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Socks Rheumatoid Arthritis Page 1

Socks Toxicity and Drugs in RA


The signs and symptoms of rheumatoid arthritis may come and go over time. They include:

  • Pain and swelling in your joints, especially in the smaller joints of your hands and feet
  • Generalized aching or stiffness of the joints and muscles, especially after sleep or after periods of rest
  • Loss of motion of the affected joints
  • Loss of strength in muscles attached to the affected joints
  • Fatigue, which can be severe during a flare-up
  • Low-grade fever
  • Deformity of your joints over time
  • General sense of not feeling well (malaise)

Rheumatoid arthritis usually causes problems in several joints at the same time. Early in rheumatoid arthritis, the joints in your wrists, hands, feet and knees are the ones most often affected. As the disease progresses, your shoulders, elbows, hips, jaw and neck can become involved. It generally affects both sides of your body at the same time. The knuckles of both hands are one example.

Small lumps, called rheumatoid nodules, may form under your skin at pressure points and can occur at your elbows, hands, feet and Achilles tendons. Rheumatoid nodules may also occur elsewhere, including the back of your scalp, over your knee or even in your lungs. These nodules can range in size,from as small as a pea to as large as a walnut. Usually these lumps aren't painful.

In contrast to osteoarthritis, which affects only your bones and joints, rheumatoid arthritis can cause inflammation of tear glands, salivary glands, the linings of your heart and lungs, your lungs themselves and, in rare cases, your blood vessels (vasculitis).

Although rheumatoid arthritis is often a chronic disease, it tends to vary in severity and may even come and go. Periods of increased disease activity,called flare-ups or flares ,alternate with periods of relative remission, during which the swelling, pain, difficulty sleeping, and weakness fade or disappear.

Swelling or deformity may limit the flexibility of your joints. But even if you have a severe form of rheumatoid arthritis (with associated extra articular featuresEAF's), you'll probably retain flexibility in many joints.

NSAIDs; Adverse events: GI adverse events associated with conventional NSAIDs range in severity. The least severe but most frequent event is upper GI intolerance, which manifests as dyspepsia, gastric pain, nausea, and/or vomiting. The ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) post-marketing surveillance program shows that dyspepsia occurs 46% more frequently in patients treated with NSAIDs than with placebo, with a prevalence of about 6%.
Dyspepsia is poorly correlated with endoscopically determined gastropathy.  However, dyspepsia is important in terms of both health-related quality of life (HRQOL) and economic cost. In addition, there are asymptomatic ulcers (found during endoscopic study) or symptomatic ulcers without further complications. The most problematic events, the ones clinicians are most concerned about, are those associated with the complications of ulcers. They include bleeding, perforation, and gastric outlet obstruction.
Importantly, there is little relationship between symptoms and the development of severe complications. Two separate analyses demonstrated that most patients with complications from NSAID therapy were asymptomatic over time. Thus the absence of a complaint of dyspepsia or abdominal pain does not preclude the possibility of a more severe form of gastropathy in the future. Similarly, a patient with dyspepsia is not necessarily at increased risk for developing complications.
Various studies have demonstrated a number of risk factors for serious GI events with conventional NSAID use. These risks include advanced age (variously defined as greater than 65 years or 75 years); history of ulcer or GI complications; concomitant corticosteroid use; major illness (eg, heart disease); concomitant anticoagulant use; and high-dose or multiple NSAIDS (including aspirin). Of these risk factors, probably the strongest is a history of ulcers or GI complications, with NSAIDs or without. The link between major illness and serious GI events associated with conventional NSAID use is more difficult to describe.
Certainly, the sicker the individual (based on multiple illnesses not related specifically to GI function), the greater the likelihood of developing severe GI events with conventional NSAID use. Many patients on traditional NSAID therapy also take aspirin, which increases the risk for serious GI complications.
A recent meta-analysis demonstrated that over a 28 month period, daily aspirin increased the absolute risk of GI hemorrhage by about 1%. One study demonstrated how the relative risk for bleeding and perforated peptic ulcers increases progressively with higher doses of NSAIDS as well as with a greater number of prescriptions. The more prescriptions and the higher the dose, the greater the risk of NSAID gastropathy.
Strategies: A number of strategies are available for managing NSAID-induced dyspepsia. First, the NSAID can be discontinued if it's no longer needed, or it can be changed to another agent. In the case of osteoarthritis, for example, acetaminophen or a nonacetylated salicylate (eg, salsalate) might be substituted for the NSAID. For reasons unknown, one NSAID may be better tolerated in a given patient than an alternative NSAID; therefore, a switch to another NSAID may be considered. Reducing the dosage to the lowest possible amount to achieve therapeutic effect is another option, since it is well understood that dyspepsia is dose-related.
Alternatively, patients can be instructed to take an NSAID with food or antacids. Other possible choices include concurrent therapy with a proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA). A final possibility would be to switch to a COX-2 NSAID, or coxib.
If patients develop NSAID-induced peptic ulcers, there are other strategies available. As with dyspepsia, the NSAID can be discontinued, if possible. Acid-suppressant therapy may be used to acutely heal the ulcer, followed by treatment to prevent ulcer recurrence. There are a number of ways to prevent ulcers from recurring. They include eradicating Helicobacter pylori if that organism is present, prophylaxis with acid-suppressant therapy if NSAIDs need to be continued, and the possible use of a COX-2 inhibitor or non-NSAID analgesic.
A COX-2 inhibitor, or coxib, is defined as a drug whose efficacy is comparable to that of a traditional NSAID at therapeutic concentrations but lacks effects on gastric mucosa or platelet function (bleeding time; platelet aggregation) that can be attributed to COX-1 inhibition. Three COX-2 specific inhibitors are presently available: celecoxib, rofecoxib, and valdecoxib. Additional compounds in this class are currently under review at the FDA.
Considerations: First, patients receiving COX-2-specific NSAIDs who need prophylactic aspirin therapy for cardiovascular protection should receive aspirin because coxibs have no effect on platelets. Second, it is unclear whether the increase in MI rate among rofecoxib users found in the VIGOR trial was the result of a prothrombotic effect of rofecoxib or of a cardioprotective effect of naproxen. However, a recent observational cohort 12-year study of the Tennessee Medicaid database argues against traditional NSAIDs being cardioprotective.
New users of NSAIDs (n=181,441) aged 50 to 84 years were compared to matched controls, examining the endpoints of acute myocardial infarction or coronary heart disease death. The risk ratios of current and former NSAID users versus controls were 1.05 and 1.02, respectively. The risk ratio of naproxen specifically was 0.95, not significantly different than controls. Finally, whether coxibs remain gastroprotective in the face of concurrent aspirin therapy remains unresolved. While the CLASS study suggested that there was no GI benefit in this patient population, the analysis involved a smaller subset and was not powered to show this difference.
In summary, there are two overall points to be made: first, aspirin and conventional NSAIDs are associated with increased morbidity and mortality; and second, proton pump inhibitors are effective in symptom relief, acute ulcer healing, and in secondary prevention of NSAID-associated ulcers.
Given the experience with coxibs and the existing data on proton pump inhibitors, recommendations for treatment begin to emerge. For individuals with a history of ulcer disease, a mixed inhibitor NSAID with a PPI or coxib is seen as appropriate. For those patients with a documented complication, the ideal regimen might, in fact, be a coxib AND a PPI, especially if low dose aspirin is required. Additional randomized studies will clarify the cost effectiveness and utility of these current strategies.

Methotrexate (Rheumatrex) has become the preferred drug in the aresenal of DMARDS for the management of RA. "Preferred" applies to those patients with the more severe form of RA,i.e.,those who have bone erosions,or are likely to develop them
MTX if effective,usually begins to have some benef icial effects within several weeks of starting therapy. The typical,once-weekly oral dose is convenient and relatively inexpensive (about $600 per year),although for children the dosage is higher and is often given by injection.
MTX and steriods are the only DMARDs that are contin ued by more than 50% of people with RA versus 20% for the other DMARDs. Not everyone responds to MTX ,about 40% do not. MTX is usually started at low-dose,7.5mg and worked up until respose is established. If respose at say,19 mg oral, is not obtained,subcutaneous injection (25mg)is given with less reported side effects,with more efficacious results.
As with any potent drug,there are possible side effects that warrant careful monitoring. The main concern is with potential damage to the liver (rare),so that physicians need to be made aware of risk factors such as obesity, diabetes, alclhol intake or a history of hepatitis B or C,all of which can put additional stress on the liver.
Severe liver damage to people receiving long-term MTX is low,and their are sensitive blood tests for monitoring liver function. Folic Acid use,also helps lessen some side effects.
Hydroxychloroquine (Plaquenil): A regimen of one or two inexpensive tablets daily and its low toxicity make this a convenient choice,for milder forms of RA. Despite the relatively low incidence of adverse effects,including skin rash and stomach upset,there remains the concern over the very slight possibility of severe damage to the retina of the eye (rare).
Plaquenil is usually prescribed for people who usually lack the rheumatoid factor in their blood. Almost half the people in this category who take Plaquenil achieve some relief from symptoms within two to six months. If not,it is discontinued.
Regular eye exams are always recommended for those taking this DMARD The effectiveness of this medication in a relatively small group of people underlines the fact,that what works for some will not work for others,but that applies to nearly all RA medications.
Sulfasalazine (Azulfidine) now available in coated tablets to minimize stomach upsets. Like plaquenil, sulfa salzine is prescribed in milder cases of RA. It shows some positive effects after up to two or three months in over 30% of people who take the tablets.
There may be moderate side effects,including anemia and stomach upset,and it should not be taken by people with kidney or liver disese,asthma,or during pregnancy.

During the past decades gold injections were given at rather high concentrations and often proved quite effective against RA,but with far too many side effects,including mouth sores,skin rashes,and serious kidney problems.
Lower doses were introduced and studies showed these caused fewer side effects,gold was used more often. After a delay about two to three months after beginning therapy,about 60% experienced a welcome reduction of pain and inflammation
A capsulse became available (now discontinued) for fairly mild,slowly progressive RA, Oral gold or auranofin (Ridura) had fewer side effects than injectable gold,as gold sodium thiomalate (Myochrysine) or aurothioglucose (Solganal),but was less effective.
Gold is used fae less now than in the past,given the increased use of methotrexate and availability of newer medictions.
Penicillamine is a great example of how one has to balance the "good" with the "bad" about a particular therapy. In the 1960s Dr. Jaffe in New York reasoned that this substance because of its chemical structure,might be able to break up the rheumatoid factor,that protein circulating in the blood of most people with RA.
Jaffe and 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.--"good news."
The "bad",is that penicillamine is a very toxic substance. Almost half the people who started on this drug had to stop taking it because of side effects. Those includ 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.
Cyclosporine appears to have some quite specific,identifiable effect on the immune system. It is particularly effective in blocking T cells,those white blood cells that pump out lots of inflammatory chemicals,from releasing IL-2 a chemical signal that provokes inflammation in the joints. In theory it sounds good.
However,cyclosporin or cyclosporine and its newer formulation,Neoral,a more easily absorbed solution is seldom used by rheumatologists. It is expensive ($4,700 per year) and fairly toxic.
Despite its powerful ability to suppress certain parts of the immune system,only about one-third of those who turn to this treatment have a greater than 50 %improvement
The side effects can be severe,espicially stomach and intestinal irritation,kidney damage,and elevated blood pressure Typically it is used in combination with methotrexate for people who have severe RA and have not responded to the methotrexate alone.
Cyclosphamide and Azathioprine are powerful and very toxic medications that have come out of decades of searching for anti-cancer compounds. Because cancerous growths contains lots of actively dividing cells,the goal has been to isolate or make chemicals that will selectively kill such cells.
Using the same chemicals,referred to as cytotoxic drugs,against RA is intended to kill off rapidly 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 in the body may be killed indiscrimiinately,causing many side effects ,including serious blood disorders and infections,and may even trigger new cancerous growth.
Cyclophosphamide (Cytoxan) is more powerful and toxic than azathioprine (Imuran). It is used only when RA is severe and has not responded to other treatments,or in cases where there is severe inflammation of blood vessels Ivascilitis).
Azathioprine,while less toxic,still can trigger serious infections and blood problems. It is usually reserved for people whose RA has not responded to other Dmards. Recently,physicians are including azathioprine in combination with other DMARDs for RA therapy.
These drug will rarely be used to-day in RA therapy,with the newer biologics available but,there are still people who do not react favourably to biologics or the regular DMARDs..

There is still widespread skepticism in the medical community as indicated by the fact that the "Guidlines for the Management of Rheumatoid Arthritis" prepared by the ACR did not mention antibiotics as an RA treatment (1999).
The updated 2001 guidlines,under,Tetracyclines mentions one trial,with patients who were positive for the HLA shared epitope (HLA-DR4+). The trial showed long-term benefit and  a decrease in radiographic progression in a subset of patients. It concludes that further research is necessary to define the exact role of tetracyclines in the treatment of RA.
A careful look at the process of inflammation and damage in RA reveals one of the reasons why confusion reigned over the effect of these antibiotics. The tetracycline group,including minocycline and doxycycline,as Minocin and Doxy (among several other U.S. brand names),does not just inhibit bacterial growth,it also interferes with production of inflammatory prostaglandin chemicals and T cells in the joint.
In addition,they reduce the supply of destructive enzymes that can erode cartilage and bone. Whatever beneficial effects these antibiotics have may be due to their influence on the immune system.
Further studies are needed to determine exactly how the tetracyclines affect the RA process,but despite a residue of reluctance to use these antibiotics, rheumatologists are beginning to reconsider them as a valid and useful ingrediant in their combination of RA therapies. Currently rheumatologists may use it for the milder non-aggressive,type of RA.


Minocycline as Treatment for Rheumatoid Arthritis

In the January 15, 1995 issue of the Annals of Internal Medicine, investigators in the MIRA (Minocycline in Rheumatoid Arthritis) Trial Group reported the results of a double-blind, placebo-controlled trial of minocycline in patients with rheumatoid arthritis. These data were reviewed in a November, 1993 Hotline, following presentation at the Annual Scientific Meeting of the American College of Rheumatology.

Patients in this trial were randomized to receive either minocycline (109 patients, 100 mg bid) or placebo (110 patients) for 48 weeks. Approximately one-half of the patients had previously received disease-modifying drugs, although therapy during, or 3 months prior to, the trial was not permitted. One-third were receiving low-dose corticosteroids (<10 mg of prednisone/day), and NSAIDs were permitted. Primary outcome measures included joint tenderness, joint swelling, evaluator' s global assessment, patient' s global assessment, duration of morning stiffness, Modified Health Assessment Questionnaire (MHAQ), hematocrit, erythrocyte sedimentation rate, platelet count, IgM rheumatoid factor, and radiographs. The majority of patients were classified as having mild to moderate disease with some evidence of joint destruction.

Statistically significant reductions (50% or greater improvement) in joint swelling and tenderness were noted compared to placebo-treated patients (54% versus 39% of patients; 56% versus 41% of patients, respectively). Significant changes in hematocrit, ESR, and rheumatoid factor were also observed, although no statistical differences in other parameters were appreciated.

At 48 weeks, approximately 80% of both groups continued to receive study medication. Therapy was discontinued most frequently secondary to inefficacy in the placebo group and toxicity in the minocycline group. In this regard, 6% of drug-treated patients dropped out because of possible toxicity, although only slight differences in the frequency of dizziness were reported.

Based on these results, the authors concluded that minocycline was a safe and effective medication for treating patients with mild to moderately active rheumatoid arthritis.

A similar study has been reported by Kloppenburg et al (Arthritis & Rheumatism 37:629-636, 1994). Although this Dutch study was of shorter duration (26 weeks), it included patients with more severe disease than in the MIRA trial. Again, the drug was well-tolerated, but the improvement in clinical parameters was modest.

The precise mechanisms whereby minocycline may be efficacious in RA 2re unclear. Apart from the potential anti-microbial effects of this medication and the interest in Mycoplasma as a causative or contributing agent for the development of RA, minocycline has been demonstrated to be an inhibitor of metalloproteinases, including collagenases and gelatinases. Conceivably, reduction in enzymatic activity induced by minocycline might exert a beneficial effect. Other potential mechanisms of action might include inhibition of phospholipase A2, suppression of neutrophil function, and reduction in T cell proliferation.

Although these results are clearly of interest, enthusiasm for minocycline in the treatment of RA must be tempered. The patients in the MIRA trial appeared to have moderately severe disease, and many had required remittive therapy prior to inclusion in the trial. Modest responses were noted for some, but not all, parameters. Both minocycline- and placebo-treated patients showed improvement in joint swelling and tenderness, although statistically significant changes were observed in the comparison of agents. Many patients received either NSAIDs or low-dose corticosteroids during the study which may have influenced disease activity. Furthermore, the duration of response after discontinuation of treatment is unclear. Finally, longer treatment periods and comparison with disease-modifying drugs will be necessary.

Additional trials are required before minocycline can be favorably compared with, or used instead of, current second-line agents in RA.

Perched on top of each of the body's two kidneys is a thin wedge of brown tissue,about the size of a large dollar coin. These small but powerful adrenal glands,in synchrony with the needs of the body,release minute amounts of dozens of different hormones,critical to the normal functioning of our cells,tissues,and organs.
The inner part of the glands produce the familiar adrenaline,which increases the heart rate,blood pressure, and blood sugar levels,quickly preparing us for strenuous physical activity. The outer layer of the adrenals makes, among other hormones,glucocorticoids.
These are more familiarly called steriod hormones, which means they are formed from the steriod chemical cholesterol circulating in our blood. These adrenal hormones should not be confused with synthetic anabolic steriods that some people take to increase the size and strength of their muscles (at risk to their health).
These glucocorticoids trickling out of the adrenals into the bloodstream fine-tune our metabolism,they can speed up the breakdown of fat and proteins, raise our blood sugar,and increase sugar storage in our muscles. We are interested in the effects that they have on the immune system.
The principal glucocorticoid hormone is cortisol. This is an anti-inflammatory substance that the body uses to decrease the number of white blood cells an to stifle the secretion of inflammatory chemicals from tissues. The familiar term is cortisone.
Cortisone is the name of another adrenal hormone that the adrenal first converts into cortisol,and also is the name given to one of the several synthetic forms of cortisol. Cortisone and other synthetics have become central to the treatment of RA,as well as other inflammatory conditions.
The unmistakable relief from pain and suffering wrought by large doses of these medications for extended periods of time inflicts a range of serious side effects including diabetes,dngerously high blood pressure,weight gain,thinning of the bones (osteoporosis) to the point where they fracture easily, cause infections ,and may lead to depression.
It was soon evident that a balance had to be struck between the real benefits and the real dangers of these hormones.

Because of the potentially devastating effects of cortisone there are general guidlines for its use. When NSAIDs are not able to control symptoms,and DMARDs like methotrexate are given but have not yet taken effect,low doses of glucocorticoid tablets can halt the symptoms in the interim (bridge).
Sometimes,when neither the combination of NSAIDs and DMARDs is effective,physicians add low doses of glucocortcoids to the mix. Ideally,one uses the lowest effective dose for the shortest possible time.
Sometimes severe complications of RA require much higher doses. Glucocorticoids also are injected directly into very swollen,painful joints,giving relief for several weeks without wide-ranging side effects.
Research published in 1999 offered some encouraging news. People taking only 5 milligrams of the synthetic glucocorticoid predisolone for two years showed a substantial improvement of disease symptoms,and had no significant bone loss.
Recent studies also have revealed some of the secrets of exactly why glucocorticoids have such good anti-inflammatory effects.
When cortisone and its synthetic forms like prednisone or prednisolone come in contact with cells,that meeting turns on certain genes in the cells so that they make anti-inflammatory proteins,and it turns off other genes that are making inflammatory substances.
A recent clinical trial study indicated that patients using  low-dose predisone, 7.5 mg., displayed disease modifying properties (less erosions) and the results,  also, showed a positive action,on IL-1 reduction.

Unfortunately,the use of NSAIDs can cause serious gastrointestinal complications. It can occur suddenly with little or no warning.. For people taking NSAIDs who are considered at greater risk,e.g.,those with a history of ulcers or the elderly,there are medications to help prevent these complications, such as misoprosol (Cytotec).
People with normal kidney function are at low risk of NSAID induced kidney damage but people who have deceased kidney function because becauce of e.g.,congestive heart failure,and the elderly are at a greater risk
NSAID works by blocking the activity of an enzyme,COX. This enzyme is resposible for making prostaglandins. There are many different types of prostaglandins. Some contribute to the pain and inflammation of RA,but other kind of prostaglandins are beneficial. For example,the help the stomach resist ulcer formation.
In the early 1990s,further research on the COX- enzyme revealed there are two distinct forms of the enzyme,COX-1 and COX-2 (scientists believe there may be a COX-3).
The COX-1 form makes the kind of prostaglandins that are always found in many tissues such as the stomach and the kidneys,and helps to keep them healthy and free of irritation. for example,in the stomach these prostaglandins stimulate mucus and bicarbonate secretion (the active ingrediant is Alka-Seltzer). In the kidneys,they help to maintain a healthy blood flow and stimulate salt excreation.
It is the COX-2 type that makes the prostaglandins that are found at sites of tissue inflammation. It turns out that the typical NSAIDs slow down the activity of both forms of the enzyme. On the one hand,they can suppress inflammation by inhibiting COX-2,but simultaneously turn off the helpful COX-1-a mixed blessing.
Given this important insight,it makes sense that scientists turned to creating drugs that would specifically block COX-2 and therefore suppress pain and inflammation, while sparing COX-1,the helpful enzyme
This research soon resulted in the late 1990s in a revolution in the world of NSAIDs,new NSAIDs available,that selectively inhibit COX_2 and have fewer undesirable side effects.
As true with so many medications,response to NSAIDs differ greatly among individuals,and NSAIDs can and do give some relief from pain and swelling.
Pain relief is generally quick,while the anti-inflammatory effect may not take hold for some weeks (4-6). NSAIDs do not modify or  stop the disease progression in RA,but they have helped millions through their use.