Rheumatoid Arthritis:
Rheumatoid arthritis develops when the immune system which normally protects us from things like viruses and infections attacks parts of the body. It is not clear why The immune system goes awry in rheumatoid arthritis. The disease is systemic, meaning,if the left side of the body is affected,more-then-likely the right side will also be affected,it may eventually affect other parts of the body besides joints (EAFs) and adversely affect one's quality of life. RA is a disease of the synovial membrane while osteoarthritis is a disease of the cartilage. Fortunately new treatments provide options that did not exist before.
One of the distinguishing features of rheumatoid arthritis is the number and types of joints affected. Unlike osteoarthritis,which usually affects one joint at a time,rheumatoid arthritis tends to affect several joints at once. And generally,the same joint on both sides of the body will be affected at the same time. Severity of the disease varies with each patient.
The disease affects only the mobile joints,such as the knee and wrist that enables us to move. Fixed joints are those such as those that connect the bones in the skull. Mobile joints are surrounded by a synovial membrane,a protective covering that produces a slippery substance known as synovial fluid that lubricates the joint and facilitates movement. Most often rheumatoid arthritis affects the ankles, elbows, feet,hands, hips, jaw,knees,neck and shoulders. It tends not to affect the lower spine.
Symptoms of rheumatoid arthritis differ from one person to another. There are certain hallmark signs of the disease. The more obvious symptoms are swollen or deformed joints,reduced movement and pain,occur as the disease progress. Early symptoms can be much more subtle. Recent research has showen that,even as early as a year or two after the onset of disease RA can cause irreversible destruction of joints. Rheumatologists urge primary care physicians and others to stay alert to the early signs of RA. The earlier the treatment begins,the better chance of avoiding disability. Generally,there are three forms of RA;mild,moderate and severe. Rheumatoid arthritis almost always eventually causes joints to become inflamed,making them sore and warm to the touch. The area may swell and turn red. The joints may become painful and hard to move, Although joint inflammation is a hallmark sign of rheumatoid arthritis,it can vary from one person to another. In some people,joint infammation flares up and subsides,only to flare up again. In others, inflammation is always present and may even worsen as the disease progress. Approximately 10% of patients experience a type of RA that is characterized by marked stiffness rather then swelling. This usually leads to abnormal tightness. These patients will have profound mobility problems. A small minority,about one person in ten,experience a single or few episode of joint inflammation and then goes into remission. Also,with progression of the disease,rheumatoid arthritis may also create flu-like symptoms. Listless and weak,run a low-grade fever and have no appetite. In time,this may lead to weight loss and anemia.
Less often,symptoms of RA include inflamed tendons and tingling in the fingers.(carpel tunnel syndrome). One person out of five,will develop small bumps,known as rheumatiod nodules,appear under the skin on the elbows or on other parts of the body (usually over nerve pressure points). Although rare,these bumps may develop anywhere on the body and even internally.
The patient may begin to have trouble with personal management and at work or during a activity. These changes should be mentioned to the rheumatologist. It not only helps him determine the advancement of the disease,but it will
pinpoint activities that one may need to rethink and even learn how to do things in a different manner so one can continue to live a normal life-style.
If the patient have a particularily severe form of rheumatoid arthritis or if the disease has progressed unchecked,the joints may become deformed.
Diagnosis is all the more challenging because RA causes different symptoms in different people. To further complicate the situation,some symptoms, particularily pain and stiffness in the joints,are also symptoms of osteoarthritis and other rheumatic diseases. The feeling of overall weakness and lack of energy mimic symptoms of some forms of lupus. A few patients may develop some characteristics of lupus("rhupus"). Some patients will have the non-erosive type of arthritis with a short course of the disease,while others,will have the progressive x-ray,destructive,and erosive kind that may last for a life-time. To ensure that a diagnosis of RA is accurate,the rheumatologist will order various medical tests to supplement what he/she observes and what the patient have said about the symptoms. The healthcare provider may suggest that you return periodically for in-depth checkups that may involve the same questions and tests. Since RA can vary vary so much from one person to the next,time and reassessment offer valuable perspectives about the course of the disease. Plasma Viscosity,or C-Reactive Protein (CRP): Rheumatoid arthritis cannot be cured but it can be managed and controlled through a combination of wholesome diet, exercise, medication, supplemental therapies and regular monitoring of disease activity by the patient and healthcare professional. Because the disease varies among patients
and symptoms may come and go,the rheumatologist will rely on the patient to keep track of new developments such as disease flares and how they respond to various medication therapies.
DMARDs sometimes take weeks or months to take effect,and they do not interfere with basic pain mechanisms,as NSAIDs and analgesics do. And yet DMARDs do eventually reduce pain,sometimes more effectively than NSAIDs,because they act on the underlying problem of inflammation that causes pain in the first place. DMARDs are generally used in conjunction with NSAID treatment. Rheumatologists are now using combination DMARD therapy.and are studying ways that best benefits the patient. There is a new class of Biologic medications like Embrel,Remicade(TNF inhibitors)and Kineret (IL-1 inhibitor ) available but the cost factor limits broad useage. Biologics are not for everyone.
One research-scientist has called macrophages the "messenger" of the immune system. They sound an alert and wait for the immune system troops to arrive. It is a war going on in our bodies. Immune system sentries known as helper T cells are the first to respond. They assess the situation and decide what type of immune system soldier should be called to the scene. At this stage there are no symptoms. The immune response escalates: Now that the immune system has recognized a foreign invader,it initiates a cascade of events meant to ensure that the invader is destroyed.
The helper T cells call for the soldiers. There are two broad categories of soldiers in the immune system:killer T cells,which can attack an enemy head-on,and B lymphocytes,which manufacture and release antibodies specifically designed to home in on and destroy the foreign invader. Meanwhile,other changes take place to enable additional immune system cells to reach the area. The macrophages(white blood cells) which originally helped sound the alert about the invader,now help new blood vessels to form. They are assisted by hormone-like substances called cytokines (they have a good part and a bad side),which enhance and amplify the process of inflammation that has now begun. Other immune system cells (billions) that are circulating elsewhere in the body home in on the joint,attracted by all the commotion. (simplified analogy) these cells start to accumulate in the synovial membrane surrounding the joint.
Meanwhile,other immune system cells known as neutrophils,aanother type of white blood cell,begin to accumulate in the synovial fluid that fills the joint cavity. Neutrophils exist as a type of cleanup mechanism at the site of infection,they consume the debris of an immune system assault and any other unwanted particles or bacteria. They do this by releasing digestive substances known as lysosomal enzymes that break down and dissolve their targets.
At the same time another component of the immune system known as the complement system is activated. this unleashes proteins that further speed the destruction of foreign particles by antibodies. In some ways it sounds like a war is going on. In RA for reasons that is still unclear,the attack not only continues beyond the original goal of destroying virus and bacteria but also escalates. As many as a billion neutrphils may be circulating in the synovial fluid of the knee that is moderately inflamed. The enzymes they release,once directed at a foreign invader,start to attack healthy cartilage and ligaments.
By this time,you are quite aware that something is wrong in your body. You might feel stiff upon awakening,and it may take as much as an hour or more to limber up (some patients claim it never eases up),for some people,increased fatigue. If it continues without treatment.--loss of mobility,visible swelling of the joint. Unchecked joints may become deformed, or even become disabled. Immune cells initiate and control the inflammatory process in part by releasing messenger proteins called cytokines (e.g.,interleukins and tumor necrosis factors ),which act like distress signals to all relevant immune cells. Specifically, cytokines tells other immune cells to initiate "cascade" reactions that yield hormone-like chemicals called inflammatory mediators.
In RA,the inflammatory mediators that immune cells release in response to cytokine "messengers" include histamine,leukotrienes,and certain prostaglandins. There are different prostaglandins in the body. These inflammatory mediators make small capillaries wider and "leakier",permitting more immune cells to flood the area,where they release enzymes that dissolve connective tissues. Normally,inflammation is an appropiate immune response to injury or infection. But RA is charachterized by a ungovernable,ongoing inflammation. We know that when synovial fluid contains high levels of cytokines,collagen damage and the risk of arthritis is increased-and the cells that send the first inflammatory messages,via release of cytokines,may be distant from joint tissue. We also know that damage to the synovial capsule corresponds to abnormally low levels of antioxidant molecules,including certain enzymes. Furthermore, damage to collagen correlates with high level os inflammatory messenger molecules in synovial fluid (e.g., tumor necrosis factor-alpha,interleukin-1 etc. )
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. Less favourable prognosis : Possibly,rapid onset at a young age,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. Two decades ago,the typical RA patient was kept on NSAID therapy until they showed evidence of joint damage or increased disease activity. During the last 10 to 15 years,however,rheumatologists have become more aggressive about starting DMARDs much earlier in the course of the disease. The principle agents used are hydroxychloroquine (HCQ),sulfasalazine (SSZ),and methotrexate (MTX). Gold salts while still available,are not often utilized,especially in their oral form. D-penicillamine has fallen out of favor,predominantly because of its side effects. Other medications, such as cyclosporine,are generally reserved for combination therapy or refractory disease.
During the last 5 years,our therapeutic options increased significantly. The introduction of leflunomide (Arava),a pyrimidine synthesis inhibitor (suppresses cells that are rapidly dividing),has provided an alternative for patients who cannot tolerate methotrexate or provide another option. Etanercept (Enbrel),a fusion protein that interrupts the inflammatory cascade by binding to tumour necrosis factor (TNF)-alpha,can be used in early disease or when conventional therapy do not work (limited by cost factor and insurance coverage). Another TNF-alpha inhibitor, infliximab (Remicade),would probably work very well in early disease,but currently its use is limited to refractory (people who do not respond to conventional therapy) cases,in which it is given in combination with traditional medications such as MTX (high cost).
Recently (2003)another TNF-alpha inhibitor Formerly known as DE27,now called Humira has been approved by the FDA for RA therapy. In the U.S.,the manufacturer,Abott Laboratory has introduced a promotional aspect to senior citizens on medicare whereby the drug is offered,free of charge. The manufacturer estimates it will cost them 30 million per annum.
Kineret is a Il-1ra (interleukin family)inhibitor introduced in early 2002. It can be used with MTX,but currently, combination with other TNF inhibitor is not recommended because of recent poor clinical trials results. Researchers believe the serious side effects may be dose related and scientists are working on the problem. It is a useful additional biologic when another therapy fails.
Both Remicade and Enbrel improve function,and there is good evidence they slow radiographic progression of RA(Arava also,but Arava ,a DMARD,might be more suitable for patients that cannot tolerate MTX). This would argue for both etanercept and infliximab use early in the disease,especially in patients who seem likely to have a aggressive or a destructive course.
Traditional disease-modifying agents can also slow radioraphic progression,however,and they are much less expensive then the newer agents. Consequenty,governments (provincial health plans have different guidelines in different provinces in Canada) and third-party payers impose restrictions on the use of the new biologic drugs. They may stipulate that patients must first be unresposive to as many as three traditional agents before they will pay for treatment with a TNF-alpha inhibitor.
These restrictions are being relaxed somewhat,slowly,as evidence of the new agents, efficacy and safety accumulates. Enbrel recently released a 5 year safety data,but drugs like methotrexate (what to expect-side effects-safety)-has a long track record.
For physicians whose choice of initial therapy is limited to traditional agents,the first question is whether to start with a single agent or combination therapy. Possible combinations include HCQ with SSZ or MTX,SSZ with MTX,or all three together. The choice of initial therapy can be a difficult one. They do not want to administer more medication than is necessary,yet we want to be aggressive enough to improve function and prevent the development of radiographic destruction,therby ultimately minimzing functional impairement and keeping down the long-term cost of care.
At present the most common strategy is to start with methotrexate alone. However,to minimize the risk of hepatoxicity, the patient must agree not to consume alcohol (or to do so only very modestly). If a patient is not tolerant to MTX,Arava can be tried.
Most rheumatologists choose not to start treatment with HCQ monotheraphy (single),except perhaps in patients with mild disease. Physicians are beginnining to use,more and more,use of HCQ in combination with MTX or SSZ,then in the past. Another alternative would be to start with SSZ alone,but the approach is less common (increasing) in North America than in Europe.
In the past a typical RA patient's MTX doseage (7.5 mg orally once a week) would have been titrated up slowly over six months or even a year. Now rheumatologists tend to move much faster,starting with up to 10 mg per week and taking dose to as 20-25 mg a week within the first two to three months. In 1998 a clinical trial was conducted with subcutaneous MTX injection with a equivalent dose of 25 mg and they found it more efficacious on patients,along with less accompaning side effects. Faster dose escalation requires more frequent follow-ups. Some physicians will try another approach. But they all look for abnormalities on liver function tests,mouth sores or ulcerations,significant fatigue,nausea,or discomfort during the first 24 hours after taking the drug. Patients are asked to return two weeks (more or less)after first taking the drug,at which point the dose may be increased to 12.5 mg. Then they usually,return within four weeks. If they have had not a good response,the dose might be increased to 15 mg-17.5 mg. Four weeks after that,if patients still have not responded well enough,the dose may be increased, further,to 20 - 25mg. But at that point,more than likely, subcutaneous injection of MTX will be introduced. Clinical trials suggest that about 50 % of patients respond to methotrexate monotheraphy. Unfortunately,the average degree of improvement tends to be about 25 %. For example,the number of tender or swollen joints may decrease from 20 to 16,but there are always exceptions to the rule. A few years ago,monotherapy was usually continued for six months to a year,and patients who had not responded might be switched to another drug. Today,if patients do not respond sufficiently to a adequate dose of medication, another DMARDs-HCQ,SSZ,or (if possible) Enbrel,Remicade,or Arava. Arava is the least-cost wise of the new drugs,but is less efficacious of the other two-Enbrel and Remicade. Arava can stay in the body for up to 2 years after discontinuation of the drug A loading dose of 300 mg is given,100 mg for the first three day,at the start,and given in 10 or 20 mg ,tablet form, there after. The physician might consider switching to one of the newer agents,but if the patient has shown some improvement and has not been troubled by side effects, most rheumatologists will add rather then switch. HCQ can be added at a doseage of 400 mg once a day or 200 mg twice a day. SSZ is usually added at a doseage of 500 mg once or twice a day,escalating to a total dose of 1 gm twice a day. The escalation schedule traditionally recommended is for the patient to take one tablet a day for the first week,one tablet twice a day for the second week,one in the morning and two in the evening during the third week,one in the morning and two in the evening during the third week,and two tablets twice a day during the fourth week and thereafter. For patients on combination therapy,physicians generally follow the same schedule for toxicity monitoring as with methotrexate, They obtain a complete blood count and liver function test and look for myelosuppression. The other medications do not need to be monitored as frequently as methotrexate,but since the patient is in the office anyway,all the monitoring can be done at the same time.
If combination therapy does not produce substantial impprovement within three months,the physician has a good clinical basis to move to biologic (anticytokine) therapy,and hope there should be little difficulty in convincing a third party payer of the necessity of using these agents.
If a patient responds well to DMARD treatment,the physician should eventually think about reducing doseage or withdrawing the agents one by one-if possible. The goal is to provide just enough therapy to keep the disease under control, which drug is kept for maintenance purposes will depend on the rheumatologist and the patient.
Patients must undestand that current treatments can provide significant improvement,but complete remission is unlikely. Patients need to learn the importance of avoiding trauma or stress in involved joints and of physical and occupational therapy to improve structures around the joints to decrease pain and improve function Education about the disease and medication is also vital Patients need to know the potential complications and toxicities of the drugs they are taking. They must be aware that some DMARDs take time to display their benefits,and be aware of a drug ,once efficacious,has become less effective. The bridge is usually low-dose glucocorticoid therapy (e.g.,up to 7.5 mg of predisone/daily).
Many RA patients are at risk of gastrointestinal complications from standard non-steriod drugs (NSAIDs). These patients tend to be older,have existing diseases such as diabetes,kidney,liver etc., and take glucocortoids and they may or may not have a history of coronary artery disease. The cyclooxygenase (Cox-2) inhibitors ,since they appear to have a lower risk of gastrointestinal toxicity. The improved safety of these drugs shoud not be assumed to imply improved efficacy. No NSAID alone can alter the course of RA,they do not change radiographic progression or slow joint destruction For that reason,they should be used as adjuncts,never as monotheraphy. If a patient has heart problems, selection of NSAID may be important and that also applies to others, existing disease present,must be fully recognized and adjustments made in therapy.
With chronic treatment with aspirin or an regular NSAID (in some existing disease conditions,it may be necessary to use a standard NSAID like Naprosyn),and add a gastroprotective agent (e.g.,misoprostol (cytotec) or a proton pump inhibitor).There are no "cures" or short-cuts in treating your disease. See a rheumatologist. DMARD (Disease Modifying and Control)therapy is essential in RA. There are differences in effects and form in most RA patients. *Note: Disregard any reference to Vioxx (NSAID) which was taken off the market by the FDA because blood pressure rose,resulting in fatality in some patients.* All sites Build Date: 7/16/02
The subtle early symptoms that might easily be mistaken for other disease include:
In some cases the disease may also involve other areas;Extra-articular features of RA (EAFs):
To determine whether the symptoms are signs of RA or something else,the rheumatologist will look at the following:
Blood;X Ray;Tests:DMARDs,NSAIDs and Corticosteriods are the three main types of medicine used in therapy:
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