Chapters Transcript Update on Gout - Enter the Endothelium Course: NYU Langone Seminar in Advanced Rheumatology Uh, as Doctor Top Rover talked about, I'm, I'm very interested in gout as a VA physician. It's hard not to be very interested in gout, and, um, I, I'm also very interested in the intersection between rheumatic and cardiovascular diseases, as Doctor Top Rover mentioned, uh, we work together and we work often with our cardiology colleagues. So what I wanna talk to you about today is gout and cardiovascular disease with a particular emphasis on the endothelium. These are my disclosures. So when we think about the elements of gout, uh, we typically, I think, think about these four different features. First of all, there's hyperuricemia which proceeds and continues through gout that's really a metabolic, genetic, dietary, and excretory disease. Uh, we then add on the process of monosodium. You're a crystal formation and deposition, something that is uh vastly understudied and something that we don't really talk about very much then there is the gout flare, the one thing that our patients care about, the one thing that they tend to think is their gout, which is the articular inflammatory responses to that crystallized urate. And then finally Tofi and faus gout, those uh massive accumulations of crystals interspersed and surrounded by an inflammatory corona and then oftentimes surrounded around that by a by a fibrous capsule but the case I want to make today is that we ought to think of of at least one more process as an element of gout, and that is the effect of gout on the vasculature and as I say, we'll talk particularly about the endothelium. As 1/5 elemental state in gout and perhaps as a distinct target for treatment. So, uh, we should start with the recognition that patients with gout have a high risk of cardiovascular disease. Uh, gout holds its own among the other rheumatic diseases that people, uh, acknowledge and take for granted carry high risks such as rheumatoid arthritis and psoriatic arthritis. Uh, clearly some of this has to do with comorbidities and, and nascent innate risk, but some of it is added on in each of these diseases and particularly uh in gout. Um, if we want to understand how the vessel might be playing a role through gout into the risk of cardiovascular disease, uh, the first and most obvious place to start is with the gout flare, and this is a slide that I use in my summer lecture to our fellows talking about how gout flares happen. It's pretty basic and it only shows the first couple of steps, but here we have a set of crystals encountering a tissue macro. Which is really the first step in the in an acute gout flare. Those macrophages undergo activation of their particularly uh of of their inflammosomes uh and their NLRP3 inflammosomes which leads to production of IL1 and subsequently other cytokines and these cytokines bring us to the endothelial cell because they act on endothelial cells to cause upregulation of adhesion. Molecules such as ICAS, which helps lead to the uh what's going on in terms of coactivation of leukocytes that can then stick to the endothelium can then get down to the endothelium and through it. So when we think about gout flares, we must invoke the endothelium as a key part of gout flares. Now that doesn't sound like it's going to figure in to uh to cardiovascular risk because this is an 8 or 10 or 15 day process perhaps and then it. And then it goes away, but in fact there's some really interesting data recently by Abhishek's group in England, uh, that ties gout flares to cardiovascular risk. Uh, Abhishek had all used a very large, um, patient data population, did a retrospective study. Time won't let me go into the details of how this worked, but what they found was that within 120 days after a gout flare, our gout patient. Patients are at twice the risk of MI and twice the risk of stroke as they were before they had their gout flare so something does happen in a gout flare that transiently raises the risk of myocardial infarction. What is that? Well, we don't know from this study. It's, it's a clinical data set study, although perhaps this the message is inflammation, whatever that means it's a very broad term, isn't it that we throw around. Here's a study that we've only published in abstract form so far, uh, but that I think does raise this question of how can you link 120 days of cardiac risk to what we usually think of as 8 or 10 days of gout flare. Well, I had the opportunity to work with the horizon folks, now the Amgen folks, uh, who make pelotacas and to look at their phase 3 data and, um, uh, what we looked at was the number of very early gout flares after the, uh. A lotta case was instituted because you know when you start your rate lowering you typically induce a risk period for gout flares and how that related to a marker for inflammation, not the marker we usually use so the marker that the cardiologists like to use which is called the neutrophil to lymphocyte ratio which is probably a little more sensitive than what we do and it's been established by the cardiologist as to indicate at least over a long period of time cardiovascular risk and what you can see here. Is that those patients who had the highest cardio uh I'm sorry, the highest number of flares in the early going 4 or more had a significant increase in the neutrophil to lymphocyte ratio. Those who had a few flares, 1 to 3 had an increase and those who had no flares in the early going had no increase in the neutrophil to lymphocyte ratio. But what's interesting about this in the context of Abhishek's data is how long did that inflammatory state actually persist? Was it 8 days or 10 days or 14 days? It was 120 days, so there is evidence post flare of ongoing continuous inflammation for about 3 months. Maybe that's a window of risk we should be aware of. In fact, um, we know though that patients with gout, even between flares, even in intercritical states do indeed have subclinical low levels of elevation of inflammation of things like CRP, uh, and ESR. So gout is a chronic state of inflammation and I want to turn to the chronic state of gout, um, next because nonetheless, in spite of this data, most of the time gout patients are not in flares. And in the next part of my talk, I want to talk about urate itself, soluble urate as a potential risk factor for cardiovascular disease and in particular for the effects of soluble urate on those endothelial cells. A lot of this work actually has been done over the last decade or two by Rick Johnson's group. Rick is a nephrologist who's now at the University of Colorado. And um here are some studies these are in vitro studies um so we have to take them with a grain of salt, but they tell us something about what endothelial cells uh might be doing when they experience urate and in these studies the urate is always soluble and what you can see in this first of these studies is that when endothelial cells are. Exposed to urate they lose part of their ability to secrete nitric oxide. Nitric oxide is of course a really important thing that endothelial cells do because that's how endothelial cells tell smooth muscle cells to dilate. So, uh, uh, an endothelial cell that can't make nitric oxide can't cause vasodilation results in things like hypertension and inability to respond to stress. Here's another thing that happens it's not all endothelial cells here we're looking at smooth muscle cells in again in vitro, and I wanna call your attention to the black bars against in comparison to the white bars. The black bars are smooth muscle cells exposed to urate and what you can see here is that at least in a dish smooth muscle proliferates in response. To your age, so now we've got an endothelial cell that can't tell a smooth muscle cell to relax. And if you can sort of put this in a mental model, maybe you have smooth muscle cells that are actually kind of muscle bound if you will and may even have a harder time relaxing. The gray bars here are kind of interesting compared to the black bars that's actually cells exposed to probenecid. And normally you would say why are you using probenecid here it's a it's a kidney drug right? it promotes urate excretion from the kidney, but it actually acts on transporters on endothelial cells that the cell uses to take up urate and probenecid will block that and so you can reverse this effect of urate by keeping it out of the cells with probenecid. Interestingly, when we go back to the endothelial cells and you look at the black ver versus the white bars, urate teaches endothelial cells not to proliferate. The population of endothelial cells here declines. So while smooth muscle cells are growing endothelial cells are waning reversed by probenecid, you get the sense perhaps of the possibility at least of a very sick vessel, um, if this happens in vivo. Um, another aspect in which the endothelial cells may be sick is in their energetics, and again, uh, this, this is a study not by Rick Johnson's group. This is by Sanchez Lozada etal, and what you can see in this study of, uh, energetics in the endothelial cells is that their mitochondrial mass goes down and their ATP levels go down when exposed to soluble urate. So again, a cell that isn't really very well that probably can't do the things uh that it it is supposed to be doing. And yet not everything um uh about the effect of urate on endothelial cells is a diminishment. Some things that happen to the endothelial cells are actually um uh activating in a certain sort of a sense. One thing I, I didn't know until about a year ago is that endothelial cells make a glycocalyx on their surface and in a blood vessel. On the surface of the lumen, the endothelial cells basically putting up a briar patch of glycoprotein molecules, and that is a healthy thing for those cells to do and some of the, uh, components include lectin and syndican which you can see uh here uh well expressed, but what happens when those cells are exposed to uh to soluble urate they greatly. Reduce the expression of their glycocalyx and this is not a passive process. This is not a waning process because this is a process of enzymatically based shedding so the cells in their program stop making things that are a marker of their healthy function and interestingly again you can avert, uh, you can reverse this effect of urate if you treat the cells with probenecid and keep the urate out. And then finally, in this little in vitro tour that I've been giving you, there is the possibility that uh both smooth muscle cells, as you can see here, And endothelial cells as you see here contribute to the inflammatory state of the entire body. Normally we think that CRP is mostly produced by the liver in response to acute phase reactants, but in these studies again by Rick Johnson, exposure of smooth muscle and endothelial cells to urate induces the production of CRP, so the vasculature may contribute to the inflammatory state. There's another feature that I think may partly explain what we've been seeing or maybe something unique and different and that is the concept of trained innate immunity something that uh uh Leo Jousin in the Netherlands has done a lot of work on and this is a definition from one of Juuston's papers. He says trained immunity, trained innate immunity refers to the long term. Modulation of the innate immune response based on previous interactions with microbes, microbial ligands, or endogenous substances. So what does this mean? What it means is that a leukocyte that lives in a tough neighborhood gets tough, gets toughened up, learns to expect and respond to stimuli in a bigger and more inflammatory way. Um, now, why are we talking about this here? Because one of the main endogenous substances that Justuston's group has recognized as signaling trained in native immunity is in fact soluble urate, uh, uric acid. And so it sort of looks like this in a uh a cartoon from Gary Hoe in our group on the left you see a a non-primed uh white cell, a monocyte soluble urate gets taken up it induces both metabolic and epigenetic changes, DNA methylation changes. That basically turned the cell into a prime cell that is expressed uh in greater depth the machinery for a future inflammatory response. So for example, an increase in NF kappa B molecules and when that cell sees a true stimulus, it could be a bacterium. In this case though, it could be monosodium urate crystals, it will respond with a bigger response and so this may partly explain why people with long standing gout with higher urate levels tend to get worse and worse gout. The system is being trained to respond bigger. Um, white cells are very important in cardiovascular disease, certainly, uh, in acute MIs and the like, but there's also increasing evidence that endothelial cells may undergo the same kind of trained innate immunity and because these changes are epigenetic although not permanent, they're very durable so these cells and therefore these patients become a different chronic inflammatory, uh, kind of a patient. So I want to turn now from hyperuricemia to gout itself and what does gout add to the endothelial effects of hyperuricemia? Well, you know, in a, in a nutshell, probably inflammation, the inflammatory state we've already mentioned both the acute flare state of high levels of inflammation. And probably a chronic low level of persistent inflammation in the setting of a diagnosis of gout and how does that happen? Well, so you'd think a disease that we've been treating for 2000 years, we'd have it all locked up, but we don't really know everything about, uh, gout to this day. One possibility is just that there are crystals around even not in a flare and that these crystals induce a chronic state of inflammation and just to show you that the crystals are there, here's a study by Rennie Howard and our group uh Renny took um 25 gout patients, 25 hyperuricemics, 25 controls, and did ultrasound of both of their knees and both of their first MTP joints and looked for the presence of urate. Position and just looking at those four joints, 50% of gout patients not in flare have evidence of urate deposition on the cartilage or in the tissue probably presumably if you look at a lot of other joints you get a higher number and also the asymptomatic hyperuricemics, by the way, about 30% of them have that so this raises the possibility that this persistent urate between flares can have an adverse impact on inflammation and the vasculature. Another sort of interesting idea, uh, and one that remains controversial is that urate crystals might participate by precipitating directly into the vasculature, and this is a study by Barzani et all from up at Mount Sinai using dual energy CT to look at that. Um, here you're looking at the coronaries on the left, the, uh, thoracic aorta and the abdominal aorta on the right, and. If you have seen dual energy CT studies, you know that they are supposed to allow you to identify urate with a high degree of specificity and typically they are pseudo colored green on most studies and so where you see the little green dots here, you're seeing evidence we think of urate deposition. Um, Barzania had all looked at 31 gout patients and 18 controls, and this was the difference between the gout patients and the controls, a much higher, uh, uh, level of urate volume and a much higher number of these individual deposits or spots. What remains controversial about this is that some but not all dual energy CT radiologists think that the technology is just not specific and sensitive enough to look at these kinds of small deposits that's very up for grabs right now, but the idea that you could do this is supported by another study by Clause. In Geneva I think who basically did the same thing and saw the same result but also looked at 6 cadavers and in these cadavers 3 of 6 of them had vascular urate on their dual energy CT and because they were cadavers they could be dissected and you could look at the tissues where that, uh, where that, um. Uh, urate purported to be and indeed on polarizing microscopy in those three cadavers and not in the other three cadavers they could identify urate. So this is uh kind of an ongoing question, a recent abstract presented at ACR supported this idea and you can imagine both driving systemic inflammation but driving local tissue inflammation in the vasculature if this is indeed the case. So that's all kind of hypothetical, but can we see the effects of gout on endothelium in the clinic? Well, we can if we work with our cardiology colleagues to do physiologic studies and to do something called brachial artery flow mediated dilation. So this provides a surrogate for arterial endothelial function and it's actually. Pretty simple, you know, we, we rheumatologists, we're complicated, but the cardiologists, they're pretty simple. So all you do is you take a blood pressure cuff, you wrap it around the forearm and you blow it up, uh, so that you greatly reduce blood flow for about 5 minutes. In the meantime, you slap an ultrasound probe over the brachial artery and then you release the. Cuff and you let the blood flow and in a healthy artery it will the endothelium will sense the sheer force it will produce nitric oxide it will produce prostacyclin and uh endothelial derived factor and it will induce relaxation and you can measure this by measuring the change in the diameter on the ultrasound so we decided to have a look at this. And Svetlana Krasnikutsky and Aaron Garza in our group, uh, took 34 gout patients and 64 controls and put them through FMD and what did we find? We found that gout patients have about um uh a 50% decline in what is probably in. Filial function, uh, in the setting of gout. We also looked at their urate levels and their CRPs, we'll call it their inflammation index, and, um, although this is not a proof of causation, the higher the urate, the poorer the FMD and the endothelial function. The higher the CRP, the poorer the urate and the endothelial function. So patients with high urates and inflammatory states, which presumably I've made the case go together, have poor arterial function presumably due to the endothelium. Which ought to raise the question, can gout treatment improve endothelial function at least as we look at it with flow mediated dilation and Mike Toover right there, uh, decided to have a look at this, uh, for us and um took uh a similar. approach to what I showed you before but extended it into treatment and so what he did was he took 38 previously untreated gout patients, um, surprising that we had that many untreated gout patients and we tried to be clever about the study design. We he treated them with colchicine BID for 30 days so we could get a look at what the anti-inflammatory effect of colchicine might do and then he instituted urate lowering with the xanthine oxidase inhibitor probably 95% of these patients got allopurinol, treated to target and checked again and looked at FMD and inflammatory markers at each step of treatment and what we were hoping to do with this design was to. Meet the ACR treatment guidelines of give uh a colchicine prophylactic with the urate lowering agent in the beginning of treatment but also separate them so we could try to see the different effects of the different drugs. I think we were too clever by half, but uh, but you can see some of the the data as it separates out. So this is what happens when we look at inflammation in this setting and what you can see after 4 weeks of colchicine, the CRP fell but it wasn't significant. The ESR also fell and it wasn't significant either. Now we don't know we were surprised because studies have shown that colchicine can drop these. Was that because we. didn't treat long enough, uh, because the dose wasn't adequate we just don't know but what we know is that by the time we had treated to target with the colchicine still on we had reached significant lowering of CRP and ESR reduction of inflammation. Again, was that because Colchicine continued? Was that the effect of allopurinol? Was that both the study design will not let us sort that out, but when we looked at endothelial function in FMD we actually saw exactly the same thing in an inverted state so a non-significant increase in flow with colchicine when both were treated to target a significant increase. So I'm very comfortable making the statement that ACR guideline concordant gout treatment. Increases endothelial function in our gout patients, which is deficient by about 50% before they get treated. Nonetheless, we thought we were gonna see a much bigger improvement in flow, and we were disappointed in that. We wondered, were there factors that played a role in keeping the flow from responding as fully as it might, and the answer was at least, uh, to some extent yes and the. The main question was how many other comorbidities did your gout patients have. We published with Rob Keenan, uh, about a decade ago that gout patients have lots of comorbidities. The median number is 4, and what you can see here is that the more comorbidities that you had. The less likely your treatment was to improve your endothelial function, and these were the three biggies hypertension, hyperlipidemia, and obesity. Um, I can't tell you rigorously how this works, but my assumption is that if you've had a lot of comorbid. For a long time and you have cast iron arteries, they, it's probably they're probably not going to respond to a short gout treatment which I think would raise the question if we are trying to reduce vascular risk in gout, should we be starting earlier before the comorbidities accrue. So these, this is all functional, of course, we'd, what we'd like to know is. Are, are we changing the biology with this treatment and is, is there a biological difference in the endothelium between the gout patients and the controls and Mike has just started, uh, to look at that working with our colleague, uh, Mike Garchik, one of the cardiologists who we work with regularly. And there are too many mics here, but Mike Garchik, um, has developed uh an assay where he can harvest uh brachial vein endothelial cells using a J wire. Uh, we haven't taken it into arteries yet, so this is venous, uh, and he can basically scrape them off. It's shockingly painless. There are no nerves and veins who knew that and you can then. Analyze them. You don't need a lot of them and put them through, um, unbiased RNA sequencing and so we have just begun to do this. We've only done it, uh, with 4 gout patients and 4 controls, uh, and we only saw the results about a week and a half ago and we haven't even started analyzing them, but I'll share it with you anyway because I, I think it's pretty striking. Um, on the, uh, upper left you're looking at a volcano plot of all the genes that were picked up 18,000 different messages expressed because technology is like that these days. Uh, this line marks the, uh, the significant differences up here. The red ones are genes, uh, overexpressed in the gout patients, the blue ones are the genes under. Expressed in the gout patients and you can see uh a very significant separation of a large number of the genes we've looked at. This is a heat map of those genes that were different and you can see how strikingly different the gout endothelial cells are from the control endothelial cells. It's a really, really excuse me, sharp demarcation between these two groups. So um perhaps next year we'll be able to tell you what those genes were. There was an interferon signal, but we've just even begun to look at just simply read those genes to see which ones they are, um, so can anti-inflammatory therapy reduce cardiovascular risk to turn back from the endothelium. To the cardiovasculature, uh, in gout patients and perhaps others, and the question may have to do with which anti-inflammatory you pick because most of our anti-inflammatories and DMARTs raise cardiovascular risk, uh, or they have confounding many confounding effects so just by way of example, you know that steroids raise cardiovascular risk, but that's because of their induction of hyper. Retention and lipids not because of the inflammatory state. So what is needed is a pure anti-inflammatory drug and at this point we probably really only have one, and that's colchicine, and we were very interested in that and uh one of the nice things about gout is that patients take colchicine so you could do retrospective studies and so we decided to do some retrospective studies and the, the very first one we did. It was a cross-sectional study in our own VA patients. I'll spare you the heavy details of all the studies just to get to the point, but we ended up with about 1300 gout patients. We divided them into colchicine users and non-users. We excluded people who had just gotten one or two doses in the ER, uh, you know, over the course of. In years, but we didn't ask otherwise how long were they using colchicine and we basically looked at cardiac end points and we were really surprised to discover a 50% reduction in myocardial rate in the Colchicine group, also a reduction in death in C reactive protein. Those did not, however, achieve statistical significance. It was a cross sectional study. There there were relatively small number of events and so we wanted to do a retrospective cohort study, uh, but, um, Dan Solomon up at the Brigham beat us to it and did a very nice retrospective cohort study showing over time essentially the same thing about a 50 to 60% reduction in my. Cardial infarction and other major coronary and vascular events and it was after this study that the two cardiology studies interventional and non-gut patients, the lidoco 2 and the um Colcot study were done showing uh a significant effect post MI or in very high risk patients. But we weren't done. We wanted to understand things in gout patients, so we developed our own new retrospective cohort and we split it in order to do two nested studies. That was the goal. And so, Long story short, we identified Colchicine users and Colchicine non-users again basically the same way we did in the cross sectional study, but now we're looking longitudinally over a 10 year period, but what we did next was I think a little bit unique because we stopped and we pulled out and. Looked at only the patients without known coronary artery disease, so these are gout patients who've never had a diagnosis of MI, never had angina, never had a positive cath, never had a positive stress test, and we asked what does taking colchicine do to the future incidence of clinically apparent coronary artery disease and what we actually found was that. The patients who use colchicine had a lower rate of incident coronary artery disease although it did not quite achieve significance and interestingly remember when I talked about those comorbidities on the endothelium well when we looked at patients who lacked individual comorbidities those became significant so in particular here patients who. Went into this study into this retrospective study who had no kidney disease, had a 70% uh decrease in the incidence of coronary artery disease, and this was statistically significant so this raises the possibility that keeping inflammation down on a chronic basis may be statin like in the sense that it may prevent the future of coronary artery disease but then we went back and we did. Uh, a study that was a little bit more like the two large cardiology studies but again retrospective, not prospective this time we got rid of all of those patients who had no cardiac risk and included only those with defined coronary artery disease. His history of MI positive cath, positive, um, PCI, uh, positive stress test and the like, and we asked. And those patients just taking colchicine reduced the risk of incident major cardiac events and this was a study by uh uh by Gary Hoe in our group. I'm leaving out the, the disappointing slide. The disappointing slide said that there was no difference, and we were kind of shattered by that, but we went back because remember I told you earlier we weren't really distinguishing how much colchicine people were using so we went ahead and we divided this group, uh, into a quartiles and what we found was that. Only in the highest quartile were people really using colchicine steadily, uh, up to 90% of the time in the lowest quartile, some of them had been on Colchicine only 10% of the time over somewhere between 5 and 10 years, so we decided to ask. Does the extent of colchicine use make a difference when you're looking at acute events? And so we compared that highest group, that 90% group with the other three lower quartiles who on average had used colchicine about 30% of the time. And when we did that we saw quite significant reductions in uh overall combined mace that's, you know, major events, um, uh, by about 30% uh also significant reductions of MI cabbage, and, uh, stroke, although interestingly, uh, PCI was not, uh, reduced, and I have some thoughts about that. We also asked, did you, what was the benefit of colchicine. Occurring when patients were taking it as opposed to when they weren't taking it and the answer was probably at least partly this this looks at when events happened and events happened less often among patients who were actively on the colchicine as opposed to periods when they had sort of fallen off the wagon and weren't taking colchicine so I think this raises the possibility that colchicine may be aspirin like as well that is. You know, you take aspirin and it probably doesn't prevent your incident coronary artery disease, excuse me, but in the right person you sure want it on when that plaque ruptures because it reduces the inflammatory state at that moment of potential disaster and we have some evidence of different ways in which colchicine may act so we think the colchicine may be both preventive or statin like and therapeutic or aspirin like. And finally, in just uh a last couple of slides if you'll bear with me, we've gone from the endothelium to talking about the coronaries, but the endothelium is all over it's not just in the coronaries and so I wanna tell you that we've been looking a bit at other vascular implications of gout and uh just share a couple of those with you, uh, uh, very quickly and the first one. Is the question of peripheral artery disease and uh Nicole Young, who I think is in the audience, has been studying this in a large VA data set in fact in the entire VA data set because she's been looking at the national VA data set and so um we're looking here at the, the raw data, the first cut of about 7 million veterans and we chose to compare. Are gout patients with patients who had no gout but also with patients who had diabetes as probably the most uh well regarded positive control for peripheral artery disease and what you can see is compared to the non- gout non-diabetic group if you were in a group that had gout you had more than twice the prevalence of peripheral artery disease compared to the controls. If you had diabetes, it was actually more if you had the misfortune to have gout and diabetes, that was the worst it's about a fourfold increase in peripheral artery disease and in fact about 20% of our gout patients have diabetes, so, um, these people did kind of lose the lottery in this case, but it's, it's a real risk and has real consequences. Because in a subset of about 2 million gout patients you can see here that the prevalence of peripheral artery disease in the gout patients tracks also with the rate of revascularization and amputation, uh, bad outcomes presumably, and the patients who have gout and diabetes once again, uh, have the worst of it. So gout patients have peripheral artery disease. It's probably something you want to ask about when you're taking care of your patients. Probably less expected would be the impact of gout on heart valves. We were very interested with our cardiology friends to look at, uh, valvular disease because it's pretty common aortic stenosis is pretty common, has no treatment but the surgical if gout could contribute to it, maybe we'd have a disease we could treat the lower risk. So we've done a couple of studies that we published on this, um, and. Um, you may be surprised to know that, um, if you not on this slide, if you have, um, aortic stenosis compared to patients who don't, you're much more likely to have precedent gout than if you don't have aortic stenosis, but on this slide, if you have gout, you are more likely to have severe aortic stenosis and more to the point if you have aortic stenosis and you have. gout, you are more likely to progress from non severe to severe aortic stenosis. Does this mean we can treat gout to slow the process of aortic stenosis? I think we hope to do that study sometime, but I have no idea right now this is just association, but uh it does perhaps link, um, the inflammatory state of gout with risk in the valves and actually a publication just out this month. Um, found a similar finding that valvular disease is up in gout patients. So, uh, to conclude, uh, there's good evidence that urate affects the vasculature in multiple ways and that patients with gout have abnormal endothelium in ways that convey vascular risk. We've seen that initiating gout, uh, guideline concordant treatment of gout improves arterial physiology, and it may potentially excuse me, reduce future cardiovascular risk. But whether gout is driving vascular changes in vivo that's not fully explicated by the data that we have and um this does suggest though that I think that the biologic changes in the vasculature and gout are worth thinking of as an independent element of gout and potentially as a target for treatment, uh, and with that I thank you all very much and um take a question or two and then we should wrap up. Doctor Golden, Doctor Pillinger, so you know how much I think you're a, uh, brilliant and erudite thinker, so thank you for your talk. Um, you taught me that, uh, hyperuricemia may have evolved in humans as a mechanism of, let's say I don't know, bioanthropology or call it what you will, um, that once we started walking on two limbs instead of 4 that it helped us to maintain our blood pressure and that's why we can stand up. So I don't know, I'm just asking a dumb question. Is it possible that, you know, in a sense kind of interfering with this mechanism could lead lead to maybe unforeseen, uh, uh, um, what's the word, the human body might fight back and say, oh, I'm gonna make more renin, I'm gonna make more minerallic corticoid, or, you know, there could be some unforeseen untoward effects of, of this. Yeah, um, so, uh, the, the obvious answer is yes because the answer to is it possible is almost always yes. um, I, I, I, I think that, uh, first of all we don't know the off target mechanisms of any drugs that we use so I think that's. An important thing to to state when we started standing up straight we were a different group of people we had a very different diet it was very low in salt um we had a hard time getting uh calories and energy and so. Probably we're not well evolved even today to our bipedal state and to our current diet. Does that mean that we shouldn't be cautious about trying to reverse us after all? I mean, what is Piglotic case except a restoration of the enzyme that that we lost way back when, uh, I think we'd have to watch. I, I think that we know a couple of things though, Brian, we know that we've been using Colchicine since at least Hippocrates and. Uh, it, the only people it's killed so far are the people who took large massive overdoses of it, uh, and maybe a few others, and, uh, and we know at least that you're a lowering within reasonable standards, um. I'm not talking about lowering down to the peglottic case level for lifetime, you know, less than one because there's a, there's some epidemiologic evidence on a J curve that patients who live at very, very low ur rates, they're rare people, but they have poor survival and we don't know why that is but I think moving people from high rates of urate down to levels that many others of us walk around with all day is probably an OK thing, I agree. Right, you talk a lot about the risk factor or coronaryity that with gout. What about people with asymptomatic hyperureemia? Yeah, so, um, there, there is, um, you know, I, I, I think if you look at the effects of your aid in the in vitro studies, you would think that there probably was an impact. There are a couple of studies, including one of our own that we never published that do indeed suggest that it gets a little noisier because the impact seems not to be uh as great it may be step wise and uh the other thing that gives urate lowering for that affect a bad name is that they've actually been a number of urate lowering studies um which have not shown a benefit um. In MI risk or in or in renal risk, however, they mostly weren't in gout and they weren't in patients with hyperuricemia. They were just being given allopurinol for antioxidant effects. So I think we don't know the answer yet. I think based on the the three large cardiovascular cardiology studies and non-gut patients, 10,000 patients took colchicine or placebo and it dropped their rate. I think there's no reason not to think that what we see in. Cols and and gout patients wouldn't hold true if we could get to a perspective study but we're not cardiologists and we don't have that kind of money. Uh, very fast. So in macrophages, urate crystals are highly efficient in activating the inflammasome and inducing lytic deaths. You think the same happens in endothelial cells. Uh, first of all, thank you for that comment, and obviously it's very true, and it, it does let me bring the meeting down to an an end. By going back to Jerry Weissman, who was actually the one who showed that urate crystals engaged the phagocytic vacuole, which is highly rich in cholesterol. And melts them and then you get you start to get the process of lytic cell death because the crystals get out of into the cytosol um so um they're highly there it's highly inflammatory to be sure uh and you know there's nothing more inflammatory I think than killing leukocytes in an inflammatory location. I, I don't know. I don't think people have looked very hard at that. I don't think people have looked very hard at whether endothelial cells are taking up crystalline urate. And they haven't looked at what I'll say is I think the novel hypothesis that sometimes urate can get into cells and crystallize. There's a very interesting literature on the role of urate crystals intracellularly in I guess they're, I guess they must be white cells, uh, for killing malaria. Uh, and, and so Yuri can crystallize intracellularly, uh, but Doctor Wayan, uh, it's, it's just way above my ability to think about without your help. So perhaps we can talk about it. Thank you, Doctor Mina. Doing a great talk, of course, and, uh, just on the um. Wanted to make a few comments and I only have a very simple question here but uh the few comments obviously 10 years ago when I was about to leave the work with Doctor Benidiaha and others was really taking off and obviously we've come a long way. I've shared with you over the time that uh I've just been nothing but impressed with. What has been accomplished since in light of our discussions here and some of the questions, um, some of the things you already mentioned in terms of should we be thinking of having patients or coaches, you know with the colchicine one aspect is the statin like and the other aspect like aspirin like um in that light. And given the fact that a lot of uh this go patient beside. The diet aspect of things, some of them have autoimmune stuff and we had the aging, uh, lecture this morning. It just Makes me think as we go along down the road maybe someone could come compound something like colchicine, hydroxychloroquine and metformin see just one pill this not and a lot of red wine. So but quickly I think you mentioned that for the study you did for 30 days with uh Michael Doctor Tropover, did you guys said you were going to do it for 120 or 90 days or as part of the addition of the allopurinol you got some data there just a little convoluted question there but. I, I'm not sure. I said that the 30 day colchicine. Study, yeah, did you guys think about extending extending it out to see where things go? Um, it, it's a bit labor intensive, but yeah, we certainly have. Thank you. Is the anti-inflammatory response of cosine dose dependent? Is there a dosage you recommend? What how much coine you want to use? It's thank you for that question. It's a very complicated question actually, um. And it can be looked at in a number of different ways. There, there are in theory a therapeutic range of colchicine and uh when you when you model the dosing scheme between once a day and twice a day, uh, in people with normal kidney function, patients who take colchicine once a day on a daily basis temporarily drop below the therapeutic index, and patients on a twice a day dose typically temporarily go. Over the toxicity index a little bit so we probably need a different middle dose if that's what you're looking at. Most of us rheumatologists have always thought that twice a day is better than once a day, and I suspect that's still true, but the cardiologists have taught us that once a day, 0.5 mg of colchicine. Um, in patients post MI or in patients at high risk, that is enough to reduce cardiovascular risk so it may have to do with the intensity of the inflammation you're trying to treat, uh, obviously the safety, obviously balancing out other things like, you know, renal function and other drug use, so it, it's a little bit. A moving target we also don't know what happens at all surprisingly, uh, to the extent of whether larger people need bigger doses of colchicine. It has not been studied and one of our cardiology colleagues could not get a grant to study that, to actually know what happens with volume of distribution and how you should adjust for for body mass and BMI and the like so it's an important question. Hello, how are you? So thank you for your talk. So our usual paradigm for treating gout is to start with colchicine as a bridge, add allopurinol to colchicine, get the uric acid well below 6 or 5 depending on the patient, continue it for several months until or until to resorb, and then remove the colchicine. So now in these lodokco times, would you continue colchicine indefinitely with allopurinol? Will you give me the grant? Because that's, that's the study that we'd like to do 3 months of colchicine for everybody randomized to daily colchicine or placebo, go a couple of years. I don't know the answer to that, but I will say, uh, because I'm, I'm a clinician, not a lab person, so I can say on non-data. That my inclination based on that Abhishek 120 day study is I tend to carry out if I'm using colchicine for a flare, I tend to let it stay on a lot longer than I used to so I would take a stable gout patient who's now well at goal with allopurinol and typically you'd say, Well, I'm taking you off a drug. I'm weaning you off your colchicine. If they, they're a big vascular path, would you just say, you know what? We're just gonna keep you on QD or QOD colchicine with the allopurinol I've, I've I've done. I, I, I wish we had data to let me tell you it's the right thing, but we've certainly done it. Thank you. Thank you. OK, so I think, I think there are just a few hardy people in the audience, but, uh, as the last organizer I'd like to thank you all for attending. uh, I'd like to encourage you if you haven't to fill out the evaluations of the course we take those very, very seriously we do make changes and I do hope to see you all next year and I wanna thank the speakers for what a great job today. Thank you. Published March 14, 2024 Created by Related Presenters Michael Pillinger, MD View full profile
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