Medications

Sock's Rheumatoid Arthritis Page 1:

Medications

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NSAIDs can be terribly troublesome drugs for particular individuals, particularly elderly people or people with a past history of ulcers, and although the lower the dose that you use, the safer they are, the problem seems to be that sometimes people think if a little is good, then more is better. And so people adjust the doses up and take three tablets instead of two tablets like they're supposed to. There can be a lot of problems with high blood pressure or edema, ulcers, kidney problems. These are difficult drugs to use, particularly if you push to higher doses.

Side effects from RA medications are often compounded because these same patients have other underlying diseases such as diabetes,heart,liver and kidney,underlying diseases already present. Rheumatoid arthritis is often referred to as a disease of mutiple consequences in many patients. Some patients will have minimal or no side effects of major consequence. Overall health is a major concern in RA patients.

There's a subset or a group of patients where we need to be worried. Those are the patients with edema or swelling, congestive heart failure, renal or kidney problems, people with stomach problems such as ulcer disease, and people who happen to be older.

One of the problems is too often these are the same people that physicians take care of who have rheumatoid arthritis. Another problem with the NSAIDs is that some patients and even sometimes their physicians will see a response and will think this is a sufficient therapy, and not realizing that the progression of the disease and the cartilage and bone wear continues despite these medications.

It's really a great idea from the beginning to help people understand what the goals are is to control symptoms and signs, and to try to prevent joint damage. And to use the disease-modifying drugs is a continuous process that's necessary.

Cortisone is such an important drug that we have, but it needs to be used very carefully because it can cause a lot of problems. And that using intermittent injections of cortisone into the joints can be a real godsend and can really improve people's function. For example, if someone's shoulder is limited in its ability to move, an injection of cortisone in the shoulder can provide rapid relief that can really provide benefits while you're waiting for the disease modifying drugs to take effect.

Gold is an old treatment, and in some ways that's really nice because we know a lot about it. We know what's good about it, and we know the bad about it. It is an effective treatment in about 55 percent of people who use gold. Gold suppresses the disease partially, but it's very slow. You need to use it with weekly injections for 20 weeks often to see clinical benefit.

And sometimes people can have problems with rash or low blood counts. Others can have oral sores or even problems with protein or blood leaking from the kidneys. So, while gold can be used safely and there may be particular patients that's a really good drug to use, it is something that is sometimes a troublesome drug, too.

Rheumatologists now look at this window of opportunity in the rheumatoid arthritis patients when they find the disease early and can intervene early. One of the problems with gold is that physicians have to wait often the 20 weeks or more to make a decision whether this is an appropriate therapy, and they may have lost six months of ability to treat the patients.

Gold is probably not a very good first choice of a second-line agent or of a disease modifying drug unless there's some reason that you didn't want to use methotrexate.

One has to come to the office once a week, has to get a urine test and a blood test once a week to be sure that they don't have the kidney and bone marrow troubles.

Plus there is not a lot of gold in it, so it's not quite like using a gold ring every time, but there is a cost to the gold itself, and then there's the cost of losing time from work or losing time from the family or having to hire babysitters to come to the office every week. So, its cost is not so much in the fact that it is gold but the way it's administered. There are individuals who do benefit from gold. The problem is just not enough.

Methotrexate is actually a therapy that's been around for a very long time. The way it actually works is still not perfectly clear. We do know it does work by decreasing inflammation, but it also works by decreasing immune cells. And a very large study that was published in 1999 showed that, finally, that it is not only a medicine that makes the patients' signs and symptoms or their joint pain and swelling better, but it slows the x-ray progression down, so it truly is one of our medicines that modifies the disease.

There are always risks involved with medications such as methotrexate. It's important also to understand that there are risks with not treating rheumatoid arthritis, and that's the perspective or the frame in which you've got to look at the possible risks of methotrexate. Methotrexate is very well tolerated by most people, and even in relatively high doses, more than 85 percent of people will be able to continue it for at least a year,many for many years.

And also, one of the other signs of its safety is that at five years, more people tend to stay on methotrexate than any other drug. So,before you can say anything specifically about side effects, it's important to note that generally it is very well tolerated by most people.

There are two types of side effects. One is the relatively common kind of minor side effects. Occasionally people are a little tired or may have a little bit of nauseousness or loose stools after they take their weekly dose. And then there are probably the less common or more sporadic type of problems which can be more serious, which are methotrexate-associated serious liver scarring, which occurs approximately in one in 1000 people who take it for five years, or serious lung scarring which can occur in around one and a half or two percent of people.

Methotrexate can be administered either by pill, which is the most common way that it's used in the United States, but it also can be administered by injection. The injections offer possibly a little more safety, a little more regulation of the dose, and in higher doses we're able to have to switch our patients to injectable methotrexate.

Leflunomide is a drug which is similar in some ways to methotrexate in that it impairs the ability of inflammatory cells to reproduce rapidly. It is a bit expensive, about 280 dollars a month, and so that's actually somewhat of a barrier to people who don't have health insurance, but it is generally well tolerated by people.

The side effect most commonly is loose stools associated with it, but for most people that's not too much of a problem. It has some benefits in that it does seem to have some benefit within the first six to eight weeks of use, and it appears that its ability to suppress swelling and pain and to prevent joint damage is perhaps close to or similar to methotrexate. Arava does not work for everyone.

The good news is it would be an alternative to patients who either did not respond or could not take methotrexate.

Plaquenil has been used for a long time, and there are some really nice features about it which physicians include that it really doesn't need frequent blood monitoring, and it does not have a significant toxicity to liver. However, at least in patients with recent-onset rheumatoid arthritis, there has never been a published study that has shown that it slows or prevents joint damage, so that in someone who has significant and functionally limiting rheumatoid arthritis. Plaquenil is not a good first choice.

Sulfasalazine can be a very helpful drug. It is relatively inexpensive. The mode of onset is not as fast as methotrexate, but certainly faster than gold. The side effect profile, unless it causes stomach upset, is generally pretty good. And actually in the research studied, it may not be as effective as methotrexate or leflunomide, but it is certainly an effective treatment. So, for some people, it is a very useful drug. In people with the most severe arthritis, though, again,physicians would think that a faster-acting and more potent drug would be their personal choice.

It's a rare thing, a need to use D-Penicillamine, and Rheumatologist.rarily or use it currently. With the advent of the biologics, happily we don't need to use it because it is a troublesome medicine

Now that we have a number of better-tolerated, faster and more effective treatments, these are clearly treatments that aren't used as often. Azathioprine is a drug that is effective to some degree in reducing joint swelling and pain. The data supporting the idea that it prevents joint damage is really not as robust, and it's really quite slow. And it's largely been supplanted in its place by Arava.

Treatment with cyclophosphamide was tested in the '60s, late '60s, early '70s, and it's certainly a very potent agent, but unfortunately it does carry with it a substantial risk of developing leukemia in the ten years after being treated with it. At least in most practises,it is rarely used.

In summary, in someone who has either very mild rheumatoid arthritis or maybe you're not sure it's rheumatoid, you might consider Plaquenil early, but choices such as sulfasalazine, Arava or methotrexate would be the first choices.

Many people who have rheumatoid arthritis, and many people who have arthritis, think of their arthritis sort of like having a bad flu. They feel fluish all the time with fatigue. They have aches and pains in their muscles and their joints, and it just feels like you have the bad flu that just lasts the last ten years. And it would suggest that maybe there's an infectious trigger. Rheumatoid arthritis oftentimes, will start acutely or suddenly, and oftentimes will follow an infection so that there was a lot of interest, and there has been for many, many years, looking for the infectious cause or trigger of rheumatoid arthritis, and this has not been found. (antibiotics story).

It is said minocycline works not because it's an antibiotic but because it inhibits a specific protein which causes inflammation and cartilage decrease in rheumatoid arthritis.

That's a backdrop to say that physicians do use an antibiotic for rheumatoid arthritis, but not because it is an antibiotic that's killing bugs in our system. It's because an antibiotic called minocycline, which is a tetracycline derivative -- this is the antibiotic that all of our teenage kids have taken for years for acne, so it's a pretty safe antibiotic -- has been shown by a research group headed by Dr. James O'Dell at the University of Nebraska to improve rheumatoid arthritis. They think it works not because it's an antibiotic but because it inhibits a specific protein or enzyme which causes inflammation and cartilage degradation or decrease in rheumatoid arthritis.

A few Doctors use minocycline in very early patients when they're deciding whether they should be on methotrexate or a biologic. They use it in patients with very mild arthritis. But if the patients have more long-standing or severe rheumatoid arthritis, They will skip minocycline and either go to methotrexate or a biologic. (see did doc make a mistake about a case involving minocycline).

Enbrel has started all of us thinking that these cytokines, especially the TNF cytokine and the IL-1 cytokine, are pivotal, let's say, bad actors in rheumatoid arthritis and need to be inhibited or slowed down. And adalimumab (huminra recently approved )-- and this blocks TNF somewhat like Remicade does, but it is fully human. Where Remicade is part mouse, part human, this is a fully human protein that blocks TNF and decreases it. And it's been shown, like Enbrel, to not only improve signs and symptoms, so, pain, swelling and inflammation, but slows x-ray damage as well, and this will be a choice in our biologic armamentarium for our patients with RA. New choices for patients who are not responding are obviously very much needed.

One of the biggest questions now. Really, with all of these new agents, how are physicians going to order them? How are they going to choose? It's nice for the patients with rheumatoid arthritis where they get, let's say, a 60 to 70 percent response rate with Enbrel, a 50 to 60 percent response rate to methotrexate, physicians still have many patients who don't respond. So, sometimes new choices for patients who are not responding are obviously very much needed.

Arthritis is a complicated and confusing disease. Doctors really understand so little of it themselves,it's hard for them to explain things in a way that makes a lot of sense to the patient,particularily in the time they have per patient. The situation generally improves with subsequent visits,but on a single visit,particularly on a initial visit, doctors rarely gets any real information through to them, especially if they're faced with a diagnosis such as RA,which is pretty frightening, in itself. Often patients just block out any information given to them.

Compliance isn't simply a matter of choosing to take or not take medication. There are any number of factors that come into play, communication failure,shortage of time,fear,ignorance,even,how hard it is to stick to a strict regimen over a long period of time. We're not very good at maintaining a wholesome all aroud nutritious diet or exercises,and the same thing applies to drugs. Doing things regularly, properly,is hard for all of us,and it's it's unrealistic to expect patients to take these drugs the way the're prescribed on a regular basis

Patient's do comply if time is spent dealing with areas where there might be a problem. Some physicians will take the time,not just give the prescription,but really take time and tell the patient what to expect,be candid and leave the door open for patients to contact them when there are side effects.

You,as a patient,may not be so lucky. You might not have a doctor who's willing or able to take enough time to answer all your questions, so you've got to be prepared to take advantage of the time available to you. Write down any questions you have beforehand,the most important queries at the top of the list. Deliberate on exactly what your problem is,medications you're taking,unusual symptoms you've noticed,and so on. If you don't do that, you may well forget the questions you wanted to ask.

Some people think they're complying but have misunderstood what the doctor said for example,one patient, thought she was following doctor's orders. She had been taking one NSAID,but the doctor changed prescription. Unfortunately,she failed to understand she was to stop taking the first NSAID-she continued with both. She became hard-hearing,when the first NSAID was stopped,her hearing became normal.

Another problem may arise because people don't realize why they're been prescribed a medication. If they think they're taking a NSAID just for pain,they might stop taking it when they discover they get more effective pain relief from a straight-forward analgesic,such as tylenol 2. Unfortunately the analgesic loses its effect over time,and before long they are up to six,eight,or more tablets a day,to get the same effect they once had with two. And,because they're no longer taking the prescribed NSAID,the disease management is lost. Patients have to ask themselves two questions:"Why do I need this medication ?" and "What could happen if I don't take it ".

Most anti-arthritis drugs,while they may have a pain-relieving component,are prescribed to control the disease (DMARD ) Making patients feel better is obviously a major goal,but not the only one.

That's something few of us are likely to understand without coaching. To a greater or lesser extent,we're all victims of our conditioning,and we may expect"painkillers" to ease our pain more or less instantly,and prefeably permanently. That's a partial truth at the best of times, and it's even less pertinent to most arthritic illnessess. If people expect arthritis medications to do for their disease what ASA does for a headache,they're in for a dissapointment. Understandably, some of them are going to become frustrated. At some point in the long hand of their chronic illness,they ditch their doctor-prescribed regimen and try one of the many unproven remedies,either for pain relief or in search of a "cure".

At the same time.patients should be urged to gently wean away from the idea of looking for a complete " cure". Doctors should be informed if the patient is experiencing pain that's not being controlled by their prescribed medications. The physician should be able to prescribe things that are very often very effective at getting the pain under control.

Patients can do themselves real harm through noncompliance, especially if they're on a regimen of ant-inflammatories or a more particular regimen of DMARDs. If they allow the disease to break through by not sticking to their medications, they do run the risk of increased joint damage and deformity over a longer period of time.

Compliance sounds like a negative word,but patients can get themselves into a lot more trouble by deciding to stop taking something than if they talk to their physicians and say,"I've been feeling great for some time now. What are the long term goals with respect to my medication ?"

The medication can often be gradually reduced over time,but stopping it on your own is not an informed decision,it is foolish. The goal is to keep patients on the smallest long-term dosage that will control the disease.

One of the biggest danger is when a patient looks at side effects accompanying the medication without weighing them. The patient only hears or reads "side effects";they don't hear the frequency or chance of getting them. Even if its only one in a million,it bothers them. It's hard for physicians to convey the idea that the drug is clinically been tested,used with success on patients,and approved by the FDA. Obviously it's safe to use in people,and the vast majority of people have no side effects,whatsoever.

On the other hand,the physician can't guarantee his patient won't have any side effects either. Therefore physicians monitor the patients for possible side effects and if the patient feels or sees any unusual symptoms,then the physician will either reduce the dose,stop the medication for a while,until symptoms subside,reduce the dose or stop the medication completely.

The patient has a role to play,they must educate themselves about all aspects of the disease. Keep in mind that every form of arthritis is different,and no two patients will exibit the same symptoms or have the drug affect them in the same way. Remember that there is many articles written on RA and medications may not have the same effect on the individual patient. We react differently to the disease,itself, and treatment.

Taking responsibility for your own health care isn't as daunting as it may sound,and the benefits are significant. The patient has a co-manager,the physician,who oversees the overall treatment regimen. certainly becoming more knowledgeable about your illness and treatment will have you less anxious and better able to cope with an occasional set back,or side effect if it does appear.

And getting actively involved will ensure the patient isn't overwhelmed by side effects from the medications. Merely knowing how to tell major from minor side effects,and what to do about both,strips them of their mystery and possible potential danger.

Medications:

One of the disadvantages that is not truly a disadvantage but a theoretical disadvantage is that physicians have been using methotrexate now probably for over 20 years in rheumatoid arthritis, and easily in many of the patients,for the last dozen years in rheumatoid arthritis. So, there is a long track record with methotrexate, and physicians know many of its side effects including liver and bone marrow troubles.

They have a long track record with methotrexate, and they know many of its side effects including liver and bone marrow troubles.

With biologics we don't have this large, robust group of patients who've been on it for ten years. As a matter of fact, we don't have that at all. However, researcher-investigators just presented the five-year data on Enbrel at an arthritis meeting showing that Enbrel over a five-year period of time was safe. They've published in The Journal of Rheumatology the four-year data, again showing that Enbrel as a biologic was a safe therapy in patients with rheumatoid arthritis. So, again, a theoretical disadvantage would be,not knowing what the ten-year data shows, as of to day.

Remicade has some other concerns that Enbrel doesn't. Since it's called a chimeric protein -- chimeric definition means it's made of two animals, or one is mouse, and one is human -- one has this allergic problem and one does have to take it with something else such as methotrexate, although recently scientists presented data showing safety in taking Remicade or infliximab with a newer drug called leflunomide or Arava. One takes this intravenously so that you go to the doctor every two months, and that may be an advantage to the patient, but one could have more allergic problems with the Remicade with the Enbrel.

Arava or leflunomide came on the scene about the same time, actually, or just before Enbrel, about 1998. I've been working with this compound since the mid-'90s and actually some patients are on it over five years now, and it can be used as what's called monotherapy, meaning as a single agent, much as physicians would use Enbrel as a single agent or they would use methotrexate as a single agent.

Remicade needs to be used in combination with something else. Arava has been shown to be able to be mixed with,Remicade in clinical trials, and it's been able to be mixed with methotrexate in a study from the Albany Medical Center showing again that again careful monitoring, that one could mix these compounds, and it adds a choice to patients with rheumatoid arthritis.

It would be wonderful if a drug was available that worked for everyone. Then they wouldn't need rheumatologists. They could just go to the local pharmacy and say that they want the treatment for rheumatoid arthritis.

Methotrexate is the gold standard of DMARDs,but unfortunately it doesn't work for everyone. Scientists doing their clinical research and clinical trials and evidence-based medicine, they often do placebo-controlled trials, meaning the patients and the doctors don't know if they're getting methotrexate or if they're getting placebo. They also do comparative studies such as comparing head to head, which they've done in clinical trials and have published -- methotrexate versus Arava, methotrexate versus Enbrel.

And if you look at the data, methotrexate again, in a research unit where the patients are carefully followed and the patients are blinded and don't know if they're getting methotrexate or not and the physician doesn't know, really is about a 50 to 60 percent good medicine. We're looking at about 40 percent of patients who really don't respond to methotrexate. And that's why the 1990s were the age when rheumatologists before they had biologics were mixing many medicines with methotrexate, and physicians still do mix many medicines with methotrexate, and that's because patients have incomplete responses or don't have responses to methotrexate.

If we look at the clinical information, and one has to do this with a special caveat because none of these groups of rheumatoid patients are exactly equal, but if we look at the group of patients on Remicade, we're getting responses in the same ballpark as we did with methotrexate alone although those probably were more difficult patients. Not that the patients were difficult, but their arthritis was.

If we look at the Enbrel data, on the other hand, we're getting responses that are better, and if we look at our long-term studies over the long haul, it looks like that Enbrel is probably a little bit better and more likely to work than methotrexate. Biologics are currently costly and health administrators (payers) feel methotrexate will do the "job".

This protein called TNF is increased in rheumatoid arthritis in the joint as well as in the joint fluid of patients with rheumatoid arthritis. This protein is called a cytokine. A hormone is -- much like thyroid hormone is a protein that's made in the thyroid gland in the neck and then is shipped around the body to tell the rest of the body what to do. Normal people have TNF in their bodies,but it is kept in balance. People with RA have an excess of tumour necrosis factor (TNF).

A cytokine is a hormone. It's a protein shipped around the body to tell the body what to do, but it can be made not just in one place like thyroid but it could be made in many different cells and many different places in the body. One should think of the cytokine, as the communication centre in immune system. It says "Foward March-," and it goes to all of your joints and causes arthritis and goes to the rest of the system and causes things such as fatigue,pain etc.

The other cytokine besides TNF that is increased in rheumatoid arthritis is a cytokine that's called called IL-1, and IL-1, much like TNF, has a naturally occurring blocker that's in balance like TNF,has a natural soluble TNF receptor, which Enbrel is, that puts us back in balance in the body. The anakinra or Kineret, the new biologic, is a balancer of this increased cytokine that causes arthritis, and it's an interleukin-1 cytokine balancer.

Many physicians now,have gotten very comfortable using methotrexate, and therefore methotrexate is often the first therapy started just because of comfort levels.

Biologics, or especially the anti-TNF agents, are becoming actually traditional choices in rheumatoid arthritis, and Kineret will probably be used in patients who are not doing quite as well either on one of the older biologic agents such as Enbrel or Remicade or patients who are not quite doing as well, let's say, on methotrexate or Arava.

"Kineret will probably be used in patients who are not doing quite as well either on one of the older biologic agents such as Enbrel or Remicade."

Investigator-scientists actually did a study and presented this at the last national arthritis meeting where they combined anakinra or Kineret with Enbrel, and there was a slight increased risk of infection. Right now,they're studying that to see if that's dose-related or how they can adjust the doses to make this work,currently, that is not a standard recommendation, but mixing Kineret with methotrexate or with Arava has been shown to be safe and efficacious.

Huminra (under clinical trials-DE27) is a totally humanized TNF inhibitor,recently approved for the treatment of RA by the FDA.

Enbrel, which is etanercept, and infliximab, the trade name is Remicade. They both are targeted towards the inflammatory messenger called TNF or tumor necrosis factor, and these are similar in many ways. Enbrel is actually the receptor that TNF binds to on the inflammatory cell, and this brilliant biotechnology company figured out how to make that little receptor and how to help it circulate in the blood, and so what it acts as a sponge to take this out of circulation. The infliximab or Remicade is a little different in that instead of just a receptor floating around, infliximab is an antibody, and that is it binds specifically to TNF and in the same way sponges it out of the blood.

Enbrel is really a nice drug because individuals can administer that to themselves, and so that gives them a measure of control and independence. It's also not really associated with a meaningful immune response, so it can be taken all by itself.

Remicade is also a terrific treatment, but it is a little different in that it needs to be given as an intravenous treatment, and because one third of Remicade comes from a mouse, they have to take a drug like methotrexate with it to suppress making anti-mouse antibodies

If patients fail on an initial agent such as methotrexate need to be considered for a biologic, if it is infliximab or Remicade, because of the mouse protein in it, one has to continue the methotrexate whereas with Enbrel or etanercept, it can be used as a single agent with very good success.

The most important message is to treat early and to treat aggressively and to do whatever it takes to suppress an individual's inflammatory arthritis, and , using a potent disease-modifying drug like methotrexate immediately is often the correct answer, but if they don't have substantial suppression of their disease that moving along and adding biological therapy be very rapidly considered, even perhaps in individuals with very aggressive disease in the first three to four months of therapy.

The other important point for the patient is,if they or some of their loved ones may have rheumatoid arthritis is that not all of these medicines work for every patient, and physicians have to make decisions which are go, no-go decisions whether this is the right medicine and the right dose of medicine for the patient. Being on one of these medications is not enough.

The rheumatologist and the physician taking care of the patient has to make a decision whether it's really doing the job that it needs to be done. Therefore, physicians will look at the patient's joints and they'll actually do a joint count (not always )so they can find out how many of the joints are tender and how many are swollen, and most physicians will follow x-rays on a periodic basis to be sure that there is no damage that's progressing to make decisions whether or not this is an effective medicine, whether it be a biologic such as Enbrel or a synthetic such as methotrexate.

Why not start on the biologics immediately for most of the patients? --One could really make a case for that.-- One of the things that we as a society have to come to grips with is that the cost of biologics is much more than methotrexate is. And , while there are individuals that without any question should be started on the biologics first, like people with significant liver disease or someone who has moderately severe kidney disease, in most individuals who do not have those processes, probably an initial trial of a potent disease-modifying pharmaceutical like methotrexate is probably from a financial standpoint the most sensible thing, and probably from a societal standpoint

Also, many of the patients with rheumatoid arthritis often come already on methotrexate. Many internal medicine doctors have already started them on methotrexate, and a decision needs to be made is that the right medicine and if so, is it the right dose, and often it's too low, and one pushes the dose. A comparative study has been shown that higher doses of methotrexate work better. This is a very individual decision with the patient and the physician.

What physicians focus the most on isn't necessary what is the first drug that is used but that these biologics are not something that should be saved until there are no other options. These are drugs that should be used easily in the first six months to a year of disease if traditional therapies don't very effectively suppress the arthritis.

People should not wait because, the pace and the progression of joint damage is a continuous and rapid process, and if we can in a rapid fashion suppress people's disease, that over many years will reduce the amount of joint damage which should translate into better work, better health, and better social function.

The good news for our patients with rheumatoid arthritis is that we are in a new era of therapeutic intervention. Physicians,25, 27 years ago, were making patients some better. Now,rheumatologists and the rheumatoid arthritis patient are asking and doctor's are trying to return them to normal lives, and they're trying to slow if not stop the progression of their disease.

Hopefully, we're going to do see this, and hopefully,going to do this with less side effects, especially with some of these targeted biologics.

Note: Physicians are being advised to "use caution" when prescribing Wyeth and Amgen's arthritis drug Enbrel (etanercept) in patients with congestive heart failure (CHF) because of the possibility that the therapy may worsen their condition.

An updated European summary of product characteristics says: "There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking Enbrel."

"Two large clinical trials evaluating the use of Enbrel in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to Enbrel treatment."

The drug label's special warnings section says allergic reactions have been reported commonly.(other warnings are listed on label)

"In postmarketing experience, allergic reactions have included angioedema and urticaria as well as serious reactions. If any serious allergic or anaphylactic reaction occurs, Enbrel therapy should be discontinued immediately and appropriate therapy initiated."

It also notes that sepsis and serious infections have been reported and advises that "administration of Enbrel should be discontinued if a patient develops a serious infection.

Individual patient factors account for a substantial proportion of the between-patient differences in response to disease-modifying antirheumatic drugs (DMARDs), according to a report in the January issue of the Annals of the Rheumatic Diseases.

About a quarter of patients with rheumatoid arthritis (RA) fail to respond to DMARDs from the outset of treatment, the authors explain, and another quarter may stop responding after an initial period of efficacy. The reasons for these differences are unclear.

Ms. Cathy Morgan from the University of Manchester Medical School in the UK and colleagues studied 265 patients with RA to identify those with resistance to at least one DMARD and to determine what portion of the variance in drug response arose from patient-related factors.

Forty percent of patients experienced failure of at least one DMARD due to inefficacy, the authors report, and 11% experienced failure of at least 2 DMARDs. Only 5% of patients had multidrug resistance (unresponsiveness to at least 3 DMARDs).

The 13 patients in the multidrug-resistant group were significantly younger than patients who had responded to DMARDs, the report indicates, and all were women.

In a random effects model, 35% of the variance of the probability of DMARD failure derived from differences between patients, while the remaining 65% arose from differences between drugs or from chance alone.

Rheumatoid factor status accounted for 3% of this variance (with a positive result increasing the likelihood of treatment failure), the results indicate, but the remainder of the between-subject variance remained significant.

Among the patient-related factors mentioned by the investigators that may contribute to DMARD failure were patient non-adherence to treatment, undiagnosed malabsorption states, and the irrelevance of particular drugs to the responsible disease mechanisms in some RA subgroups. This study was not, however, designed to identify such variables.

"Further understanding of the variance in drug response between subjects may suggest new therapeutic strategies and targets in RA," Morgan and colleagues write

Ann Rheum Dis 2003;62:15-19.

Analgesics are medications that relieve pain without reducing imflammation. Analgesics are highly effective at reducing mild or moderate pain similar to that of a headache or toothache. They do do not have the side effects have the side effects common in other medications such as NSAIDs.

Analgesics work quickly,usually within an hour. The relief from pain generally lasts from 4 to 8 hours. These medications work by preventing pain signals from being sent in the first place or by preventing your brain from receiving and interpreting pain impulses.

Acetaminophen,one of the most commonly used analgesic is the active ingrediant in a number of over-the-counter medications including brand names such as Anacin, Excedrin, and Tylenol.

Sometimes acetaminophen is combined with other substances such as caffeine, which might make you jittery and keep you up at night,or antihistamines,which might make you drowsy. Acetaminophen at high doses is not recommended,in fact it can be damaging to the liver.

Topical analgesics provide pain relief locally-at a particular joint or joints-rather then systemically. This type of medication is available in creams, lotions, or gels that are spread on the surface of the skin and then penetrate within. If you have mild arthritis pain that is limited to one or two joints or if you want to supplement the effectiveness of an oral medication,topical analgesics may be a good option.

A variety of topical analgesics are available in drugstores. Most work in one of three ways. Some distract the nerves with another type of irritant. Known as counter irritants,these contain ingrediants such as menthol, eucalyptus oil,or turpentine oil. Typical brand names are ArthriCare,Icy Hot,and Mineral Ice. How effective they are are uncerain.

Some topical analgesics relieve pain tenporarily by delivering salicylates ( aspirin ingrediant ) through the skin. The topical form appears to inhibit the chemical prostaglandins just as the oral form does and also dis tracts the nerves through counterirritants. Brand names include Ben-Gay,Mobisyl and Sporscreme. The effectiveness of these is still being debated.

The third type of topical analgesic works by counter ing a chemical substance in the body called substance P,a neurotransmitter that appears to transmit nerve signals to the brain. These creams contain a derivative of a natural ingrediant found in cayenne (hot) pepper. As such,they may burn or sting when first used. They are marketed under the names such as Capzasin-P and Zostrix.

Topical analgesics are not recommended for use on broken or irritated skin. They also should not be used with a heating pad because it may result in a burn. After applying the cream,be sure to wash your hands before touching your eyes.

At low doses NSAIDs relieve pain;at higher doses they also reduce inflammation Such non-selective NSAIDs include aspiring,ibuprofen (brand names include Advil and Motrin )and naproxen. Aspirin has many risks therefore it is not recommended for the treatment of arthritis. The Cox-2 was so highly publisized when it first appeared,they were the saviour,but in medicine it is not that simple. Those medications also have risks involved-some are dose related and some on the condition or age of the patient.

Although all NSAIDs share a common mechanism of pain relief.they vary in the amount of time that they remain active or half-life. Short acting NSAIDs with half-lives ranging from one to eight hours include ibuprofen (Advil, Motrin),ketoprofen ( Actron,Orundis ),and Flurbiprofen ( NSAID) These are taken more often per day.

NSAIDs with a longer half-life ( ranging from 12 to 24 hours and sometimes longer ) include naproxen,piroxicam ( Feldene ) and nabumetone ( Relafen which is supposed to be also easier on the stomach ) These longer-acting agents provide pain relief over an extended period and may be taken less often.

Another important point is that two NSAIds made be similar,but patient reactions to one medication may be different from another. Put simply,if one NSAID does not appear to work,try another. You must work with your doctor to find one which is appropriate for you.

No medication is risk free. NSAIDs in some patients may cause more problems then DMARDs,especially with some one who has another underlying disease present or with elder patients. The risk of NSAID side effects generally appear to be directly related to the dose and the amount of time one takes it. Sometimes we also grow more sensitive to the effect of a given drug as we age,possibly because of differences in how we metabolize drugs or because we are taking other medications.

When side effects are experienced or when the NSAID seems to be not working for you,consult your physician who in turn may switch medications.

Ironically,it is the very ability to block a pain signal that gives a NSAID such power not only to help,but hurt. At the centre of this paradox is the enzyme, COX (cyclooxygenase). This enzyme then helps produce chemicals called prostaglandins, around the site of inflammation. By inhibiting production of COX,NSAIDs prevent this from happening Cox-1 produces prostaglandins that help maintain the lining of the stomach.

Cox-2 also produces prostaglandins, but these are primarily involved in sending pain signals and encouraging the process of inflammation. Because traditional NSAIDS block both types of Cox enzymes,they relieve pain but may also adversely affect the stomach and kidneys. In fact,the most frequent cited side effects of NSAIDs is mild stomach upset ( which affect 30 to 40 % of those taking it ).

But NSAIDs use can also lead to more serious problems. These include the develoment of stomach problems which can hemmorage and perforate. Researchers have identified others at risk for such complications those with a history of ulcers,advanced disability,taking higher dosage of NSAIDs and corticosteriods at the same time,and older age groups.

NSAIDs can cause a whole host of problems in some people (with underlying other disease ) but in the majority,it can be found,if detected,before more serious problems arise. Many people do not get serious side effects.

COX is not one enzyme,as scientists once believed,but two (and new research suggests there could be several versions ). Cox-1 produces prostaglandins that help maintain the lining of the stomach. Cox-2 also produces prostaglandins, but these are primarily involved in sending pain signals and encourageing the inflammatory process.

An overdose of acetaminophen can cause liver damage. This damage occurs in a dose-related manner. (Some other medications can cause liver injury in an unpredictable fashion that is unrelated to the dose.) In other words, liver injury from acetaminophen occurs only when someone takes more than a certain amount of the drug.

Likewise, the higher the dose, the greater is the likelihood of the damage. What is more, this liver injury from an overdose of acetaminophen is a serious matter because the damage can be severe and result in liver failure and death. In fact, acetaminophen overdose is the leading cause of acute (rapid onset) liver failure in the U.S. and the United Kingdom.

For the average healthy adult, the recommended maximum dose of (Tylenol )acetaminophen over a 24 hour period is four grams (4000 mg) or eight extra-strength pills. (Each extra-strength pill contains 500 mg and each regular strength pill contains 325 mg.) A person who drinks more than two alcoholic beverages per day, however, should not take more than two grams of acetaminophen over 24 hours, as discussed below.

For children, the dose is based on their weight and age, and explicit instructions are given in the package insert. If these guidelines for adults and children are followed, acetaminophen is safe and carries essentially no risk of liver injury.

On the other hand, a single dose of 7 to 10 grams of acetaminophen (14 to 20 extra-strength tablets) can cause liver injury in the average healthy adult. Note that this amount is about twice the recommended maximum dose for a 24 hour period.

In children, a single dose of 140 mg/kg (body weight) of acetaminophen can result in liver injury. Amounts of acetaminophen, however, as low as 3 to 4 grams in a single dose or 4 to 6 grams over 24 hours have been reported to cause severe liver injury in some people, sometimes even resulting in death.

It seems that certain individuals, for example, those who regularly drink alcohol, are more prone than others to developing acetaminophen-induced liver damage. To understand this increased susceptibility in some people, it is useful to know how acetaminophen is processed (metabolized) in the liver and how the drug causes liver injury.

How is acetaminophen processed (metabolized) in the body? The liver is the primary site in the body where acetaminophen is metabolized. In the liver, acetaminophen first undergoes sulphation (binding to a sulphate molecule) and glucuronidation (binding to a glucuronide molecule) before being eliminated from the body by the liver. The parent compound, acetaminophen, and its sulphate and glucuronide compounds (metabolites) are themselves actually not harmful.

An excessive amount of acetaminophen in the liver, however, can overwhelm (saturate) the sulphation and glucuronidation pathways. When this happens, the acetaminophen is processed through another pathway, the cytochrome P-450 system. From acetaminophen, the P-450 system forms an intermediate metabolite referred to as NAPQI, which turns out to be a toxic compound. Ordinarily, however, this toxic metabolite is rendered harmless (detoxified) by another pathway, the glutathione system.

There's a menu of many laboratory tests involved in inflammatory arthritis,an inevitable consequence of employing most DMARD therapy,beginning with a blood sample. The rheumatologist will use the information from several test categories to help diagnose our condition,check for side effects,and monitor response for treatment.

Usually,there are 5 to 7 tests per DMARD,but all can be done from one blood sample;if the DMARD is switched,another sample will be taken,since each medication is tested for different specifics.

Some DMARDs can lower the production of white blood cells,which are critical to the body's defence against infection and other health concerns. Others can affect how the liver or kidneys work. Lab tests can detect such changes long before symptoms are experienced,giving the physician a chance to adjust dose or switch DMARDs.

Without that critical information.DMARD therapy is definitely riskier. Whether it's weekly ( for blood and urine tests,as with gold injections ) or 6 -8 weeks (blood tests for methotrexate,sulfasalazine;and azathioprine ) or semi-annual or annual eye examinations ( hydroxochloroquine ) keep your lab appointments faitfully.

If a severe or persistent infection develops ( lasting longer than a week ),some DMARDs,such as methotrexate and azathioprine,may be stopped until it clears up or switched. If you are going to a family doctor,make sure your rheumatologist knows,so steps can be taken to prevent a flare-up,which can occur as the amount of medication in your body decreases.

Ask the rheumatologist to explain what the different tests are for and how they're interpreted. Being in the know will reduce anxiety about those mysterious results and help put adjustments to the medication regimen into perspective. That may help make it easier when the going gets tough,and staying on course can make a big difference in our health