Rheumatoid arthritis develops when the immune system attacks parts
of the body. It is not clear why the immune system goes awry in rheumatoid arthritis since the disease
is systemic,it may eventually affect other parts of the body besides joints and adversely affect one's health.
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 typically 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.
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. The normally,thin synovial tissue becomes thick and forms a tumour-like tissue called the pannus that contains inflammatory cytokines.
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 such as,stiffness,first thing in the morning. The more obvious symptoms are swollen or deformed joints,reduced movement and pain,occur as the disease progressesses. Early symptoms can be much more subtle. Recent MRI analysis have revealed signs of early erosions occuring as early as 3 months after onset of disease. 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.
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 progresses. A small minority,about one person in ten experiences 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,weakness,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. One person out of five,displays,small bumps,known as rheumatiod nodules that appear under the skin on the
elbows or on other parts of the body (over 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 differntly 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. The feeling of overall weakness and lack of energy are symptoms of some forms of lupus. Fibromyalgia will have muscle,joint pain,fatigue,and morming stiffness,but will not have the physical findings of swelling that physicians see in RA. Lupus arthritis can look like RA,but again,the rheumatologist can differentiate.
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. Some patients may have cross-over of other arthritic disease.
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 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
and symptoms may come and go,the rheumatologist will rely on the patient to keep track of new developments,disease flares and how they respond to various medication therapies.
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.). 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 are a family of Interleukins,involved in the disease process,IL-1 (tends to affect the bone),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.
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. RA may return later,and you may need to start taking NSAIDs again,but for a while,you might 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 for the management of RA, recommends DMARD therapy to all RA patients upon diagnosis. Factors that correlate with prognosis: More favorable factors; Absence of manifestations, outside of joints,absence of rheumatoid factor in the blood and perhaps male gender.
Less favourable prognosis : Rapid onset at a younger 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 ), involvement of 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. Scientists are debating the issue. 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.
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,slowly,(except in Canada)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 starting, 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 to 20 to 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 newer 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,thereafter.
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. 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 relief 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 Naproxen),and add a gastroprotective agent (e.g.,misoprostol cytotec or a proton pump inhibitor). Don't waste your time,money or endanger your health on "cures". See a rheumatologist to treat your disease. There are no short-cuts.*Every RA maybe quite different - effects and form from another. Build Date: 7/10/02.
The subtle early symptoms that might easily be mistaken for other disease include:
In some cases the disease may also involve other areas:
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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