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Sock's Toxicity And Drugs In RA:
Side Effects
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New medications may arrive on the scene with great expectations,only to have it dampened that it is not useful for every patient. Often,the relief they give is accompanied by side effects that limit their use. Drugs that bring relief in the beginning become ineffective over time.
For many patients,timely and careful selection and use of medications,has eased their pain,slowed the progress of their disease,and improved the quality of their lives in a way that would have seemed impossible 10 years ago.
The years,1998-1999,seen the approval by the FDA of five new medications . Leflunomide (Arava ) arrived in 1998 as a new, useful DMARD,especially for those patients who could not tolerate methotrexate. 1999 marked the arrival of two Cox-2 NSAIDs,Celecoxib (Celebrex) and Rofecoxib (Vioxx), which was originally used for osteoarthritis and recently approved for RA
These NSAIDs were designed to provide a lower incidence of gastrointestinal problems then the older NSAIDs such as Naprosyn.  Bextra another NSAID, was recently approved by the FDA which the manufacturers claimed,provided better pain relief than the other two NSAIDs.
Also in 1999,the Prosoba column,a blood filtering device,became available to treat people in the more severe stages of RA. One of the challenges to rheumatologists is the treatment of refractory RA (disease that does not respond to treatment.)
Etanercept (Enbrel) and infliximab (Remicade),approved in late 1998 and 1999,respectively, are both targetted at blocking the effects of TNF-alpha. This protein or chemical,is  one of the most used small proteins that "talks to each other",or communicate with one another in the disease process.
 These proteins,unleashes a whole cascade of inflammatory reactions that enhances and perpetuates joint damage. There are many cytokines involved in the inflammatory events associated with RA (Il-1,IL-6 etc.)
The positive (yet cautious) responses by rheumatologists to the appearance of these new medications were shared by the manufacturers of these "smart bombs". Total world wide sales were $1.5 billion in the year of introduction.
The high cost of some of these new medications is a particularily problem that factors in the decision to use them (Remicade-Enbrel )
These recent arrivals,hailed as the "savior" by some,has brought with them, both new hope and also hype. Not all patients will respond to biologics and also,not all patients respond to conventional therapy. They are a wonderful,and necessary addition to the rheumatomologists "ammunitions" in the battle with RA.
The newest approach to RA treatment is one in which combinations of DMARDs are used in the early stages od the disease.
Many rheumatologists now maintain that therapy with DMARDs should begin as soon as a diagnosis of RA is made. There is a growing conaensus that confronting RA in an early phase with powerful medications could make all the differences in avoiding disease progression and hopefully induce long-lasting remission or at least slow down the dvance of the disease.
In 1996,the ACR wrote a new set of guidelines that all people"whose RA remains active despite adequate treatment with NSAIDs are candidates for DMARD therapy". They recommend that this addition of DMARDs not be delayed beyond three months.
They point out that people who have active RA marked by pain and swelling in mutiple joints and who have rheumatoid factor in their blood stand a greater than 70 % chance of developing joint damage or bone erosions within 2 years of the beginning of the disese.
That is why current treatment of RA tends to feature early,agressive treatment, which means the use of DMARDs,often in conjunction with NSAIDs. According to the guidelines,"the goal of treatment is to intervene in the disease before joints are damaged.
Methotrexate has been used for the treatment of rheumatoid arthritis for decades. It was only ,in tests conducted in 1999 that confirmed it delays disease progression. The long term prospect is excellent,but only 60 % of patients in clinical trials showed they respond to MTX.
 Rheumatologist know what MTX can do and it's side effect and know what they can do to ensure safety to the patient. MTX has been further proved efficatious by using 25 mg subcutaneous injection with lesser side effects,in late 90s tests.
Enbrel has a excellent 5 year history and surpass MTX in early RA,but the ACR criteria is not that far to bypass MTX completely. We do not have a 10 year history on the biologics. Mtx can be used in combination with the biologics. Arava has been substituted for MTX in combination therapy,with relative safety.
There has been combination therapy done on Kineret (Il-1ra) in combination with other biologics,but infection was higher then normal. Scientists are looking at if it is dose related and at what dose can they use safely.

 Side Effects:

Side effects are adverse reactions to drugs taken properly-at normal doses and without other complicating factors such as use of other drugs. Before drugs appear on the market, the FDA usually mandates testing in healthy people as well as treatment of people suffering from the disorder. Then the benefits of the drug are compared with the risks, and guidelines for its use are drawn up. However, this testing may not reveal side effects that occur in less than 1 out of 1,000 cases, only in special cases (e.g., adverse effects during pregnancy), or only after long use of the drug or as a delayed reaction.

Adverse reactions to drugs can range from a change in laboratory results, noticeable only with sensitive testing, to life-threatening allergic reactions. They can affect any organ or organ system, and often, confusingly, mimic new or exacerbated symptoms of the disease they were prescribed to cure.

 Reducing Side Effects

In some cases, side effects can be minimized or avoided by:

  • Reducing the dosage
  • Changing the route of administration
  • Taking the drug at different intervals
  • Changing medication to a similar,but different brand
  • Stop the medication

  • There are several forms of adverse reactions to drugs. Physicians distinguish among intolerance, idiosyncrasy, and allergy to any given drug. Intolerance occurs when a patient shows undesirable effects like those of overdosage at normal therapeutic dosage levels. Idiosyncrasy occurs when a patient's metabolism handles a drug in an unusual, unpredictable way. These two forms of adverse reaction do not depend on previous exposure to the drug.

    In drug allergy, which does depend on previous exposure, the reaction may be immediate, especially if the drug is taken intravenously, or the reaction may take a week to develop. Common allergic reactions to drugs such as insulin, penicillin, and barbiturates include low fever, itchy rashes, and hives. Treatment consists of discontinuing the medication.

    Probably the most drastic drug reaction is anaphylaxis, a violent form of drug allergy (see below). The first symptoms are all-over itchiness, especially on the soles of the feet and the palms. The skin of the face and ears may swell, mimicking a bad sunburn. The bronchial muscle (the muscle in the airway leading to the lungs) constricts, and the patient struggles for breath. The blood vessels dilate, blood pressure drops, and the patient faints. Deprived of oxygen, the brain and nervous system cannot narrow the blood vessels again, and the body cannot recover without immediate medical aid. Treatment consists of epinephrine, a drug that constricts blood vessels and dilates the bronchioles to open the airway. Steroid drugs may be given for a few days to aid recovery.

    Other signals of allergy or serious adverse reaction to drugs include bleeding, wheezing, vomiting, impaired sight or hearing, and muscle weakness. Hives (itchy red lumps on the skin), headache, rashes, nausea, and drowsiness are less serious side effects. A physician should be consulted when side effects occur. Often another drug can be substituted; sometimes the patient must learn to tolerate the unpleasantness.

    A person who has experienced an allergic reaction to a drug should carry a wallet card or wear an ID necklace or bracelet with the information even if the initial reaction was slight. Subsequent exposure to the drug may provoke more severe reaction.

    Types of Allergic Reactions

    Mild Allergy

    • Itching
    • Rash or hives
    • Headache
    • Nausea and other GI symptoms <LIDROWSINESS < U>

      Antihistamines can be used to prevent certain allergic responses. However, because of their slow onset, they are not very effective in treating reactions already underway.

      Anaphylactic Shock

      This is a life-threatening allergic response that occurs within 1 hour (usually within minutes) of taking a drug. Emergency treatment is necessary. Treatment consists of an injection of epinephrine (adrenaline), which opens the blood vessels and airways, antihistamines, and sometimes steroids.

      Symptoms include:

      Extensive itchiness (especially on the soles of the feet and the palms)
      Severe swelling of the eyes, lips, or tongue
      Swelling of the throat, causing difficulty in breathing
      Extensive dizziness
      Nausea and vomiting
      A rapid drop in blood pressure that can lead to fainting and even death

      Serum Sickness

      This usually appears 1 to 3 weeks after the drug is taken, and disappears within a week after discontinuation. Symptoms include:

      Skin rash
      Aching muscles and joints


    Did you know that taking your medications properly is one of the best ways to avoid future health care costs? Each year, thousands of people end up in the hospital, fail to get better, and spend more than they should, simply because they do not take their medication properly.

    Pharmacists can educate you about your medications, both prescription and nonprescription. The American Pharmaceutical Association, the national professional society of pharmacists, says that every person should be able to answer the following questions before taking any new medication.

    1. What is the name of the medication and what is it supposed to do?

    2. When and how do I take it?

    3. How long should I take it?

    4. Does this medication contain anything that can cause an allergic reaction?

    5. Should I avoid alcohol, any other medicines, food, and/or activities?

    6. Should I expect any side effects?

    7. What if I forget to take my medications?

    8. Is it safe to become pregnant or to breast-feed while taking this medication?

    9. Is there a generic version of the medication that my physician has prescribed?

    10. How should I store my medications?

    Remember, it is important to establish a relationship with your pharmacist—and work with him or her to help medications work for you. Pharmacists want you to know that they are always available to advise you about your medications.

    Rheumatoid warning signs can represent a worsening or complications of the rheumatoid disease, side effects of medications, or a new illness that is complicating the condition of patients with rheumatoid arthritis. Patients with rheumatoid arthritis should be aware of these rheumatoid warning signs so that they can contact their healthcare practitioner before their health is jeopardized.

    Worsening of Joint Symptoms: This includes more pain, more swelling, additional joint involvement, redness, stiffness, or limitation of function. The doctor will determine whether or not these are significant, not the patient. Sometimes, patients have just begun a medication and some minor increase in joint problems might be occurring while the medication is taking effect. However, worsening symptoms can also mean that the medications are not working and that they require adjustments in dosing or a change in the medications.

    Lack of Improvement of Joint Symptoms: One major purpose of seeing the doctor is to get better. The doctor knows this. If a patient with rheumatoid arthritis has seen the doctor and is started on a treatment program and is not showing improvement, but is worsening, notification of the doctor is appropriate. After starting a new treatment program, it sometimes takes time for the medications, physical therapy, etc. to control the inflammation. It is up to the doctor to decide if things are on course.

    Fever: A mildly elevated temperature is not unusual in a person with active inflammation from rheumatoid arthritis. However, a true fever (temperature is above 100.4 degrees F or 38 degrees C) is not expected and can represent an infection. Persons with rheumatoid arthritis are at increased risk for infection because of their disease and frequently because of their medications. Many of the medications used to treat rheumatoid disease suppress the immune system of the body that is responsible for defending against infectious microbes. Furthermore, these medications can increase the risk of a more serious infection when a bacterium or virus strikes. It is important for persons with rheumatoid arthritis to notify the doctor as soon as a fever occurs so that infections are treated at the earliest time possible. This can minimize the chances for many serious complications of infections.

    Numbness or Tingling: When a joint swells, it can pinch the nerves of sensation that pass next to it. If the swelling irritates the nerve, either because of the inflammation or simply because of pressure, the nerve can send sensations of pain, numbness, and/or tingling to the brain. This is called nerve entrapment. Nerve entrapment most frequently occurs at the wrist (carpal tunnel syndrome) and elbow (ulnar nerve entrapment). It is important to have nerve entrapment treated early for best results. A rare form of nerve disease in patients with rheumatoid arthritis that causes numbness and/or tingling is neuropathy. Neuropathy is nerve damage that in persons with rheumatoid arthritis can result from inflammation of blood vessels (vasculitis). Vasculitis is not common, but it is very dangerous. Therefore, it is important to notify the doctor if numbness and/or tingling occurs.

    Rash: Rashes can occur for many reasons in anybody. However, in persons with rheumatoid arthritis, the medications or, rarely, the disease can cause rashes. Medications that commonly cause rashes as side effects include  (Solganal, Myochrysine) gold, (Rheumatrex, Trexall) methotrexate, (Arava) lefluenomide, and  (Plaquenil)hydroxychloroquine. A rare, and serious, complication of rheumatoid arthritis is inflammation of blood vessels (vasculitis), which can cause rash that most commonly appears in the finger tips, toes, or legs.

    Eye Redness: Redness of the eyes can represent an infection of the eyes, which is more common in persons with rheumatoid arthritis because of dryness of the eyes (Sjogren’s syndrome). Redness can also result from blood vessel inflammation (vasculitis), especially when pain is present.

    Vision Loss of Red/Green Color Distinction: A rare complication of the commonly used rheumatoid arthritis drug hydroxychloroquine (Plaquenil) is injury to the retina (the light-sensing portion of the back of the eye). The earliest sign of retinal changes from hydroxychloroquine is a decreased ability to distinguish between red and green colors. This occurs because the vision area of the retina that is first affected by the drug normally detects these colors. Persons who are taking hydroxychloroquine (Plaquenil) who lose red/green color distinction should stop the drug and contact their doctor.

    Nausea: Nausea is a common problem in patients with rheumatoid arthritis, usually because of the medications that are required to keep the joint inflammation minimized. Medications frequently used to treat rheumatoid arthritis that can cause nausea include non-steroidal antiinflammatory drugs (NSAIDs such as ibuprofen,naproxen and many others), (Imuran) azathioprine, predisone,prednisolone,and methotrexate (Rheumatrex, Trexall). Nausea is usually not serious, but it is always annoying. Depending on the particular situation, the doctor may have the options of stopping the drug, lowering the dose, and/or adding a medication to treat the nausea.

    Persons with rheumatoid arthritis are at increased risk for infection. This risk occurs because the rheumatoid disease is an immune suppressed condition and because many of the medications that are used to treat rheumatoid arthritis can suppress the immune system. Examples of rheumatoid medications that suppress the immune system are methotrexate (Rheumatrex, Trexall), azathioprine (Imuran),(Remicade) infliximab, enterecept (Enbrel), cyclosporine (Neoral), and (Cytoxan) cyclophosphamide. An infection should be treated with appropriate antibiotics as early as possible before it becomes serious.

    Cough or Chest Pain:
    Chest pain that is caused by arthritis of the chest wall is not an emergency and does not warrant notifying the doctor immediately. However, unexplained chest pain or cough can represent serious underlying disease of the heart or lungs. It should be remembered that persons with rheumatoid arthritis are at increased risk for infection of the breathing passages and lungs. Such infection requires antibiotic treatment. Furthermore, methotrexate (Rheumatrex, Trexall) can cause lung inflammation, the first sign of which is often a persistent cough. Chest pain can also be caused by the reflux of acid from the stomach into the esophagus. This condition can be aggravated by aspirin and other NSAIDs.
    The warning signs above are not meant to be all inclusive. There are many other symptoms of illness that also are reasons to contact the doctor urgently. For example, vision loss from a  chest pain or stroke,from a  heart attack are reasons to contact a doctor immediately. The symptoms listed above are warning signs that occur more commonly as a result of rheumatoid disease. Persons with rheumatoid arthritis, therefore, should have a heightened alertness for these symptoms. They should also feel free to contact their doctor about any health issues or concerns at any time

    The toll that NSAIDs take on the stomach is due to the fact that they cut down on the amount of protective prostaglandins,which normally inhibit acid secreations and protect the stomach lining with a layer of thick mucus.  NSAIDs,increase the acid secreation and interfere with mucus production.
    Not everyone takeing NSAIDs runs the same risks. There are variables to consider such as the specific drug,the dose,the duration of exposure to the medication,and as usual,the great variety of individual characteristics of the individuals who take the drug,including age (elderly increases risk) and tendency to develop stomach ulcers.
    Taking NSAIDs is a trade-off between benefits and possible harm In the U.S.,1.2 percent of the population takes NSAID daily,consuming 40 billion aspirins and 70 million NSAID prescriptions yearly.
    Researchers discovered that there are two distinct forms of the Cox enzyme,Cox-1 and Cox-2. Finding that the Cox-2 form makes the kinds of prostaglandins that are active in RA,scientists set about to find a substance that could block Cox-2. The Coix-1 type of enzyme is always active in our tissues,making prostaglandins that help to maintain the healthy functioning og our kidneys,lungs,and gastrointestinal tract
    The typical NSAIDs,to varying degrees slow down both types of Cox. This results that while NSAIDs are providing welcome relief,they also reduce the amount of helful prostaglandins,paticularily in the stomach. This can lead to ulceration and bleeding in the stomach in some patients.
    NSAIDs such as Celebrex and Vioxx are referred to as Cox-2 inhibitors.

    The Immune System:
    The human immune system is an intricate,dynamic drama or stimulaus and response featuring a cast of of billions of cells,a language understood  only by the players,and a setting that includes every scene in the human body.
    Cells are living sacks of chemicals. Cells communicate with each other. The language that cells use is spelled out in molecules. The chemical messages that arrive at the cell borders are translated by the cell into commands that alter the cell's own chemistry in some way.
    Cells detect these signals when the chemicals combine with specific receptors on the cell membrane,which then relay the information to the cell interior's interior. These receptors are special proteins. Proteins,which can be thought of as locks,they will open up only in response to the right key.
    Depending on the chemical message that the unlocked lock lets inside, the cell may respond by switching on or off specific genes or may slow down or speed up the activity.
    Through this constant monitoring of the chemistry of the environment, a cell acts in a way in keeping with the  messages brought to it from near and far.
    The result is a living,active human individual whose countless cells,by responding to what they recieve as chemical commands,react by adjusting their own chemistry.
    But,things can,and do go wrong. We face two dangers,one from within the body,the other fromm without. Within each cell the very genes inherited from our parents,can include in their numbers that can bring havoc in the form of genetic diseases.
    While many  diseases have genetric components,only of which some have been identified,there are other contributing factors required for the expression of disorders such as RA.
    There are schools of thought (among others) that RA begins by an attack by viruses and bacteria,( none of which has been proven as the factor.) Some of the protective responses of the body to the arrival of those dangerous organisms mirror some of the same responses that the immune systems of RA make towards their own tissues.
    In a normal immune system viruses and bacteria are attacked and destroyed by cells and chemicals. In the case of RA patients,the same efficient weapons are turned against the tissues of the joints and elsewhere,and the destruction wrought,brings pain and disability,if left unchecked.
    The reactions of our immune systems require cell workers and chemical messages and also a means of carrying these messages throughout the body. For that purpose we use two quite distinct but interconnected anatomical networks,the blood circulatory system and the lymphatic system.

    The lymphatic system is much more than simply another route available for recirculating tissue fluid. It is the essential framework of the immune system,a critical resource for the recognignition of danger a supplier of the tools that defend us against the damages.
    Situated along the course of the lymphatic vessels are hundreds of lymph nodes,masses of organized lymphatic tissues, which act as filters through which the tissue fluid,now called lymph,trickles. Large aggregates of these nodes are located under the arms,in the groin,in the neck,and elsewhere. Several organs including the spleen,the appendix,and the tonsils are masses of lymphoid tissue.
    These lymphatic filters are filled with cells that are waiting to detect the slightest hint of danger in the tissues. If invaders such as bacteria get beneath our epithelium they are met by scavenging cells (white blood cells) such as the macrophages. These scavengers engulf the invaders and eat them. Some of the macrophages slip into nearby lymphatic vessels and are carried in the lymph stream to the nearest lymph node.
    There,the macrophages present specific fragments of the remains of the invaders to cells waiting in the node for just such a signal. These presented fragments are the antigens,specific pieces of the invader,usually proteins,that the immuhe system recognizes as dangerous.
    Alarmed by the prospect of an attack on the body,these waiting cells spring into action and set off a series of interdependent events that result not only in the production of protein antibodies ,specifically manufactured to combat the specific offending antigen,but also part of the bacterial cell itself. The antibodies mark it for destruction.
    The newly recruited cell helpers leve the lymph nodes,flow through the lymphatic vessels to the blood and soon arrive at the affected tissues. There,powerful chemical signals persuade the cells to slow down,stop,and work their way through the capillary walls to join the ongoing struggle.
    This scenario is so much a part of what goes on in RA. There is much more to the complicated,complex,long,equation. 

    We continue to hear about new treatments for RA. However, it seems that so many of the treatments available have side effects. What about the side effects involved in biologics- infection ,MS,and TB ?
    Some people have side effects to almost any treatment where other people seem to tolerate lots of things, and you can never know in advance.  
    A lot depends on the patient and how they individually respond to an agent. Some people have side effects to almost any treatment where other people seem to tolerate lots of things, and we can never know in advance. Should a side effect appear,the physician can intervene and change the dose or change the medicine or adjust things so that we don't get severe side effects.
    Patients need to know what are the potential side effects so they have an idea what to look for when they are taking a new medication. It just goes back again to the importance of taking control of your illness and your management of your illness as well as good communication with your physician. Sometimes rheumatologists are puzzled as to why a side effect had occurred.
    It's extremely important to,just pay attention to what are some of the possibilities. When you start to notice something, don't be afraid. As soon as you think something's going that shouldn't be occurring, contact your physician right away.
    We need to read the brochures about the medicines, know what some of the side effects are. Sometimes it's how you're taking it, when you're taking it, with what other medications you're taking. It's also critical that the primary care physician works with the rheumatologist and doctors talking to one another in addition to talking to the patient.
    People are very worried about the new warnings concerning Arava, Enbrel, and Remicade including some deaths and instances of MS symptoms and TB. Are some people more susceptible to these complications than others?
    As many people may be aware, there was recently a petition to ask the FDA to look at the potential for liver complications from Arava or leflunomide. The FDA have addressed the issue,in question. There's a tendency when these get reported by the news media, perhaps who themselves have not seen the data, to perhaps raise an alarm that doesn't exist.
    Tuberculosis is an infection you never really get rid of. Your body just effectively walls it off, and these macrophages are very important in sort of walling that off. Anyone who's considering going on a TNF inhibitor like Remicade or Enbrel, they need to be checked for a skin test for tuberculosis.
    If the skin test is negative, odds are there's really no increased risk, there are situations where that's not true, but generally speaking, and there probably isn't any substantial increased risk.
    However, if you have been exposed to tuberculosis in the past, then that would mean a swelling would occur where you got the skin test for tuberculosis, then you need a chest x-ray from the doctor, and to make sure there isn't active lung involvement right now.
    Depending on a person's age, the rheumatologist might say, "Well, we're just going to follow this." In the whole situation, they might say, "Yes, we can use a medicine like Enbrel or Remicade, but follow it closely with regular chest x-rays," or they might even consider putting you on medicine to prevent tuberculosis coming back.
    There are a number of factors that fit into this -- one is if you're on high doses of steroids because being on more than 10 milligrams of prednisone for sure, that increases the risk of waking up tuberculosis. There are a couple different factors of that.
    Now the second is a question about MS, and it comes down to the idea that rare events can occur in populations, and it's like birth defects. We don't really know how often MS really occurs in people with rheumatoid arthritis.
    We know that people with rheumatoid arthritis get more lymphomas -- that's a kind of lymph node cancer -- than the general population, but we don't really know exactly how often MS occurs. Maybe it occurs more frequently or not as frequently.
    The other answer is in on multiple sclerosis and any of these TNF inhibitors, but scietists feel strongly that if a person had MS in the past,they should not be treated with these medicines, and if people have new or strange symptoms that worry them, they should be talking with their doctor, and these are questions that most of the time can be pretty easily addressed.
    Another issue is that.anyone who's using alternative therapies, particularly if these are therapies that are ingested, whether these are herbs or nutriceuticals or whatever one is using, it's really important that the doctor know about this for a couple reasons.
    One, the therapy may actually be working, and the doctor is giving credit to something else. That's one thing. More importantly, there's always the possibility that the therapy could in some way potentially be interacting with what the doctor is giving the patient,it's very important that there's an open dialogue as to things that people are  doing.
    Alternative therapies can range from things like acupuncture, ways of exercise, biobehavioral therapies, and everybody, including rheumatologists, believe that some of these things are probably terribly important. They've not been well studied, so when we say, "Take control," some of the alternative therapies are probably the patient's best way of personally taking control, and therefore,health-care professionals would encourage people,to open up with their doctor. Have a dialogue about this.