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- [00:00]
A
Welcome back to Run the List, a medical education podcast in internal medicine. As a quick disclaimer, this podcast is made for educational and informational purposes only and should not be understood as medical advice under any circumstances.
- [00:23]
B
We're back with Dr. Pillenger and ready to tackle part two of our series on gout. For this episode, we'll be discussing triggers and treatment both in the inpatient and outpatient setting, as well as management strategies after this acute flare. Just to remind us a little bit about our case, we had a 55 year old gentleman with a history of hypertension and hyperlipidemia who's presenting with severe pain in his big toe. This is a recurrent acute monoarthritis in a typical location for gout with overlying erythema, his inability to walk, and his X rays just came back showing a large punched out erosion at the first MTP. So at this point, Dr. Pillenger, we've ruled out other causes of monoarthritis and we can confidently diagnose this patient with gout. Can you tell us why now what might have triggered this gout attack in this patient right now?
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A
Well, that's a great question, Dr. Gutowski. And the reality is we don't entirely know, but there are some things that we can think about. First of all, there's just time. You wait long enough and you get something. Time and exposure to high levels of urate. And time because urate crystals tend to deposit slowly. So our patient who has an acute attack right now, if we look harder, we'll find evidence of crystals that have been sitting there a long time. And in fact, we already have found some of that evidence in that punched out lesion. So the presence of crystals is one reason why somebody may get an attack today as opposed to tomorrow. When urate levels drop, those crystals tend to flake off of these joints, at least we think so. And that means fresh crystals in the joint that can trigger an attack. But any fluctuation can kind of perturb that. So that will include things like dehydration, metabolic stress, acidosis to some extent. We often see people on the inpatient side develop an acute gout attack in the setting of an mi, in the setting of sepsis, in the setting of a procedure, those things are all common. Another thing is that immediate rapid perturbations that raise a urate seem to cause this, maybe because they can precipitate some more crystals. It's actually never been shown, but people will tell you that whenever I drink, you know, a dark Alex, I get an attack. Whenever I eat steak, I once had a patient who was a food critic who said, whenever I eat venison, I get an attack. The interesting thing there is sometimes it's an amnestic, sometimes it's a very specific trigger. But ultimately the answer is we really don't know.
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B
Yeah, it's interesting. I remember during my inpatient time a lot of our gout consults were actually in patients who had undergone a huge amount of diuresis or had recently undergone a procedure. So moving on now to treatment. And I know this actually turns out to be quite a bit more complex than it might seem at first. There are elements of acute management, but also this is the beginning of a long journey that we have with these patients to get their gout under control over the long term. So Dr. Pillenger, what are our options for this acute gout flare treatment?
- [03:22]
A
Right, so as we talked about last time, these things hurt, right? This is very painful. The good news is that even if you leave it alone most of the time, the flares go away at least early in the course of disease. We'll talk about sort of lifelong gout. It becomes a little bit of a different story. But they will self resolve, but nobody wants to wait for that. So we're looking at the problem in front of us and the problem in front of us is inflammation. The good news is we have a number of anti inflammatories and I'm sure everybody who's listening pretty much knows what they are. And the main thing about them is to pick the one that will do the least harm to the patient because they all will pretty much work. So what are they? Nonsteroidal anti inflammatory drugs. The classic one is indomethacin, but most of us rarely use indomethacin anymore because it's more toxic. It works. It's good that it's short acting, but people don't get along with it very well. As far as we know, any of the nonsteroidals are good. If you're a rheumatologist, you're a little bit obsessed with these things and you ought to know not just two or three, but five or ten different non steroidals and fit it to the patient. The selective COX2 inhibitors like celecoxib, as far as anybody knows, are just as good as the traditional NSAIDs. So people with more stomach sensitivity, pick that one. I do try to avoid non steroidals in virtually anybody with kidney disease. If I need to use one, I try to use one that I know is a little bit safer. It's marginal. But drugs like celecoxib are a little bit safer on the kidneys. A drug most of your listeners have never heard of, called Solendac is a little bit safer on the kidneys. But avoid it if you can. When you use those drugs, you have to use them at the higher doses. So if we're talking about something like ibuprofen, we're talking about 800 milligrams, three or four times a day, just to give you an example, not like a headache dose. The alternatives, the next alternative are glucocorticoids or steroids. And prednisone is the usual oral go to. It works great. The dose for prednisone is about a half milligram per kilogram, so probably a little more than people might imagine. You know, if a 70 kilogram man, it's a 35 milligram dose and then you'll use it for five to seven days and then either taper or stop. I don't think I have to tell people about the side effects of glucocorticoids. The longer you use them, the higher you use them, the more trouble you might get into. Elevated glucose, elevated lipids, weight gain, agitation, osteoporosis, and increased rates of atherosclerosis and heart disease, and on and on. But if you're using it for a week, it's not a terrible alternative. A great alternative in people with kidney disease. How about colchicine, Dr. Gutowski? I think, you know, it's my favorite drug in the an extremely old drug first recorded in an Egyptian papyrus in the BC era. It comes from a cross crocus that grows in Asia Minor. We could do a whole session on that. But it's a really effective drug. You have to be careful with it in certain settings, like the setting of kidney disease. It interacts with certain drugs that are what we call CYP3A4 inhibitors and P glycoprotein inhibitors. You can look in the package insert to know if you need to dose adjust in that setting. But for most people, it's okay. It works best early in the disease and you want to get it started pretty much on the first day. And the really important thing about colchicine is that very safe drug for most people at low doses, potentially toxic at high doses. The dose for an acute flare is two pills followed by one pill an hour later. So that's 1.2 milligrams followed by 0.6 an hour later and nothing for 24 hours. And then you decide whether to continue it once a day. And in case you have any listeners abroad, just translate 0.6 to 0.5. So those are your three core options. I neglected to mention steroid injections. We rheumatologists like to do that. You need to be able to access the joint. You need to have confidence that it's not infected. Finally, one of the big breakthroughs over the last number of years for gout was the discovery that IL1 is really, really important in gout. It's sort of the first cytokine in gout. There's a whole biology of that as well. Hard to believe we had a 2000 year old disease and just figured this out now. But once we knew that, we could approach agents that block IL1. And by the way, colchicine does that. But we have three biologics that block IL1. Only one of them is a pre approved for this use, but rheumatologists will go to them periodically. And those are Anakinra, which is an IL1 receptor antagonist. Kanakinumab, which is an IL1 antibody, and relanocept, which is an IL1 sort of pseudo antibody. Only kanakinumab is approved. They have all been shown to improve acute gouty attacks. So the goal is just to get the patient feeling better so you can deal with the long term risk of future problems.
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So just to summarize, we have NSAIDs, which are typically at a higher dose than your headache dose. Glucocorticoids, typically oral, and prednisone would be your option there, although intra articular is also an option and colchicine are our big three. Although IL1 inhibition can also be considered in certain cases. But at that point you're probably going to have your rheumatology consult on board. All right, Dr. Pillenger, we're sending this patient home with a couple new prescriptions and telling him to come to rheumatology clinic in a week. So a week later you see him in clinic, he's feeling great, he has no pain anymore. What is your discussion with this patient look like?
- [09:11]
A
It can be a little bit tricky actually, because patients have a concept that gout is what they have when their toe hurts. But you know that we call that a flare, a gout. Flare gout is a metabolic condition that you have all the time. And so if we're going to prevent gout flares and maybe affect the comorbidities of gout, which I think is a very important area of research right now, we're Going to need to address the underlying problem, the metabolic problem, and not just deal with the flares when they come. There's some controversy about this, Dr. Gutowski, but basically the rheumatologists say if a patient's had a single attack, will let it go because the next attack may not come for years, Especially if their rates aren't too high. But if they've had more than one, especially if they've had more than one in the past year, especially if their rate is particularly high, let's say over eight or nine, or if they have renal disease, we know that they are a setup for starting to get more and more frequent attacks. And then we have to go back and address the root cause, which is hyperuricemia. We talked about this in the first issue. So when we start to treat with urate lowering therapy, we take a treat to target approach. We have a target, and for most patients, that target is less than 6.0 milligrams per deciliter of uric acid in the bloodstream. Why is that? In a beaker on the lab table, you, uric acid becomes insoluble above 6.8 milligrams per deciliter. So our goal is to get the urate below the level where it can form new crystals. So how do we lower the uric acid to prevent problems? Well, first we do a couple of common sense things, right? We ask the patient to try to eat a diet that is at least lower in some of the risk factors for hyperuricemia. So less meat, less seafood. But we don't ask people anymore to go on a draconian diet because it only works to a certain extent and they don't follow it. It's unreasonable to ask people to do that. So we ask do healthy things. Modulate your meat intake, modulate your seafood intake, modulate your intake of fructose, modulate your intake of alcohol, do it all in the direction of healthy eating rather than trying to cure gout. And then don't tell the patient that the gout is somehow their fault because of the diet. It isn't about. The best you can do with diet is drop your urate about a point. In most of our patients, we're going to need to drop their urate 3, 4, 5, 6 points. So it's helpful. It's a good idea to eat healthy, but we don't want the patients to feel like it's put upon them. So that's number one. And number two is they're almost certainly going to need drug therapy. We have two agents available that lower urate by blocking uric acid production. And again, I'm talking in the US and then we have one agent that helps urate be excreted by the kidney. And then we have an agent that eats urate like a pac man. I'll go through each of these very briefly for the audience. The urate lowering therapies are two drugs called allopurinol, which if you think about it, just means another purine alcohol. And it is an analog of purines and it's a competitive inhibitor of the enzyme that converts purines into uric acid. And so it blocks that enzyme, which is xanthine oxidase, and lowers the production of purines. The other drug that we use is a drug called Fabuzostat, much newer, about 10 years old, and it is also an inhibitor of the same enzyme, but by a different biochemical mechanism. It's a non competitive inhibitor. They both work great. How do we pick? We mostly pick allopurinol first because it's cheaper and older. To be honest, there has been some concern on the for buzastat side of an increased cardiovascular risk. I can't tell you that it's been entirely debunked, but it was a key study mandated by the FDA and it showed this cardiovascular risk. And the problem with it was it was a study that in the end had a lot of problems and other studies have not supported it. Nonetheless, the FDA saw the study, they mandated and responded. So one of the reasons why we tend to use allopurinol first is because of this FDA mandate. But I think that risk is actually very low if existent. So a patient who needs fabuzostat should get it. Why might you not use allopurinol? One thing is that very, very rarely people taking allopurinol develop hypersensitivity reactions. Even more rarely, they can die. And I have encountered two of those cases in my now longer and longer career. Clearly you don't want that to happen under any circumstances. So how do you prevent that? Number one, you be careful in the setting of kidney disease because the issue is basically you don't want to give the patient a higher dose than they need too suddenly. And so we use allopurinol in a titrating manner. We usually start with 100 milligrams, if that's okay, we go up 200, if that's okay, we go up 300, all the way up to 800 milligrams if need be. At Any renal dose, although I go 50 milligrams at a time with renal failure. And I watch the patient and make sure that they're okay. And I make the patient watch themselves too, because if a patient gets a rash, it doesn't mean they're on their way to a horrible outcome, but there's just no reason to keep going. So a patient gets a rash on Allopurinol, I stop it. I don't want to see Dress or Stevens Johnson or the like. How else can we lower the risk? Well, very interestingly, there's a group of people who turn out to be at much higher risk. And they are people with a particular HLA type called B5801. The increase in risk is hundredsfold, although the risk remains low when people are positive in HLA B5801. Therefore, most of us will avoid the drug. We don't test everybody for this, but we test the people who have a bigger chance of having it. So who are those? There are certain groups of Asian people, Han Chinese, Koreans and Thai. I believe there's about a 10% positivity rate in those groups. African Americans have a 4 to 5% positivity rate. That's enough of a risk also for us to check. Generally speaking, white people, people of Hispanic descent, whether white or black, tend to have a lower rate. Definitely white, Hispanic and whites I don't bother to test, but I warn everybody to be careful. Is either one of these drugs better than the other? We did a big national study to look at that, and the answer is no. They work just as well. They have different features, they have different titrations. One just may fit the patient a bit better. The most important thing is compliance. Lots of people have these drugs not work because they don't take them. Go figure. The second class of drugs are these urate lowering drugs that work by pushing urate out the kidney. And right now we only have one of those drugs, and it's an old drug called Probenecid. The idea is perfectly good, but Probenecid is not a great drug. It's not that potent. Take it several times a day. You need lots of hydration. And so it's not our favorite first line, but it may be right for some people, people who haven't tolerated the others. We sometimes use it as an add on as well. So those are the easy ones. Sometimes people don't respond to those, or sometimes people have let themselves go without care for such a long time that they're turning into a pillar of Urate, like Lot's wife turning into a pillar of salt. That is, they have so much urate deposited that these drugs are just not going to be potent enough. And right now we have one agent that we roll out, like rolling out the big guns. And it's a remarkable drug. It's an agent called pegloticase. And, and what it is is a recombinant uricase. We humans, you may remember, lost our uricase about 15 million years ago. We talked about this. The good news about pegloticase is we can kind of give it back to the appropriate patient. And like I said before, it's kind of like Pacman. It just eats urate at a remarkable rate. It digests urate in the bloodstream. And we can see a patient have a uric acid level, serum uriate level of 15 and give them this drug and by tomorrow their uric acid level is close to zero. And then we have to maintain it until we eat up all the uric acid in the body in these patients. And that's kind of a reset. It's phenomenal, it's very expensive. It needs to be given with methotrexate because it's immunogenic and the methotrexate helps with that. But I have seen it be life changing for some of our patients and I imagine that you have as well, Dr. Gutowski.
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Yes, definitely. A few cases.
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Yeah, it's not a drug for every case, but where it is needed. Wow. It's just amazing.
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So allopurinol, febuxostat and pegloticase. So after discussing all the different options with our patient, the two of you decide together that allopurinol makes the most sense for him, at least as far as initial therapy. What else are you talking to him about as far as prophylaxis during this time when you're lowering his urate level?
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A
Yeah, that's a, that's a really, really important question. So thank you for asking it. So you remember I made the comment that sometimes a trigger for gout can be the lowering of uric acid. And probably it's because crystals slough off the joint. That happens when we lower uric acid deliberately as well. So when we start any of these urate lowering drugs, we go through a period of, rather than decreased risk, increased risk for gout flares. And this can be a big problem, frankly, because one of the reasons why patients don't comply is if we don't give them instructions to manage that, they come back and say, doc, you started me on this allopurinol, you started me on this Fabuzostat. It didn't help me, it made me worse. And so our job is, is to make it possible for them to get through the process of urate lowering into a point of stability without having too many attacks or any attacks, so that they appreciate the drug. Basically the idea is that we want to put them on an anti inflammatory agent to prevent attacks until the urate deposits are gone and stabilized. And we go back to our same choices. Colchicine, prednisone, non steroidals and anti IL1 therapies, which are sort of last resort because they're expensive. If you think about it, this is going to require an extended period of treatment. And so we should probably try to do it the safest way possible. So I'm not a big fan, for example, of using a non steroidal drug as a prophylactic agent. But if I were going to, I'd probably use something that's Cox2 selective. I'm also not a big fan of using prednisone for long term, not for this. For most of our patients, I think the best and also most reasonable option is going to be colchicine. It's safe at a low dose and it works quite well. And so for most people, the big enough dose is going to be one pill a day. If they break through, it's probably a pill twice a day and that should be enough to keep them from having attacks. Another trick you can do, although it's not always practical, is to do the titration slowly. I don't really like to do that because my experience is you tend to lose patients. I want to get my patient at the urate level. I want them within a number of months. If I can't get them to where their medicine is stable, I'm probably going to lose them. So how long do we keep this prevention, this prophylaxis going? The minimum is about three months. There is some evidence that you really need to wait 12 months to see the benefit of the urate lowering. So in some patients I'll leave them on longer, especially if they're still having a flare. So I keep the colchicine on as long as it takes to know that the patient is out of the woods for a flare and they're unlikely to have another attack, and then I'll pull it back. There are some other tricks here though, right? As you know, both the FDA and the Canadian equivalent of the FDA have approved colchicine for prevention of Myocardial infarctions and gout patients are at high risk for that. And we were some of the first to show in studies that patients who are on colchicine with gout seem to have a lower MI rate than patients who are not. So, and in some patients, I may make a decision, usually with my cardiologist colleague, that this patient actually is gonna stay on for the long term. So there are some reasons like that. And then, on the other hand, there may be patients who I see as a little bit more at risk for colchicine toxicities, and I may be trying to pull that back a little bit early.
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B
Got it. Okay. So customizing the plan for each patient, as always, and also keeping in mind that these can be pretty confusing medication instructions with lots of different changes at every visit. So making sure that your patient understands what you're talking about and sometimes using things like drawings and diagrams can be helpful for our patients as they're learning about their new diagnosis of gout. All right, Dr. Pillenger, this was wonderful. Thank you so much for all of your expertise.
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Some content from this episode was generated with the assistance of artificial intelligence.