Gout and Cardiovascular Disease
Transcription
Hi everyone. My name is Michael Pillinger and I'm a rheumatologist at NYU Grossman School of Medicine. I'm here today to share some thoughts with you about gout and cardiovascular disease. How big an issue is this? Well, studies indicate that patients with gout compared to similarly aged populations experience cardiovascular disease and major CV events at a rate of somewhere between 1.5 and threefold the general population. This rate is comparable to that of patients with rheumatoid arthritis, which is increasingly recognized as being associated with CV risk. So when a patient with gout walks into your office, at the very least you want to be aware of the potential for cardiovascular disease.
But why do gout patients have this increased cardiovascular risk? Well, like most things in gout, it's complicated. First of all, gout patients have much higher prevalence of both hypertension and kidney disease than the general population. And this may be a chicken and egg situation since studies that I don't have time to discuss here suggest that hypertension and kidney disease may both be made worse by gout. But even after adjusting for these comorbidities, patients with gout continue to have increased cardiovascular disease rates.
Another explanation may be the direct effects of hyperuricemia. In vitro studies show that exposure to higher levels of soluble urate causes endothelial cell dysfunction and smooth muscle hypertrophy. More recent work by Leo's group indicates that urate is a driver of so-called trained innate immunity. That is, soluble urate can cause white cells to reset their activation levels, potentially driving an inflammatory state that could promote vascular disease. In any event, population data mostly suggest that patients with asymptomatic hyperuricemia have increased CV risk, but not as much as patients with actual gout.
So, what happens with gout? Well, in gout, we can add on to hyperuricemia the fact that gout patients have baseline levels of inflammation that are increased even above those of pure hyperuricemia, with elevated CRP and many other cytokines, and even between acute flares. Part of the reason for this may be that many gout patients have persistent urate deposition in their joints, and possibly these crystals can cause a low-level but ongoing inflammation. Also, although controversial, dual energy CT studies are suggesting that patients with gout may actually have urate crystal deposition within arterial walls, possibly driving local inflammation.
From a functional point of view, my group has demonstrated that the arteries of gout patients are physiologically impaired and don't dilate in response to flow, a recognized marker of future MI risk. We've also directly sampled vascular endothelial cells from the brachial vein and found that these are activated and quite different from normal endothelial cells. Finally, we looked at markers of neutrophil activation and found that neutrophils in intercritical gout patients are semi-activated. That is, they might be primed for a rapid response should an event transpire.
All of these add up to a sort of powder keg of cardiac events waiting to happen. Then add to this the highly inflammatory nature of the actual gout flare, which in some cases could be the match that lights the fuse. In fact, Abhishek's group has reported that after a gout flare, the risk of major cardiac events has essentially doubled for up to 120 days. And we have shown that 120 days is the actual window during which inflammation is elevated post flare.
Well, if gout can raise cardiovascular risk, can treating gout lower it? This is an area of ongoing investigation, but the data do point to a CV benefit. As you know, there are two aspects to treating gout. The first involves addressing the inflammation and the second addressing the urate level.
When it comes to inflammation, we need to talk mainly about colchicine, since NSAIDs and steroids raise cardiovascular risk by different mechanisms. We and others have shown in retrospective studies that patients with gout who are on colchicine experience fewer cardiovascular events than those not on colchicine. We've also shown that gout patients without cardiovascular disease are less likely to develop it if they are on colchicine, and that patients with cardiovascular disease are less likely to get MIs when they are taking their colchicine than when they aren't. And when it comes to gout flares, two groups have reported that patients starting urate-lowering therapy and experiencing gout flares as a result had fewer MIs if they were taking colchicine than if they were either taking nothing or NSAIDs.
And finally, what about the impact of urate lowering not in the immediate period but over the long haul? As recently presented in a RheumNow Tuesday night journal club, Cipeta et al. recently reported a large emulated trial in which, compared to no urate lowering, patients who got urate lowering had significantly fewer cardiac events than those who did not get urate
lowering. So what are the take-home messages? Well, first of all, be aware — be very aware — that your patients with gout have increased cardiovascular risk. It's not trivial. Make sure you or another physician is appropriately managing their comorbidities.
And when it comes to gout therapy, be aware that reducing cardiovascular risk may well be at least an important side benefit of guideline-compliant treatment. Remember, gout is more than the joint. Thank you.
But why do gout patients have this increased cardiovascular risk? Well, like most things in gout, it's complicated. First of all, gout patients have much higher prevalence of both hypertension and kidney disease than the general population. And this may be a chicken and egg situation since studies that I don't have time to discuss here suggest that hypertension and kidney disease may both be made worse by gout. But even after adjusting for these comorbidities, patients with gout continue to have increased cardiovascular disease rates.
Another explanation may be the direct effects of hyperuricemia. In vitro studies show that exposure to higher levels of soluble urate causes endothelial cell dysfunction and smooth muscle hypertrophy. More recent work by Leo's group indicates that urate is a driver of so-called trained innate immunity. That is, soluble urate can cause white cells to reset their activation levels, potentially driving an inflammatory state that could promote vascular disease. In any event, population data mostly suggest that patients with asymptomatic hyperuricemia have increased CV risk, but not as much as patients with actual gout.
So, what happens with gout? Well, in gout, we can add on to hyperuricemia the fact that gout patients have baseline levels of inflammation that are increased even above those of pure hyperuricemia, with elevated CRP and many other cytokines, and even between acute flares. Part of the reason for this may be that many gout patients have persistent urate deposition in their joints, and possibly these crystals can cause a low-level but ongoing inflammation. Also, although controversial, dual energy CT studies are suggesting that patients with gout may actually have urate crystal deposition within arterial walls, possibly driving local inflammation.
From a functional point of view, my group has demonstrated that the arteries of gout patients are physiologically impaired and don't dilate in response to flow, a recognized marker of future MI risk. We've also directly sampled vascular endothelial cells from the brachial vein and found that these are activated and quite different from normal endothelial cells. Finally, we looked at markers of neutrophil activation and found that neutrophils in intercritical gout patients are semi-activated. That is, they might be primed for a rapid response should an event transpire.
All of these add up to a sort of powder keg of cardiac events waiting to happen. Then add to this the highly inflammatory nature of the actual gout flare, which in some cases could be the match that lights the fuse. In fact, Abhishek's group has reported that after a gout flare, the risk of major cardiac events has essentially doubled for up to 120 days. And we have shown that 120 days is the actual window during which inflammation is elevated post flare.
Well, if gout can raise cardiovascular risk, can treating gout lower it? This is an area of ongoing investigation, but the data do point to a CV benefit. As you know, there are two aspects to treating gout. The first involves addressing the inflammation and the second addressing the urate level.
When it comes to inflammation, we need to talk mainly about colchicine, since NSAIDs and steroids raise cardiovascular risk by different mechanisms. We and others have shown in retrospective studies that patients with gout who are on colchicine experience fewer cardiovascular events than those not on colchicine. We've also shown that gout patients without cardiovascular disease are less likely to develop it if they are on colchicine, and that patients with cardiovascular disease are less likely to get MIs when they are taking their colchicine than when they aren't. And when it comes to gout flares, two groups have reported that patients starting urate-lowering therapy and experiencing gout flares as a result had fewer MIs if they were taking colchicine than if they were either taking nothing or NSAIDs.
And finally, what about the impact of urate lowering not in the immediate period but over the long haul? As recently presented in a RheumNow Tuesday night journal club, Cipeta et al. recently reported a large emulated trial in which, compared to no urate lowering, patients who got urate lowering had significantly fewer cardiac events than those who did not get urate
lowering. So what are the take-home messages? Well, first of all, be aware — be very aware — that your patients with gout have increased cardiovascular risk. It's not trivial. Make sure you or another physician is appropriately managing their comorbidities.
And when it comes to gout therapy, be aware that reducing cardiovascular risk may well be at least an important side benefit of guideline-compliant treatment. Remember, gout is more than the joint. Thank you.
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