RA Disease Process leading to RA begins in the synovium the soft, membrane(synovial lining or intimal layer)that surrounds
a joint and creates a protective sac. This sac is filled with lubricating liquid,the synovial fluid.
In addition to cushioning joints,this fluid supplies nutrients and oxygen to cartridge,a slippery tissue that coats the
end of bones.
Cartridge is composed primarily of type II collagen, (and proteoglycans) the structural protein in the body, which forms
a mesh to give support and flexibility to joints.
In RA,its integrity,resilence and water content are all impaired. This appears to be due to elaboration of proteolytic
enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Polymorphonuclear leukocytes
in the synovial fluid may also contribute to this degradative process.
Bone; Composed primarily of type 1 collagen,invading synovium causes erosions of contiguous bone via release of prostaglandins
and proteases by synovial cells and possibly,by osteoclasts.
Synovial Cavity; Normally only a "potential" space with 1-2 ml of highly viscous (due to hyaluronic acid) fluid with
few cells. In RA,large collections of fluid ("effusions") occur which are,in effect,filtrates of plasma (and,therefore, exudative-i.e.,high
protein content).
The synovial fluid is highly inflammatory. However,unlike the rheumatoid synovial tissue that is infiltrated with lymphocytes
and macrophages but not neutrphils,the predominent cell in the synovial fluid is the neutrophil.
Subintimal area of the synovium; This is where the synovial blood vessels are located,this area normally has very few
cells.
In RA however,the subintimal area is heavily infilterated with inflammatory cells,including T and B lymphocytes,macrophages
and mast cells. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenenesis).
In RA,an abnormal immune system produces destructive molecules that causes continuing inflammation of the synovium. Collegen
is gradually destroyed, narrowing the joint space and eventually damaging bone.
If the disease develops into a form called progressive RA,destruction to the cartridge accelerates fluid and immune system
cells accumulate in the synovium to produce a pannus,a growth compound of thickened synovial tissue.
The pannus can be thought of as a tumor-like tissue(although mitotic figures are rare and,of course,metastasis does not
occur) produces more enzyme that destroy nearby cartridge, aggravating the area and attracting more inflammmatory white
cells, thereby escalating the process
This inflammatory process not only affects cartridge and bones but can also harm organs in other parts of the body--it
is part of the 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 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 activated and causes marked inflammation of the synovial memberane-the
thin synovial membrane becomes inflamed and filled with cells called lymphocytes, macrophages, polymorphs,and fibroblasts
(cytokines)--pannus. This process does not occur in O.A.
The normally thin synovial membrane which normally is only 1-3 cell layer thick. In RA,this lining is greatly hypertropied
(8-10 cell layer thick). Primary cell populations in this layer are fibroblasts (primitave white blood cells) and macrophages.
This layer can be felt by a arthritis specialist who are trained to feel this manifestation. It becomes squishy like
"bread-dough".
As RA progresses,these abnormal cells begin to invade and destroy the cartilage and bone within the joint. The surrounding
muscles, ligaments, and tendons that support and stabilize the joint become weak,and unable to work normally. All of these
effects lead to the pain and deformities often seen in RA.
The inflammation is called synovitis,and it results in the warmth, redness, swelling, and pain that are typical symptoms
of RA. During the inflammation process,the cells of the synovium grow and divide abnormally,making the normally thin synovium
thick and resulting in a joint that is swollen and puffy to the touch.
Normal synovium lines,and is anchored to,both sides of the joint. The hypertrophied rheumatoid synovium begins its invasion
of bone at these sites of attachment and this is seen radiographically as erosion, the height of cartilage is progressively
and symmetrically reduced, consistent with a degradative process from exposure to synovial fluid (neutrophil mediated)
or within cartilage (chondrocyte mediated).
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 rest or disuse.
This is particularily common in RA.
Morning stiffness can last from a few hours to all day long. To regain normal mobility inflamed joints must be loosened
up by applying heat or doing exercise.
Many of the drugs used to to fight RA have anti-bacterial and/or anti-immune activity.Although we do not know the cause
of RA,joint damage is caused by inflammation in the synovial membrane.
RA is the most significant treatable cause of disability in the Western world. If left untreated,RA may lead to serious
damage and disability.
Fortunately there is a window of opportunity for preventing disability in RA, If the disease is treated early,it can
be controlled in most people.
Effective treatment depends on early recognition,a knowledgeable doctor,and proper treatment. Early treatment can make
a lot of difference in the world,but treatment no matter when,will make a difference.
RA does not affect everyone in the same way. Just as different people have different personalities. Some will have mild-moderate
and some severe form of the disease.
Historically RA was classified in terms of how it interfered in terms of how it interfered with normal everyday functioning.
Normal function-Mildly limited function-Moderately limited function-Severely limited function (disabled). and by bone
damage caused by the disease that shows up on a x-ray film: Normal bone-Some bone damage-Moderate bone damage-Extensive bone
damage. This classification shows how much damage the inflammation associated with RA has already done, but it does not help
to show how severe or how fast your RA will progress.
The course of RA could be better classified by type: Mild-Moderate-Severe and by its duration (how long it has been present):
Early (less than 2 years)--the best time for treatment.--Progressive-The majority of patients at this stage have intermittent
or steady progression of the disease and need continuing treatment. Controlled- when the symptoms of the disease have subsided
or have been successfully treated.
When determining the type of a patient's RA.the following should be considered:The severity. Is the arthritis mild,moderate
or severe? Is it charachterized more by "stiffening" than by "swelling"?
The features other than those that affect the joints,or extra-articular features.(EAFs): Extra-articular features are
more often present in moderate and severe disease. They are usually absent,in the mild type. The level of rheumatoid factor,an
antibody found in the blood that has known effect in the immune system,is partially related to the severity of RA.
Patients with moderate or severe disease activity usually have much higher levels of the R.F. than people with the mild
form.
However,20% of people with RA,never develop a rheumatoid factor. The HLA -DR4 gene may be important in predicting the
type,the severity, and the future course of RA(mild type usually,do not have it).
Laboratory tests such as C-reactive protein (CRP),which measures inflammation,and the bone density test may also increase
the accuracy of predicting the course of RA--but the tests are not used everday in clinical practise.
In most patients,the type or temperament of RA diagnosed at the onset persists for the entire course of the disease.
However,in some patients,the course does change. This usually happens early in the disease,before the full features of
either moderate or severe RA have developed, making them difficult to distinguish from the mild form of the disease.
Unfortunately,the disease most often "comes in quitely and goes out with a roar". The opposite is rarely true.
It is uncommon for moderate or severe disease to become mild without treatment.
Rheumatoid arthritis is an inflammatory disease as opposed to non inflammatory osteoarthritis. RA causes joints to swell,they
become stiff,they become very sore.
To have a inflammatory respose is quite normal. If we cut ourselves,have surgery,there will be some redness, some swelling
about the areas, an that's quite a normal part of the healing response.
But in people who have rheumatoid arthritis, something has gone awry and that inflammatory response starts for unknown
reasons,and it continues,it doesn't go away.
It stays day in and day out. And then instead of that inflammatory response helping to heal,this actually can cause harm
in the body.
Scientists have learned a lot about the inflammation in rheumatoid arthrits in the last several years.
They don't know what triggers it to begin it,but they have learned a lot about what happens.
They have learned a lot about the cells that are involved,a lot of immune cells;cells called T-cells,macrophages,B-cells,and
they have learned a lot about their function and see that they are in many cases overactive and actually responding as they
would initially in an acute inflammatory response,where there has been some injury to the body and then they see that they
just keep going.
They have learned a lot about,how the inflammatory cells talk to each other and interact with each other,and about certain
triggers that may activate them.
They have learned in the inflammatory response a lot about the cascade of events that happens,and they know a lot about
the players in that cascade, cytokines or proteins.
They have learned a lot about what causes damages to the joints as far as what they have learned about enzymes,proteins
that can help to cause some destruction. And these are often released in response to inflammation.
Scientists still,don't exactly know what triggered the inflammatory response.
We have learned that rheumatoid arthritis is not just a benign process that causes the joints to hurt.
We know,now,that RA is a disease that causes a fair amount of damage to joints,and it can start causing that damage
within the first couple of years.
We know that there are certain patients who may respond better to very aggressive treatment early on.
We have learned a lot about markers and the individual patient to help us profile patients,as to who is going to have
more severe disease,or who is going to have a more slow,not as damaging or disabling course.
What you are starting to see with some of our newer therapies is that knowledge learned is starting to translate into
earlier treatment of disease,more aggressive treatment of the disease early on in the course.
We are starting to see therapies that reflect our knowledge about inflammation and the various players and how we can
interact in a different way with those players in the immune and inflammatory response than that we have in the past,and hopefully
get a better outcome.
The newest category of medications that are currently used are drugs that inhibit cytokinesis. Cytokines are the proteins
that cells use to signal from one to another.
Now,scientists have a better understanding of those signals,so they can understand which ones they want to turn off to
try to shut the process down.
One of the most important seems to be is a cytokine called TNF-tumour necrosis factor, and they are beginning to (find)
drugs now that can block the signallying, that blocks the TNF from getting from one cell to another where it's supposed to
be going.
Enbrel or etanercept is a viable receptor for TNF--essentially it soaks up excess TNF in the joints between the cells,prevents
it from getting to the cells that it's trying to reach and in the process slows down or shuts down the inflammatory process
in the cells.
The outcome of that is reduced inflammation,reduced pain,and hopefully reduced damage to the joints in the long run.
Remicade(infliximab) uses another method of blocking TNF(produces antibodies against TNF).
There is another cytokine called interleukin-1,which works in a similar fashion in the inflammatory process. Kineret
or anakinra is the drug recently approved by the FDA to target interleukin-1. Kineret may be more suited as a additive to
another drug used in therapy,such as MTX.
In Remicade's case scientists were able to engineer a TNF antibody through genetric engineering. An agent that cling
onto TNF.
They have taken TNF inject into animals (mouse) to make a antibody against it,purify,humanize and infuse it into the
body. Remicade will bind to TNF irreversibly. Once bound,it permanently disables TNF. It is given as a intravenous infusion,or
IV every 8 weeks.
Enbrel also binds to TNF but it binds to it reversibly.TNF will bind and unbind,or disassociate from Enbrel.
Remicade resides in the blood longer than Enbrel Also Remicade binds to TNF only.Enbrel is administered by an injection under
the skin,and is given twice a week(subcutaneous injection).
Remicade is referred to as a monoclonal antibody. Enbrel utilizes the receptor for TNF to block ("sop-up" excessive TNF)
its biologic activity.The objective for both drugs is to inhibit TNF.
The antimalarial agent hydroxychloroquine and cloroquine have been used since the 1950s to treat inflammatory disorders,including
systemic lupus and rheumatoid arthritis.
Soon after their introduction for chronic use, concerns rose about their ocular safety. The first report formally linking
chloroquine to retinopathy appeared in The Lancet in 1959 and has been followed by many others describing choloroquine-associated
toxic effects on the eye. Reversible deposition of chloroquine salts in the cornea is common,but the most serious ocular effect
is irreversible retinopathy charachterized by a "bulls-eye" maculopathy with paracentral or centre visual-field scotomata.
Early detection by opthalmological examination is critical because cessation of treatment generally arrest progression
of the retinopathy. On the basis of these points therapeutic regimens emphasising low daily doses and regular ophthalmoligical
monitoring have been suggested for both chloroquine and hydroxychloroquine (HCQ).
However,confusion about the risks of HCQ has resulted from the failure by early researcher- investigators to distinguish
between HCQ and chloroquine when reporting ocular toxicity,and this has led to the longstanding perception that both agents
require equally vigilant opthalmological follow-up . Although the association of chloroquine with retinophathy is now widely
accepted,it is increasingly evident that HCQ is substantially less toxic.
It is clear that the risk of retinopathy among patients receiving appropiate doses of HCQ is vanishingly low, especially
during the first 6-7 years of therapy,and it may equal that of untreated patients. On the basis of existing knowledge, one
recommendation should be that HCQ dose,do not exceed 6.5 mg/kg lean body mass. Ophthalmological monitoring need not be started
until the patience's tolerance of the drug is established and a long therapeutic course is likely.
The drug ;is relatively safe but is not recommended for moderate-severe therapy regimen in RA patients in that group
because of the possible,lack of efficacy for those patients. It may be more suitable when the disease course is unknown or
questionable, to ensure some form of DMARD therapy until a more established prognosis has occurred.
Whether HCQ provides joint protection is unclear,some experts claim it does,others differ. Clinical trials up to now
have not clarified the point in question.
Sulfasalazine has been used more in Europe. Although its mechanism of action is unknown, studies have shown it controls
RA.
Sulfasalizine begins working after 4 to 6 weeks of therapy,faster than gold or HCQ. It is also well tolerated;the most
frequent side effects are gastrointestinal pains, nausea, malaise, dizziness,and headaches.
However,allergic skin rashes and a decrease in all blood cells do occur. Most side effects occur during the first 3 months
of treatment.
Sulfasalazine is usually taken as a daily dose of 2 to 3 grams. Ideally the dose is increased slowly; 500 mg daily during
week 1; 1000 mg daily during week 2; 1500 mg during week 3;and 2 grams during week 4. Blood test should be scheduled monthly
for the first 3 months; then every 3 months.
In some cases sulfasalizine has been combined successfully with methotrexate and hydroxychloroquine. Since sulfasalizine
may interact with other drugs,review your medicine with the physician Sulfasalazine is a fast-acting,moderately effective,less
toxic DMARD; its beneficial effects may decrease more rapidly then other DMARDs.
Unfortunately RA often gets treated in a uniform manner without consideration of the severity of RA. Each RA suffer is
different. Individual differences must be considered when a treatment plan is devised.
Treatment with drugs singly or in combination, at full therapeutic doses is essential for the best efficacy. Full doses
have the best chance of controlling RA in the majority of patients
Combinations of the three drug types, NSAIDs, DMARDs,and steriods,often work better than a drug used singly,especially
with the moderate and severe types of RA. Aggressive treatments works best.
If one treatment program fails,another should be implemented promply. Each patient have a slightly different response
to inflammation, probably due to our unique genetric makeup,and this may make us less likely to react to various drug groups.
Initial failure with one group tells the doctor little,the experience may affect the patient negatively,stop trying,
or feel discouraged, exactly when an alternative plan should be tried.
It is not sufficient to know how the drugs are used generally in all patients,but to use them specifically in particular
cases.
This is where communication with the physician comes in play. Effective and informative conversation will assist the
MD in determining the course of treatment to pursue.
Recent studies in patients with early RA have shown that combining lower doses of several DMARDs may be better than using
one DMARD at high dose.
Currently evidence suggests that MTX combined with HCQ and/or sulfasalizine may be effective for people who
do not respond to one drug alone. On-going research is been done to help determine the best combination.
Combination therapy is used more in the moderate-severe typ of RA. Biologics are ideal,but the high cost is the limiting
factor.
Mild RA usually starts with NSAIDs or mild DMARDs such as HCQ. Moderates always start wit DMARDs or even combination
DMARDs. Severe RA should always start with DMARDs or a combination.
Most patients with the mild disease will always have the mild form of the disease,and only rarely will they suffer
joint damage. In many mild RA patients is sporadic characterized by flare-ups and subsequent remissions. In mild disease,the
main aim of therapy is to stop the inflammation with the milder,safer drugs,like the NSAIDs,and when required (i.e. during
a flare up),a DMARD.
In the past,most patients with moderate disease eventually developed damage to joints and tissue DMARDs,which can bring
about remission have significantly changed the outcome in most RA patients. Moderate RA,can now usually be controlled,thus
limiting the damage.
Severe RA is the type that has given the reputation as a "crippler". The severe type is usually diagnosed at onset,but
not always. Severe-moderate may regress to another type,but mild normally stays mild.
A patient with the more aggresive disease will require more medical attention and assistence from the health support
team. If DMARDs in combination do not work,the next step is the newer biologic drugs.Confusion on which drugs to use can be
damaging to the patient.
Significant differences between the treatment approach to mild, moderate and severe disease must be considered. NSAIDs,DMARDs
and steriods must be harmonized appropriately.
The patient and the physician must make informed choices as to what is the best treatment in an individual case.
Lack of focus,delay in getting treatment, and slow or inappropriate treatment will seriously undermine the process to
get the disease under control. A disease under control means minimal pain and RA fatigue.
Since the disease can be extremely aggressive, the treatment should be early and aggressive. The outdated practise of
waiting for disease progress then adding DMARDs is gone.
It misses the opportunity of disease control.Holding off till damage or deformity appears is nonsense.
Predisone is a two-edged sword in that,as well as being effective in controlling inflammation, it can cause significant
side effects over time.
If needed,it should be used for the shortest time as possible and the lowest dose for efficacy,with protection from the
possible, resulting effects of osteoporosis.
Protection from ulcers is vital in the case of older NSAIDs. Patients usually assume that if they have no symptoms they
are fine,but this is not true. The first sign may be bleeding.
Use a stomach protectant such as cytotech for older conventional NSAIDs. The newer Cox-2 are designed for stomach protection.
Do not accept arthritis as a diagnosis, since there are over 100 different types of arthritis with various symptoms,outcomes
and different therapies.As one rhuematoligist said "if it talks like a duck,its a duck".
Persistence,despite ongoing disease is essential to limiting the damage and possible disability of RA when it is not
controlled. Unfortunately the terms used to characterize RA are confusing. Terms such as early, late, chronic prolonged,active,intercurrent,
or end-stage are only some of these.
These terms may do not suggest treatment can help. Some patients may consider it hopeless, but RA can be controlled.
The term "progressive",however, means that further treatment is necessary and persistence in treatment is beneficial,and
essential.
Often,extra-articular effects appear later on in the course of the disease when the disease is still,not under control.Once
the disease is controlled EAFs will not appear.
A specialist- rheumatoligist said at the large medical centre in which he works,wheel chair RA patients are rare. He
also said in the past it was not the case.
