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Drugs Used
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Non-steroidal anti-inflammatory drugs (NSAIDs) reduce inflammation by preventing the formation of natural inflammatory substances called prostaglandins. NSAIDs are used commonly for everything from headaches to colds to nagging pains. They are also used frequently in the treatment of rheumatoid arthritis (RA), to alleviate joint pain and swelling.
 
While NSAIDs can be effective against RA, they have a number of side effects, including potentially serious side effects such as bleeding stomach ulcers, kidney damage, liver damage and decreased blood cell production. While rare, these side effects can be severe. In particular, bleeding stomach ulcers can be an emergency, life-threatening complication of NSAID use.
 
Several risk factors for developing a bleeding ulcer while taking an NSAID medication have been identified. Of these risk factors, a previous episode of ulcer bleeding presents a particularly high risk. Since patients with RA are often prescribed NSAID medications for many years, they often develop a bleeding ulcer at some time, and thus are at high risk for a second bleeding ulcer. To decrease rates of bleeding ulcers in patients taking traditional NSAIDs, ulcer-preventing and ulcer-treating medications such as misoprostol or the “proton pump inhibitors (PPI’s)” have been used.
 
The new subclass of NSAIDs target specific prostaglandin-producing enzymes (called COX-2). In patients with RA, clinical trials have shown a lower rate of bleeding ulcers for these new COX-2 NSAIDs relative to the “non-selective” NSAIDs 1. However, the safety of these COX-2 NSAIDs for high-risk patients with a previous episode of bleeding ulcer remained unknown.
 
To address this issue, a group of investigators studied the safety of a COX-2 NSAID compared to traditional NSAID plus anti-ulcer therapy in high-risk arthritis patients.  They published their results in a recent issue of the New England Journal of Medicine.
 
In this prospective, randomized, double blind trial, researchers identified 290 arthritis patients who had recently experienced an episode of bleeding ulcer. They then randomly treated these patients with either celocoxib (Celebrex®), a COX-2 NSAID, or diclofenac (Voltaren ®), a non-selective NSAID plus the anti-ulcer therapy omeprazole (Losec®), a proton pump inhibitor (PPI). These patients were followed for six months and assessed for recurrent bleeding ulcer as well as arthritis activity.
 
These researchers found that the treatment group which received the COX-2 NSAID (celocoxib) had lower but statistically similar rates of bleeding ulcer compared with the non-selective NSAID (dicofenac) plus PPI (omeprazole) (4.9% vs. 6.4%).  Both treatment protocols demonstrated similar effectiveness in relief of arthritis symptoms.
 
From their results, these investigators conclude that treatment with a COX-2 selective NSAID was as effective as treatment with a non-selective NSAID plus an anti-ulcer PPI medication from a bleeding ulcer standpoint.  They also noted that while these treatments show similar safety profiles, the rates of recurrent bleeding ulcer in both group were high (approximately 5% in 6 months); thus, neither treatment strategy completely prevents this serious medical event.  In addition, both groups demonstrated similar rates of side effects on the kidney, suggesting no additional benefit from the COX-2 selective NSAID.
 
Overall, this study provides RA patients and their physicians with important information regarding options for continued NSAID treatment after an episode of bleeding ulcer.  In addition, this study again underscores the importance of careful administration of these medications in RA therapy.
 
Notes: Valdecoxib (Bextra )is an oral drug that belongs to the family of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are used primarily to treat pain and arthritis. Other NSAIDs include aspirin and aspirin-related drugs, ibuprofen (Motrin), indomethacin (indocin), naproxen (Naprosyn), diclofenac (Voltaren), sulindac (Clinoril), ketoprofen (Orudis), etc.
 
Valdecoxib works by altering the production of prostaglandins, chemicals manufactured by the body that promote the inflammation of arthritis and cause the pain, swelling and tenderness of arthritic joints. Valdecoxib, like the newer NSAIDs celecoxib (Celebrex) and rofecoxib (Vioxx), blocks one of the enzymes that makes prostaglandins (cyclooxygenase 2), resulting in lower concentrations of prostaglandins.
 
As a consequence, pain, swelling and tenderness of joints due to arthritis are reduced. Valdecoxib (like celecoxib and rofecoxib) differs from most other NSAIDs in that it causes less inflammation and ulceration of the stomach and intestine (at least with short-term treatment) and does not interfere with the clotting of blood.
 
PRESCRIPTION: Yes GENERIC AVAILABLE: No PREPARATIONS: Oblong white tablets containing 10 or 20mg of valdecoxib. STORAGE: Valdecoxib tablets should be stored at room temperature, 59-86 °F (15-30 °C).
 
PRESCRIBED FOR: Valdecoxib is used for the relief of pain, fever, swelling, and tenderness caused by osteoarthritis and rheumatoid arthritis, but it does not prevent the destruction of joints by the arthritis. Valdecoxib also is approved for the relief of pain of menstrual cramps (primary dysmenorrhea).
 
DOSING: For osteoarthritis or rheumatoid arthritis, the usual approved dose of valdecoxib is 10 mg once daily. For dysmenorrhea, the dose is 20 mg twice daily. Valdecoxib may be taken with or without food.
DRUG INTERACTIONS: NSAIDs can reduce the actions of diuretics such as furosemide (Lasix) and hydrochlorothiazide (Hydrodiuril) in some patients and lead to retention of water.

Nonsteriodal anti-inflammatory drugs NSAIDs are the first level of medications used to relieve pain,lower fever and reduce inflammation but they do not alter the course of the disease. There is a wide variety of them,ibuprofen,or Advil,or Naprosyn etc.,--both prescription and nonprescription.
 
They can be very helpful in treating the symptoms,and they often are a important part of managing some patients and relieving some of their symptoms,but in the long run they are not enough. They are not satisfying enough and there are very few patients who do well on just anti-inflammatories alone.
 
One of the advances that has come up in the last couple years,is the advent of so-called Cox-2 inhibitors (Vioxx & Celebrex),those are very much like the anti-inflammatories we have had up to now,but they block a specific enzyme called Cox-2.
 
Basically they have the same anti-inflammatory properties of some of the more traditional medications, but they don't have some of the gastrointestinal side effects. That's often,been a major problem for people over the years who get some relief from ant-inflammatories,but have difficulty tolerating or have problems with them.
 
Nonsteriodal anti-inflammatory drugs are all different,they have different chemical formulas. Therefore,their actions in different persons may depend on the disease and dose.
 
They are also different in terms of effectiveness,side effects,and ease of use. If a NSAID loses effectiveness  or has side effects which are serious,another NSAID should be administered.
 
Disease modifying anti-rheumatic drugs DMARDs are a group of drugs that have the ability to alter the course of the disease,that they somehow stop the progression of the disease,or slow the progression of the disease,slow the damage that gets done to the joints,and change the natural history. 
 
Its pretty clear that if somebody with rheumatoid arthritis and have them take Naprosyn or Motrin,say for a number of years,over five or ten years,whatever damage is going to happen to their joints is going to happen regardless of the medication,which in itself,won't stop that. They may feel better,but they will have problems in the long run.
 
The DMARDs that had been used slow down or alter the over-active immune system. Unfortunately,over course of time,they may lose effectiveness and another drug is chosen. Each drug has side effects associated  with the particular drug being used.
 
 The third type of medicine used in RA are steriods or corticosteriods which include Cortisone and its synthetic derivate, Predisone. They are taken by mouth or injected.
 
Sometimes they are used as injections intramuscularly,or injections in a joint. these have made a big difference in managing a lot of patients.
 
And,essentially,they are the most potent ant-inflammatory that we have. Over the long run, continuous  or chronic use  of steriods have a lot of side effects. So as chronic long-term therapy it is discouraged.
 
However,in the short run they provide a lot of benefit to some patients. They are the quickest,most effective way to relieve pain and inflammation, particularily in a flare,and they are often used as a bridge before instituting some type of longer range therapy or chronic therapy.
 
Corticosteriods or predisone are very useful to just tide people over for a few weeks until doctors can get them responding to something that they are going to be able to take in the long run.
 
If people have diabetes steriods can exacerbate that. Side effects can be cataracts and osteoporosis.
 
It is not known which is the best initial DMARD for patients with RA. Because of safety,convience,and cost HCQ (Hydroxchloroquine) or  (Sulfasalazine) SSZ is often the initial selection for patients with milder disease.
 
Generally well tolerated. HCQ  requires no laboratory monitering, although patients need periodic ophthalmologic examinations for early detection of reversible retinal toxicity (i.e.,maculopathy manifested by decreased night vision or loss of peripheral vision).
 
SSZ (used more in Europe)requires monitoring (i.e.,periodic CBC) for rare hematoligic complications. Within 1-6 months,the response  to these agents should be apparent and the need for a change in therapy may be determined.
 

Many rheumatologists select MTX (Methotrexate) as the initial DMARD, especially for patients with severe disease as evidenced by the presence of RF positivity,erosions, or extra-articular manifestations.  MTX is the DMARD  with the most predictable benefit.
 
More than 50% of patients taking MTX continued the drug beyond 3 years longer than any other DMARD.
 
Disadvantages of MTX include its expense and the need for laboratory monitoring. Stomach,nausea,diarrhea,and perhaps alopecia from MTX use may decrease with concomitant folic acid or frolinic acid treatment,without loss of efficacy.
 
Liver disease, renal impairement,significant lung disease,or alcohol abuse are relative contraindications for MTX therapy.
 
The risk of liver toxicity is small, but liver function must be monitored. The ACR guidlines for monitoring toxicity in patients receiving MTX state that liver biopsy should be performed in patients who develop liver function blood test abnormialities that persist during treatment with,or after discontinuation  of the drug.
 
Rare,but potentially serious and even life-threatening pulmonary toxicity may occur any time with MTX at any dosage. A trial of injectible methotrexate can be valuable,because it often eliminates the gastrointestinal side effects seen with the oral route.
 
Intramuscular gold treatment is effective,but weekly intramuscular injections are required for 22 weeks before less frequent maintenance dosing is initiated. Monitoring for proteinuria,thrombocytopenia.and neutropenia should be performed prior to each weekly injection.
 
In patients receiving long-term gold therapy ( > 6months),toxicity monitoring may be performed with every other injection. Although oral gold is more convient than injectable gold,there is a long delay (up to 6 months) before benefit is evident,and it is less efficacious.
 
D-Penicillamine is effective,but its use is limited by an inconvient dosing schedule (i.e.,slow increase in doseage) and infrequent but potentially serious complications of autoimmune diseases such as Goodpasture's syndrome or myasthenia gravis.
 
AZA (Azathioprine),a purine myelosuppressant,has demonstrated benefit for controlling RA Low-dose cyclophosphamide is effective,but arcinogenic. Although recent studies have documented the efficacy of cyclosporin A in treatment of RA but it's use is limited by cost and potential renal toxicity.
 
Today,hydroxychloroquine and cholroquine are well-established agents for mild to moderated RA and mild lupus,with a good safety profile,though HCQ (plaquenil)  has largely supplanted the use of CQ: It has less potential to cause renal toxicity,which can cause permanent eye damage.
 
In the 1950s,a small number of people suffered irreversable eye damage before it was learned that the risk can be minimized simply by reducing the doseage.
 
The maximum daily doseage recommended for HCQ is 6 to 6.5 mg prt kilogram of body weight (meaning lean body weight,not actual body weight). A common daily doseage is 400 mg: at recommended doseage,retinopathy is now extremely rare.
 
HCQ is considered safest of all DMARDs. It is slow acting taking up to six months to display its effects. Semi-annual evaluations by a ophthalmoligist (eye ) is recommended.
 
Sulfaszlazine is best tolerated with meals; typical regimen may start at one daily 500 mg tablet,then one tablet twice daily (breakfast and dinner),then two tablets twice daily. Benefits can be expected after about three months and,depending on results,may increase your daily dose.
 
Drink 1.5 litres of fluid daily. the urine may show a yellowish colour while on the medication. Efficacy may be slightly lower than methotrexate. It is used more in Europe,but is being used more in North America,especially with combination therapy.
 
Immunosuppressive drugs,such as azathioprine (Imuran),are thought to interfere with immune cell division,and are also classed as DMARDs;cytotoxic drugs such as cyclophosphamide and cyclosporine destroy cells outright (cyto means cell;toxic means poison)
 
Approximately 10 % of people taking azathioprine experience severe side effects,including GI problems and a increased risk of infections. Doctors take the "go low,go slow" approach with the drug,starting with one or two tablets daily and gradually increasing the dose to three tablets daily It is infrequently used today. Taken with meals. Azathioprine can be taken with NSAIDs,but it interacts with allopurinol (Zyloprim ),a medication used in the treatment of gout.
 
Cyclosphamide (Cytotoxan) is used only in most severe cases of immune-system disorders and with the most stringent monitoring because of it's blanket destruction of cells,both healthy and harmful.
 
It can suppress bone marrow production of blood cells,cause bleeding,and leave the patient open to infections. It's also associated with an increased risk of hemorrhagic cystitis (bleeding from the bladder ) and,over time,increased risk of cancer and increased infertility. It is rarily used today.
 
Cyclosporine,formerly known as cyclosporine A,is also an organ transplant rejection fighter. It's dampening effect on white blood cell production is more closely targetted to the inflammatory aspect of arthritis than cyclophoshamide, but it's still used only after other DMARDs have proven effective,but with the newer biologivs available.it's use is further diminished.
 
Side effects include possible kidney damage,muscle tremors,problems with the gums,and hypertension.
 
For women of childbearing age,effective contraception is required with most DMARDs when prescribed. The drug regimen will need modification if the patient is or wishes to become pregnant or if breastfeeding is contemplated.
 
Whether DMARDs should be given in sequential or additive manner for patients with persistently active disease remains controversial. Rheumatology referral is strongly recommended for patients with refractory disease in whom combination DMARDs are considered.
 
Some rheumatoligists initiate treatment with a combination of several DMARDs and gradually withdraw the drugs as disease control is achieved.
 
Most rheumatologists use combination DMARDs to treat patients who have had a partial response to a DMARD or whose disease has been refractory to different individual DMARDs.
 
The most commonly used combinations are MTX/HCQ,MTX/SSZ,and Gold/HCQ. Studies are needed to determine the most effective combinations for use in RA.
 
The majority of patients with active RA receive an NSAID and at least one  DMARD with or without low-dose oral glucocorticoids. If disease remission is observed regular NSAID or systemic glucocorticoid treatment may no longer may be needed. DMARDs control RA but do not usually cure the disease.
 
For that reason if remission or optimal control of RA is achieved with a DMARD. Therapy should be continued as a maintenance doseage. Discontinuing a DMARD may reactivate disease or cause a 'rebound flare' with no assurance that disease control will be re-established upon resumption of the medication.--ACR.

Use Of Antibiotics:
 
The use of antibiotics,particularly minocycline,in the treatment of RA has received widespread media attention. the treatment of RA with anti-infectious agents is not a new concept. Gold was first introduced because of its presumed effect against tuberculosis. Sulfasalazine and hydroxychloroquine are used widely for mild to moderate RA and are undoubtedly effective.
 
Minocycline,and perhaps doxycycline,also appear to be effective clinically in early disease,however,as yet,studies have shown no visible improvement visible on x-ray films.
 
Minocycline does not appear effective in later RA,and it may cause autoimmune disease as a side effect. It's exact role is not clearly been established,and its effectiveness is thought to be because of its antibiotic properties.
 
Other immunologic or cartilage-protective effects seem more likely. Minocycline is prescribed at a dose of 100mg taken orally twice a day,and requires monitoring by complete blood counts and liver function tests every 4-12 weeks.
 
Immunosuppressive agents are used in the management of systemic manifestations of autoimmune diseases and vasculitis. These agents include azathioprine,cyclophosphamide,chlorambucil,cyclosporine and methotrexate.
 
 Cyclophosphamide can be administered orally in daily doses or in intravenous monthly pulses,the latter method has been studied in the treatment of lupus nephritis,but is now used more widely. Its main advantage over oral administration is the reduction in risk of some of the side effects. Contraception is essential for men and women in view of the high risk of teratogenesis. Strategies are available to reduce the risk of sterility.
 
The use of corticosteriods results in rapid,potent and reliable suppression of inflammation. This explains their wide use for the inflammatory manifestations of rheumatic diseases and for systemic vasculitis. However,their effect in suppressing the synovitis in RA is not sustained and requires a progressive increase in doseage to maintain the benefit. The precise role of orally administered corticosteriod in RA remains controversial.
 
Despite recent evidence suggesting that corticosteriods may reduce the rate of radiologic progression,most clinicians prefer to limit their use to the short term because of the substantial side effects associated with long-term use (e.g. osteoporosis,hyperglycemia,hypercholesterolemia) and the difficulty in tapering of dose.
 
Short courses of low-dose steriods can be useful as :bridging therapy" to control symptoms while waiting for DMARDs to take effect or to control severe flare-ups. Patients can decrease the dose as soon as symptoms are under control. The injection of steriods into the most affected joints can often alleviate the need for oral steriods. (at the rate of 1-2 large joints every 2-6 weeks).
 
Intramuscular injections of corticosteriods are advocated by some to prevent difficulties in tapering off  the dose of oral corticosteriods. Patients with exacerbation of the underlying disease or withdrawal syndrome may require even more gradual tapering off,especially in the low-dose range.
 
The addition of corticosteriod-sparing agents can be useful when disease exacerbations prevent tapering off. Depending on the clinical situation, azathioprine, methotrexate, cyclosphamide or chlorambuci can be used for this purpose.
 
The use of an alternate-day regimen is associated with a lower incidence of some of the side effects. Maintenance of control of the disease can be a problem. Switching from daily to an alternate-day regimen must be done gradually (by tapering off the dose on alternate days down to zero) to prevent both adrenal insufficiency and exacerbation of the disease.
 
Administeration of the dose in the evening,a divided dose and the use of longer acting forms are associated with greater adrenal suppression.