TU: Systemic Burden of Gout Part 2 (24 plus) Save

Hi. I'm Jack Cush with RheumNow. In this video, we're going to discuss obesity and gout. Can you think of two diseases that fail to reach their target as much as gout and obesity? Are these then not the two most difficult disorders to manage in primary care and in rheumatology?

Is it surprising that they are so intimately connected? They both have dietary issues. They both have behavioral tie ins. They both, when not well managed, end up in cardiovascular risk, if not death. Gout is a substantial problem in The United States, as is obesity.

And having both leads to significant medical consequences. The thing about it is that a, gout is treatable, and that obesity is the strongest modifiable risk factor for gout. So we do know that, as your BMI goes up, you know, for every unit above twenty five, the upper limit of normal, there's a a five percent increased risk of gout for every one unit of BMI. Seventy percent of gout patients are overweight or obese. So gout is often, when you're considering gout, we often talk about obesity as being one of the comorbidities.

It's not the most common one. The most common one is probably metabolic syndrome in three quarters, but it's, and hypertension and renal disease in seventy percent or more. But obesity is at least present in, fifty three, fifty four percent. And again, important because that's a modifiable risk factor through behavioral interventions. It is nonetheless interesting that as I have slides on gout and its prevalence, And I think it started at a prevalence of eight point three million in The United States, and then it went up to nine something, and it went to ten point one.

The most recent prevalence statistics is twelve point one million Americans have gout. What's happened in period, these different years? The obesity epidemic. The frequency of obesity has gone up and up and up. In The United States in 1990, if you looked at the prevalence of gout and then compared it to almost thirty years later in 2019, the prevalence of gout rose by almost one hundred percent in males and almost fifty percent in females.

If you look at obesity, it's tripled in the last six decades in The United States. It was thirteen percent in the 1960s, it was twenty three percent in 1990, it was thirty percent in 2000 and it's reached forty two point five percent in 2022. This is a problem. A BMI of greater than forty increased from less than two percent to over nine percent in the same era. If you look at normal weight, the risk of gout is about one percent.

If you look at a BMI of greater than thirty five, the risk of gout is like seven percent. So again, these problems are interconnected. They're connected through behavior. They're connected by being, I think, key elements of the metabolic syndrome. I think gout should be a member of the metabolic syndrome, but they haven't called me about this yet.

We do know that obesity will increase uric acid production and decrease uric acid excretion and lead to more adipokines that are pro inflammatory that can lead to not just gout, but gout flares. Obesity does all this through increase in purine turnover and purine synthesis that then, again, why we have more uric acid. Overall, BMI of greater than 30 has at least a twofold increased risk of gout. In a study of urate lowering therapy, six thirty three patients taking febuxostat, if they looked at the patients who were obese, they were less likely to achieve their treat to target goal of less than six. The obese patients only thirty nine percent, the normal weight patients sixty four percent.

And similarly, obese and overweight patients in that trial had more gout flares. We do know that the I think it's a 2016 ACR guideline says that for every increase in BMI of more than 5%, there's a resultant higher risk of gout flares, maybe a sixty percent or higher risk of gout flares. If you look at the 2020 ACR guidelines on the management of gout, number one on the list of recommendations is address education, diet, lifestyle, and comorbidities. That includes obesity. Now all of that is just a conditional recommendation.

They do admit that lowering weight has a variable effect, but should lower uric acid and should be beneficial to the patient. But there isn't like great data on this, right? Kind of the same for you are when they've addressed this. So what happens when people do lose weight with gout? First off, I would state that diet alone is no way to treat gout and to achieve targets.

It's adjunctive. There are systematic reviews of, like, 20 or 25 trials that show that weight loss of between three and thirty kilograms lowers uric acid significantly by almost three milligrams per deciliter, and those people are less likely to have Gaudi attacks, seventy five percent reduction. Sustained weight loss lowers uric acid. That's we know is true. And it does so by improving insulin sensitivity and uric acid handling.

Interestingly, the diabetic drugs Jardiance, Farxiva, and Invokana, the SGLT2 inhibitors that are being used in diabetes and renal disease and heart failure, our uricosuric have other effects that lower uric acid, result in moderate, modest weight loss and also lower cardiovascular risk. Of all the diabetic drugs, the SGLT2 drugs are the most beneficial in gout, much more so than GLP-1s. GLP-1s interestingly, while they're so fabulous in so many rheumatic disorders, they are good in gout, but it has a modest effect or an inconsistent effect on uric acid. And in fact, has been shown to not reduce the number of gout attacks and flares. That's GLP-1s.

The other strange tidbit here is that other measures to produce weight loss, one is especially effective giving rapid, dramatic weight loss, like from bariatric surgery or strict ketogenic diets like Atkins, these lead to more gout flares because one, they don't affect uric acid. They cause uric acid fluctuations because of the induced ketosis and tissue catabolism that's so rapid leading to this transient, hyperuricemia and uric acid fluctuations resulting in attacks. You don't get more attacks with GLP-1s, however. So my practical guidelines is that urate lowering therapy is important in gout, but so should be obesity management, and that they should occur contemporaneously. Because you're starting on one doesn't mean you should avoid the other.

That SGLT2 inhibitors are preferred in diabetes management and for weight loss and for gout management as well. I think you should pitch the fact that weight loss has both short term benefits, less flares, and long term benefits with better outcomes. That's been shown, I think, repeatedly. So obesity and gout are strange metabolic bedfellows. Treating one well requires anticipating its effect on the other, especially now that our weight loss tools are more powerful and faster acting.

Again, this is the goal that we want to have with our patients, not just control their gout, but control of their weight. Do it.

Hello, my name is Tony Merriman. I'm a professor in the division of Clinical Immunology and Rheumatology at University of Alabama Birmingham and I'm speaking from my office there. I'm going to talk to the RheumNow folks today about genome wide association studies and gout and the advances and knowledge we've got from them over the past twenty years or so. So a genome wide association study, it really has revolutionized the understanding of complex diseases like gout which we know are caused by dozens if not hundreds of inherited genetic variants but also there's the environmental aspect to it as well. In order to identify these genetic variants and then look at the pathways these variants are operating in which will open up new target therapeutic possibilities.

These genetic variants have a weak effect so we need very large cohorts to genome wide association to do GWAS studies. So the first thing is very large cohorts and I'm talking the size of hundreds of thousands of people. The second thing is being able to measure throughout the genome as much of the genetic variation as you can and we measure these days millions of single nucleotide polymorphisms, SNPs or I probably call them common genetic variants. So we need technology to do that. So those are the two important things, large cohorts and technology to measure these variants and need very large cohorts because you're simultaneously testing millions of genetic variants so you have to account for those simultaneous millions of variants in your p value at the end of the day.

So we have to have a p value that's in the order of 10 to the minus eight to identify a locus or a gene is associated gout. Initially the first GWAS were done not in gout but in serum urate levels and we know how critical and causal hyperuricemia is for gout. So GWAS done in twenty to ten years ago in serum urate levels led by Professor Anna Kukten from Germany yielded a lot of insights, in particular that emphasised genetic variation and genetic control of the expression and activity of urate transporters particularly in the kidney and the genes with the largest effect on urate levels and also gout are genes like SLC2A9 which is a reuptake transporter in the kidney. It has extremely large effect on urate levels explaining about three percent of variation in urate levels in the general population and that's a really large effect for a gene and a common condition like hyperuricemia. Another transporter is ABCG2 which is a efflux transporter working in both the gut and the kidney There are other transporters found as well but that emphasize the importance of genetic control of excretion of urate as central to the genetic basis of gout.

More recently genome wide association studies have been done in gout itself and you know I have led them along with colleagues in China, Japan and Europe and we were essentially looking for and addressing the question not everyone with hyperuricemia goes on to get gout, what contribution does genetics have to that and what genes might they be? So we published a very large study two years ago including a hundred thousand gout patients, one hundred and twenty thousand gout patients actually and two and a half million controls and we found a total of about 400 loci or genetic variants but what was kind of surprising was only ten percent of them seem to be exclusively involved in the inflammatory aspect of gout, in other words these ten percent of genetic variants didn't associate with U rates so therefore we hypothesize that they associate with inflammation and gout and these genetic variants are in genes that we sort of weren't surprising like IL-one beta, the IL-one receptor and other cytokine genes and there was also another very interesting gene called colony stimulating factor one which is important in controlling the differentiation of monocytes into macrophages and controlling their response to crystals and I bring up this gene as an example because we've studied it further and it epitomizes this the type of genetic complex genetic control, genomic genetic control that's happening at low size.

So this gene CSF1 is transcribed when monocytes see monosodium urate crystals that cause gout but the genetic control is complex, it involves long non coding RNAs, two of them being initially transcribed and then connecting up with the promoter of CSF1 and you get transcription there. I just want to finish off by highlighting another pathway that we found in the genome wide association study in gout. What we noticed was that genes controlling in the pathway called clonal hematopoiesis of indeterminate potential were coming up quite regularly and this pathway which I'll call CHIP is it was identified with somatic mutations in these genes in older people that increase the chance of hematological cancer and so we were able to we noticed that genes like TET2 or TET2 were coming up and TET2 was very commonly mutated and somatically and hiatal pneumatic ooiesis have been determined at potential and this may reflect the genes that are involved in the chip pathway generally are involved in remodeling the genome epigenomically and it may be involved in what we do know is that when monocytes are exposed to high levels of urate you get epigenomic remodeling that increases the responsiveness of these cells to urate crystals so we think it may be involved in that aspect of in other words sort of training the immune system to be more responsive to urate crystals.

So that was another finding from the gout genome wide association study. So to summarize, the genetic control of urate and gout is very complex many many you know hundreds of genes and we expect we will find more as the cohorts get larger, the genes have weak effect size but collectively they modulate a person's proclivity to develop gout under the right environmental conditions. Thank you very much for listening and if you have any more questions, head to the RheumNow site. Thank you.

Well, thanks everybody for listening today. I'm Lisa Stamp. I'm a rheumatologist and professor of medicine in Christchurch, New Zealand. Although it looks like I'm in the middle of the sky at night, it's actually winter here, freezing cold outside, but no snow. I'm going to talk to you today about managing gout in people with chronic kidney disease.

We know that gout is very common in people with CKD, and it has implications for how we manage gout. That's mainly around the dosing of medications that we use to treat gout, and also interactions with medications used for their other comorbidities. When we think about managing a gout flare in people with chronic kidney disease, we have our standard three options, that is colchicine, non steroidal anti inflammatories, or steroids. Now non steroidal anti inflammatories, as we all know, are contraindicated in those with CKD. So that option is off the cards.

Colchicine we can use. Typically we would use a dose of 0.6mg once or twice a day in people with a GFR above 45 mlsmin, but reduce the dose in those who have a GFR of less than 30 mlsmin. For some patients, it may be that steroids are considered the safest option. And certainly if there's one or two joints involved that are amenable to injection in people with CKD, then intra articular steroid can be a very effective therapy. The other rule of ownership is oral steroids.

Short courses for flares may be appropriate. This can be problematic, obviously, for people who also have concomitant diabetes. One of the tricks with steroids for FLAIR management is not to reduce them too quickly, otherwise you might see a gout FLAIR rebound. It's important to also just be aware of potential drug interactions. As I'm sure you're all aware, colchicine does interact with P glycoprotein and CYP3A4 inhibitors, and so the dose does need to be reduced or potentially colchicine avoided in patients on these therapies.

Although there's concern around the interaction between a statin and colchicine, this is not something that we commonly see, and I have no concerns about using colchicine in those on a statin. Now, as we all know, urate lowering therapy is the cornerstone of the long term management of gout, and there has been a lot of concern about the use of urate lowering therapy in people with CKD. This particularly is in relation to allopurinol, which is the record amended first line agent for most people. I think it's fair to say that we do know that CKD is a risk factor for the hypersensitivity syndrome, and that is what most people fear, because this is a very severe adverse effect and has a high mortality rate. Our own research would suggest that you can use allopurinol safety in people with CKD, but there are two factors to consider.

The first one, and most importantly, I think, is the starting dose. Now we have evidence that the starting dose is an important risk factor for the hypersensitivity syndrome, and based on this, we would recommend that no one start on more than one hundred milligrams daily. For people with a GFR between 30 and 60, I would start on fifty milligrams daily, and for those with a GFR of less than 30, I'd probably start at an allopurinol dose fifty mg every alternate days. The second issue is then the maintenance dose, and by that I mean the dose that's required to achieve target urate. As you'll all be aware, the handy criteria said we needed to restrict the allopurinol dose based on renal function.

I think we now have good evidence that that is not the case, and the most important thing is to titrate the allopurinol dose in a systematic approach to achieve the target U rate of less than zero point three six millimoles per litre. If you start allopurinol and don't increase the dose, you're potentially exposing the patient to the risk without giving them the potential benefit of getting to target. So we would typically increase the dose monthly. Some people do this two to four weekly. That's absolutely fine.

Just a systematic approach, increasing by either fifty or one hundred milligrams with each increment until you reach target urate. Although most people consider you that you need very high doses of allopurinol for some people, main dose of allopurinol to achieve a target is generally around three hundred to four hundred milligrams, so it's not that much much higher. And in people with CKD, we can see that they do need lower doses. The other urate laureate therapies that are available, obviously for buxastat, we have less data on the use of buxinav in people with CKD, but certainly it's a reasonable option. Again, I would start at a lowish dose and dose titrate up.

Other options such as probenecid, the uricosuric agent, we know that this becomes less effective as the GFR drops, and generally I expect it to be ineffective when the GFR is less than 50. We don't need to worry about renal function with peglodecase, because it is not renally cleared. So when you're thinking about managing gout with people in CKD, think about the medication, think about the potential effects on the kidney, and think about the drugs that the patient is already on that may interact with the medications that you're using. More information about gout can be found on RheumNow, and there's a wealth of resources available there. Thank you very much.

Hi, this is Mark Fisher. I'm a rheumatologist in Southeast Massachusetts, and I'm here to talk to you about gout and mortality. So as you all might guess, gout is associated with increased mortality. It is more than just episodic joint inflammation, and it's associated with a twenty to twenty five percent increase in all cause mortality. A 2023 meta analysis by Shuyin Wang and others with 11 cohort studies covering twenty ten to twenty twenty two, and including fourteen point eight million patients with follow-up of up to sixteen years showed a twenty three percent increase in mortality.

Cardiovascular mortality was increased by twenty nine percent, infectious disease mortality by twenty four percent, and digestive disease mortality by forty two percent. More striking, but not necessarily surprising, renal disease mortality was increased by seventy eight percent as shown by Doctor. Vargas, Stone, and others using a Swedish registry. More surprising, however, Doctor. Disvelg and colleagues evaluated a cohort of five seventy three gout patients and found that the standardized mortality ratio for cancer was an incredible three point five eight.

There are a number of risk factors associated with gout and mortality, including tophaceous disease, a high uric acid of 9.4 or greater, coexisting chronic kidney disease, history of myocardial infarction, and history of heart failure. Doctor. Lee and colleagues using the Korean National Health Insurance Service database showed that the combination of gout, CKD, and type two diabetes confers the highest risk with the impact being synergistic and not just additive. And the bad news is we are not getting better at this. A study from Hyun Choi's group using a UK based population study compared two time periods, 1999 to 2006 and 2007 to 2014, and found an adjusted mortality hazard ratio of about twenty four percent, and that did not improve.

This is in marked contrast to rheumatoid arthritis, which did see a reduction in mortality doing a similar comparison with the same dataset. The United States data is very similar. Another study by Natalie McCormack and Hian Choi's group also showed no improvement over time, with mortality hazard ratios of about 1.19 to 1.2, and this is after adjusting for serum uric acid and cardiovascular disease risk factors. A little bit more insight into the cardiovascular piece of this, a case control study of gout patients by Doctor. Cipolletta and colleagues with over sixty two thousand patients compared those who had a cardiovascular event defined as MI or stroke with gout patients who did not have a cardiovascular event, and for those who did, they were ninety three percent more likely to have had a gout flare in the sixty days before the event, and fifty seven percent more likely from sixty one to one hundred and twenty days before the event.

There was no difference after one hundred and twenty days, and this suggests that gout flares are associated with an increased risk of cardiovascular events for up to a hundred and twenty days following the flare. Is there any good news? Well, there is some. First, gout was associated with a decreased risk of dementia related mortality as shown by doctor Vargas Santos, and second, treating gout effectively may make a difference. Some observational studies did not show an improvement in mortality, but doctor Cipolletta and colleagues showed that using a treat to target approach could lower the risk of cardiovascular events.

Achieving a serum uric acid less than six increased survival at five years by one percent, and reaching uric acid below 6.0 could reduce the risk of cardiovascular risks by nine percent. Achieving a uric acid level below five reduced the risk of cardiovascular events by twenty three percent. Further, colchicine may be beneficial. Dan Solomon and colleagues using an EMR database linked with Medicare claims found colchicine use was associated with a forty nine percent reduction in cardiovascular events and an incredible seventy three percent reduction in mortality. Of note, this was a small study.

Doctor. Cipolletta and his colleagues showed that starting colchicine when starting urate lowering therapy not only reduced the risk of gout flares, but also reduced the risk of cardiovascular events by eighteen percent over the next six months. And a meta analysis by Doctor. Shi and colleagues support the impact of colchicine on reducing cardiovascular events with a twenty four percent reduction, although this did not show a reduction in CV associated mortality. Colchicine is not surprisingly better than NSAIDs to reduce the risk of major adverse cardiac events among gout patients.

Doctor. Yakoze and colleagues showed that NSAID use was worse and more dangerous than no no prophylaxis at all, and compared with colchicine, increased the risk of major adverse cardiac events by fifty six percent, and the hazard ratio for cardiovascular death was an astonishing two point five compared to using colchicine. So in summary, gout increases the risk of all cause mortality by twenty to twenty five percent and increases the risk of specifically cardiovascular, infectious disease, digestive disease, and cancer associated mortality, and this is not improving over time. A treat to target approach that achieves a uric acid level less than 6.0 does slightly improve mortality and clearly improves the risk of cardiovascular events. Adding colchicine for prophylaxis certainly reduces the risk of cardiovascular events.

Larger studies, however, show that it does not seem to reduce gout associated mortality. This is Mark Fisher for RheumNow. Tune in for other great content. Thanks.