Gout Journal Club Save

Hello, everyone. Welcome to Tuesday night rheumatology with RheumNow. Tonight, in our first TNR of this month, which is gout month, we're going to do a journal club. Let's just start by everyone introducing themselves and where they're from. I'm Jack Cush in Dallas, Texas.

Doctor. Wei.

Good evening, everyone. It's Jay Wei from Shanghai Hospital Central South University, China, and thank you for inviting me to join this webinar and it's a pleasure to be here. And I look forward to today's presentation and discussion.

Yes, Doctor. Wen.

Hello everyone, this is Zhe Qing Wen from Shanghai Hospital Central South University. Thank you for inviting me and I'm looking forward to having a good time with all of us.

Excellent.

Thank you.

Professor Abhishek.

Oh, hi. I'm Abhishek. I'm a rheumatologist and a professor of rheumatology at University of Nottingham and Nottingham University Hospitals NHS Trust. And thank you for selecting this article for discussion today.

And doctor Dobrowski.

Hi, everyone. I'm Igor Dombrowski. I'm a second year fellow, rheumatology fellow at NYU, and I'm excited to be here.

Okay, so in this program, we want to first thank the sponsor of our gout month here in July. That would be Sobe Pharmaceuticals is supporting the education we're delivering this month. Today, we're going to go over two articles that I have listed for you there. And we have the authors here and fellows to present the articles. We're gonna also review survey results that we sent out just yesterday, and we got a lot of survey answers that will help the discussion when we get into the articles.

We're gonna hear from you, the audience. Anytime if you have a question, use your Q and A box to write in your question, not the chat box, but the Q and A box. Okay, so you've met everyone. We're going to have the fellows present our articles with Igor from NYU presenting treat to target and cardiovascular outcomes article, and Doctor. Wen from Central South University presenting the same treat to target but renal outcomes.

I want to remind the audience that ahead of these TNRs we do surveys. We send a one time survey question and two seventy seven of you answered that yesterday, half from The United States. That was 86% rooms, 2% fellows and 5% APPs. We asked a total of eight questions. We're going to review about six of them here in this program.

Again, we're going to discuss these two articles. Interestingly, both of them were from JAMA Internal Medicine. Professor Avishek's article appeared in March of this year, and Doctor. Wei's article appeared in 2025 also in JAMA Internal Medicine. But let's begin since the whole point of these journal articles was the impact of treat to target, I wanted to ask you, the audience, about treat to target.

And the first question was, again, two seventy seven people responding, 86% rheumatologists, how often do you retrieve a serum uric acid of less than six in your gout patients? Fifty five percent of you said greater than seventy five percent of the time. Twenty nine percent said sixty percent of the time. Only thirteen percent said forty percent of the time. And the shocking thing here is the research.

I'm sure all of you are doing all this, but when we look at actual data from rheumatologists, it's only about forty percent of you are achieving target. Now that same number or a little bit less thirty to forty percent is what happens in primary care. And you would think the rheumatologist would be better, but the research is not all that great. Doctor. Abishak, why do you think that is?

Yeah. I mean, it's it's, I think you gave some UK, some US data. In UK, we have the same situation. We did a national audit and thirty to forty percent of primary care physicians and hospital rheumatologists achieve treatment targets with urine loading therapy. And I think the main reason, for that in primary care is the fact that, in primary care in UK, doctors don't give follow-up appointments to patients to properly escalate therapy and engage with them.

So I think I think that there's a big problem there. And, in secondary care, we sometimes get really blindsided by rheumatoid arthritis and vasculitis and lupus and just say, oh, well, it's gout and sort of ignore it a little bit. So there's a bit of physician inertia, I think in hospital practice. But most gout is managed in primary care, and I think the bigger problem there is that there is no structured treat to target with, blood tests to check your rate levels and escalate dose. I think that's the main reason.

And you're absolutely right. One of the featured gems that we put on the website yesterday was in The United States, there's twelve point one million people with gout, but only one point three percent. Certainly no more than three percent of them are seen by rheumatologists, so that's a bit of a problem. In China, Doctor. Wei, do you have the same problem of not achieving treat to target as much as you're supposed to?

Yes, we have. And the problem is patients in China, we do not have the primary care center, so the patient only have symptoms to go to the hospital to have the prescription, and during their daily time, if they do not have the symptom, they do not have the gum flare, they always do not take the medicine. So I think the sex symptoms was severe in China. I think this is a yeah situation.

So the second question lends support to maybe what the problem is. I gave a scenario, you're managing a patient with uric acid of 6.3, you're not a target, but you're close. On three hundred milligrams of allopurinol, do you escalate the dose? Fifty three percent said yes, thirty one percent said, depends, and fifteen percent said no. You could see that strict adherence to treat the target is not being practiced by almost half of the respondents in this.

And again, half are from The US and half are outside The US. So again, maybe the point of this is that if you listen to these articles, are you more motivated to achieve target? And we're gonna get into those articles next. So let me see what we have here. All right, so let's begin with Professor Abhishek's article from March of this year.

Igor, why don't you present this paper?

Sounds great. So today I'll be presenting a study published by Chapuletta et al in JAMA in 2026 entitled treat to target urate lowering urate lowering treatment and cardiovascular outcomes in patients with gout. So we know gout is associated with approximately a twofold increased cardiovascular risk. This study evaluated whether a treat to target strategy in gout within twelve months of initiating urate lauray therapy is associated with a lower five year risk of major adverse cardiovascular events. It used the target trial emulation design and eligible adults were residing in England registered in a general practice that contributed data to the clinical practice research data link, Orum, between 02/2007 2021 with linkage to hospitalization and mortality records.

They were required to be diagnosed with gout, have received their first year lowering prescription on or after the first diagnosis date and have a latest pretreatment serum urate higher than six. Notably, this also included CKD patients. Ninety nine percent of patients were on allopurinol, eighty six percent were white. The intervention was achieving a serum URA less than six. So patients were assigned to the treat to target URA lowering therapy arm if their URA level was less than six within twelve months of the first prescription and assigned to the non treat to target arm if all serum your levels were six or higher in the twelve months of first rate lowering prescription or if it wasn't measured.

The primary outcome was the first major adverse cardiovascular event within five years following first prescription. Positive controls included the number of gout flares that you would expect to treat to target urinary tract thang if you were reduce the number of gout flares and negative control outcomes were chosen to assess for presence of unmeasured confounding, including acute bronchitis, cataracts and appendicitis, as there was thought to be no possible mechanism by which they can be caused by achieving or not achieving the target and addressed a range of mild, severe and chronic illness. So one hundred and nine thousand five hundred and four patients met eligibility criteria. The mean age was 63 years, seventy eight percent were male. The mean standard disease duration was two point five years.

Twenty seven percent of patients were included in the treat to target group. And as you can see, so after applying inverse probability waiting to emulate the target trial, the investigators estimated a five year major adverse cardiovascular event free survival in the two groups and MACE free survival was eighty nine point four percent in the treated target group, eighty eight point three percent and not treated target group, which corresponds to an absolute risk difference of approximately one percentage point. Our number needed a tree of 91. The weighted hazard ratio was 0.91 with a 95% confidence interval of 0.89 to 0.92. Cardiovascular Cardiovascular risk category also showed clear effect modification with meaningful absolute and relative risk reductions in patients with high and very high baseline cardiovascular risks.

The positive control outcome: gout flares behaved as expected with a reduction in flares among those achieving target. The weighted controls showed no association supporting internal validity and also the investigators evaluated whether achieving a stricter Urate target below five milligrams was associated with different cardiovascular outcomes and they found that in that analysis there was a dose response relationship with a hazard ratio of 0.77, absolute difference of 2.6. The main conclusion was that achieving serum urate less than six within twelve months was indeed associated with a lower five year risk of MACE. And in the next slide, I'm just gonna go over some of the baseline characteristics. The mean age you can see was 62.9 years, about seventy eight percent were male.

In terms of alcohol, only eighteen percent reported greater than twenty one units per week. In terms of smoking, only ten point two percent reported being current smokers. Forty five percent of patients were obese. Notably twenty three percent were CKD stage three to four and three points who were on dialysis. And it's notable that this population was included in the study.

Fifty five percent had hypertension and only about thirty percent were in the low or moderate European Society of Cardiology cardiovascular risk category. The takeaway here for me being that this table shows a predominantly male, older high risk population with substantial cardiometabolic disease. Now, I think Doctor. Abhishek is gonna comment a little bit more on this, but in the meantime, I can talk about the primary outcomes. So in figure A, you can see the Kaplan Meier curve shows modest separation beginning after about a year and the survival curve separate gradually over time, which makes sense if you're reducing a chronic inflammatory burden.

Among patients with gout newly prescribed rate lowering therapy, those achieving serum urity of less than six within twelve months had a substantially lower risk of MACE. The crude five year event free survival rate in the treated target urate lowering therapy and non treated target urate lowering therapy arms was eighty nine point nine percent and eighty seven point eight percent respectfully with a survival difference of 2.1 and the five year weighted event free survival rates in the two populations were eighty nine point four percent and eighty eight point three percent respectively with a survival difference of one point zero percent, ninety five percent confidence interval of 0.5 to 1.6. In terms of secondary outcomes, there was a hazard ratio of zero point eight eight with MI, zero point eight six with stroke, positive control outcome, gout flares behaved as expected with a reduction in flares and the weighted controls again showed no association supporting internal validity. Doctor. Abhishek, do you have anything else you'd like to add about this?

Thanks, thanks, Hygor. It's an excellent presentation. And as colleagues can see, there's no association with negative control outcomes. And I just wanted to comment on a couple of things. So, this was a sort of a primary analysis, but we looked at, hospitalization or death due to MACE, which is a more of a hard endpoint.

And again, there was was an effect on that. We looked at people at low people at high or very high level of cardiovascular risk. In that population, there was an even larger effect size. So I think they are the two points that increase confidence in these findings apart from the actions of residual confounding. The thing to remember is that this is not a clinical trial.

This is a new user cohort study done using an emulated target trial framework. We try and minimize any confounding that we can. Obviously, the absence of residual confounding gives confidence that what we have found is a true effect. It's a really small one percent point improvement in MACE over five years, but it's one percent of our disease is still a lot. The other thing I wanted to draw your attention to is the.

Can

I interrupt a second? I just want to use the line that you used in your paper. 1% doesn't seem like a lot, but in 2020, fifty five million people out of gout and by 2050, what was the number ninety five, ninety

six

million, percent of that is a gigantic difference. And that's why this is so impactful. I'm sorry, Nthoruk, go ahead.

That's fine. I was being Yeah, that's absolutely spot on. Thanks for coming in. I can just talk to you about the graph that is shown here on the top, graph a. And as you can appreciate, the the t two t ULT arm and the non t two ULT arm, the the events are comparable for eighteen months or so.

And then the t two t ULT arm begins to sort of show better survival. In and this, you know, may point that that this sort of the the mechanism of improved survival is sort of absence of flares or freedom from recurrent flares because in the trials that we did in Nottingham, we found that if you give somebody T2 TULT for one year, it doesn't improve their flare rate. The flare rates only improve in the second year of treatment with T2TULT. And then we did some follow on work which showed that if you continue with T2TULT, then you get almost freedom from flares thereafter. So it's possible that the improvement in base free survival into ULT arm is driven by fewer flares.

Obviously, we can't prove that because in CPR, the only those flares where there's a consultation and a diagnosis and a prescription can be called a gout flare validly. Not every gout patient consults the GP for every gout flare because they know how to self manage it. So not everything is captured.

I want to interrupt and say that the old people remember that when, especially when febuxostat was being developed and being compared to allopurinol, if you looked at flare rates with the initiation of ULT, it was horrible in the first six to twelve months. Because in lowering uric acid, you're mobilizing a lot of uric and you're causing lots of flares, which is why they need to be on prophylaxis. And so that goes along with your point that real benefit is after that first year.

Yeah, and UK primary care, colchicine prescription, if it happens with T2T ULDs for a couple of months, we did a separate, we did a different paper on that, and we found that the average prescription was like forty days or so. So it's not long term prescription by any means as ACR recommends or even the BSR recommends. Yeah, they're the only points to make really. Thanks. Thanks, Igor.

Excellent presentation. Over to you again.

I have a question since both professors Abhishek and Wei did a great T2T study with different outcomes, put it in JAMA Internal Medicine, but they both use a target emulation trial design. Professor Abhishek, why don't you take a stab at that first as to why you chose to do that? And isn't there a limitation of that because using the CPRD database, which is mostly primary care, not specialty care and whatever. But, why do you choose to do that? What's the limitations of the target emulation design?

So a good question, and thanks for asking. So target trial emulation is supposed to be used or recommended or advised to be used when a when a sort of traditional randomized controlled trial is not feasible. So this is a situation where, you can't really withhold patients from getting treated target urinary therapy if they've got active gout with flares, etcetera. So it can be unethical to randomize patients with gout, of course, symptomatic gout flares, etcetera, to not receive urinary therapy. So in these situations, where actual large pragmatic RCTs are not possible, we could use existing data to do a target trial emulation.

Now target trial emulation is not a randomized control trial and does not not involve randomization, but it does involve complicated methodologies to balance or minimize any bias from cloning. So you sort of essentially clone the participants into two arms and so that there is no difference in the two arms at baseline. Then you sort of, sense of the follow-up time when they deviate from their allocation, and you wait this this follow-up time according to the probability of of survival to to the allocated time points. So by cloning, waiting and censoring, we hope to minimize this dual confounding. And again, we can measure that by looking at negative control outcomes.

But the limitation is that it is not a randomized controlled trial. And one of the problems of looking at XTAN databases like CPRT is we sort of look at twenty, twenty five years worth of worth of data, and and and you know some of the temporal trends in cardiovascular survival etc might have an impact on the finding. We did look at more recent patients as well in the sub analysis where we found similar results. So we are happy that that doesn't have a big impact. Yeah.

So both these trials have limitations, but again, is the numbers and the cloning to represent the randomized groups. Igor, you want to just wrap up with these strengths weaknesses and conclusions?

Yes, certainly. Some of the, we already discussed that the modest reduction, but with large population implications. Some of the notable strengths are that you have linked primary care hospitalization and mortality records for all outcomes. You saw a dose response which is of interest and the positive and negative controls were validated, validated the results. Some of the limitations are we may have included patients with a history of MACE.

So there's some risk of confounding and some patients may have been incorrectly diagnosed with gout or have been for patients who were on treat to target urinary therapy might have had better patient management. But the conclusion stands that achieving serum urea levels lower than six within twelve months was indeed associated with a statistically significant lower five year risk of MACE. And just to, you know, again, reiterate that this is not a randomized control trial, so the causality here remains unproven, but it is a powerful illustration in favor of this concept that treat to target may confer other benefits than simply reducing flares, including lowering cardiovascular risk.

So I have some survey questions I want to give to the group and Professor Abhishek. But do any other panelists have questions on this paper before we move on? Okay, so one of the survey questions that we did was, what percentage of gout patients have cardiovascular disease? How important is this? Because most of us that manage gout, we know some of them have history of hypertension, there's obesity, metabolic syndrome.

It's not surprising, but what is the number? And of you are all over the map saying it ranged anywhere from ten percent, zero point one and thirteen percent of you said that, twenty percent was chosen by thirty percent of you and thirty percent was chosen by about a third as well. You know, It is, I must say a messy area. And when you get a patient who's newly diagnosed or looked at baseline, it's at least twenty percent and often as high as thirty, maybe even as high as forty seven percent in different cohort analyses. My point in asking this question was that this is a common issue and hence this goal is an important goal.

What do you think, Professor Abhishek?

Yeah, no, mean, you make an absolutely valid point. And I mean if I remember correctly, in most primary care based gout data sets, large data sets, about forty percent people have got hypertension with gout. Again another ten-fifteen percent hyperlipidemia. Obesity is very common. If you combine ischemic heart disease, heart failure, CKD as a more serious end, that's about twenty percent or people between them.

So it is fairly common to have cardiovascular disease or strong risk factors for cardiovascular disease at diagnosis. And again, there was work done by Chang Fu who was in Nottingham about ten-twelve years ago and Mike and Wei Yan, they showed that it not only is comorbidity common at diagnosis, it gets even more prevalent as time goes by in people with gout and the increase is more than the relative increases more than in general population for age sex matched controls. So it's a serious problem.

Yeah, and that's why this treat to target outcomes are really important. I asked the audience, which of the following gout drugs lower cardiovascular risk? And I put stars next to the right answers. Twenty four percent of you said allopurinol, but sixty one percent said that it's colchicine, probably thinking that colchicine has this new cardiovascular indication across the board. But the data, in my opinion, for cardiovascular risk reduction is far stronger for allopurinol than it is for colchicine, but it exists for both.

But there aren't great studies on febuxostat or other ULT therapies. Is that true, Doctor. Abhishek?

Yeah, I mean, I definitely agree with you and agree with the respondents. So, urine therapy long term and colchicine, both have got signal. And I think this is also important point that when we are starting people with gout on unit lowering therapy using a treat to target approach, then we should also consider prescribing colchicine gout flare prophylaxis for, say, six months or longer, when flares are actually common. But yeah, no, I agree and I think this is absolutely spot on correct answers.

This last question I want you to help clarify because we said, and Igor showed those lines being closed but diverging with a 1% difference over time. I asked the question, if you achieve uric acid less than six, how much does that lower cardiovascular risk by? And they were a third, a third, a third, either ten percent, twenty percent or thirty percent. That's not one percent. Do you want to explain this, Doctor.

Abhishek?

Yeah. I mean, it's possible people are thinking of relative risk reduction where we caught about a ten percent relative risk reduction. But the absolute risk reduction is is one percent. And if I can put this in context, in gout patients with a five year follow-up, the absolute risk of CV or MACE is thirteen percent. So that's the sort of overall risk, and it reduces from thirteen percent to sort of twelve percent in the whole cow population.

And in those at higher, very high risk, it reduces by a little bit more, so two percent points. So so the absolute reduction is is not huge. The relative reduction is is, as it says, by point one.

So again, in gout is mostly driven by heart and cardiovascular events, but kidney is equally important. That's why we're going to discuss the Wang et al article from Doctor. Wei's group that appeared in 2024. I asked the audience the same questions. What percentage of gout patients have CKD at stage three when you see them?

And the most common answer here by forty two percent was twenty five percent, and that's probably close to the right answer. Some thought it was only fifty percent and twenty four percent, but the right answer from literature I could find is about twenty four percent will have CKD at stage three. It's up to sixty cc's per minute. If you look at stage two, it's much higher, it's like seventy percent will have a stage two CKD at presentation. Then I want to get feedback from our panelists as to what is the goal in treating, and I didn't know the answer when I made up this question, but what is the goal in a gout patient who has CKD?

Let's say stage three or whatever. What is your goal? And you were all over the map and I don't know there is a right answer, but I'm gonna ask everybody on this panel, you had to choose one and that's the problem with these multiple choice questions, you only get one choice. Most of you chose uric acid of less than six, and we're going to see the data on that. That was 42%.

Next was uric acid of less than five, that was 21%. Preserving renal function at 1816% avoiding gout attacks. Doctor. Wei, what do you think is the right answer? What is the goal besides all these of course?

Yeah, from my opinion, I will choose less than six because first of all, this is a guide my recommendation and secondly from our data we actually I'm not sure the lower the better because we don't have the enough data to do the analysis because in the database, in the real world, the actual patients received the serum level less than five is quite low. So we cannot do the analysis to check if the lower is better. So from now, we only have the data for the less than six. So I will choose less than six.

Doctor. Wen, what would be your choice on this question?

Maybe also the six milligrams per test later.

And I think we're going to see the value of that when we look at the paper. I think those two are kind of biased a little bit, but Igor, what's your goal here?

I would say the guidelines recommend less than six, but intuition tells me that overall the lower the better, but I defer to our experts here.

And Professor Abhishek, what do you think?

Yeah, I'm happy with what others have said. Less than six would be my answer as well.

Again, all being true to treat the Doctor. Wen, go ahead and present this paper.

Okay. Good evening, everyone. Today I will briefly present this study published in JAMA Internal Medicine. The clinical question was in patients with gout and stage three chronic kidney disease or CKD is achieving the serum urates targets with Ureth Low Rate Therapy, or ULT, associated with worse kidney outcomes. Treat to target ULT is central to gout care.

Both the ACR and ULA recommend lowering serum urus to below six milligrams per deciliter. However, CKD affects approximately one third of patients with gout. Clinicians may hesitate to optimize ULT when kidney function is impaired because they worry that intensive lowering could worsen CKD progression. Previous trials didn't fully answer this question as most of the DENS focus specifically on patients with gout or evaluates kidney outcomes according to the target's achievements. Therefore, this study evaluated the association between achieving the serum uricos targets with ULT and CKD progression in patients with gout and stage three CKD.

Let me now turn to the study design and main findings. Using the IQVIA medical research database from 2000 to 2023, the investigators include eligible adults aged 40 to 89 years with gout and stage three CKD. They compared to ULT strategies achieving a serum levels below six milligrams per deciliter within one year of ULT initiation versus not achieving these targets. The investigators emulated a target trial using a cloning, censoring, and weighting approach. As ULT initiation, each patient was cloned into two copies with one assigned to each strategy.

During the one year grace period, the targets achieved copy was censored if the targets was not reached by one year. Conversely, the targets not achieved the copy was censored once the targets was achieved. When severe or end stage kidney disease, death, or loss to follow-up occurred before targets achievements, those copies remained adherence to their assigned strategies. After targets achievements, subsequent events contributed only to the targets achieved up. The probability of remaining adherence was estimated using logistic regression with baseline and the time varying covariates.

Inverse probability weights were then applied to reduce selection bias from artificial sensory. Patients were followed for up to five years and the primary outcome was severe disease. As shown in the curves, risk was consistently lower in the target achieved. Next, the third slide.

And again, what's the difference between panel A and panel B? Panel A includes people on hemodialysis to transplant. Is that right? And the other one is just just end stage kidney disease on B.

The population is the same. The outcome is different. In panel A, the outcome was severe end stage kidney disease and in panel B, the outcome was end stage kidney disease alone.

Okay.

Okay, the study included fourteen thousand seven hundred and ninety two adults with gout and stage three CKD. Their mean age was 73.1 years and sixty two point three percent for men. At five years the risk of severe or end stage kidney disease was ten point three two percent in the targets achieved up compared with twelve point seven three percent in the targets not achieved up. The adjusted risk difference was minus 2.41 percentage points with 95% confidence interval from minus 4.61 to minus 0.21. The adjusted hazard ratio was 0.69 with a 95% confidence interval from 0.8 to 0.98.

A major strength was the attempts to reduce selection bias among ULT initiators and confounding by indication because all participants received ULT. However, residual confounding cannot be ruled out. Patients who achieved the targets may also have received better health care. Overall, achieving the serum UERT targets with UERT was well tolerated in patients with gout and stage three CKD. This finding supports optimizing UERT to achieve the serum UERT targets in patients with gout and impaired kidney function.

That's all. Thank you.

Okay, that was great. Doctor. Wei, let's first begin with your views on using the target emulation trial design here, doing a trial that couldn't easily be done. But do you have any hesitations presenting that kind of data?

Yeah, so we do this analysis based on previous trials, because previous trials demonstrated that in recent trials demonstrated there's no renal benefit when treating patients with CKD and lowering their serum urate, but our concern is if the patient had gout, we should be treated and they have both gout and CKD, should we treat them to the target? So this is how we start. And we're doing the trial emulation because to do subtrial is invisible, right? We cannot control the patient not to reach the target, so we do the trial in relation. So the target trial in relation, the key is to solve the problem of the immortal time bias.

What is immortal time bias? Patients have to be treated. They must survive long enough to achieve the serum level. So this time period called the survival time. So during which the outcome cannot occur if patients are eventually classified into the treatment group.

So this artificially favors the treatment group, so our design is to assign the treatments at the start of the follow-up, So we minimize the immortal time bias by aligning treatment assignment with a start or a follow-up, we account for the time varying confounding, minimize the selection bias, and stresses the causal inference from the real world data. So as a conclusion from our study, we found that the group who achieved their target serum level did not show higher incidence of the progression of the CKD, so our data we do not support achieving the target serum level is renal protected. We do not say that we treat the chronic kidney disease. We only state that the treat to target, the strategy is safety and do not accelerate the CKD progression. So the goal is to tell the rheumatologists we could treat the gout patient with CKD to the target and it's renal safe.

That's

my I think it's very interesting that both these trials have incidence rates on primary outcomes that are kind of around ten percent with about a small difference between them, one percent with the cardiovascular trial, two point four percent here. But these are significant and significant given the deadly disastrous outcomes that occur when you don't control renal disease and don't check cardiovascular disease. So these are, I think tremendously important outcomes. When I ask the rheumatologist, if a gout patient has CKD four or five, they're advanced, What's the top dose of allopurinol that you would use? And look at this, sir.

You got the audience is all over the map. The top dose. I don't know how where this comes from is one hundred milligrams in forty five percent of people. That's totally wrong. That's your starting dose.

That's not your top dose. That's your starting dose per guidelines. And then I use, you know, three hundred, nineteen percent, four hundred, sixteen percent, And then the right answer, I'm sorry, three hundred was, I got confused here. Right answer is twenty percent here at eight hundred. You can go as high as you want with renal disease.

You just have to monitor the kidney. Renal doctors, one of our audience, docs says nephrologists keep saying increasing the dose of allopurinol worsens renal failure. How concerned should we be and should we use Uloric instead? No, I mean, you can, but allopurinol, I think has over and over and over again been shown to not be a truly nephrotoxic drug. You have to monitor renal function, but you can use up to eight hundred milligrams at any creatinine, as long as you're monitoring renal function.

Does anyone have an alternate opinion here about this?

I agree that we should monitoring the renal function and also the SU level. And the goal is to treat to the target no matter what dose you use the goal is to reach the target so I think the doctor may be too conscious about the dose the goal is that as your level target So I agree with Jack.

Yeah. Luis Torre Gross has asked, should we still adhere to the protocols of Lisa's stamp from New Zealand with regard to dosing allopurinol in CKD patients. Lisa is going to be on one of these panels, think in two weeks, and we can ask her, but I think yes, she escalates and has a formula for escalation based on uric acid levels and renal function. Catherine Garcia asks, how frequently should we be monitoring the estimated GFR and creatinine in these patients? I mean, it depends on no problem, not that much, three to six months.

If there's a problem more frequently or if you're starting out in the face of, you know, whatever. But, professor Abhishek, how do you recommend monitoring bug creatinine and e and GFR in these people?

I mean, I think that depends on what the renal doctors want to do. I mean, as my understanding is allopurinol or even fevoxostat are not nephrotoxic. So, you know, having ULT doesn't mean you need to check urate creatinine more regularly. So for most of these patients, I believe nephrologists do three monthly blood tests in UK to keep an eye on, the kidney function. I wanted to make another point about using allopurinol in CKD.

I I I think we can escalate the dose to whatever is needed to control your rate level less than six. The important thing is to start a really low dose like fifty or one hundred milligrams daily to reduce the risk of allopurinol induced scar. Right. Toxic with double necrolysis or DRESS syndrome. So start at fifty or one hundred milligrams a day and then escalate monthly to to target.

That's what Lisa and Nicholas paper shows safety of.

Yeah, John Tesser in Arizona brings up the question, is there safety data for 800? There is because the trials were done with up to eight hundred milligrams. But there's a group of gout advisors that have been setting up a lot of the curriculum for these webinars and what we're rolling out this month. And we discussed two weeks ago that there isn't a lot of guidance about what to do when you're at a GFR of greater than 60. Because Uloric data, the febuxostat data, they have data on its safety up to an eGFR of 60, not beyond that.

So there's just clinical experience and whatnot. But I think John's point is that maybe the hesitancy is that people haven't been shown the data showing that it's in fact real. But there are a lot of case series that show that you can certainly go up higher. The truth is that if you look at the average dose of allopurinol in gout patients in primary care, it's three hundred milligrams. And that's the median.

The median dose of allopurinol in rheumatologists is three hundred milligrams. The number of people that go to six and eight hundred is still very, very low. And again, I think that to me, I find that worrisome and we're kind of wimping out on treat the target. I mean, you should be pushing the dose to get to the target or using a drug that's going to get you to target. We have one person asked a question about, is there evidence for either cardiovascular or renal protection in using ULT in asymptomatic hyperuricemia patients?

Now that's not what was done in your trials, right? Those had to be patients with gout, but is there any on asymptomatic?

Yeah, yeah. I mean, for cardiovascular disease, there are a couple of trials. There's a really large trial led by Isla Mackenzie from Scotland, which showed that if you treat asymptomatic hypervoisemia patients with urine lowering therapy, you have absolutely got no effect on cardiovascular outcomes. That's the proper RCT, a large RCT published in Lancet by Eilah McKenzie. So we should definitely not be treating asymptomatic hypervoisemia with urinary lowering drugs to prevent cardiovascular disease.

I think that's been also said for use of oxypurenol in heart failure patients who have hyperuricemia. Similar results we're Doctor. Seeing Wei, I'm sorry to interrupt you.

Yeah, so there's another paper just published in this year, another group in China, they do the similar analysis, they restrict the population with symptom, asymptomatic hypercemia and CKD, and similarly they do not find a significant association between reaching the target and the CKD progression. So I would say that the benefits may be not so significant in hyperthemia population.

I like that point. We have another question. What is most disappointing about the care of gout? I'm gonna write about this because I have a survey that asked this question along with the major advances in gout that goes back to Jim Freeze from Stanford, and I think 1986. And then I did a repeat survey with 500 rheumatologists in I think 2014.

And now I'm asking the question again, and what is most disappointing with the care of gout patients? Your number one answer forty six percent was patient noncompliance. Number two answer at nineteen percent treatment by non rheumatologists. This is kind of at the base of treat to target failures, right? It's partly patients, it's partly those who aren't pushing on the numbers.

And you as rheumatologists have to take some responsibility for that as well. But what do you think of these answers? Chi, do you think that this is surprising to you?

No, not surprised. The patient non clients is very obvious in previous research, also in our research, less than thirty percent of patients adhere with their therapy and reach the target. So I think this is a number one disappointing about care of gout patient. And number two, treat them up by non rheumatology. I don't think this is a situation in China because I think people always go to the rheumatologists to treat gout.

So I don't think the second reason is not the situation in China. That's So my opinion.

But the numbers, there aren't enough rheumatologists in China to take care of forty million people with gout in China. That's projecting forward obviously. But still, how do we handle this issue of patient non compliance? I'd be interested in why gout patients are so non compliant. Is it because it's an on off again disease?

Is it because of it being men? What do you think, professor Abhishek?

Yeah. So I I mean, you you hit you you got sort of the the main problem sort of you've said that it's that it's an on off disease, an intermittent illness. But I think the bigger problem is physicians or health professionals won't explain that it's a chronic illness where the crystals are sat there, they flare up. And again, sort of lack of knowledge of effective treatment that can prevent flares if taken in the long term with urinary therapy. So lack of knowledge of effective therapy, lack of information that how much when you modify your diet, can only reduce your unit level by that much long term.

And then there is a huge amount of misinformation online or sort of all sorts of stories about different things and portions to prevent flares or treat gout. I think the other problem is that sometimes doctors perceive or clinicians perceive gout as a self inflicted illness and therefore are not as sympathetic towards their patient, not as supportive as many times we are for patients with rheumatoid arthritis, for example, where we think always an autoimmune condition. But now we know that most of hyperuricemia is not self inflicted. It is mostly genetic from renal and GI under, sort of renal under excretion and GI under excretion. So I think the non compliance, there is patient factors.

There's a disease factor, it's intermittent. There's a patient factor. There's misinformation and then there is a physician lack of sympathy and time. And physician lack of knowledge as well. I think.

And you know patients who are. They don't care about it until they get a gout attack, then they're searching for answers and they're getting treated by everybody in the world who thinks they know how to manage gout. And they give them a lot of misinformation, which says, Oh, don't worry, I can fix that with this drug or You come to me when you have this problem. As if to say, it is an on again, off again thing. I want to ask our fellows, how do you manage the non compliant patient that comes to you in clinic?

The patient is supposed to be on therapy, they're not on therapy, they're still having attacks. Igor, what do you do?

Well, would say it's important to have open channels of communication with your patients. I think that trying to communicate with them via phone, trying to like reach out and then trying to ask them, you know, what their understanding is and what their, you know, reasons are for doing x y z remaining kinda empathetic and open minded. Also just to underscore that, you know, the ACR guidelines do recommend treat to target, but the, you know, the ACP guidelines in The US for primary care physicians still recommend the treat symptoms which is basically treating gout flares not really to a target urate lowering therapy. There's like ongoing research notably like the trust trial that we're involved in that is trying to kind of assess whether one strategy or compare the two strategies. I would say that what's important though to answer your question again is to maintain open channels of communication and remain empathetic.

Doctor. Nguyen, do you have a point to add here?

Yes. I have the similar idea with eager. That's because in China there are so many patients with guards and we the doctor, the number of the doctors is more so we can only by communicating with the patients or prescription some URT medication to the patients and yeah, that's all.

Okay, we have a few comments that I want to bring up here. We got a few more minutes. Herb Barath, who's done a lot of the trials here says, is it fair to say that noncompliance is a product of education deficiencies as Professor Abhishek has pointed out? The problem with that is we can't rely on rheumatologists to do all the educating since we're only taking care of one percent to three percent of patients. Where's the rest of the education going to come from?

Luckily, there have been major initiatives in The United States to do better patient education. Larry Edwards and others are involved in patient groups. Creaky Joints is involved in educating patients on gout. I think that's important. I like John Tesser's point about maybe you can do better at managing gout by using structured clinics with advanced practice providers doing most of the work either face to face or by telemedicine.

Why not have what they have in The UK with early access clinics for PMR? Why don't you have an early access clinic for gout? If you want to make a bazillion dollars in The United States, just do gout clinic and employ 300 nurse practitioners and make sure everybody can drive up and get their gout care with no friction. But John, has a lot of nurse practitioners and physician assistants, I know that they're probably better at it than we are in my clinic. Jim Dowd asked, Do you think discussing the MACE risk with patients will get their attention and increase compliance?

So you, doctors Wei and Abhishek, can you use your data to say, we have shown and do you think that motivates patients?

I mean, used it in a couple of, I only get referred complex gout, which is difficult to treat or there's noncompliance issues. And sometimes when patients are not terribly keen, I have brought this data and discussed and that sort of seems to sway some of them towards unit lowering therapy. So yeah, have used it and I think we should use it more widely.

Yeah. Yes, I agree. I think we should use like the social media to promote our findings in general population. And our work has been reported in social media. So I think this is one of the ways to educate the population to using our data, our findings.

Yeah, I want to address the last two comments. Luis says, is there any studies proving that patient education improves compliance? I'm not aware of any. I know that there is some work here, but I don't know that data very well. But I think Leica Barbosa's point is the good final point.

And that rheumatologists, I mean, the key, what we're calling this campaign this month is gout is more than flares, which is to say gout is a systemic disease. Gout is a urate deposition tissue damage disease, and it has tremendous systemic effects. In fact, your rate lowering therapy is to say you're using disease modifying therapy. To make the point that gout is a systemic disease should be the start of an education program with your patients. So with that, I want to thank our panelists for an excellent discussion on two really important papers in rheumatology.

I want to thank our fellows for their guiding us through those papers and the audience for their input as well. Next week, we're going to have another Tuesday night rheumatology. I'll be hosting Nicola Dalbeth, John Fitzgerald and Sarah Tadeshi, where we're gonna talk about uric acid deposition and imaging. Basically what lies beneath the attack is a lot more meaning we're getting to the point that gout is a systemic disease and what's the evidence for that. We'll talk about that next week.

Thanks very much, folks. Good night.

Thank you. Thank you. Bye.

Bye bye.