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Although both NSAIDs and DMARD agents improve symptoms of active RA,DMARD agent selected should alter the disease
course and improve long term outcome. DMARDs have an effect upon RA that is different upon RA and more delayed in onset than
either NSAIDs or corticosteriod.
Once persistant disease activity (chronic synovitis for 6 weeks or when RA strikes many parts at once) is established,a
DMARD should be considered. The development of erosions or joint-space narrowing on x-rays of the involved joints is
a clear indication for DMARD therapy, however,one should not wait for x-ray changes to occur. A DMARD is usually prescribed
in addition to a NSAID or predisone.
DMARDs target the cells in the immune system causing inflammation but do not reverse permanent joint damage.
From the patient's view,the convience of administration of the drug,the cost requirements of the monitoring program,the time
until expected benefit,the actual benefit of the medication itself,the frequency,and potential seriousness of adverse reactions
are important.
The physician should access patient factors such as complience,and comorbid diseases,the severity,and prognosis of the
patient's disease, and the physician's own confidence, training, experience,and knowledge in administration of the drug. Each
drug has specific toxicity associated with it.
DMARDs have common characteristics. All are relatively slow acting, with a delay of 1-6 months before a clinical response
is evident. Efficacy cannot be predicted for the individual patient,but up to two-thirds of patients may have response
to these agents.
One DMARD or NSAID may work for one patient and another will fail. Side effects (vary with the drug) may include mouth
sores, diarrhea,and nausea. More serious side effects, monitored through regular blood and urine test, include liver damage
and excessive lowering of white blood cell count increasing susceptibility to certain infections),and platelet count (affecting
clotting). The effectiveness and severity of the disease will dictate the use of combination drugs or a mono therapy.
We now have a better understanding of what's happening at the cellular level in this disease in the joints. And we can
take advantage of that by designing therapies that somehow block some of the interactions between the cells,or stop some of
the inflammation at the cellular level in the joints themselves that are inflamed.
Some of the newer drugs that have come out are medications like Arava (leflunomide). That's a medication that slows the
turnover and growth of some of the inflammatory cells in the joints. It has been fairly effective for some patients.
The newest category of medications that are coming out are drugs that inhibit cytokines. Cytokines are the proteins that
cells use to signal from one to another. Once scientists understands those signals,they can understand which ones to turn
off to try to shut the process down.
One of the most important is TNF,or tumour necrosis factor,and they are beginning to find medications now that can block
the signaling,that blocks the TNF from getting from one cell to the other cell where its supposed to be going.
Enbrel is a viable receptor of TNF,it essentially soaks up excess TNF in the joints between the cells,prevents
it from getting to the cells that its 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 long-term.
Remicade uses another method to "kill" TNF,approved by the FDA for RA patients for use with methotrexate who have failed
to respond adequately to MTX alone. Since the antibody it uses is part mouse,and to minimize reactions to the mouse part,methotrexate,or
arava must be used with it.
And there is another cytokine called interleukin-1,(IL-1) which works in a similar fashion. Kineret or anakinra was
approved by the FDA to fight IL-1, All of these are specifically designed to interrupt the disease process. There are
many different types (and numbers) of cytokines involved in the rheumatoid disease.
Two decades ago,patients were often kept on nonsteriodal therapy (aspirin) 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
DMARD therapy much earlier in the course of the disease.
The principal agents used are hydroxychloroquine ( Plaquenil ), sulfasalazine, and methotrexate.
Gold salts,while still available is not used often because of toxicity and more monitoring is required--weekly urine
and blood tests--the oral form have proven to be less effective (auranofin-"Ridaura")although less toxic, is not
used- the effects may not show for up to six months.
D-penicillamine has fallen out of favor,predominantly because of its side effects.
Other medications,such as cyclosporine,are generally reserved for combination therapy.
The new agents are Enbrel (etanercept),Arava (leflunomide), and Remicade (infliximab)--Anakinra (IL-ra) have recently
been approved by the FDA.
Cyclosporin was introduced as a means of blocking the rejection of organ transplants (such as kidney grafts),this powerful
immunosuppressive (hard to control,at times) has been shown to be quite effective in RA. There are some advantages in combination
it with methotrexate. When other therapy has failed.
The effect may be better than the effect of either drug used alone,and a lower dose of cyclosporin can be used,which
reduces the side effects,but it is not widely used. Rheumatologists reserve it for cases in which methotrexate in full doses
has failed to put out the fire,but with the newer biologics available,its use is further diminished.
The daily dose is calculated on ideal body weight. It can be taken with food,but never with grapefruit juice,which can
increase the amount of drug your body absorbs and lead to side effects. A number of drugs can also affect the level of cyclosporin
in your body: some antibiotics,antifungal agents, anticonvulsants and even some heart and blood pressure medicine.
Because cyclosporin can cause high blood pressure and affect kidney function,blood pressure and kidney blood tests should
be carefully checked before treatment and every two weeks for the first three months,then once a month
There is no convincing evidence that cyclosporin increases the risk of infection or cancer. However,it should not be
used if there is an existing cancer or infection,just as it should not be used in people with abnormal kidney function or
uncontrolled high blood pressure.
In 1997,the FDA approved cyclosporine for the treatment of RA. However, cyclosporine as Ciclosporin and its newer formulation
Neoral,a more easily absorbed solution is seldom used by U.S. rheumatologists It is expensive ($4,700 per year),and
fairly toxic.
Despite it's powerful ability to suppress certain parts of the immune system,only about one-third of those that turn
to this treatment have a greater than 50 % improvement. The side effects can be severe.
Hydroxychloroquine or sulfasalazine have the advantage of low toxicity and therefore are generally the first DMARD
agents used,particularly in patients with mild disease who are RF negative. Although these agents are well tolerated,most
patients will have a modest beneficial response with very few patients having a complete remission. Either drug is often used
in combination with an NSAID,corticosteriods or other DMARD.
Intramuscular gold salts were recently the most often used DMARD agents,but because of toxicity,they are now used only
after failure of MTX. Additionally,patients dislike the requirements of weekly visits for injections during the first 4 months
of therapy. Oral gold has limited usefulness.
D-Penicillamine also is a relatively toxic drug,and is,like injectable gold prescribed primarily for patients with persistent
aggressive diseases who have failed to achieve remission with less toxic agents.
Gold injections or d-penicillamine may be the only alternative in patients with significant liver disease. Persistant
signs of synovitis dictates a change in the regimen of anti-inflammatory and DMARD agents
Cytotoxic drugs--other than MTX (e.g., azathioprine,cyclophosphamide) or cyclosporin A are used in patients who have
aggressive disease or extra-articular manifestations such as systemic vasculitis.
Methotrexate has become the most popular DMARD agent because of its early onset of action (4-6 weeks),good efficacy,and
ease of administration and high patient tolerability. MTX is the only DMARD in which the majority of patients continue on
therapy after 5 years.
MTX is best used in patients with persistent,active disease who may have poor prognostic factors such as the presence
of high r.f.-positive,rheumatoid nodules,poor functional status,young age or erosions on x-ray. MTX is processed in
the body through the liver.
MTX has been used for the treatment of RA for decades,but it is surprising that,clinical trials proved,the medication
also prevents joint damage in 1999. Also,subcutaneous injection at 25 mg. was done in a clinical trial in 1998, which proved
more efficacious. Unfortunately,40 % of RA patients will not respond to methotrexate.
Leflunomide,Infliximab,and Etanercept are new options,particularily in those who have failed other DMARDs.
Cyclophosphamide (Cytoxan) is more powerful and toxic than azathioprine IImuran). It is used when RA is severe and has
not responded to other treatments,or in cases were there is severe inflammation of blood vessels (vasculitis).
Azathioprine,while less toxic,still can trigger serious infections and blood problems. It is reserved for people whose
RA has not responded to other DMARDs. Recently,physicians are including azathioprine in combination with other DMARDs for
RA therapy.
Penicillamine: In the 60's Dr. Israeli Jaffe in New York began to use penicillamine as a RA treatment. He reasoned that
this simple substance, because of it's chemical structure,might be able to break up the rheumatoid factor,that protein circulating
in the blood of most people with RA.
Jaffe and then many others used penicillamine (Cuprimine) with positive results, It took several months before relief
became apparent,but eventually oral penicillamine proved to be as effective as gold injections,methotrexate,and sulfasalazine.
That is the "good" news.
The "bad news" is that penicillamine is a very toxic substance. Almost half of people who start the drug have to discontinue
because of side effects. Those include skin eruptions,kidney problems,and blood disorders.
Now,penicillamine is reserved for people with severe active RA who have failed to respond to the other available medications.
It is rarely used in the U.S.
It can be useful in vasculitis cases. Research has shown that Dr. Jaffe was right-this drug does lower rheumatoid factor
levels-but it's not known why or if that gives relief. Pencicillamine also reduces the destructive growth of the inflamed
lining in the joints,and can block other steps in the cascade of reactions in RA. Despite its effectiveness,the concern over
delibilitating side effects has forced pencillamine to the sidelines to be used as an agent of last resort.
These powerful and very toxic medications are only two of the many drugs that have come out of decades for anticancer
compounds.
Chemotherapy fights cancer by trying to kill tumours. Using the same chemicals,referred to as cytotoxic drugs,against
RA is intended to kill of rapididly dividing cells in the immune system and perhaps eliminate the cells that are driving the
disease along. This kind of "shotgun" approach may slow down RA,but at a cost.
Healthy cells may be killed indiscriminately,causing many side effects,including serious blood disorders and infections,and
may even trigger new cancerous growths. They are not commonly used.
Chloroquine (Aralen) and hydroxychloroquine (Plaquenil) were first use to treat malaria. They are both effective treatments
for rheumatoid arthritis and systemic lupus erythematosus. Very rarely do they damage the retina of the
eye causing permanent loss of vision. There is no specific treatment for this problem. Very few people experience this side
effect. There is no lobby or support group but the Canadian National Institute for the Blind (CNIB) should be helpful.
For
anyone else on chloroquine or hydroxychloroquine, please take these precautions: The damage to the eyes is related to the
dose of these drugs and does not usually occur during the first 2 years of treatment. The daily dose of chloroquine
should not exceed 3.5 mg per kilogram of your ideal or lean body weight and hydroxychloroquine should not exceed 6.5 mg per
kilogram of your ideal or lean body weight.
Therefore, if you weigh 50 kilograms, you should not take more than (3.5 x 50 = 175) 175 mg of chloroquine per day or
(6.5 x 50=325) 325 mg of hydroxychloroquine per day. Keeping below these doses will reduce the chances of getting eye damage
but will not eliminate the risk completely. If you lose weight, then reduce the dose accordingly.
If your disease improves, then reduce the dose slowly to a maintenance dose, for example, hydroxychloroquine 200 mg taken
only 5 days per week. Eyes should be checked by an ophthalmologist every 12 to 18 months. These drugs are removed from the
body very slowly by the liver and kidneys. Therefore, if you have impaired functioning of your kidneys or liver, the dose
should be reduced and your eye examinations done more frequently.
The ophthalmologist should give you a card with an Amsler grid on it and show you how to use it at home between visits.
Using the grid could alert you to early changes that would not progress if the drug was stopped at that point. It has been
suspected but not proven that sunlight may contribute to the problem. Good sunglasses would be worth wearing in the sunlight.
These
drugs are very useful and safe otherwise. The damage to the retina is a rare side effect. The above precautions should be
followed.
Corneal melting is a rare condition consisting of corneal thinning which can lead to perforation. There are several associated
conditions including such rheumatic diseases as rheumatoid arthritis, Wegener's granulomatosis and Sjogren's syndrome. It
occurs late in the course of rheumatoid arthritis but is rare.
It may be more common if the eyes lack tears as a result of Sjogren's syndrome complicating the rheumatoid arthritis.
It may be due to vasculitis (inflammation of blood vessels) caused by the rheumatoid arthritis. There are no blood vessels
in the cornea but the ones adjacent to the cornea on the periphery may be inflamed.
Sometimes the melting of the cornea is precipitated by cataract surgery or corneal surgery for correction of nearsightedness.
It is not at all related to gold treatments. Although gold salts may deposit in the cornea or conjunctiva, they are harmless
to the eye and gradually disappear after the gold injections are stopped.
Treatment of corneal melting in these circumstances includes local drops and ointments, corneal transplant and immunosuppressant
drugs such as cyclosporin.
Cortisone injection; Usually there are no long-term effects if the dosage is reasonable and the frequency is less than
4 times per year per joint and the physician is skilled in the procedure. It is a valuable therapeutic measure.
There is some controversy as to whether or not too many injections may damage the joint (accelerated damage or Charcot
joints) or the local bone (avascular necrosis and osteoporosis) but other studies indicate that the injections can retard
joint damage and help preserve the joint. Frequent injections may weaken ligaments and tendons. Rarely calcification
may form in the tissue at the injection site.
The cortisone can be absorbed from the joint into the circulation. If the injections are too frequent and high
dose, then the side-effects of systemic steroids can occur such as adrenal gland suppression, weight gain, fluid retention,
hypertension, elevated blood sugar, cataracts, thin fragile skin and uterine bleeding.
There are many reasons for fatigue in persons with arthritis. One of them is drugs. Folic acid and Plaquenil do not cause
fatigue. Drowsiness is listed as a side-effect of Vioxx but the chances of it causing your fatigue are slim. You could stop
it for 2 days to see if your fatigue lessens.
Of the drugs you are taking, methotrexate is the one most likely to cause fatigue. It can be associated with constant
fatigue or with post-dosing fatigue (fatigue that occurs within 24 hours of taking the methotrexate and that lasts just 1
to 2 days with or without increased muscle and joint pains). Lowering the dose of the methotrexate might help but the arthritis
might worsen.
Another anti-rheumatic drug like leflunomide could be added to this lowered dose of methotrexate if the arthritis worsens.
Taking up to twice the dose every other week instead of weekly might give more days free of fatigue. Changing the route of
administration from oral to injection or vice versa might help. I do not know of anything specific to take that would combat
the fatigue.
Arava does not work for everyone like any DMARDs or other arthritis medication.. Some patients will complain of extreme
fatigue,diarrhea,and find it less efficacious then methotrexate,when taken alone.
Some rheumatologists will have second thoughts about using leflunomide with methotrexate because of possible side effects
exibited by the two drugs in combination,but this is a individual decision based on differences in patient factors.
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