Diabetes Prevention

Debunking The Myths of Gout and Crystal Diseases

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in the 1800's the Reverend Sidney Smith described in some of his writings the feeling of gout and I think this is a very appropriate way to look at this disease from the patient's standpoint first let's talk about what gout is gout is an intense inflammatory rhetoric disease it occurs in episodic fashion that is patient soil report and acute onset of pain swelling and extreme tenderness it is usually a mono arthritis though with time patients can develop a polyarticular gouty arthritis it occurs episodic ly it the episodes are separated by a quiet period or an intra critical period during which there is minimal to no symptoms it is by far the most common inflammatory arthritis recent studies have population studies have shown that over 8 million Americans suffer from gout it is predominantly in May and but we are starting to see it increasingly in women in general we are seeing it with increasingly frequent occurrence ten years ago the estimated incidence was about six and a half million there are a few things it's important to realize about what gout is not first of all gout is not a an elevated uric acid not everybody with an elevated uric acid is going to develop gout similarly it is not the cause of all foot pain I've seen many patients who have presented with a little soreness and their foot have been told must be gout simply because it's in the foot third it is not something that is triggered by a glass of wine on an occasion finally it is a good lifelong chronic disease it is not a disease that can be treated with just an occasional short course of nonsteroidal medication and a few weeks of allopurinol when one tries to look at the patients that are more likely to develop gout there are variety of lib risk factors that have been identified first we do know that it its incidence increases as the patient's get older as I said earlier it is also a disease predominantly of men although we are seeing it increasingly in women generally females who have it are postmenopausal it is extremely unusual to see it in a premenopausal female there are a variety of comorbidities have been identified first hypertension is a very common comorbidity similarly a metabolic syndrome diabetes and cardiovascular disease this is somewhat interesting because we are now starting to see that hyperuricemia may be playing a more active role in diseases such as metabolic syndrome diabetes and cardiovascular disease finally lip dyslipidemia is another common comorbidity there are a number of medications that can actually trigger or increase the risk of gout as well thiazide diuretics and low dose salicylates are to the more common levodopa nicotinic acid and cyclosporine or other medicines that have been shown to increase the serum uric acid finally lifestyle issues we know that certain food stuff such as high fructose corn syrup such as it is found in most soft drinks in the United States heavy alcohol intake particularly beer is one that's known to increase serum uric acid levels also a diet that is rich in organ meats and shellfish and finally patients who are obese have an increase in their serum uric acid in order to better understand this disease I think it's important to look at the natural history of hyperuricemia by far the most common grouping is that of patients in asymptomatic hyperuricemia this is a required precursor to attacks without hyperuricemia you essentially cannot have classic gout the vast majority of patients are in this category about six out of seven patients with hyper yours see mia will never ever have an attack this is the kind of patient who comes in and has what they used to call an executive panel and is found to have a uric acid of seven point eight or 8.5 or whatever these patients have no history of attacks they don't have any physical findings clinical manifestations once the first attack occurs this is when we start to see problems it is an acute inflammation usually a sudden onset and this is generated by the phagocytosis of monosodium urate crystals these patients will report that it is an extremely painful attack and they often use the term the sheet hurts to touch subsequently the patient's enter into enter critical periods that monosodium urate crystals are still within the tissues and during this time more crystals can be deposited while the patient's not seeing a lot of pain there is some level of chronic inflammation and tissue destruction going on there is active inflammation in the space and it's important to realize that just because they are not having an acute attack doesn't mean they're not having gap and finally there are the patients who will have chronic advanced inflammatory disease and this is where they have a poly arthropathy they will have persistent inflammation and the pain just continues on and on and on as I mentioned previously patients must have hyperuricemia to develop the gout normally the patient is at hyperuricemia wyndham dump when their serum uric acid levels are above 6.8 at this time the serum has are the serum solubility has reached a super saturates place and we will start to see monosodium urate crystals developing and being deposited in tissues it should be noted that maximum solubility is 6.8 at normal body core body temperature if you start to drop the temperature such as one sees in colder parts of the body such as the feet elbows ears external ears and so forth then the solubility will drop to about six point 0 monosodium urate crystals are then in their microscopic they're about the size of a bacteria they are engulfed by inflammatory cells they get coated with inflammatory mediators and this is what triggers an inflammatory response with time we start to see large collections of the crystals these are the classically described Toph I and also we will start to see the development of a chronic inflammatory arthritis this slide shows a few of the causes of hyperuricemia it should be noted that the vast majority of patients with high PE racemia are having it due to under excretion the most common by far is renal insufficiency but we also see a number of other areas where we can start to see problems with excretion these include thiazide diuretics ethanol abuse cyclosporine ap resent amide and also low-dose aspirin while high dose aspirin could actually stimulate can be a heavier because York effect the problem is that most patients who have with heart disease are on low-dose aspirin and so that's going to be a big problem in terms of overproduction that's a smaller percentage and there are a number of different disorders we can see again alcohol has an effect on stimulating production especially beer certain genetic diseases can be seen to cause this myeloproliferative disorders can do it another disease that has been associated with a high uric acid is psoriasis and that's due to the increased cell turnover cytotoxic chemotherapy when they Roy cells that increases uric acid and finally sickle cell anemia is another one that we can see hyperuricemia again we look at hyper asymptomatic hyperuricemia this is a definite precursor to gout it must be present for the patient to develop gouty arthritis it is not the same of scout and it is not something that necessarily needs to be treated in general a patient who has serum uric acid greater than 6.8 is felt to be hyperuricemia again it's very important to realize just because a patient has a serum uric acid above 6.8 does not mean at this time that they need to be treated there are studies ongoing as we speak where they are looking at whether patients with gouty arthritis without gali arthritis but with a significant hyperuricemia would benefit from a cardiovascular standpoint from treatment but in the standard of Medicine at this time patients without a history of gouty arthritis but have a higher uric acid should not be treated for their gap as I alluded to on previous slide we are starting to see that hyperuricemia is an extremely common finding in patients with metabolic syndrome with cardiovascular disease and with diabetes there are some studies that are starting to evolve in which we are thinking that the presence of uric of a high uric acid may have a more active role rather than being coincidental vanna Sulis and his group noted that patients who were on allopurinol had a lower mortality rate from congestive heart failure than patients who were not taking allopurinol there are also other studies that show that hyperuricemia is an independent risk factor for the development of atherosclerosis and young adults there are as I said earlier ongoing studies looking at whether lowering the serum uric acid might be beneficial in the management of patients with congestive heart failure corner writer disease metabolic syndrome and diabetes so this is something to be watching for in the future the next and most common step in gout is the development of the acute gouty flare there the flare is usually rather intense it has an abrupt onset of pain swelling and the tenderness is such that many patients will even state that a sheet hurts to touch it the first attack is usually manan articular and the most common sight of a first attack is the first MTP joint giving us the classically described padega the attacks usually current night and if you don't treat it they will subside with time but it usually takes three to ten days for this to happen if the joint is aspirated during an attack your monosodium urate crystals will be present in that fluid it's important to realize that during an acute gab attack the serum uric acid levels may actually be normal and so it's important to keep this in mind because if a patient comes in and under it with an acute attack but has a serum uric acid of say six point oh it's may be artificially lowered because of the inflammatory process going on as the patient continues to have gout attacks they'll occur increasingly frequently and with time without treatment the patient can often develop into a chronic polyarticular inflammatory disease that may look just the same as rheumatoid arthritis or other inflammatory arthropathies if one looks at the pathophysiology of an acute attack we can see a number of different events that are actually being looked at and might in the future have an effect on how we address these attacks first Montezuma sodium urate crystals are deposited in the synovial space with time monocytic cells will start to engulf the crystal and when they start this trigger of an inflammatory response interleukin 1 is released subsequently other inflammatory cytokines are released including interleukin-6 aisle 8 tumor necrosis factor and in a variety of chemokines that help to recruit other inflammatory cells into the synovial space these chemokines for instance help to bring in neutrophils and with the influx of the neutrophils we get the classic inflammatory reaction this is a slide that shows a classic Goudy attack in the first MTP or pad agri the ankle on this patient also looks a little bit inflamed when I look at this picture the toe is swollen at the MTP joint it is extremely tender the patient will not want you even to touch his foot at this time once the attack has quieted down the patient Center what we call an inter critical period while there is no acute active inflammation crystals can still be present if we were to aspirate the quiet joint quite often we can find both intracellular and extracellular monosodium urate crystals we can find low levels of inflammation going on studies have demonstrated that even though there is no acute inflammation going on there is a low level of chronic inflammation with time the crystals start to coalesce and we start to see the development of toe fascias deposits these two patients deposits can cause damage to the joint with time because the crystal levels increase we start to see an increased chance for development of recurrent attacks as well with time the patient will progress on to advanced gout at that time we're seeing polyarticular flares we're seeing a persisted persistent destructive arthritis and we start see clinically apparent toe fascias deposits these patients may actually have an appearance that looks every bit as destructive and every bit as active as diseases such as rheumatoid arthritis this is a photo of a patient who has 80 fost that has developed over his electron on process they may or may not be tender they grow with time and if you were to aspirate these you'd get large amounts of a chalky material which is consisting of the monosodium urate crystals this is a photograph of a patient who has a chronic toe fascia scout some of the highlights in this include the very large collections of the monosodium urate crystals almost having the feel of a golf ball on the top of their hand if you'll notice in the right second digit you can see that there has been rather extensive destruction of the bone so that you have a telescoping of some of the phalanges if you look at the right thumb you can also see in the thumb tip some white plaques this is most likely deposit of the toe fascia material away as well and these will often use with the chocolate material coming out and can be easily expressed looking at these under a microscope and you will see the classic crystals and we will have some pictures of these later on this is a radiograph of a interphalangeal joint and you can see an erosion that is classically seen with gout what you see is a rather sharp margin of the erosion and it sort of has the appearance that there's a bite taken out of it the classic description has been that of a right rat-bite erosion and these can actually get bigger and bigger the area where the erosion is is usually filled with a office the Toph I are largely radiolucent there may be a little bit of a haziness to it but generally the toughest will not show up on standard radiography it is somewhat counterintuitive but the establishment of the gout diagnosis can be a little bit confusing now the attack history is a pretty good way to establish a gap when the patient comes in and tells me that they've had a sudden onset of foot pain at night it's in one joint that it is so tender that this feature to touch it it's pretty much likely to be gout nevertheless if there is a history of infection other inflammatory modern arthropathy or trauma then I think you have to look and make sure there isn't something else going on the gold standard is to perform a joint aspiration and identify both intra and extra cellular monosodium urate crystals serum uric acid levels can add confusion to the diagnosis first of all during an acute attack they may actually drop to normal levels if you're going to be using the serum uric levels to help you the most appropriate time to get this is about two weeks after the attack is done during the intro critical period in terms of treating gout it is important to separate this disease between the acute gouty Flair and the treatment of the chronic hyperuricemia it should be noted that each of these components require the to be required being addressed directly and that there really is not just one medication that works for both processes a list here is some of the medications that are used for both Goudy flares as well as for chronic hyperuricemia and we're going to discuss each one of these a little bit more in depth first let's take a look at the choices for creating a cute attacks and currently we have several different ways we can go with this and there are some ongoing studies that are looking at a few new ones such as interleukin-1 anti-ige 01 agents but the standards are ones that are available in the clinical practice include nonsteroidal anti-inflammatory drugs colchicine and corticosteroids by far the most commonly used medications for gaba texts at this time are the non-steroidal anti-inflammatory drugs this is one area where into medicine still is used quite frequently and naproxen has also been FDA approved other end sets probably work as well although these two are a couple of the more potent cyclooxygenase inhibitors and they seem to do quite well it is important to realize that nonsteroidal anti-inflammatory drugs have significant risks associated with their use in 1996 over 16,000 deaths and over a hundred thousand hospitalizations occurred due to nsaid into disgrace droppeth ii similarly cardiovascular risks such as fluid retention increase in the blood pressure renal effects can be seen CNS effects can occur and it's important to realize that all of these effects increase their frequency whereas the patient gets older if you look at a patient who has cardiovascular disease diabetes GI problems these are the ones that are unfortunately more likely to have gout attacks and nsaids may not be the best choice if the patient has a lot of problems with these their underlying diseases another medication that has been used for literally millennia is colchicine this is a chemical that is derived from a plant known as the colchicine plant it is found throughout the Middle East it colchicine has been used for years and the standard mantra for many years has been that a patient takes one cold seen every hour until their attack is under control or until they to have gastric side effects fortunately we have started to do some reassessment of this and a ready by turkel top in his group in San Diego looked at whether just taking three doses of colchicine in 24 hour period did as well and what he found is that in patients who were given just three doses of colchicine over a 24-hour period their response was every bit as good as the patients who took it every hour the most important thing they also found was that the patients who were on the low dose cultural saying that is just three doses in 24 hours they tolerated the medication significantly better I very tongue-in-cheek say that the only patient that I would ever consider giving colchicine every hour on the hour is a patient that I really really did not like unfortunately colchicine also has its potential side effects and it is dose-related it is a medication that has a very low therapeutic to toxic window and so patients who are taking more than 2 to 3 milligrams a day are at a significant increased risk of complications and side effects obviously the gastrointestinal ones that of diarrhea abdominal pain vomiting are very well known particularly if you take too much of it bone marrow suppression can occur rhabdomyolysis and is another problem with it has been shown with chronic use to result in problems with neuropathy hepatotoxicity and nephropathy finally it is important to keep in mind patients on we're taking colchicine chronically can have increased problems if they are also put on clarithromycin one area that a lot of rheumatologist feel might be the least bad choice for treating a gout attack is corticosteroids Johnson's in 2008 published a study looking at patients who and comparing the use of prednisolone to naproxen and actually saw that the response was just about equal when you look at a patient who has cardiovascular disease diabetes renal insufficiency GI problems it may be that when trying to find that a medication for this patient for their acute attack a short course of corticosteroids may be the least bad choice you have now we'll switch over to looking at when do we treat an elevated serum uric acid and I think it's important to look at this from the state standpoint of the patient at this time and in this era the feeling is that we do not treat a patient with benign hyperuricemia if a patient has established gout where they've had one or two attacks that is the time to begin serum urate lowering therapy normally one of the things we always do is we will use an attack preventing prophylaxis because during induction of the therapy one can see a attack of the gout anytime you have a rapid increase or rapid decrease in the serum uric acid levels this can help to trigger a gaudy attack some of the medications that are used are nonsteroidal anti-inflammatory drugs low doses of colchicine at one or two pills a day and low dose steroids to be very honest in terms of when rheumatologists uses get colchicine most of us reserve the use of cultural scene for a attack preventing prophylaxis when treating a patient with hyperuricemia and established gout we aim to lower the serum uric acid level below 6.0 first the timing is very important the standard has been that once a patient has had an attack we try and get them calmed down for at least two to four weeks before we start the urate lowering therapy generally what i will do is at the time of a patient's attack i will give them something to get their attack under control i will then start them on a load of whatever prophylaxis i'm going to use have them back in a couple of weeks at which time i'll check their serum uric acid levels and then i'll start the appropriate urate lauren agent there has been some recent data that looked at starting the urate lowering therapy earlier and they've actually looked at starting it during any time of an acute attack I'm still a little skeptical of this because of the fact that we've seen too many patients who when started on these medicines it helps to propagate an attack it is important to realize in a patient who has Gaddy arthritis treatment with urate lowering therapy must be lifelong or they will have a recurrence of attacks quite often it's asked why in the heck do we shoot for six point oh when the normal serum urate hyper solubility maximal is 6.8 there are a couple of different reasons as i pointed earlier when you drop the temp body temperature to around 34 degrees centigrade such as one would see in cold feet the maximum solubility drops a six-point oh if we want to get the monosodium urate crystals out of the tissues in the feet and the elbows colder parts of our body then we need to get it well below six another reason why it's important to try and get the serum urate lower and lower down is based on a study by Shoji in his group and what they saw that in patients who have had an acute attack of gout if their serum uric acid level is above 9.4 they have an 80 plus percent chance of another attack within a year contrast that to if they get their serum uric acids down below six the chance of another Goudy attack drops to about fifteen percent so what we try to do is get the uric acid level as low as we can as quickly as we can and this does reduce the chance that the patient has another Goudy attack now let's take a look at medications that are available to help lower the serum uric acid level by far the one that is used most commonly in the United States today is allopurinol this is a medicine that blocks the enzyme hypo xanthine oxidase it is one that is clear primarily via renal excretion and this does raise a problem in patients who have renal insufficiency it does inhibit the production of uric acid it does not have an effect on a uric acid excretion its side effects are well known we do worry about neuropathy we'd also worried about hepatic disease and mild suppression and blood abnormalities the one thing that most of us worried about the most is the development of topics epic epidermal necrolysis and a dermatitis of all the medications that cause this rather rare complication allopurinol is probably the most common you need to have the adequate renal function become n you may have to adjust the dose if the patient is put on this creatinine clearance of 20 or 30 may cause a problem in using this medication another medication that is available although we are not using is frequently now is probenecid this is a Urich of Surak agent that is that it increases serum uric acid excretion for it to work you need adequate renal function it starts to really lose its effectiveness in patients who are under excrete errs when the creatinine clearance drops below 50 if a patient has a history of nephrolithiasis that is a definite contraindication because the last thing you want to do is help to aggravate patient patient who already has been shown to cause kidney stones in a patient who has gali arthritis and is at maximal doses of allopurinol without effects probenecid can be used with it and may have a beneficial effect again you want to make sure the patient has adequate renal function and no history of stones some of the side effects that can be seen include nephrolithiasis anemia rashes and hepatic damage we are blessed with the development of couple of new medicines for the treatment of hyperuricemia the first one that came on the market is fabulous stat this is another xanthine oxidase inhibitor it inhibits at a different site in the enzyme then does allopurinol it is hepatica Lee excreted so it probably has its felt to have a safer side effect profile in patients with renal insufficiency normally what we do is start the patient at 40 milligrams a day have them come back in about two to four weeks at which time we look at their serum uric acid level as well as looking at liver studies and increase the dose to 80 milligrams if we have not reached and reached the target goal of six point 0 or less side effects with this it can have some adverse effect on liver function and there was some question at first as to whether it increases the risk of cardiovascular disease since the more recent studies have demonstrated that allopurinol lowers cardiovascular problems it is possible that in the studies in which it was compared with allopurinol it wasn't a factor of increased cardiovascular risk compared allopurinol as well as much as it was allopurinol lowering the cardiovascular risk finally we have a new medication that has only recently been approved and this is peg Lhota case this is a polyethylene glycol conjugated serum uric case this is a biologic composite agent and it is administered parenteral II this is an incredibly effective agent in lowering the serum uric acid and it is very good in patients who have failed previous medications I highlighted a phase 2 trial that was done with PEG loader case they had 41 patients and they found that the most effective dosing was 8 milligrams every two weeks again this is given only IV and so you can see giving a patient dose every two weeks can be rather difficult serum urate lower levels were reached below six within six hours of administration my experience has been that patients who have received this may drop their serum uric acid levels as low as 2 or even one it is an incredibly effective agent one of the biggest problems we've seen is that it rather has a rather high side effect possibility first about twenty-five percent of patients on it chronically can develop infusion reactions and anaphylaxis there are some recent studies that suggest that patients who are at a high likelihood of having this reaction I see a drop in the effectiveness of the agent that is we will do a serum uric acid just prior to administering the agent and if their uric acid has come back up to seven or eight that's a patient where the body seems to be making antibodies against the medicine and those are the patients that seem to be at a rather increased risk of developing an infusion reaction it also has been shown to exacerbate congestive heart failure so it's not one that I feel is used very hastily we use this as a last resort in patients who really do not have any alternative choice now most of my patients are going to come in with gout and they're going to ask what can they do diet wise to help lower the uric acid obviously we try to avoid alcoholic beverages especially beer we talk about cutting back on organ meats and shellfish and they often will tell me there are certain foods that seem to trigger their gout attacks trying to get away from the fructose the high fructose corn syrup containing beverages such as soft drinks that might help too there are actually some foods that have been shown to may to possibly help lower serum uric acid levels skim milk has been shown to decrease it but coffee both caffeinated and decaffeinated and finally intake of vitamin C can help the only problem with these is while they do up and they might provide some benefit the drops in making major dietary changes only constitutes maybe at the very most one milligram per deciliter monosodium urate is not the only crystal that can be found in synovial fluid another one that is seen quite commonly is calcium pyrophosphate dihydrate and this has been associated with a number of diseases most notably pseudogout calcium pyrophosphate deposition disease can actually have a variety of presentations the classic acute synovitis or pseudogout is well documented but we can also see a chronic arthropathy such as an atypical osteoarthritis a variety of different a typical spinal or through these neuropathies and what can look like rheumatoid arthritis radiographically we see deposition of the crystals within the cartilage giving us the classic chondrocalcinosis this is a photo micrograph of the classic calcium pyrophosphate crystals these are not as strongly birefringence they also are not as a strong and their polarizing lens while they are sort of a needle shape they are usually little thicker a little fatter not quite as long and if you look at the arrows you can see that these are the positively birefringence crystals that is they are blue when they are parallel to the polarizing filters orientation and they're yellow when they're perpendicular being the exact opposite of the monosodium urate crystals see PPD has a variety of disease associations some of the things we look for include hyperparathyroidism it can also be seen in classic osteoarthritis but it is often seen in patients where who have a rather atypical a typical osteoarthritis such as in patients who have a the arthritic changes in joints that it's not normally associated hemochromatosis is one can see hypomagnesemia hypophosphatasia are also some others in which we ought to look we look at in patients with calcium pyrophosphate deposition disease if a patient is having a acute arthritic attack first thing we want to try and do is identify and see if there is under any underlying connective tissue disease or other endocrine disorder for the attacks we may use colchicine or non-steroidal medications as well as local steroid injections for a mono articular Tech we have patients who require low doses of colchicine or nonsteroidal medicines sort of as a prophylaxis to help prevent gabi or the CPP attacks finally one other crystal I wanted to mention is that of cholesterol crystals this is a rather unique appearing crystal and that it looks sort of like a sheet sort of like a sheet of mica would would be that I describe it they usually are sort of a parallelogram and they often have a little chip out of the corner this is one directly from one of my patients and these are also very birefringence the one area that this is of importance is that this can be seen in fluid collections of patients who have rheumatoid arthritis in fact I've had two different patients who came to see me with some nonspecific arthralgias but had rather large fluid collections when we found the cholesterol crystals we actually did some searching and found that they actually did have early rheumatoid arthritis and so this is something to be aware of and keep a watch for in your patients in conclusion it's important to realize that Gaddy arthritis is far more common and more of a serious difficulty with in the clinical practice then it has been normally recognized it is more common than rheumatoid arthritis lupus and psoriatic arthritis combined patients will generally start off with a mono articular inflammatory process but if not adequately treated may progress to a polyarticular arthritis in terms of treating this disease we do lower the uric acid and we aim for a uric acid below 6 this helps to lower the development of future attacks it's also important to impress upon the patient that allopurinol and other urate lowering treatments are not treating the gout attack but by lowering the serum uric acid we will see in the future fewer and fewer Goudy attacks finally it is important that in a patient with gout urate lorne therapy must be a lifelong you

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