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.

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 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.