Noting that gout is common yet under-recognized and undertreated, rheumatologist Kerstin Morehead, MD, presents a valuable update on risk factors, associated conditions, and treatments for both acute flares and chronic disease. She explains how to distinguish gout from rheumatoid arthritis; describes the potential consequences – such as severe joint damage – from lack of appropriate treatment; and provides essential info on medication safety and dosing protocols. Also: Learn gender-specific dietary modifications to offer patients.
Thank you for having me here. I'm very excited to be talking about gout. Um, I primarily work in clinical work at Parnassus, um, at UCSF, and I'm in charge of also resident education at Parnassus as well. So I see a lot of gout. I'm going to turn off my camera cause it's a little bit distracting and then we'll get underway. All right, I like talking about gout, not just because it's pretty under the microscope, but also because it's a severely under-recognized and undertreated disease. In fact, with modern rheumatoid arthritis treatments, I would say the patients that I see who have Disabling joint damage or 24 more likely to be gout patients than RA patients. And unfortunately, there was an AMA guidelines that were published a couple of years ago that severely restricted treatment, so I'd like to sort of try to undo that. So the goals for this talk, uh, primarily since you all are on the front lines, is to sort of put gout on your radar, especially gout that's turning into a chronic problem. So, we'll talk a little bit about the differences between an acute attack and chronic gout, um, mostly because there are different treatment approaches for both. And I'll give you a few updates on pathophysiology, diagnosis and treatment, um, but I'll keep the science at the minimum and I'll always show you sexy science. I really want this talk to be more of a practical for you guys. So, I'll start out with a little bit of the pathophysiology, um, then we'll talk about risk factors and associated conditions because those play an important part not only in the genesis of gout, but also on your considerations for treatment. Then we'll talk briefly about clinical presentations and some of the newer tools for diagnosis, and finally, we'll spend a good deal of time talking about approaches to treatment. Treatment is a little bit problematic when people have comorbidities, and unfortunately, most people with gout have comorbidities. So just sort of a snapshot of gout, it's a very common and treatable inflammatory arthritis. It affects about 4% of people in the US. What happens is, is that you get deposition of monosodium urate crystals in and around tissues and joints. And the way you get those crystals is that you have increased urate concentration. Uric acid comes from de novo synthesis in the body, also can be ingested, and when cells turn over, they release their DNA into the bloodstream, and that's a major source of uric acid. What happens then is when the uric acid crystals deposit themselves, that induces a really severe inflammatory response. In fact, um, they were, we were just talking about a gout flare and the classic description is that it's so painful you can't even have a sheet on the affected joint. Treatment of acute gout flares tends to be geared towards reducing the inflammatory response, but to really treat chronic gout, to prevent destruction of joints and other comorbidities, you really want to reduce the uric acid burden and dissolve the crystals. So hyperuricemia sort of comes in a progression of um instances. The first one is people who have hyperuricemia without crystal deposition. Then you can get crystal deposition but no symptoms. And then you get periodic acute intermittent arthritis of what we think of as a classic gout flare. After time, this can become a chronic arthritis with deposition of crystals called toi that are destructive to the joints and other tissues, and these also produce the radiographic changes that are classic of gout. This is not a done deal. It's not necessarily. A rule that things are going to progress this way. So hyperuricemia can be a little bit confusing to think about because it has sort of different clinical and physiologic implications. You really often need a serum uric acid level above 8 mg per deciliter to have a gout flare. That's typically when they start to happen. Physiologically though, things start getting going when you have a uric acid level of 6 or more milligrams per deciliter, uh, and that's why that ends up being one of our treatment goals. Uric acid is typically excreted through the kidneys and the GI tract, and the way that it builds up is typically because there's a fault in this excretion. So they, these are under-excreters as we call them. And you can see this in renal disease and GI disease. And as you know, the GI can cause imbalances in the acid-based metabolism which can then affect the kidneys. So it, it can be both that are effective in terms of the under-excretion. I think I skipped this slide. So The where and why and how and when crystals are formed has a lot to depend on the temperature, um, and the pH around that area and the salt concentration around that area. That's why yaggra, the large toe involvement, is sort of the classic, uh, presentation, and that's because that's a very cold joint, that's a small joint, and so the pH and salt concentration may really predispose it towards being sort of the first place you, you end up getting a flare. So this is a little bit of the path of physiology as we understand it now. It starts with the innate immune system when monocytes ingest crystals. They then Activate what's called an inflammasome. And basically what an inflammasome is, is just an aggregate of, of polymers that induce the immune response. In this case, the immune response is interleukin beta and also something called NETS that we'll talk about in just a minute. In order to produce the interleukin beta, however, there has to be a second signal on the toll receptor. And let me see if I can get my pointer here and I'll show you. So you get the hyperuricemia, you get the deposition of crystals. These are the crystals ingested by the macro monocyte. This is the inflammasome, and here's a toll-like receptor that then induces the the inflammasome to make interleukin one beta. The second signal is very interesting. Um, we think that it's probably fatty acids and oxidized LDL. So that obviously has implications on what we think of the typical dietary no-nos for gout. So high fat foods, uh, high cholesterol foods. Also, another interesting thing is toll-like receptors are very instrumental in the body's surveillance for cancer cells and also keeping those cancer cells in check. So there's a hypothesis that gout is actually a beneficial adaptation that really sends an alarm signal that there's something amiss in terms of the cells that have uncontrolled growth. So these are nets, and you see these lacy things here. These are net stands for neutrophil extracellular trap, and what happens is is that the neutrophils spew out this lacy material that entrap things, and here you can see they're entrapping bacteria. When these nets are activated by the inflammasome, they bind the the urate crystals and you get resolution of their building up. However, they can also be activated without the inflammasome, and it's thought that these nets actually end up being the scaffolding for toy. So looking again at this slide. You can see the uric acid is ingested, it activates the inflammasome. You have a second receptor here. You get interleukin beta. A net can come out and if it's with pro-inflammatory molecules, you get degradation of the uric acid crystals. But if you don't, you just get uric acid crystals in a net, you can get tohi formation. There is also adaptive immunity involved in the gout response. Um, T helper cells are activated and they produce IL-22 and IL-17 overexpression. Um, as you may or may not know, these interleukins are very instrumental in psoriatic arthritis. So, for psoriatic arthritis patients have a double hit in terms of being at risk for gout, not only with this overexpression, but also because high cell turnover is a large source of purine, which then turns into uric acid. As the uric acid crystals build up, they become toi, which also become erosive in bones. The flares tend to worsen and to last longer. And finally, it's essentially one big flare. You get pain during intercritical periods. This takes about 10 years after the advance of an acute attack, and typically the serum uric acid tends to be fairly high, like above 10. You get to sit about 3 to 6% of men and 1 to 2% of women, and that's because estrogen is instrumental in helping clear uric acid through the kidneys. This prevalence will increase with age until people get about 70 and then it tends to level off. There are very strong associations with other disorders, um, the main one being hypertension. And this is mostly because of oxidative stress. Chronic kidney disease can also have an effect, and as you can imagine that affects the way that uric acid is cleared. Obesity is also an interesting risk factor. It Also is thought to be due to activated stress and then there was that second toll-like receptor, uh, hit that we saw with the fatty acids and diabetes as well for a variety of reasons, oxidative stress, the effect on kidneys and things like that. Um, it is a risk factor too for cardiovascular events. Ingestions are also independent of weight, um, can precipitate effects fairly easy. Alcohol is a big one, red meat is another one, and sugary drinks, again, independent of weight, can precipitate effects. Lead is also, um, a sort of an ingestion. Uh, we, it's called saturnine gout. We got this from Uh, the Romans who used to line their wine vessels with lead, and during Saturnalia, which was one of their big festivals, there was a huge increase in gout. Um, you can also see a lot of this with people emigrating from China. Drugs are a big risk factor for precipitating gout effects, uh, diuretics for obvious reasons, cyclosporine, pyrazinamide, ACE inhibitors and ARBs are a little bit murky, um, as they often are when the renal function is affected. They're very good at reducing hypertension, so that helps gout, but it's also, they can affect the kidneys which can hurt gout. Ritonavir, beta blockers, and low-dose aspirin, which, um, Affects the way the kidney clears uric acid. Other risk factors include age, um, for a variety of reasons, menopause again because estrogen helps the kidneys clear uric acid, psoriasis for a couple of reasons that we talked about, hematologic malignancies again, increased cell turnover, which leads to increased purine load, anemia, which is Usually involved with oxidative stress as is trauma. So, one classic history that you can often get if someone has a repetitive injury, that can precipitate a gout flare. So people going on hikes, people operating jackhammers, that sort of thing. Genetic risk factors are pretty um obvious from the genome-wide associations. It basically has to do with urine metabolism, so urate transplanters, metabolic pathways, and that's why at this point, serum uric acid control remains our key for preventing and treating chronic gout. There are gene environment interactions that are not well understood, just as there are gene gender interactions as well and epigenetics. This work is just starting to get underway, um, as an area of interest. So, I think we're all familiar with the typical presentation of gout, um, Pydagara, the great toe being the classic example. Gout can affect any joint in the body, however, and here you see a large tophus in the T-spine. You can also get different atypical presentations of gout. Um, systemic symptoms are very common. Fever, Toi can present before people have an actual flare that they recognize. Again, we think of it as uh affecting the, the peripheral small joints, but it can also affect axial joints. You can get extra-articular manifestations, particularly cardiovascular disease, um, kidney disease, stroke, and renal failure. Mm The gold standard for diagnostic evaluation remains being able to see crystals under the microscope. Uh, however, in reality, this happens fairly infrequently. The serum uric acid level can be problematic during an acute attack because it is often spuriously low. Nonetheless, we usually send it just to get another data point. You can sometimes see a mild leukocytosis, and typically you do see elevations in the inflammatory parameters, the erythrocyte sedimentation rate, and the C-reactive protein. Tophage can show up on the soft tissues, um, so places like the ears are pretty classic, and here you see some examples of that. Tendons, so elbows and Achilles, um, are places where uric acid crystals often build up and cause problems. And then when toy build up in the joint, that is what we think of as a gouty erosion. That's actually a tophis. Oops, sorry. X-rays are also helpful in in evaluating it. You can see soft tissue swelling. You can see cystic changes in the bones which are sort of non-specific, but they can be indicative of early erosive changes. There is the classic rat bite erosion that is a corticated erosion that is away from the joint, and that's to distinguish it from, say, rheumatoid erosions where you, they're not corticated and they're close to the joint line. However, these changes can also look a lot like inflammatory osteoarthritis, which is to say osteophyte formation with joint space narrowing, and psoriatic arthritis where you get this kind of resorption of bone and erratic osteophyte growth. Here is um A classic A set of erosions. This is a slide from the ACR, but I actually have several of these in my, uh, collection. Here you can see corticated bone where you see it's wider than usual, and it's got this classic kind of overhang, like a rat bite. This is the joint line. This, by the way, is, is a, a DIP, um, and here you can see another erosion again, the cortication and the overhang shape of it. Here's another example where you see a really horrible tofu here with soft tissue swelling, and then in the metacarpal and midfoot, you can see these cystic changes. Newer modalities include ultrasound, where you see something called the double contour side, which is a sort of a pre-ophi buildup of uric acid along the joint line, which is here. It's not Quite ready for prime time at this point. It is very operator dependent and so it varies not only from institution to institution, but also radiologist to radiologist. And it's not particularly sensitive. The, it's a wide, um base here, but, you know, at best 80%, probably more like 40 to 50%. And it's also not entirely specific, although it's a little bit, has a little bit of specificity than, than sensitivity. What's a little bit better is seeing both the tofu and A double sign, so there's the tofus there, and that increases the sensitivity and specificity quite a bit. Again, not sure you're getting much more than a a General, uh, radiograph out of this because once you see a TI, that ship is sort of sailed and it's a little bit late for treat. I mean, you definitely want to treat it, but we do like to get people treated before they develop toi and erosions. One of the newer things is a dual energy CT which has a little bit more sensitivity and specificity than the ultrasound, and it can pick up. Toi in people who are asymptomatically hyper or ischemic. Um, in fact, on one study, 25% of a group, I think of about 200 had, had findings. So, it's better for ultrasound than extraarticular deposits, um, and that means deposits along the tendon lines that you see. It does tend to underestimate the size of to, and it doesn't detect inflammation, so it's a little bit difficult to know if That people have active disease. Although an active gout attack is generally pretty obvious. In early disease, again, it's not quite as sensitive and so not quite as helpful in terms of really understanding if people have TI or not. But it's pretty cool. Um, this is what it looks like, um, and you can see. The Tofi here and here. And so we're getting these more and more, and we're finding them fairly helpful. One way in which they're very helpful, and I've had a couple cases of this, is that, as you know, the differential diagnosis of a gout attack can be an infected joint, it can be pseudogout, it can be rheumatoid arthritis, it can be psoriatic arthritis, and all these things can coexist together. So I found it very helpful in people with psoriatic arthritis who also have gout. Determining what process is causing the destruction or if both of them are causing the destruction, because you won't see this light up in, say, just a regular erosion. Calcium pyrophosphate disease, a little bit confusing. I can't quite get uh, a straight answer from the radiologist uh about whether that shows up on gout or not. So, uh, I'm sorry, on the CT or not. So that I think is a work still in progress. But that would also be very helpful because calcium pyrophosphate deposition disease can really fake you out for things like rheumatoid arthritis and inflammatory osteoarthritis. So moving on to treatments, and this will be the bulk of the talk because I think um this is the most important part for us. Typically, the teaching is you don't treat asymptomatic hyperuricemia, um, but we'll talk a little bit more about that because I do think there are instances when it should be addressed. In acute attacks, your goal is usually just to reduce the symptoms and make the patient more comfortable, and the faster you can do that is usually the better. For chronic treatment, what you're looking for is a long-term reduction in the serum uric acid concentration. And when we define chronic, that's defined as more than one flare per year, or people who have toi, either interosseous or cutaneous. If they have greater than stage 2 kidney disease, uh, it's often, um, thought that it's a good idea to go ahead and treat. And if they have renal calculi that are uric acid stones, obviously that's an indication as well. So asymptomatic hyperuricemia, um, the party line is that it's not recommended. However, if the uric acid is greater than 10, The thinking is, you know, if they don't have Tofi now, they're definitely going to get Tofi. And it's also If you can see if they have Toi even though they're asymptomatic, then that's also an indication to treat, and that's where the imaging becomes so important. So, there's a lot of discussion about lifestyle modification and what to do about this goes in and out of fashion, um, over the years with different fads coming into play. And that's because the data are very mixed and conflicting. Weight loss is always thought to be a good idea. Um, but as a professor of mine used to say, the body is not a chemistry set and especially the immune system. So you can often get paradoxical reactions and things that seem like a good idea. So, weight loss actually leads to the, um, Does it really affect the uric acid levels, and you get The thinking behind it is that it leads to decreased de novo purine synthesis, excuse me, and also Insulin can reduce renal purine excretion. That being said, um, there are some actually decent data on the DASH or Mediterranean diet. Um, it tends to be more effective in men than women, and it tends to be more effective in people who have pretty high uric acid levels. And it's also good for treating the associated diseases, so things like hypertension, diabetes, obesity. Other lifestyle modification, we all hear that legumes are precipitants of gout flares, but they're actually OK for everyone in moderation. For women specifically, avoidance of red meat seems to have a positive effect on gout flares. For men, vitamin C. Avoidance seems to have a positive effect and all people should avoid high dose, high dose fructose. Other things that seem to have a trend towards being effective are low-fat dairy, um, a low protein, low purine diet. Increased intake of short chain fatty acids, and that's probably because of the fiber in most of the, the carbs that are recommended in in with those. And then polyphenols, which are things like berry and grains, and that's probably where the whole cherry juice mythology comes from. Alcohol is a definite no no, um, because it's a triple threat. It not only increases oxidative stress by converting ATP to AMP, it's very dehydrating, and it can cause a metabolic acidosis that affects the renal clearance of urate. Beer ends up being a quadruple threat because it also delivers a huge purine load. So treatment for acute flares are pretty familiar probably to everyone except for the last one, the IL-1 inhibitors. Um, typically you start with colchicine or NSAIDs, and steroids are tend to be reserved for people with comorbidities. Colchicine is a very interesting drug in terms of its history. It's been around for a very long time. There's evidence that the Cro-Magnon people used it for probably gout flares. It comes from the stamen of the crocus, um, similar to saffron. And it has um Unfortunately, even though it has an interesting history, it's not a particularly good drug and it has a lot of potential for toxicity. In fact, every year in the hospital, we'll have an M&M about colchicine overdose. It can cause renal failure, it can cause hepatic failure. It can cause a bland myopathy, um, it can cause neuropathy, and with chronic use, it can cause bone marrow suppression. It's also not a very effective drug. You really need to start it. They say within 12 hours of onset, but probably at the first tickle of a gout flare. And most important, it doesn't alter the progression of disease and so it only treats in the short term and so it doesn't prevent things like Toi formation or monotonic crystal formation. We used to say, uh, take it until you get diarrhea. Um, so you can imagine that was pretty unpleasant, especially if you were taking enough to induce something like a myopathy. Uh, but a recent new protocol has been recommended, and that's where you take 2 pills followed by 1 pill in an hour or so. And then once a day until the, the flare subsides. This tends to have a lot fewer GI side effects. You do want to reduce the dose in kidney disease, um, and if people are using the cytochrome P450 inhibitors like macrolides, antifungals, or HIV meds, and you wanna be very careful in people who have liver disease as well or who are using statins at the same time. NSAIDs are another mainstay of treatment. The teaching is indomethacin is the go to drug, but there's really no data for that, so it doesn't look like one class is better than another. And I'm sure you all are aware of the potential side effects. So you can get GI irritation and bleeding. Um, PPIs can help mitigate this, but only in the upper GI tract. You can get renal toxicity, um, which becomes an issue for a lot of these patients. It can magnify or even induce hypertension. It's not good for congestive heart failure patients. It has antiplatelet effects, so to make it an issue when people who are on prophylactic aspirin or warfarin. If you have a patient who is taking aspirin, um, what you want to do is make sure that they pace out the NSAID at least 4 hours before or after they take their aspirin because the NSAID will temporarily block that site where the aspirin binds on the platelets. There is one exception to using NSAIDs with warfarin, and that's celecoxib. It doesn't, it interacts, so you have to keep an eye on the level, but it doesn't block or or potentiate its effect. And like all drugs, that can also cause a rash. In patients with kidney disease or hepatic disease, we often use steroids. Um, injections are a nice way to get around any comorbidity, obviously, but if there are multiple joints or if after a while, a flare tends to become diffuse involving the soft tissues, that ends up not being so effective. The standard uh oral dose for steroids is typically much higher and you have to use it for much longer than you would think. So we start out with 30 to 60 mg and do it for, with a slow taper for 2 weeks or even 21 to 30 days. One trick is you can abort an attack if you give someone 20 mg for 3 days, again at the first hint of The attack Steroids again have a very familiar and very disturbing list of side effects. They can potentiate hypertension, they can induce CHF. Obviously, they cause hyperglycemia. And with long-term use, there's osteoporosis, and this happens in as little as 5 mg for more than 2 weeks in most people. And it's very clear that osteoporosis happens early in the steroid treatment. And so there, there will be new guidelines coming out on when to institute. Prophylaxis like bisphosphonates, uh, when you give people steroids. It can cause skin changes which can be very problematic in older people, um, because it's an immunosuppressive. If you get a skin infection that will take much longer to heal. And a lot of people are very sensitive to the CNS infection and so you get sleep disturbance, you can get mania, uh, you can get anxiety. And immunosuppression, uh, can happen in doses as little as 2 to 5 mg, especially in older folks. So that's something to be aware of. It also, again, at those very low doses, looks like it reduces the efficacy of immunization. So the response to the immunization is greatly diminished. I have one inhibitors have come on the scene in the last 5 years or so and we typically use these in the hospital because they're so expensive. But anakinra is very effective in controlling a flare. It's given as an injectable and you do that once a day for 3 days and that typically knocks, knocks it out quite well. And this has been very handy and, you know, the diabetic. Patient with congestive heart failure and chronic kidney disease. Canakimumab theoretically should do the same thing, but it hasn't been tested enough or approved for this. Anakinra is mildly immunosuppressive, um, so pharmacists are very adamant about TB screening beforehand and aggressive immunization as well. And as I mentioned, it's very expensive, which makes it pretty much an inpatient drug, um, because the cost is so prohibitive. So, moving on to chronic therapy. So the indications for uric acid lowering therapy include, as I said, more than one flare a year, uh, TI, and renal calculi. So the serum uric acid goal depends on the severity of the disease. If they just have a few gout attacks and no evidence of Toi, the goal is serum uric acid, 6 mg per deciliter. However, if they have tophus and of any size and or severe gout or frequent attacks, then the goal is closer to 5 mg per deciliter. And frankly, I tend to, to try to shoot for 4. Milligrams per deciliter. So the, again, the party line is that you begin uric acid lowering therapy two weeks after an acute flare, and the thinking behind this is that most of these medicines can actually precipitate a flare because they're mobilizing uric acid and making it more available to the immune system. However, usually when you're starting uric acid lowering therapy, people are in either prolonged flares or constant flares, and it can be hard to get in there to start it. So, it's generally OK to start it as long as that flare is pretty much controlled, because you're gonna need to use prophylaxis anyway. You do want to monitor the serum miracle acid frequently, um, that's every month for the first couple of months until you get to the goal. Unfortunately, um, there's a problem with adherence for most of these medications. One of the reasons is, is that there's a misunderstanding that they're going to help an acute flare, and so patients often feel that the medicine isn't doing much for them. As I mentioned before, the flare can actually be precipitated by the uric acid lowering therapy. And, um, even if you're at goal, usually 6 months or even up to a year, you're still going to have breakthrough flares. But the importance of it is that it not only prevents acute attacks, it also prevents damage and disability down the line. So there are sort of 3 flavors with this. There are the xanthine oxidase inhibitors, that's allopurinol and fabucistat. There are the uricosaurics, um, and that's pretty much probenecid here in this country. And then there's pegylateduricase, which is again probably more of a hospital thing. Allopurinol. So allopurinol remains first line for uric acid lowering therapy. You start at dosages of 50 to 100 mg a day. You wanna keep a close eye on people's renal clearance. Remember that it's also hepatotoxic. Remember that it's gonna need prophylaxis at least for a couple weeks or until you get to goal. And remember that there is a severe hypersensitive reaction that can happen where people can get a descomating rash, uh, and even die of that. And people who are more prone to that tend to have an HLAB 5801. And We thought that that was mostly people from Asia, um, but it's turned out that it's much more widespread in this country, especially, mostly because There's less monoformity in the population. It's generally very safe and very well tolerated, but you do want to be cautious and aware that at higher dosages, uh, in people obviously with renal disease, especially fluctuating renal disease, in people with hepatic disease, in people who also use diuretics because that can potentiate it, and in people who use statins again because of the potentiation. So before you start allopurinol, you wanna check a complete metabolic panel to look for renal and kidney dysfunction. And I am more and more checking the HLAB58 in almost everybody just because you'd hate to miss it. Typically, Assuming everything is, is OK, you begin 100 mg per day and check a level after a month, both of the serum uric acid and the CMP. Typical dose is 300 mg per day, but as I mentioned in my last slide, you can actually go up to 800 mg with proper monitoring. If a GFR is less than 30, you do wanna start at 50 mg per day. If it's less than that, you even wanna go lower and slower. Two drug interactions that are very important to think about is azathioprine and warfarin. Azathioprine is an anti-metabolite chemotherapy, but it's also used in autoimmune diseases. It can permanently suppress the bone marrow if it's at too high dosages, and so allopurinol's interaction with it can be very dangerous. Warfarin, the same thing is potentiated by allopurinol and it's not cleared as much and so you can really increase people's risk of bleeding. The second xanthine oxidase inhibitor is called fabucistat or Uloric. Um, it starts at 40 mg per day and can go up to 80. It's cleared hepatically, um, and there's limited data on dosing for people with pretty severe chronic kidney disease. It's thought that it's probably OK. It also needs prophylaxis like allopurinol. There may be some cross reactivity with allopurinol hypersensitivity, um, so, Be aware that you can still get a rash with it. Uh, the HLA-B2 B58 is not a risk factor for that. There was some data um that there was increased cardiovascular deaths with it, um, but that has now been muddied a little bit by recent studies. The main study that was done was published in the Journal quite a while ago. It was a multi-center randomized control trial that was looking at Cardiac deaths in patients who took allopurinol versus those who took fibicistat. After 32 months, the rate was pretty much equivalent, a little bit higher in the Fubucistat group. However, the hazards ratio for all cause of death was higher in Fbucistat, and cardiovascular mortality was also higher as well. And that's why it has a black box warning. As I said, there were 2 studies published last year suggesting that this isn't the case. Um, they're not quite as robust as this study, but they're also, the data is less confusing with them. But this is that, um, there was, and this was probably by the manufacturer, there was some lore that it was more effective than 300 mg of allopurinol. That doesn't look like it's the case. There are again, a couple of studies last year that suggested that it's not. There is less concern about chronic kidney disease with it, however, it is much more expensive, and we really don't have the data if it actually prevents erosions. We're assuming that it does. To monitor it, again, you want to check a complete metabolic panel, you begin at 40 mg per month, and again, monitor monthly until you get to goal. I also think shared decision making is a good idea and so there should be a frank discussion about the risk versus the benefit. Probenecid is a uric auric uh lowering agent, and you start out at 500, I'm sorry, 100 to 500 mg twice a day. It is renally excreted almost exclusively, so it's contraindicated with people with reduced creatinine clearances. It can also precipitate flares, although we don't think about it as doing that that much, and it can precipitate your acid stones, especially in people with Toi. Um, so it's typically avoided in people with tofaceous gout. It can be used as monotherapy, but it also is often combined with the xanthine oxase inhibitor. So if you've maxed somebody out, um, you could sometimes add probenecid. Sorry. Before starting, you do wanna do a basic metabolic panel. I tend to start at a very lowest dose, so 250 BID. Uh, I monitor monthly and I counsel patients to increase their fluid intake. It can interact uh with aspirin and also with methotrexate, and so that becomes a concern in people who have Psoriatic psoriasis and gout, um, and as we mentioned, psoriasis is a risk factor for gout. We don't use methotrexate that much in treatment of psoriasis simply because there are better agents that are less toxic, but in some of the older folks, you will see this. There was a medicine that was approved a while ago called lazarinab, um, and it was used, usually as a combination pill with the xanthine oxase inhibitors. Um, it worked really well, but you needed to use it at pretty high dosage of 400 mg. However, it's been taken off the market, um, because it's very toxic. Um, so it's not available anymore in this country. You will, however, see patients coming in from foreign countries who are bringing their medicines with them, and they will be on it. So you do need to monitor their renal function quite closely. Two other agents that were never available in this country, but again, you will see people coming in from other countries, especially China, are been Benzbromeone and sulfurrazone. Um, these are all very Hepatotoxic, um, but there, it's cleared renally, so that's why you keep an eye on their renal function. Pegylatedurritase, um, as I mentioned, is probably more of a hospital thing. It's given in hematologic malignancies to prevent kidney problems. However, after the first infusion, almost half of patients have infusion reactions. Therefore, if we have to use this therapy chronically, we tend to start people on methotrexate for a month beforehand, and that seems to lower the incidence. Of infusion reactions. This is probably outside the scope of primary care, but I wanted you guys to hear about it. So prophylaxis, so when you start these uric acid lowering medicines, as I mentioned, you can precipitate a flare. So there are many strategies for preventing that. Colchicine is a good one in people without kidney oropathic disease, um, and you can start 1 to 2 pills every day. NSAIDs are also used, although, I, I have to say of all the medicines here, these make the most uncomfortable in terms of their side effect profile. I like 5 to 10 mg of steroids. Um, that can be very effective too if the patient doesn't have diabetes. If you need more, you wanna be slow on the up titration of it. The teaching is, is that we're supposed to use it 3 to 6 months after you reach goal. However, in practical use, I think, you know, you wanna cut back on pharma polypharmacy. Um, you want to improve compliance in the patients. So I tend to just use it until we hit goal. And although there is a subset of patients who will need these medicines as well as their uric acid lowering medicine to control their flares. And that's the people you continue indefinitely on. Other drugs that can have a mild effect on lowering uric acid are losartan, which is why there was the asterisk next to ARB in our previous slide, and fenofibrate, and this probably has to do with the way the gut functions. Um, we talked a little bit about the metabolic balance of proper gut function. There are some new data too that the microbiome may affect the way uric acid is processed and cleared. So, moving forward, um, as I mentioned, we're just starting to really take a close look at gout both in terms of its pathogenesis and hopefully that will lead to novel treatments. And hopefully, the new imaging modalities will become sophisticated enough that we'll be able to really improve prognosis by having a quick and early diagnosis. So in summary, acute gout and chronic gout are a little bit different, both in terms of their presentation and treatment options and treatment implications. Do think about treating chronic gout early. Reducing uric acid remains the cornerstone of therapy. And to sort of contradict myself from what I said a little bit earlier, no one ever died of gout, especially not acute gout. So remember that all medications have potentially serious side effects. There will be a subset of patients who the only safe treatment will be pain control. When you do start a medicine, you wanna monitor closely, definitely consider their comorbidities and don't forget drug interactions.
