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Sock's Toxicity And Drugs In RA:
DMARDs
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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.

DMARDs:
 
During the past 20 years,DMARDs have been combined with steriods and NSAIDs. Recent studies in patients with early,RA have shown that combining lower doses of several DMARDs may be better than using a higher dose of only one.
 
Currently,evidence suggests that MTX combined with sulfasazine  and/or hydroxychloroquine  may be effective for people whose arthritis does not respond to one drug alone.
 
A group of U.S. researchers demonstrated the benefit of combining three medications (hydroxychloroquine,sulfasalazine and methotrexate relative to treatment with a single medication (methotrexate).  The question was whether the three drug regimen was superior to a combination of two of the drugs. The researchers compared the benefits of treatment with two drug combinations ("double therapy") vs. the three drug combination ("triple therapy)
 
For this clinical trial,171 patients with active RA were divided into three treatment groups and their clinical response was studied for two years. The three treatment groups were: MTX + SSZ (double therapy),MTX + HCQ (double therapy) and triple therapy with all three drugs.
 
Analysis of the effectiveness of these treatment combinations showed a significant response for all combination therapy formulations. The triple therapy regimen consistently outperformed double therapy at all levels of the ACR response criteria, although  this was not statistically significant at the ACR 70 response level.
 
Upon analysis of patients previously treated with MTX alone,these investigators noted a substantial number of patients achieved clinical benefits with implementation of combination therapy.
 
These combinations of medications were generally well tolerated with only 14 patients withdrawn from trial over 2 years due to potential side effects from therapy. No drug combination was noteable for increased toxicity.
 
From those results,the authors of the study concluded that triple therapy provides superior results to their double therapy regimens. They added that they note that the addition of a second medication to patients not fully responsive to MTX alone,while inferior to triple therapy,still received substantial added benefit.
 
This correlates with results from other clinical trials. The authors highlight the importance of continuing research into the efficacy-effectiveness of combination therapy with other drugs and future combination  analysis with biologic agents.  Futher discussion between patient and physician will be encouraged by the studies. --O'Dell J.R. et. al. New England J. of Medicine/96--Arthritis and Rheumatism/02.
 
Plaquenil (hydroxychloroquine has sometimes been referred  to as a slow-acting,second-line medication to treat a variety of rheumatic diseases including RA. It is generally used for 3 to 6 months in order to determine its effects in a given patient.
 
The good news is that it usually tends to be be one of the least toxic of the second-line rhematic medications-a major advantage in the elderly. Also, at the beginning of a disease the physician may not be sure of the severity of the disease,until at a later date,the medication provides joint protection in the interim.
 
Some older DMARDs are declining in usefulness and have been relegated to the third-level. They simply cannot compete with the recommended,or first-level,DMARDs. Others are not yet well tested and,therfore,are not widely used.
 
These drugs include D-penicillamine,oral gold, cyclosporine, azathioprine, cyclophosphamide,and tetracycline. Cyclosporine A has recently been reintroduced as Nerol This drug works well especially in early RA or in combination with gold or MTX.
 
TNF is a highly inflammatory protein that is overproduced in RA and is,therefore,thought to play a pivotal role in its pathogenisis.
 
The impressive clinical response of RA patients to inhibitors of TNF,and the ability of genetically-induced overproduction of TNF to induce inflammatory arthritis in animals,have reinforced the concept that tumor necrosis factor is not necessary for the development of severe inflammatory arthritis.
 
 However,not all patients respond to inhibitors of TNF,this raises the possibility that inflammatory arthritis may not be absolutely dependent upon TNF.
 
There have been many research studies (on animals)done to support the theory-subject.The studies illustrate that TNF is important but not essential for the development of inflammatory arthritis. The research data reinforce the complexity of mechanisms of inflammation in RA,and support continued efforts to identify more effective therapies.
 
There has been concerns that chronic TNF inhibition may be associated with increased incidence of infection.

 The name "second-line" comes from the fact that in RA the NSAIDs were used first. When their effects has effects has been determined ( in the old days ).assuming there is still a problem,theDMARDs were called upon.
 
They used to call it remitting drugs,but it's clear that they don't cause the disease to go away completely.  Some doctors call them SAARDs ( Slow-acting anti-rheumatic drugs,which they are.  The two major differences,in pratical terms,between these drugs and NSAIDs are they take much longer to have an effect ( usually months ),and they are much more effective in (pain relief) suppressing  the disease process.
 
 Unfortunately,another characteristic of drugs in this category is the fact that they often lose their effect as time goes by.
 
This means that,after several years,many patients will have experienced with quite a number of these agents. Fortunately,research into new drugs in this area have kept up.
 
These drugs were unrelated to each other chemically. Almost all were first used in arthritis for reasons that were later shown to be wrong,or as a result of a series of chance observations
 
Gold,was used because RA was once thought to be caused by tuberculosis and gold salts have some activity against TB in a test tube.
 
Methotrexate ,when it was first used in psoriasis,was observed to work even better It in only now,in the age of biologic engineering we have found drugs specifically designed to treat RA.
 
In RA DMARDs should be introduced as soon as the diagnosis of RA is established. We have come to appreciate that effective treatment must not be delayed,that this class is far superior to NSAIDs and the risks of side effects have been deeply exaggerated.
 
Investigations makes a convincing case that many DMARDs are actually less harmful then NSAIDs in practise. But each drug has many possible side effects which can be controlled by careful monitoring,should such side effects appear on the scene (DMARDs and NSAIDs).
 
Unfortunately,these agents are not uniformly effective in all forms of arthritis. They are used primarily in just two forms of inflammatory arthritis,rheumatoid and psoriatic (generally speaking).
 
Some are used as "supportive" treatment in a few other conditions,in particular ankylosing spondylitis,systemic lupus erythematosus,polymyositis and dermatomyositis.
 
There is no "second-line" treatment available for the most common problem of all,osteoarthritis. Nor is there specific treatment for fibromyalgia,scleroderma, choncrocalcinosis,polymyalgia rheumatica,or Sjorgren's syndrome.
 
There is non-erosive RA,but this is in the minority. The typical polyarticular rheumatoid arthritis is a progressive,systemic,sero-positive (R.F.),on-going disease where radiographic disease process is occuring on a daily,(however,minute) progressive basis,and the purpose of DMARDs is to partially,or if possible,completely stop,this destructive radiographic damages from continuing.
 
There are many DMARDs,some more suitable,w.r.t. severity and type,then others. There are many other important factors such as patient suitability. Not all patients can take the present "gold standard" methotrexate due to patient differences in "tolerability",effectiveness,and side effects.

GENERIC NAME: sulfasalazine;BRAND NAME: Azulfidine;DRUG CLASS AND MECHANISM: Sulfasalazine is a pro-drug, that is, it is not active in its ingested form. It is broken down by bacteria in the colon into two products: 5-aminosalicylic acid (5ASA), and sulfapyridine. There is some controversy as to which of these two products are responsible for the activity of azulfidine.
 
Whereas it is known that 5ASA has therapeutic benefit, it is not clear whether sulfapyridine adds any further benefit. In the colon, the products created by the breakdown of sulfasalazine work as anti-inflammatory agents for treating inflammation of the colon.
 
The beneficial effect of sulfasalazine is believed to be due to a local effect on the bowel, although there may also be a beneficial systemic immune-suppressant effect as well. Following oral administration, 33% of the sulfasalazine is absorbed, all of the sulfapyridine is absorbed, and about 33% of the 5ASA is absorbed. Sulfasalazine was approved by the FDA in 1950.
 
PRESCRIPTION: yes GENERIC AVAILABLE: yes PREPARATIONS: Uncoated and enteric coated tablets, each containing 500mg.
STORAGE: The tablets should be kept at room temperature, 15-30C (59-86F).
 
PRESCRIBED FOR: Sulfasalazine is used for the treatment of mild to moderate ulcerative colitis; as adjunctive therapy (i.e. with other medications) in the treatment of severe ulcerative colitis; for the treatment of Crohn's disease; for the treatment of rheumatoid arthritis or ankylosing spondylitis.
 
DOSING: Doses range from 500mg to 2000mg, and dosing intervals range from every 6 hours to every 12 hours, depending on the clinical condition of the patient. Higher doses have also been used.
 
Sulfasalazine should be taken with a full glass of water after meals or with food to minimize stomach upset. Patients with kidney diseases may need to use lower doses of sulfasalazine.
 
DRUG INTERACTIONS: Sulfasalazine may cause reduced absorption of folic acid and of digoxin.
 
PREGNANCY: In hundreds of pregnant women with ulcerative colitis or Crohn's disease treated with sulfasalazine, there has been no increase in the risk of fetal malformations relative to other women with these illnesses who have not been treated with sulfasalazine.
 
Additionally, there have not been ill effects on pregnant animals given high doses of sulfasalazine. Thus, sulfasalazine may be used during pregnancy if the physician feels the benefit outweighs the possible risk.