly from ASA ti the disease-modifying drugs. Where things got complicated was in the "70s and "80s,when we had 13 other NSAIDs come into the market. It made the base of the the pyramid so deep that many physicians started to go with the concept that you just keep trying these non-steriodals,which would give you up to two or three years' worth of alternatives before you move on to a stronger,slow-acting,anti-rheumatic drug. And this led to immense,damaging delay in the management of RA."

At the same time,it was clear that NSAIDs weren't stopping the disease in most people,while the slower acting drugs showed greter potential to put the disease to rest,if not temporarily, and sometimes permanently. In addition, doctors were becoming aware,from clinical experience if not from academic studies,that DMARDs also worked best with early-stage RA-before it caused irreversible cartilage or bone damage

Diagnosis:

The first step in the diagnosis of rheumatoid arthritis is a meeting between the doctor and the patient. The doctor reviews the history of symptoms, examines the joints for inflammation and deformity.

Inflammation can be detected by:

1) Tenderness with pressure over a joint.

2) Swelling.

3) Pain ( when the patient move the joint through a full range of movement,pain is experienced towards the end of the range ).

4) Redness or warmth,(redness is not a criteria for RA)

5 )The number and severity of inflamed joints,whether or not the inflammation is symmetrical,gives the doctor a sense of what type of arthritis is present.

The doctor will also examine the skin for rheumatoid nodules, and other parts of the body for inflammation. Certain blood and x-ray tests are often obtained. The diagnosis will be based on the pattern of symptoms, the distribution of the inflamed joints, and the blood and x-ray findings. Several visits may be necessary before the doctor can be certain of the diagnosis-(rheumatologist).

The distribution of joint inflammation is important to the doctor in making a diagnosis. In rheumatoid arthritis, the small joints of the hands, wrists, feet, and knees are typically inflamed in a symmetrical distribution (affecting both sides of the body). When only one or two joints are inflamed, the diagnosis of rheumatoid arthritis becomes more difficult. The doctor may then perform other tests to exclude arthritis due to infection or gout.

The detection of rheumatoid nodules , most often around the elbows and fingers, can suggest the diagnosis. Rheumatoid nodules are bumps,the size of corn to that of a small grape,that develop under the skin. the most typical location is on the forearm,just below the elbow. Pressure seems to trigger their development;habitually resting a forearm on the arm of a chair or on a table is thought to be a factor.

Less commonly,people develop nodules over the Achilles tendon (where the back of a high shoe or boot presses),or over knucles of fingers or toes where pressure is applied repeatedly. Nodules may be single or in clusters. Some can be moved about under the skin,while others seem stuck to the underlying bone. They aren't painful unless they are injured or infected.

They may be mistaken for other bumps including "tophi" (deposits of uric acid),seen in some with gout. Very uncommonly,rheumatoid nodules are present by themselves,without any evidence of RA. The exact cause is unknown but there must be some more cause then pressure.or injury,since less than 20 % of RA patients develop nodules.

In some patients,treatment with methotrexate,even though it helps control joint inflammation,causes the nodules problem to get worse when one has it-doctors don't know why.

Since almost all patients with nodules have rheumatoid factor (RF) in their blood. ( Eighty percent of RA patient's have a positive RF,in their blood stream.) RF may be involved in "vasculitis" (inflammation of a small blood vessel) possibily triggered by local injury from pressure.

The body may react locally to the vasculitis inflammation,and the attempt at healing may result in a lump of scar tissue below the skin in some patients. Nodules may eventually go away,but they often persist after all other evidence of Ra has been suppressed. They tend to exist in patients with more moderate-severe RA patients,but that is not a general rule. In most cases they do not cause trouble in the majority of patients who have it.

Abnormal blood antibodies can be found in patients with rheumatoid arthritis. A blood antibody called "rheumatoid factor" can be found in 80% of patients. Another antibody called "the antinuclear antibody" (ANA) is also frequently found in patients with rheumatoid arthritis. ANA testing is associated more with Lupus patient diagnosis.

A blood test called the sedimentation rate (sed rate) is a measure of how fast red blood cells fall to the bottom of a test tube. The sed rate is usually faster during disease flares, and slower during remissions. An elevated "sed rate" can be seen in other diseases.

Another blood test that is used to measure the degree of inflammation present in the body is the C-reactive protein.

The rheumatoid factor, ANA, sed rate, and C-reactive protein tests can also be abnormal in other systemic autoimmune conditions. There- fore, abnormalities in these blood tests alone,are not sufficient for a firm diagnosis of rheumatoid arthritis.

Joint x-rays may be normal or only show swelling of soft tissues early in the disease. As the disease progresses x-rays can show bony erosions typical of rheumatoid arthritis in the joints. Joint x-rays can also be helpful in monitoring the progression of disease and joint damage over time. Bone scanning, a radioactive test procedure, can demonstrate the inflamed joints.

The doctor may elect to perform an office procedure called arthro- centesis. In this procedure, a sterile needle and syringe are used to drain joint fluid out of the joint for study in the laboratory. Analysis of the joint fluid, in the laboratory, can help to exclude other causes of arthritis, such as infection and gout.

Arthrocentesis can also be helpful in relieving joint swelling and pain. Occasionally, cortisone medications are injected into the joint during the arthrocentesis in order to rapidly relieve joint inflammation and further reduce symptoms.

Inflammation in RA is a very complex process. Scientists believe it starts when one of the class of cells that guards the body against foreign invaders( in ordinary inflammation these are usually viruses or bacteria )comes into contact with something that triggers the alarm. One form the alarm takes is a whole battery of chemical messengers,called cytokines,that are released into the joint.

These recruit other cells,the white blood cells that attack and kill other cells and bacteria. One form this killing takes is the release into the immediate area of very "corrosive"" chemicals. Joint tissue,an innocent bystander,is damaged. Furthermore,cytokines stimulate the lining of the joint to grow and produce other chemicals that break down cartilage.

Cytokines are released into the blood stream,and cause fever and fatigue. Because the body is so finely balanced,there are also cytokines released that tend to damp down the inflammation. Unfortunately,in the RA joint these "good" cytokines tend to become overwhelmed by the "bad" or pro-inflammatory cyctokines.

One of the key cytokines that promotes inflammation is a substance called TNF-alpha. Produced by both the "guard" cells (macrophages) and the joint lining tissues,it is released into the surrounding tissues,joint fluid,and blood. It stimulates other while blood cells to expand the inflammatory reaction. To do this it must attach itself to the other cells a a specific binding site-like a key in a lock.

Etanercept (Enbrel) and infliximab (Remicade) have been designed to interfere with this stimulatory action of TNF-alpha. Etanercept does this very cleverly;it's a molecule that looks exactly like the keyhole. As long as there is enough of it in circulation (it has to be self-injected twice weekly under the skin ),it will prevent enough keys from finding the lock they were intended for,and the inflammation will be damped down. It absobs excessive TNF

Infliximab has a similar effect,but it consists of an antibody ( a protein specifically designed to attach to another protein ) against TNF-alpha. Once the key has a antibody stuck to it,it no longer fits the lock. Infliximab too has to be given by needle-in this case into a vien-once every two months. Infliximab is called a monoclonal antibody,meaning it's a protein made with a mouse part,and a human protein is added to make it less allergic or immunogenic. Methotrexate is added because it decreases the mouse part reaction. Chimeric definition means,it's made of two animals,one is mouse and one is human. It "kills" excessive TNF-alpha (tumour necrosis factor). Humira is a recently aproved TNF inhibitor.

Leflunomide (Arava) is different. It doesn't block TNF-alpha,but it interferes with the normal functioning-one of the key cells ( the lymphocyte) affected by TNF-alpha,and thus interferes with the development of joint inflammation.

People with rheumatoid arthritis tend to have excess TNF-alpha. There is a family of Interleukins,involved in the disease process,too. IL-1,Il-2,IL-'s etc, Anakinra or Kineret inhibits IL-1 alpha. Scientists are working on a pill form of TNF inhibitors. Not everyone,will benefit from biological therapy,and some patients will not react favourably to conventional disease modifying medication.

We have often heard about one of the cytokines central to RA-tumor necrosis factor-alpha,(TNF-alpha) TNF-alpha is a vital member of the group of many other different cytokines that drive the destructive reactions in RA.

These cytokines play an important role in maintaining normal health. They are produced in response to infection or energy and stimulate our immune systems to fight back. Unfortunately,in RA,the natural control mechanisms that normally turn off the immune response after it has done its job are unable to do so. Scientists do not yet know all the details of why this happens,but they do know,e.g.,that uncontrolled TNF-alpha is a serious problem. It can transform cells in the synovium,the delicate membrane lining the joints,into a growing,invading mass of tissue-the pannus-that eats away at the cartilage and bone. It also attracts more inflammatory cells to the area,aids in the formation of additional small blood vessels,and helps make enzymes that can break down cartilage and bone.

The major source of TNF-alpha are the macrophages-plentiful,active cells that move aroun in the joint tissues. The macrophages' normal job is to pick up material in the tissues that the body recognizes as foreign and dangerous to it,like bacteria or perhaps pieces of injured cells. The macrophages,carrying these foreign fragments-called antigens-come in contact with special kinds of white blood cells,the T cells. This meeting stimulates the T cells to make cytokines that attract other T cells and macrophages to the sit. Soon there is an abundant supply of TNF-alpha coming from the macrophages,which can transform joint cells to divide and destroy. In addition,TNF-alpha induces other cells in the area to make inflammatory cytokines,like interleukin-1 (IL-1) and interleukin-6 (IL-6).

Under ordinary conditions,if we develop a minor bacterial infection in a hand,for example,we may experience some local redness,swelling,and pain tht may last for a few days,and then disappear. The macrophages,T cells,and the cytokines have done their work,and then they slow down until the next invasion. The exact trigger(s) that begin this inflammatory process in RA is yet unknown but we do know that our challenge is to slow down its abnormal destructive continuation.

When molecules of TNF-alpha are released by cells like macrophages,the soluable molecules can attach to special protein receptors on the surface of cells in the joint,such as cells in the synovial membrane,or cells that line the tiny blood vessels in the area. Once attached to the receptors on these cells,the TNF-alpha induces the cells (by turning on some of their genes) to keep th inflammation going. In the fluid surrounding these cells there is a variable amount of those protein TNF-alpha receptors that are free-floating. These are part of the natural control system,because they can grab onto TNF-alpha and thereby not allow it to bind to receptors on cells which cause the inflammation. This allows some "fine tuning" of the effects of TNF-alpha. However, in the joints of someone with RA,even though there are increased amounts of these dissoved receptors grabbing TNF-alpha and keeping it from making trouble,they are unable to stop it from prodding the immune system down the path of RA. There are many other family members in the interleukin group which may also contribute to the inflammatory process.

Once again,RA shows its many characteristics-there is a wide variety of levels of TNF-alpha and other inflammatory cytokines in the joint tissues of people with RA.-which may explain the new treatments work so well in many people with RA,but not in all.

Rheumatoid arthritis may be better classified into four different types: spontaneous remitting disease,remitting,remitting progressive,and progressive.

Spontaneous remission means that without treatment or just with NSAIDs,the symptoms of the disease disappear. They may return later,and you may need to start taking NSAIDs again,but for a while you have complete relief or almost. In rare cases,about 5 to 10 % of people with RA,the symptoms never return.

Remitting disease means that the person has a series of flare-ups with a return to normal in between. This can be difficult to deal with,because it is not known when a remission is going to occur and when the symptoms will return. DMARDs may be needed to prevent joint damage during the flare-ups.

People suffering from remitting progressive disease experience flare-ups but never quite return to normal in between. There is a good chance that the joints with this type of disease will be damaged without DMARD therapy.

The person with progressive disease never experiences remission or flare-ups,just a gradual increase in the pain,swelling,and joint damage over time. Usually the progression is slow,but in some cases one can become disabled rather quickly.

New ACR guidelines recommended DMARD therapy to all RA patients upon diagnosis.

Factors that correlate with prognosis: More favorable factors; Absence of rheumatoid nodules (small bumps over pressure points),absence of,or few,manifestations outside of joints,absence of rheumatoid factor in the blood and perhaps male gender.

Possible less favourable prognosis : High levels of rheumatoid factor,early in the disease,early involvement of large joints,female,presence of rheumatoid nodules,early appearance of erosions in the joints,vasculitis (blood disorder ).manifestations outside of the joints,and scleritis. It was once thought that the marker HLA-DR4 in the blood was a indicator of severe disease,but some recent research suggests it may not be related to severe disease. It remains debateable.

The initial drug treatment of RA usually,involves the use of salicylates NSAIDs,or a selective COX-2 inhibitor to reduce joint pain and swelling and to improve joint function. These agents have analgesic and antiinflammatory properties,but do not alter the course of the disease or prevent joint destruction. Nonsteriodal antiinflammatory drugs (NSAIDs),glucocorticoids should be considered for control of symptoms. The majority of patients with newely diagnosed RA should be started on disease-modifying antirheumatic drug (DMARD) therapy within 3 months of diagnosis Some patients have resistant disease and experience a progressive disease despite exaustive trials of DMARDs.

Given the chronic waxing and waning course of RA,a longitudinal treatment plan needs to be institued with patient participation. If,monitoring of disease activity (i.e.,ongoing disease activity after 3 months of maximum therapy),or progressive joint damage continues the regimen may require considerations of significant changes in the DMARDs. If disease activity is confined to one or few joints,then local glucocorticoid injection may help. For patients with severe symptoms.systemic glucocorticoid may need to be initiated,or the dosage may need to be increased,for a short period of time.

Baseline laboratory evaluations should include a complete blood cell count (with white blood cell differential and platelet counts),rheumatoid factor (RF) measurement,and measurement of ESR or CRP. Evaluation of renal and hepatic functions is necessary, since many antirheumatic agents cause renal or heptic toxicity and may be contrainindicated if these organs are impaired.

Since the hands and feet are so frequently involved in RA,radiographs of these joints as well as other affected joints establish a baseline for future assessment of structural damage. Arresting and preventing structural damge is the primary goal of therapy,and radiographic studies of major involved joints may be needed periodically.

Selection of the treatment regimen requires an assessment of prognosis. Poor prognosis is suggested by older age at disease onset,high titer of RF,elevted ESR,and swelling of >20 joints. Extraarticular manifestations of RA,such as rheumatoid nodules,Sjogren's syndrome, episcleritis and scleritis,interstitial lung disease, pericardial involvement,systemic vasculitis and Felty's syndrome,may also indicate a worse prognosis,but have not been widely adopted for clinical practise.

The ACR criteria for 20 % clinical improvement (the ACR 20 ) requires a 20 % improvement in 3 of the following parameters;patient's global assessment,physician's global assessment,patient's assessment of pain,degree of disability,and level of acute-phase reactant. These criteria have been expanded to include criteria for 50 % and 70 % improvement measures (i.e.,ACR 50,ACR 70). Other criteria,such as Paulus criteria,have bee employed. More recently,radiographic progression (e.g., the Sharp score ) has been utilized as an outcome measure.

Optimal management of RA involves more than pharmacologic therapy. Early in the course of the disease the patient needs to know that polyarticular,RF positive have a 70 % probability of developing joint damage or erosions within 2 years of onset of disease. Since studies have demonstrated that treatment with DMARDs may alter the disease course in patients with recent-onset RA,particularily those with unfavourable prognostic factors,aggressive treatment should be initiated as soon as the diagnosis has been established.

At each followup visit,the physician must assess whether the disease is active or inactive. Symptoms of inflammatory (as contrasted with mechanical ) joint disease,which includes prolonged morning stiffness, duration of fatigue and active synovitis on joint examination,and active synovitis on joint examination,indicate active disease and accessitate consideration of changing the treatment program. Occationally,findings of the joint examination alone may not adequately reflect disease activity and structural damage,therefore,periodic measurement of the ESR or CRP level and functional status,as well as radiographic examinations of involved joints should be performed.

Functional status may be determined by questionnaires such as the Arthritis Impact Measurement Scale or the Health Assessment Questionnaire.It is important to determine whether a decline in function is the result of inflammation,mechanical damage,or both,treatment strategies will differ accordingly. The ACR has developed criteria for defining improvement and clinical remission in RA. These criteria have become accepted for outcome assessment in clinical trials.

The patient will need to become involved in the process of making decisions about treatment. If treatment does not fully control the disease,the patient may struggle emotionally as well as physically in adjusting to this chronic disease,it's flares,and the concomitant loss of function.

Rheumatologists,other physicians and their office staff should play important roles in educating the patient and the patient's family about the disease and providing longitudal supportive care.Other health professionals, familiar with RA,including nurses,physical therapists, occupational therapists,social workers,health educators, health psychologists and orthopedic surgeons,may be involved in interdisciplinary team approach in the comprehensive management of RA.

Instruction in joint protection,conservation of energy,and a home program of joint range of motion and strengthening exercises are important and essential in achieving treatment goal of maintaining joint function. Physical therapy and occupational therapy should help the patient who is compromised in activities of daily living. Regular participation in dynamic and even certain selected,suitable aerobic conditioning exercise programs improve joint mobility,muscle strength,aerobic fitness and function and psychological well being without increasing fatigue or joint symptoms.

The initial evaluation of the patient with RA should document symptoms of active disease (i.e.,presence of joint pain,duration of morning stiffness,degree of fatigue},functional status,objective evidence of disease activity (i.e., synovitis,as assessed by tender and swollen joint counts,and the ESR and CRP level) mechanical joint problems (i.e., loss of motion-joint instability, malalignment,and/or deformity), the presence of extraarticular disease and the presence of radiographic damage. The presence of comorbid conditions should be assessed. The patient's and physician's global assessment of disease activity and a quantitative assessment of pain using a visual analog scale or other validated measure of funcion or quality of life are useful parameters to follow during the course of the disease. This baseline information greatly facilitates assessment of these progression and response to treatment. Baseline laboratory evaluations should include a complete blood cell count (with white blood cell differential and platelet counts), rheumatoid factor (RF) measurement,and measurement of ESR or CRP. Evaluation of renal and hepatic functions is necessary,since many antirheumatic agents cause renal or heptic toxicity and may be contrain -indicated if these organs are impaired. Since the hands and feet are so frequently involved in RA,radiographs of these joints as well as other affected joints establish a baseline for future assessment of structural damage. Arresting and preventing structural damge is the primary goal of therapy.and radiographic studies of major involved joints may be needed periodically. Selection of the treatment regimen requires an assessment of prognosis. Poor prognosis is suggested by earlier age at disease onset,high titer of RF,elevted ESR,and swelling of >20 joints. Extraarticular manifestations of RA,such as rheumatoid nodules, Sjogren's syndrome,episcleritis and scleritis,interstitial lung disease,pericardial involvement,systemic vasculitis and Felty's syndrome,may also indicate a worse prognosis,but have not been widely adopted for clinical practise. The ACR criteria for 20 % clinical improvement (the ACR 20 ) requires a 20 % improvement in 3 of the following parameters;patient's global assessment,physician's globl assessment,patient's assessment of pain,degree of disability,and level of acute-phase reactant. These criteria have been expanded to include criteria for 50 % and 70 % improvement measures (i.e.,ACR 50,ACR 70). Other criteria,such as Paulus criteria,have bee employed. More recently,radiographic progression (e.g., the Sharp score ) has been utilized as an outcome measure. When rheumatologists in this country were surveyed in 1999, 47% of them viewed combination DMARDs as appropriate initial therapy, and 46% of that group had used combination DMARDs for more than 30% of their patients. Aggressive therapy, usually in combination, may be appropriate for some patients. That is counter-balanced by a second survey of Canadian and US rheumatologists in 1996, where there was some preference expressed for a single agent, if possible, in the treatment of rheumatoid arthritis. With our new drugs, we have changed our vocabulary and our goals when we think of treatment for rheumatoid arthritis. Our goals are: no constitutional symptoms, returning to work, minimizing the impact of this disease on daily living, and changing the course of disease progression. We have made our biggest leap in the last several years with discussion about slowing, stopping, and perhaps even reversing this previously relentless chronic disease. Ideally, you would like a drug that is effective not just for symptoms, but one that inhibits disease progression, has that efficacy sustained over long periods of time, and is safe and well tolerated with minimal monitoring required. We would like that to be simple, perhaps monotherapy. Rheumatologists are moving from that first treatment paradigm to this. Our current approach still may be initial treatment with traditional DMARDs, but then quickly adding drugs, including a biologic agent. That evolution emphasizes early aggressive treatment, biologics, monotherapy if possible, or combinations for non- or partial responders, and the potential to reduce or discontinue our previous drug. What is the paradigm change in terms of therapy for rheumatoid arthritis? In the last few years, we understand the severity and the nature of rheumatoid arthritis more than we ever have. What are those paradigm shifts? We're using disease modifying antirheumatic drugs (DMARDs) earlier. We're using aggressive methotrexate therapy. We're using combination therapy. We're using biologics. In terms of early DMARD use, there are 2 issues that most physicians want to address. If I use a DMARD early, will it make a long-term difference to my patients? And, if I use a DMARD early, will I have a better clinical response? The concept that initiating a DMARD early may have a longer-term benefit on the patient. Are there any data to support that? There are at least 2 studies to suggest it. The first is a study by Lard. He took a group of patients who, within 2 weeks after presenting with their diagnosis, were started on a DMARD. He took another group of patients and waited a mean of 4 months and then started a DMARD. The delay, on average, is about 4 months. These populations weren't exactly matched, but they were pretty closely matched. If you look at the radiological outcome, the Sharp score, those patients who were treated early had a reasonable reduction in Sharp score, whereas those patients who were only 4 months delayed on average had quite a significant increase in Sharp score over time. That suggests earlier treatment will have a long-term benefit. The second study has to do with disability outcomes. This study by comes out of British Columbia. They did a hydroxychloroquine (Plaquenil) trial. They did a 9-month, double-blind, placebo-controlled trial. At the end of 9 months, they put the placebo patients on Plaquenil. They watched the patients who got Plaquenil at the beginning of the study, and watched those patients receiving Plaquenil 9 months later, ie a delay, to see whether, long term, there would be a difference. If you look at improvement in those patients who got Plaquenil at the beginning, in terms of disability, there is a 57, 58, and 60 in standard deviation units. The patient population that started 9 months later, out to 33 months later, didn't match their counterparts. They still had more disability after 3 to 4 years and were not up to the base of those individuals who started on Plaquenil initially. Aggressive, early therapy could make a long-term difference. We've seen it radiologically and in terms of clinical outcomes. What about methotrexate? What about better response to DMARDs in early versus late disease? If I use a DMARD early, will I have a better response than late? There are not a lot of data to support that. I'm going to give you 2 pieces of data that are certainly suggestive, but not definitive. One of these pieces of data comes from the trials with etanercept. They looked at the Stanford Health Assessment Questionnaire (HAQ) outcomes, the disability outcomes, in patients in the Moreland trial, which was monotherapy late disease, an average of about 10 to 12 years of disease, versus the outcomes in the Early Rheumatoid Arthritis (ERA) trial in patients who were treated with under 3 years of disease. Other than disease activity, for the baseline outcomes of tender joints, swollen joints, etc, they were comparable. Investigators had 2 comparable populations, 1 early, 1 late, and they asked the question: Using the same dose of etanercept, do you have a better response? These data show, in the ERA trial, there was a difference between these 2 populations, a better improvement in HAQ if you treated early. The second study is a meta-analysis. This is a study by Anderson. It's probably the only study done in terms of asking the question, "Earlier treatment, better response?" This is published in Arthritis and Rheumatism. There were various DMARDs used. They looked at Plaquenil, azathioprine (Imuran), and methotrexate. They even looked at Prosorba (protein A-based extracorporeal immunoadsorption, silica). The concept is, if you treat people with a short disease duration, regardless of their treatments, in general, your sedimentation rate is improved, your swollen joint count is improved, and your tender joint count is improved. This is the proportion of those people who are improving by at least 20%. If you treat them late, if they're treated at 5 to 10 years, there is a significant difference. Suggestive, but not definitive, data indicate if you treat earlier, you're more likely to have a response. What about aggressive methotrexate dosing? Are there any data to say that higher doses of methotrexate make a difference versus lower doses? Dan Furst did a study. He asked the question whether 20 mg of methotrexate over 14 weeks is any better than 10 mg over 14 weeks. Here is the percentage of patients with American College of Rheumatology (ACR) 50 and with improvement of at least 50%. The 20-mg dose improved more at tender joint count, swollen joint count, global joint count, and activities of daily living (ADLs) relative to 10 mg. These data say higher doses work better than lower doses, that 20 mg is better than 10 mg. The median dose of methotrexate used about 3 years ago, when they did a pharmaceutical survey in the United States, was 11 mg. The ACR recommends that 25 mg subcutaneous injection be tried before the drug is considered "inadequate" response. Many of the so called "comparison" trials e.g.,leflunomide,early etanercept etc., trials were done at the 20 mg level. In 1999 studies determined that MTX was a "true" disease-modifying drug. The trial results indicated that 25 mg subcutaneous injection of MTX was more efficacious than oral MTX of 20 mg,with lower side effects. Another study that suggests the possibility that methotrexate works well is the Early Rheumatoid Arthritis trial. We think about etanercept as one of the gold standards Can we take methotrexate, which is our gold standard, raise the dose in 2 months to 20 mg, and compete with etanercept? In the first 4 months, you don't compete. To an extent, etanercept worked quicker. By 12 months, the 2 look almost identical. There is only a 5% difference between etanercept and methotrexate in terms of clinical outcomes at 1 year. These are very good outcomes. Most of the other disease modifiers and biologics aren't going to beat methotrexate. So why use it? Or, why not use it? Here is the concept. Radiologically, at 2 years, there was a minor difference between etanercept and methotrexate. The Sharp score point differences were about 2. However, it's clear that, over time, radiological outcomes are linear. It was thought to be only 6 years, but now we're talking 15 to 20 years. The concept is, if these 2 curves continue to diverge, by 5 years, there is going to be a 5 Sharp score point difference and at least that from then on. How long does it take to notice a difference, radiologically, in terms of change in Sharp score? Nobody knows, but I'll give you a number anyway. About a 50 Sharp score point difference and your grandmother can tell the difference between those 2 x-rays. Therefore, if it's 5 years, it doesn't take very long for those 2 x-rays to be different. If you continue methotrexate, you will have different x-rays than if you were on etanercept. Over time, the tolerability isn't as good with methotrexate, so that 74% of the patients stay on etanercept for 24 months, and 59% of the patients stay on methotrexate. There is a difference between the two. Methotrexate makes some people feel sick. Etanercept makes many patients feel good. If the cost would come down, everybody would be switching to etanercept. What about combination therapy? There are 3 ways to combine DMARDs. You can add a DMARD in those partially responsive. That's called step up. We can use them in parallel from the beginning, or we can use step down. We can use multiple DMARDs at the beginning and, as the patient responds, keep removing DMARDs until you're back down to baseline, maybe with monotherapy. That's the induction and maintenance concept. You've seen lots of add-on therapies, because that's the way the trials are being designed. The step-up therapy here is leflunomide. In patients who are partially responsive to methotrexate, the combination is a 51 ACR 20 compared with methotrexate alone, which means you continue on it. There is quite a difference. There appears to be a clinical added benefit to adding leflunomide in patients who are partially responsive to methotrexate. These are some data that suggest combination therapy is not bad. Two studies recently asked the following question: At the beginning, if I initiate methotrexate and sulfasalazine, will it be better than either alone? Two studies say no. Initiating sulfasalazine and methotrexate at the same time is not better than either methotrexate or sulfasalazine alone. These are data using the Disease Activity Score (DAS) and the ACR 20 scores. What about triple therapy? Jim Ardell added triple therapy at the beginning and asked whether it was better than Plaquenil, sulfasalazine, or methotrexate alone. He had striking results. The triple therapy at the beginning was much better than the others. There were a couple of problems with the study. It was pretty long. There were long-duration patients, about 10 years. The number of patients who were methotrexate naïve was quite considerable, and most of the patients failed about .9 DMARDs. It's an unusual population, but these studies were done a number of years ago when methotrexate wasn't on everybody's "radar screen." It's still an unusual population. This study is critical to be reproduced in early rheumatoid arthritis because it says that the toxicity wasn't any different whether you were on triple, double, or single therapy. There are a couple of open-label trials. There is a triple therapy trial -- methotrexate, sulfasalazine, and Plaquenil versus methotrexate and sulfasalazine, or methotrexate and Plaquenil. It was triple therapy versus double therapy versus single therapy. The single therapy was methotrexate. They showed triple therapy worked quite well. The problem in this study is they used methotrexate at low doses up to 15 mg. I don't know that triple therapy is better than high-dose methotrexate. I don't think we'll ever see the study. This is another trial. In this trial they used combination therapy along with corticosteroids versus corticosteroids and sulfasalazine. It was actually quadruple therapy versus sulfasalazine, plus or minus cortisone. You didn't have to add cortisone. The results were very good. The combination therapy was excellent. The problem is their comparator was sulfasalazine and I'm not sure this combination is any better than high-dose methotrexate. There is step-down. The key trial for step-down was the COBRA trial (comparison of combined step-down prednisolone, methotrexate and sulfasalazine with sulfasalazine alone in early rheumatoid arthritis). It was high-dose steroids for a short period of time and then eventually tapered off. They used a methotrexate combination, and a sulfasalazine combination. All triple therapy was compared with sulfasalazine alone. Notice the clinical results. Patients on triple therapy did extremely well until you stopped the prednisone. Then they came back to the baseline. They came back to what sulfasalazine alone looked like. After you dropped the steroids, they looked clinically alike. The only difference was a significant difference in the radiologic outcomes when you added low-dose methotrexate along with sulfasalazine, and the prednisone versus sulfasalazine alone. This is triple therapy slowing progression relative to sulfasalazine. At 1 year, the patients on sulfasalazine were allowed to go onto any therapy they wanted. Over the next 5 years, those patients on sulfasalazine never caught up. That may have to do with the DMARDs they went on, but the sulfasalazine group never caught up to the triple-therapy group. At this point, remember, you're only on sulfasalazine. You've already stopped the prednisone and the methotrexate. It's an interesting concept that with early aggressive therapy, tapering off "the bad guys," and leaving a simple drug on, you may end up with a significant difference radiologically. Biologic therapy says that if you fail methotrexate and you add a disease modifier, like a biologic, you have good data. There are good ACR 20s and 50s in combination: etanercept versus methotrexate. With infliximab you have to use methotrexate, good data. Anakinra (Kineret) just came on the market recently. What you see, again, are reasonable data. These time courses are a little different. You can't compare study with study but, in general, it says if doctors add a biologic to those patients partially responsive to methotrexate, they have additional clinical benefit. This is not a positively established fact. In these trials, you never had the biologic arm alone. You had the methotrexate arm. You had the combination arm. But, you never had the biologic arm. How do doctors know that you really need methotrexate? There is an uncanny concept with the ACR 20 outcomes. If you used etanercept as monotherapy, the ACR 20 was 60. If you used it and added methotrexate, the ACR 20 outcome was 71, not very different. Leflunomide as monotherapy, the ACR 20 outcome was 46. In those patients who were partially responsive to methotrexate, it was 46. If you look at anakinra (Kineret), it was 38 by monotherapy, and adding methotrexate, it was 37. You've got to wonder whether you really needed the methotrexate if those numbers look alike. Those are the data. It's food for thought. What's new? Scientists have made great gains in terms of the clinical and radiological outcomes with tumor necrosis factor (TNF) antagonists. The new agent to come out in terms of TNF-Humira (Adalimumab). This is a fully human anti-TNF monoclonal antibody with a half-life of about 2 weeks. It fixes complement. It's able to use cells,like infliximab. It kills those cells that actually make TNF. It was given subcutaneously once a week as monotherapy. The results were quite good. The ACR 20s were comparable to anything else we've seen, around 55%. The ACR 20s were about 25% or 30%. That is good. This is once-weekly subcutaneous administration in a severe population of patients. What happens if I have a partial response patient population on methotrexate? Using an average dose of about 16.8 mg, patient disease duration was 12.3 years. What happens when you add subcutaneous Humira (DE 27-formerly )every second week in those patients who were partially responsive? ACR 20 is about 65%. Reasonable. ACR 50 at the 40-mg dose was quite high at 53%, and ACR 20 was 26.9%. This value was higher than we see in most studies, but the 80-mg dose was slightly less, in terms of efficacy, than the 40-mg for reasons that are unclear. This study was not powered to tell the difference between doses, so we still don't know what the minimally effective dose is. At least we can say there is good benefit if you give subcutaneous D2E7 every second week. Cortisone is such an important drug that we have, but it needs to be used very carefully because it can cause a lot of problems. Using intermittent injections of cortisone into the joints can be a real godsend and can really improve people's function. For example, if someone's shoulder is limited in its ability to move, an injection of cortisone in the shoulder can provide rapid relief that can really provide benefits while you're waiting for the disease modifying drugs to take effect. Gold is an old treatment, and in some ways that's really nice because physicians know a lot about it. They know what's good about it, and the bad about it. It is an effective treatment in about 55 percent of people who use gold. Gold suppresses the disease partially, but it's very slow. You need to use it with weekly injections for 20 weeks often to see clinical benefit. And sometimes people can have problems with rash or low blood counts. Others can have oral sores or even problems with protein or blood leaking from the kidneys. While gold can be used safely and there may be particular patients that's a really good drug to use, it is something that is sometimes a troublesome drug, too. One of the problems with gold is that patients and doctors do have to wait often the 20 weeks or more to make a decision whether this is an appropriate therapy, and also,may have lost six months of ability to treat the patients. Gold is probably not a very good first choice of a second-line agent or of a disease modifying drug unless there's some reason that the physician didn't want to use methotrexate. Patients has to get a urine test and a blood test once a week to be sure that they don't have the kidney and bone marrow troubles that some patients have. Methotrexate is actually a therapy that's been around for a very long time. It was used for cancer patients, and it's been used in rheumatoid arthritis for well over 20 years now. The way it actually works is still not perfectly clear. Physicians know it works by decreasing inflammation, but it also works by decreasing immune cells. A very large study that was published in 1999 showed that, finally, that it is not only a medicine that makes the patients' signs and symptoms or their joint pain and swelling better, but it slows the x-ray progression down, so it truly is one of our medicines that modifies the disease. With reference to side effects,it's important also to understand that there are risks with not treating rheumatoid arthritis,that's the perspective or the frame in which you've got to look at the possible risks of methotrexate. Methotrexate is very well tolerated by most people, and even in relatively high doses, more than 85 percent of people will be able to continue it for at least a year. The other signs of its safety is that at five years, more people tend to stay on methotrexate than any other drug. It's important to note that generally it is very well tolerated by most people. There are two types of side effects. One is the relatively common kind of minor side effects. Occasionally people are a little tired or may have a little bit of nauseousness or loose stools after they take their weekly dose. And then there are probably the less common or more sporadic type of problems which can be more serious, which are methotrexate-associated serious liver scarring, which occurs approximately in one in 1000 people who take it for five years, or serious lung scarring which can occur in around one and a half or two percent of people. Methotrexate can be administered either by pill, which is the most common way that it's used in the United States, but it also can be administered by injection. The injections offer possibly a little more safety, a little more regulation of the dose, and in higher doses doctor's are able to have to switch their patients to injectable methotrexate. Leflunomide ( Arava ) is a drug which is similar in some ways to methotrexate in that it impairs the ability of inflammatory cells to reproduce rapidly. It is a bit expensive, about 280 dollars a month, and so that's actually somewhat of a barrier to people who don't have health insurance, but it is generally well tolerated by people. The side effect seen most commonly is loose stools associated with it, but for most people that's not too much of a problem. It has some benefits in that it does seem to have some benefit within the first six to eight weeks of use, and it appears that its ability to suppress swelling and pain and to prevent joint damage is perhaps close to or similar to methotrexate. It would be an alternative to patients who either did not respond or could not take methotrexate. Plaquenil has been used for a long time, and there are some really nice features about it which doctors include that it really doesn't need frequent blood monitoring, and it does not have a significant toxicity to liver. However, at least in patients with recent-onset rheumatoid arthritis, there has never been a published study that has shown that it slows or prevents joint damage. Therefore,for someone who has significant and functionally limiting rheumatoid arthritis, Plaquenil is not a good first choice. And also I think the fact that it does take many months to see a response, we may lose our window of opportunity. In Europe and outside of the United States, sulfasalazine is very commonly used. It's less commonly used in the United States. Sulfasalazine can be a very helpful drug. It is relatively inexpensive. The mode of onset is not as fast as methotrexate, but certainly faster than gold. The side effect profile, unless it causes stomach upset, is generally pretty good. In the research studied, it may not be as effective as methotrexate or leflunomide, but it is certainly an effective treatment. For some people, it is a very useful drug. In people with the most severe arthritis, though, again that a faster-acting and more potent drug would be a choice of physicians. D-Penicillamine, is rarely used now,especially with the newer drugs available. With the advent of the biologics, doctors don't need to use it because it is a troublesome medicine. Now that we have a number of better-tolerated, faster and more effective treatments, these are clearly treatments physicians don't use as often. Azathioprine is a drug that is effective to some degree in reducing joint swelling and pain. The data supporting the idea that it prevents joint damage is really not as robust, and it's really quite slow. It's largely been supplanted in its place by Arava. Treatment with cyclophosphamide was tested in the '60s, late '60s, early '70s, and it's certainly a very potent agent, but unfortunately it does carry with it a substantial risk of developing leukemia in the ten years after being treated with it. Cyclophosphamide really is not,or rarily used for rheumatoid arthritis. Summary: In someone who has either very mild rheumatoid arthritis or maybe you're not sure it's rheumatoid, rheumatologists might consider Plaquenil early, but choices such as sulfasalazine, Arava or methotrexate would be their first choices. Biologics: Enbrel, which is etanercept, and infliximab, the trade name is Remicade. They both are targeted towards the inflammatory messenger called TNF or tumor necrosis factor, and these are similar in many ways. Enbrel is actually the receptor that TNF binds to on the inflammatory cell, and research-scietists figured out how to make that little receptor and how to help it circulate in the blood, and so what it acts as a sponge to take this out of circulation. Infliximab or Remicade is a little different in that instead of just a receptor floating around, infliximab is an antibody, and that is it binds specifically to TNF and "kills" or eliminates it out of the blood. With Enbrel individuals can administer that to themselves, and so that gives them a measure of control and independence. It's also not really associated with a meaningful immune response, so it can be taken all by itself. Remicade is a little different in that it needs to be given as an intravenous treatment, and because one third of Remicade comes from a mouse, they have to take a drug like methotrexate with it to suppress making anti-mouse antibodies Currently,these drugs are limited because of cost and the requirements are that patients if they fail on an initial agent such as methotrexate need to be considered for a biologic,unless one has private health coverage and most plans have the same limitations. Infliximab or Remicade, because of the mouse protein in it, one has to continue the methotrexate whereas with Enbrel or etanercept, it can be used as a single agent with very good success. The other important point is that not all of these medicines work for every patient, and rheumatologists have to make decisions which are go, no-go decisions whether this is the right medicine and the right dose of medicine for the patient. Being on one of these medications is not enough. The rheumatologist and the physician taking care of the patient has to make a decision whether it's really doing the job that it needs to be done. Therefore,rheumatologists will look at the patient's joints and they'll do a joint count so they find out how many of the joints are tender and how many are swollen, and they will follow x-rays on a periodic basis to be sure that there is no damage that's progressing to make decisions whether or not this is an effective medicine, whether it be a biologic such as Enbrel or a synthetic such as methotrexate. One of the things that we as a society have to come to grips with is that the cost of biologics is much more than methotrexate is. And so, while there are individuals that without any question should be started on the biologics first, like people with significant liver disease or someone who has moderately severe kidney disease, in most individuals who do not have those processes, probably an initial trial of a potent disease-modifying pharmaceutical like methotrexate is probably from a financial standpoint the most sensible thing, and probably from a society stand. The actual cost of the biologics is higher than methotrexate. Also, many of the patients with rheumatoid arthritis often come already on methotrexate. Many internal medicine doctors have already started them on methotrexate, and a decision needs to be made is that the right medicine and if so, is it the right dose, and often it's too low, and one pushes the dose. A comparative study has been shown that higher doses of methotrexate work better. This is a very individual decision with the patient and the physician. But what doctors would focus the most on isn't necessary what is the first drug that is used but that these biologics are not something that should be saved until there are no other options. These are drugs that should be used easily in the first six months to a year of disease if traditional therapies don't very effectively suppress the arthritis. People should not wait because, the pace and the progression of joint damage is a continuous and rapid process, and if we can in a rapid fashion suppress people's disease,and over many years will reduce the amount of joint damage which should translate into better work, better health, and better social function. The new COX-2 selective non-steroidal anti-inflammatory drugs (NSAID's) include rofecoxib (Vioxx) and celecoxib (Celebrex). They differ from the regular NSAID's because they are associated with a lower incidence of peptic ulcers and their complications and they do not inhibit platelets to prolong bleeding. They are as equally effective as the regular NSAID's for arthritis and pain-killing. Recently, it has been suggested that these new COX-2 NSAID's (coxibs) may increase the chances of developing heart attacks and strokes. Better studies are needed to address this issue. But what is to be done in the mean time? It seems that these drugs do not pose a problem if you do not have any risk factors for developing a heart attack or stroke. If you do have risk factors for having a heart attack or stroke, then Vioxx may add to this risk whereas Celebrex may not. In the large VIGOR study, 25 per 1000 patients on Vioxx had a cardiovascular event compared to 11 per 1000 patients on naproxen; and 5 per 1000 patients on Vioxx had a heart attack compared to 1 per 1000 patients on naproxen. In the large CLASS study, there did not appear to be an increase in heart attacks or strokes in patients on Celebrex compared to those on ibuprofen and diclofenac: 13 per 1000 on Celebrex versus 12 per 1000 on ibuprofen and diclofenac. These drugs do not affect the kidneys or blood pressure adversely in those who have no problems with their kidneys or blood pressure. In those that do have such problems, all NSAID's including the coxibs are hazardous. They can worsen the blood pressure, fluid retention (edema and heart failure) and kidney function. Celebrex appears to be no different than ibuprofen and diclofenac in these matters. If you have no risk factors for peptic ulcers, heart attacks or strokes, high blood pressure, fluid retention or kidney disease, then you can use NSAID's or coxibs. If you only have risk factors for peptic ulcers, then use coxibs. If you only have risk factors for heart attacks or strokes, then take NSAID's (naproxen may be one of the best) and probably Celebrex. If you have high blood pressure, fluid retention or kidney disease or use diuretics, then all NSAID's and coxibs could make these problems worse. Try some other treatment if possible. If you have problems in more than one of these groups, then try some other treatment if possible. If not possible, choose the NSAID or coxib of least risk for the the greatest problem that you have. *Note - Vioxx was discontinued by the FDA.