Rheumatoid Arthritis Facts:

Rheumatoid arthritis (RA) is a chronic,delibilitating disease that causes pain stiffness,swelling and loss of function in the joints. Along with painful joints. RA can cause inflammation in other body tissues and organs in some patients. Occasionally people with RA develop inflammation of the membrane that surrounds the heart,and lungs or inflammation of the lung itself. Inflammation of tear glands and salivary glands result in dry eyes and dry mouth. Sometimes RA causes inflammation of the blood vessels,which affects the skin,nerves and other organs. These effects are referred to as extra-articular features of RA. EAF's are more associated with some moderate and severe rheumatoid arthritis patients,but they can occur in all types.

The most common EAF in RA is tenosynovitis. Tenosynovitis is inflamtion of the tendon sheath. Tendons,similr to joints,are often covered with a sheath-like membrane (the synovium). The synovium becomes inflamed and swollen in RA patients. Tenosynovitis occurs most frequently in the hands,but can also occur in wrists,elbows,shoulders,around the knees,and in the feet. Tenosynovitis is typical of RA and helps distinguish it from other types of arthritis,where extra-articular features,usually,are absent.

In patients with moderate or severe types of RA,firm non-tender nodules develop under the skin,particularily in areas subject to pressure such as elbows,feet,or buttocks. These nodules are a hallmark of RA. This may indicate that the more moderate or severe type of RA is present. In such cases,aggressive theapy is indicated. Nodules rarely occur with arthritic diseases other than RA.

The heart may become involved in RA. Inflammation occur most commonly in the pericardium. The pericardium is a sac-like structure that surrounds the heart. The inflammation causes pain and occasionally an increase in fluid,which can compress the heart and impair function. This type of inflammation (pericarditis) can be detected by a simple,ultrasound test Only rarely does RA cause nodules or scarring within the heart walls,arteries,or on the valves of the heart.

With RA,inflammation of the lungs is common. The most common site of inflammation is in the pleurae,which lie between the lungs and the chest cavity. When the lungs are involved,most patients experience pain,particularily when breathing in or breathing out. In other patients,the pleural space,which separates the chest wall and lungs,fills with fluid. Occasionally RA patients develop nodules within the lung tissues,but usually,these do not cause symptoms. Unfortunately,on an x-ray film these tiny nodules may appear to be tiny lung tumors,and usualy,a biopsy or other test must be done to rule out cancer. Occasionally inflammation occurs throughout the lungs. This condition of diffuse inflammation is called fibrosis and leads to lung scarring. Symptoms are shortness of breath and cough. Breathing tests help to confirm a diagnosis of fibrosis.

RA can affect the nervous system. The most common cause arises from compression of nerves. This occurs most frequently in the hands,and is called carpel tunnel syndrome. The carpel tunnel is a narrow shallow tunnel in the wrists through which all of the important nerves,tendons,and blood supply to the hand passes. Inflammation within this narrow tunnel,caused by arthritis or other conditions,create pressure on one of the nerves passing through it,which leads to irritation. Pressure on the nerve results in numbness in the palm of the hand and the second,third,and fourth fingers. Generaly,the numbness in the hands is worst at night. RA can also affect nerves in other parts of the body. If RA causes damage to the joints in the neck,it can lead to bone shifts and compression of the spinal cord or the nerves that exit it. The result is numbness in the legs and arms.

In rare cases,RA can be so wide-spread that it causes inflammation within the lining of the blood vessels. Blood vessel inflammation is called vasculitis. Damage to the blood vessels or their closure can lead to damage in the organs that the blood vessels feed. Vasculitis is serious because it could damage organs such as the kidneys or heart.

RA can affect the eyes,either directly by inflammation,or indirectly by damaging the tear ducts. If the tear ducs are damaged their secreations decrease,and the patient will experience dry eyes,particularily at night. Inflammation of the cornea can cuse distorted vision and sometimes damage the eye.

RA can be difficult to diagnose at onset of disease because it may develop suddenly or begin gradually with subtle symptoms which progressively worsens. Blood tests and X-rays may be initially normal. The disease varies among individuals with respect to symptoms,joints affected, and the nature of other organs involved. Other types of arthritis often mimac RA. There are mild,moderate and severe types of RA. Thirty percent of patients have mid RA Joint function is only slightly decreased. In most patients diagnosed with mild RA,the disease remains mild throughout its course. In some patients,in this group,the disease may have a very short course,but in others,it may recur intermittenly or be constantly present for years with the mild form of RA,damage or deformity is uncommon. The only extra-articular feature is painful inflammation of the tendons (tendonitis).

Skill,often-patience and experience are essential to reach a accurate diagnosis and to arrive at the appropiate treatment. The majority of patients will have to take some form of therapy or medications for the rest of their lives

RA is an inflammatory disease of the synovium,or lining of the joint. The normally thin synovium membrane tissue which is microscopic in nature becomes thick and inflamed and can be felt by a rheumatologist. The synovium becomes inflamed and filled with destructive white blood cells (macrophages,cytokines,etc.,forms the pannus) and debris attacking cartilage and bone. Inflammation most often affects joints of the hands,knees and foot. The disease tends to be symmetrical or polyarticular (occurring equally on left and right sides of the body) this symmetry helps distinguish RA from other types of arthritis.

Rheumatoid arthritis is characterized by the signs of inflammation: pain,swelling,heat,and stiffness. Pain is caused by inflamed cells and chemicals that affect the nerve endings In RA,pain is felt in the joint or with joint movement. Swelling is caused by thickening of the synovial membrane and sometimes by increased fluid or debris within the joint. Increased blood-flow to the inflamed joint results in heat and redness. Stiffness commonly called "morning stiffness",occurs in almost all inflamed joints after a period of disuse. To regain mobility inflamed joints must be loosened up by applying heat or doing exercise.

RA is an autoimmune disease ,the immune system is a complex organization of cells and antibodies designed to "seek and destroy" invaders of the body,particularily bacteria and infections, normally. Patients with autoimmune diseases have antibodies in their blood which target their own tissues,where they can be associated with inflammation. It is a chronic disease that can last for a short period with no outward damage in the case of mild RA.

About 10% of RA patients have a form of RA characterized by marked stiffness which usually leads to abnormal tightness rather then swelling in the small joints of the hands,wrist,shoulders and occasionally,the knees and foot. The joints may look normal. Some of these patients will have difficulty raising their arms above their heads within a matter of weeks. Mobility and day-to-day function will be severely affected in many or these patients. With the exception of inflammation of the tendons. EAF's are rare in this type of RA. If left untreated,loss of function caused by this stiffness can be pronounced and irreversible.

All patients with RA may feel unwell but patients with moderate (30 to 35%} and severe (10 to 15%) are most affected. Like EAF's, the severity of these symptoms help to separate RA from other forms of arthritis Because it can affect mutiple joints and other organs of the body,RA is referred to as a systemic disease.

RA effects will vary with the individual patient,and type of medications will help one patient and do nothing for another. The number and severity of inflamed joints,whether the inflammation is symmetrical gives the doctor of what type of arthritis is present. The presence or absence of EAF's also gives the doctor a hint on the severity of disease present. If deformity or erosive daamage have occurred (not all patients have erosive patterns) are other clues for the type of therapy to be followed.

Some RA patients will have a negative rheumatoid factor (R.F. in the blood) A antinuclear antibody test (ANA) will indicate the presence of inflammation but it is used more for the diagnosis of lupus (patients have different type of ANA). RA cannot be detected by one test or by the physical appearance,usually,a number of tests is done and the whole "Big Picture" is analyzed. E.S.R. or "sed rate" is one of the most often used blood test to check the inflammation rate present but other diseases may also indicate a higher then normal rate. Blood tests are helpful in the diagnosis of RA but the person's medical history examination is equally important. Communication between physician and patient is essential.

Arthritis can be classified either inflammatory or non-inflammatory. Inflammatory arthritis features inflammatory white blood cells in the joint fluid. Forms of inflammatory arthritis include RA,lupus arthritis,psoriatic arthritis,ankylosing spondylitis, and many others. Forms of non-inflammatory arthritis include arthritis of tyroid disease,arthritis after injury and usually osteoarthritis (in some OA patients there are reported signs of inflammatory criteria present in some patients) and many others.

After making a diagnosis,the physician will decide on the severity of RA the patient has, and determine its course. Active or progressive RA must always be treated to stop the progression. To treat early RA (within 3 months) is always preferable,but treatment of all progressive RA,at anytime,is important. When physicians use the term "late" or "already damaged",the implication is that nothing can be done. Nothing could be further from the truth, Rheumatiod arthritis should always be treated,but the earlier,the easier to treat.

After the diagnosis,the physician will prescribe some form of treatment,usually a combination of drugs and supportive therapy. The treatment will take several weeks or months (depending upon medication) before the effects are felt,in many cases. Sometimes therapy will have to be changed or altered At which point,many follow-up and monitoring appointments will be the order of the day. The patient must communicate with the medical team,educate themselves on every aspect of the disease because of the individual charachteristics this disease will display.

Many patients are seen only occasionally,over a period of weeks and months,while trying different drugs. If after an appropriate period of time,the disease does not show signs of control the patient must be referred to a rheumatologist. Some patients will have difficulty more-so then others. This is usually poor for prognosis. The major problem is delay! Delays caused by poor diagnosis,long waiting lists,too short office visits and inappropiate treatment,which further means "the window of opportunity" to control,moderate or severe disease is missed Any type of RA requires appropriate treatment. Persistence and self-education are needed to ensure the patient get prompt and appropiate treatment. The patient must take a major role in therapy management. Moving from disease onset to control.

Management of rheumatoid arthritis involves-the onset of disease-the family physician-the rheumatologist-the institution of disease modifying drugs (DMARDs) ,non-steriodal anti-inflammatory drugs (NSAIDs) and steriodal (corticosteriods) drugs at appropriate periods of disease activity . The patient and doctor must recognize when the therapy is working and when it is not.

There will be periods of time when the patient "feels good" and times when the patient "feels worse". There will likely be times that a patient with RA "feels cured" It is important to understand that the patients who have a complete remission is not common,therefore it is essential that the patient does not stop the treatment regimen established by knowledgeable health care providers. At times,the symptoms will remit and in some cases,the periods may be longer than others. Disability is higher with with 50% being unable to continue employment. Surgery was looked upon as a last resort,but that is changing,with improved surgical techniques.

Research and development is progressing at a speed unforseen in the past and future development of cheaper medication that can be assessable to all patients is the goal of research scientists.

Formal diagnosis of RA require that the case meet at least four of the seven criterias:

• Morning stiffness lasting at least one hour. In fact,even stiffness for more than 30 minutes,strongly suggest inflammatory disease. Alleviation of morning stiffness with activity is a hallmark of inflammatory arthritis. Later in the day continued activated activity may aggravate the problem and exacerbate the pain.
• Swelling in three or more joints,simultaneously.
• Swelling in the hand joints (PIP,MCP,or wrist.)
• Symmetric arthritis-Initially,joints on only one side may be involved but the disease tend to spread to the other parts and side of the body.
• Erosions or decalcifications on x-ray of the hand.
• Subcutaneous rheumatoid nodules Some RA patients will not develop rheumatoid nodules.
• A positive serum rheumatoid factor assay. Some RA patients have a negative R.F.

Several Patterns have been described:

• A spontaneous remission particularily in the seronegative patient (mild RA-usually R.F is negative) within the first 24 months of symptoms (less than 10%).
• Recurrent explosive attacks followed by periods of quiescence,most commonly in the early phase.
• The usual pattern is of persistent and progressive disease that wanes and waxes in intensity.
• Many RA patients develop "secondary osteoarthritis" as a result of the long term ravages of RA.
• The pain of arthritis varies greatly from person to person,for reasons doctors do not understand.
• Medication response is varied among RA patients with similar disease characteristics.

• 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) etc.

• 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.

• 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.

  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. These inflammatory mediators make small capillaries wider and "leakier",permitting more immune cells to flood the area,where they release free radicals and 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. )

  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 thrd-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 to 20 to 25 mg. 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,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 endanger your health or wasre your money on "cures". See a rheumatologist and have him or her treat your disease.There are differences in most RA patients prognosis,effects and form.Build Date: 8/4/02.

Links:...Socks Toxicity And Drugs In RA....Tripod Rheumatoid Arthritis Essentials.....Sock's Rheumatoid Arthritis Links....Inflammatory Arthritis.....Socks Rheumatoid Arthritis Page 1