Upgrading & Maximizing the Classics (Colchicine, Allopurinol, etc.) Save

Hello, everyone. Welcome to Tuesday Night Rheumatology, another great session on gout. Tonight, we talk about updating and maximizing the classics. We're not talking about your record collection. We're talking about your use of gout therapy, mostly on your rate lowering therapy, but all things will be considered in this session.

I wanna thank our support from Sobe in sponsoring our gout campaign month in July. We've had a lot of great content that's been up on the website. If you haven't read some of these articles, they're really, really great, like why you get attacks at night, and advice on dosing, and really it's a never ending strain. I think you'll enjoy the content. We've done, now this is the third Tuesday night rheumatology webinar, on gout.

We have one more next week that we'll close with and talk about. Tonight, I want you to know that, your involvement in the audience is important to us, hence we want you to use that Q and A box on Zoom. Click on that when you have a question and we'll interject that into the discussion with our panel of experts. With that said, let me introduce our panel of experts. I'm Jack Cush from Dallas, Texas.

I'll ask them to introduce themselves, Angelo.

Hello, Jack, thanks for bringing me here. I'm Angelo Gaffo, I'm from UAB, University of Alabama at Birmingham at the Birmingham VA Medical Center.

Michael.

Hi, everybody. It's great to be here. My name is, Michael Pillinger. I am at NYU Grossman School of Medicine, right here in New York City, and I am thrilled to be with this particular group of great goutologists.

Ted?

Hi, thanks again for inviting me, Jack. It's very nice of you. Ted Michaels at the University of Nebraska Med Center in Omaha.

And from the other side of the world where it's nice and warm, Lisa.

Thanks Jack and thanks for inviting me. It's great to see my US colleagues online. I'm Lisa Stamp, I'm a rheumatologist at the University of Otago Christchurch and Health New Zealand. And even though it looks like I'm in the nighttime, it's actually 11:00 in the morning here.

Excellent. Okay, so as audience knows, we preempt, or prepare these discussions with a survey of rheumatologists that it's a one time email invite. We had two twenty plus responses that came in within a few hours, from 41 countries, about 58% from The US. Our respondents were as in the past, eighty eight percent rheumatologists, six percent nurse practitioners and physician associates, and a few fellows and a few others. Don't you want to know who the others are?

When we asked them where they practice, we have an even split between private practice, 46%, and academic centers and hospital based physicians at 44%. 6% of our colleagues are retired. And again, we have, about five or 6% are in training. So we asked them right off the bat, or I have to ask all of you right off the bat, what drugs in as far as gout management do you have concern about? So the question was, which gout drug has the greatest toxicity risk, asking you to declare amongst these five choices?

And, the runaway winner on toxicity was steroids according to our colleagues at forty nine percent. At eighteen percent, it was allopurinol thirteen percent, Probenecid was thirteen percent and febuxostat at six percent. I find this a little surprised. The one thing that I found really kind of interesting was probably not much difference as far as toxicity between, I think it's colchicine and probenecid. Actually, think it's allopurinol and probenecid at thirteen percent.

Then colchicine at nineteen percent. Felt to be more risky than febuxostat, thirteen percent versus six percent. What does our panel think about this? I'll ask each of you just to pick one of these responses and ask what strikes you, starting with Lisa.

Yeah, I'm surprised by the allopurinol febuxostat issue as well. I'd have far more concerns about febuxostat than allopurinol, but that probably reflects the amount that we use allopurinol. I don't see that many problems with it. But I know there are a lot of people out there who remain really concerned about its use and the toxicity syndrome, despite the fact that it's really rare.

Angela, what do you think?

Yeah, I share Lisa's comment. There's a perception that allopurinol is more problematic than fevoxostat, especially sometimes when you add the context of the high frequency of chronic kidney disease, people tend to get more worried sometimes. And allopurinol was initially commercialized as a very safe medicine in the context of advanced CKD. Now, they stopped gout, a study that Ted and his colleagues led, demonstrated very well that incidence of adverse events between allopurinol and phylloxicil was completely comparable even in advanced CKD. So we have a practice experience, many of us have used a lot of allopurinol, and now also have very good data supporting that both medicines are probably equally safe or equally safe.

Michael, what strikes you about this answer?

So in terms of the discussion of allopurinol, I think I have an insight here, which is that the term greatest, maybe needs to be unpacked a little bit because it can be most common, or it can be most fearsome. And I imagine that many of our participants here who answered this question are worried about allopurinol hypersensitivity syndrome, which is indeed very fearsome, but also extremely rare. So that needs to be balanced. And I I think, you know, if if time permitted, one of the things that I would wanna talk about is the issue of how do you actually lower that the risk of that down to almost nil. Lisa, helped guide us with that with a seminal paper a number of years ago about the idea of titrating allopurinol from a low dose to a higher dose.

That is where that comes from. So thank you, Lisa, which also prevents inadvertent overdose. And then there is the genetic issue, which is again something we can do in high risk patients so that by the time you conscientiously get to starting allopurinol, if that was the concern, you can get that down to, I can't say zero, but pretty darn close to a zero percent risk if you just pay attention. But I have seen a couple of horrific examples that would, make me think that allopurinol has a great toxicity risk when it happens.

So Ted, you can comment on this as well, but I want to go ask about steroids. Does that predominant answer, steroids being maybe the greatest toxicity risk indicate maybe why they don't use steroids? Or does it indicate that it's what they observe and they still use it? What's your feeling on the steroid issue as well? Well, I

mean, I think steroids, as rheumatologists, we use a lot of steroids and we all have great respect for what we can do adversely with steroids. And we spend a lot of our time trying to dance around that and minimize that risk. And, you know, when you think of gout, you know, you can't help but think about cardiometabolic morbidities, and we're certainly not helping that when we use lots of steroids. So I, you know, I understand that risk and I think generally most of us try to use it as sparingly as possible, but it's still a very effective and very important drug for arsenals. So, you know, I get why it's there.

Since it came up, can you give us a brief summary of the STOP RA trial that you led?

Oh, the STOP Gout trial. Yeah. So we did a study comparing allopurinol and febucisat with both drugs dosed in a treat to target fashion. It was a non inferiority study and the drugs indeed proved to be non inferior to each other. And as was mentioned by Angelo, the toxicity profiles of those agents, when they're used that way to target a goal, had very similar toxicity profiles.

And what Angelo was talking about is that a third of the study population had moderate CKV, CKD stage III. And those patients actually did quite well. There was really not a big safety signal difference in those patients between allopurinol and febustacal, which is, I think, notable because that's a patient population that I think many people have tried to stay away from with allopurinol because of perceived risks. And I think it fits quite well with data that Lisa's group had published earlier that you can use allopurinol safely in that patient population.

Yeah, so I think this concern about allopurinol versus febuxostat stems from the febuxostat development trials and everything ensued after that. There was a FAST trial that confirms the stock out and more recently CARES. And so we asked the audience about, this issue of, what drug should they be using in the face of ischemic heart disease? And sort of the runaway answer on this was allopurinol at eighty six percent with eight point six percent choosing febuxostat. Now, again, if you follow this data, there was a seesaw effect in that, oh, there is more worry with febuxostat, oh no, there isn't with febuxostat, and it's more with alaparol.

No, it swings back and whatnot. So let's ask our panelists here, is this answer well founded? And let me start with, Ted. What do you think? Is this well founded?

I'm surprised by this to see this, honestly. So I'll go against the audience and I don't think it's well founded because I really think the data suggests, so the CARES study, which showed this difference in cardiovascular risk, has been picked apart quite extensively in editorials and literature. The vast majority of cardiovascular events that were seen with febiscostat occurred well after patients were off study drug. There was a lot of issues with that study. The FAST study, as you mentioned, was done afterwards and was really quite reassuring.

And I think the thing that's missing here, Jack, is I don't see a piece of the pie for placebo. And I say that because we're making a decision to lower urate lowering therapy, and I would argue, I don't have the data to back it up, but I would argue that treating someone with nothing is far worse. You know? So I I I don't understand sort of the discrepancy in this answer.

I I I will say if I might, Jack, to support Ted, that there was a recent targeted emulation study by Abhishek's group, which didn't distinguish between allopurinol and febustep. Most of the patients were on allopurinol. And treatment and urate lowering clearly looks like it goes with at least some lowered cardiovascular risk, which again, in none of these other head to head studies was there, in fact, a placebo. So we didn't know the difference. It may just bear noting that unless it's changed to my knowledge, the black box warning still exists from the FDA on the package insert.

So I suppose from a medical legal point of view, perhaps you would be justified saying I'd rather not, you know, fight with the package insert, says if I ever had to go to court. But I I think the data's been overwhelming that that the story just doesn't stand with allopurinol versus vivuzestat.

So the Abhishek paper was covered in the first week and it showed a really small difference, if you achieve target versus those who didn't achieve target, but that small 1% or 10%, depending on how you look at the data, means a tremendous amount when you consider worldwide fifty five million people who have gout. And, so that's why it is gigantically important. Angela, what's your take on this and people, and then maybe you can explain the package insert comment that Michael brought up.

Yeah. So my overarching take is a little bit rephrasing what Ted said. There is nothing worse for ischemic heart disease risk in gout patients that having poorly controlled gout. It looks like the risk of cardiovascular onset gout is driven by flares and inflammation. And the period post flare seems to be particularly risky in patients with gout.

And in a very obvious way, patients who have poorly controlled out with under utilization of Urette lowering therapies are going to have more flares. This issue of allopurinol versus fevoxostat, it's an interesting question, But but I think that, again, the issue that there never was placebo control to tell us, you know, like the risk of actually not being treated is even worse. It's probably a very, very good point. Now, when fevoxostat was was being developed, there was this kind of very minor safety signals that that the FDA asked at that time Takeda Pharmaceuticals to continue to do a phase four a study to look at the cardiovascular safety of allopurinol versus of evoxostat. And they did it comparing it with allopurinol with no placebo arm.

Of course, you know, you cannot keep outpatients on placebo for years and years as probably might be unethical. And in general, whole kind of a black box warning was tied around a secondary result because the primary outcome was was not different. And most of the secondary outcome was not were not different. I think the total number of deaths were somewhat different statistically significant in a study that had, I think, five thousand patients per arm. And that's what led to the black box warning.

Now, all the caveats and limitations that Ted pointed out that most of the events happen after patients had already stopped the drug and probably were having flares after stopping the drug. So then we had the European FAST study that had a much better pattern of following patients consistently and having patients stay on drug. And this study did not show any difference between the two arms, maybe with some, I don't like to speak about trends, maybe a trend for feroxadustat being a little superior in cardiovascular protection. But in general, I think both drugs are very safe. Have seen patients who are a little anxious about feroxadustat because of the cardiovascular risk.

I think that's the major the major damage that this black box warning brings that that, you know, again, you have someone that is probably be hesitant or maybe not adherent because of this concern. It's even is much worse not to not to be on good treatment and to experience flares for cardiovascular risk.

Lisa, do you think the answer to this question would be any different for you if instead of ischemic heart disease, we're talking about significant CKD?

No, the answer would be the same. I'd far rather use allopurinol and CKD than I would febuxostat at this stage. I think it's really interesting if you compare this to the first slide where people thought that allopurinol had more toxicity than caboxostat. This has just kind of flipped it around based on one single potential toxicity vastly, which is kind of interesting, I think. I'd definitely still use allopurinol first up in CKD.

Yeah, in the first week, because we were talking about two different papers that were target emulation trial, one looking at cardiovascular outcomes, the other one looking at renal outcomes when you did or did not achieve target, We asked the audience about the use of allopurinol in the setting of CKD and as many as 40 of our respondents said that you would dose adjust based on the creatinine. Anybody want to tackle that? Say that again, Doctor. Stapp.

I said, I feel my life's work is failing if we're not getting that message out there. Michael. You know?

Yeah. Well, I I I think, you know, I I think some things are probably true, which is probably that allopurinol clearance or oxypyranil clearance, which is the active metabolite of allopurinol, probably reduced in bad kidney failure, but that just means that you have to use common sense. And so the idea of titrating to a target covers that. It tells you really tells you how much allopurinol your body needs. And, you know, some of the problems that people used to get into in the old days was when they just started with three hundred milligrams that weren't necessary that, you know, led to the handy equation where dose was adjusted and under adjusted, and then it didn't, then the drug didn't work.

So the idea of titrating lets align the use of the drug with the renal function is how I see it. ACR guidelines, say that no matter what your renal function is, your final target can be, not should be, but can be as high as eight hundred milligrams a day. The Europeans say nine hundred milligrams a day. Very, very few people need that. Most people, though the average dose seems to be about three eighty milligrams a day.

So make a note of that. That means that something like half of the patients who go on allopurinol need a little more than the average practitioner thinks is okay. Maybe they need four hundred, but it's okay to go beyond that as long as you're watching the urate level, taking doing what doctors are supposed to do and taking good care of your patient and making sure that they're not having any adverse events. And by the way, most of the adverse events come in the first month if they're going to come, so you really wanna pay attention early. But to get to stability, these patients do really well on allopurinol.

Well, I'm glad you bring up the issue of dosing. Oh, before we get into dosing, I wanted to ask a really hard question of our panel because you won't see this much gout brainpower together, in a long, long time. Everyone points to one of the biggest problems that we have is the issue of, non compliance, either non compliance with medicines, not taking them, stopping them without advice, not coming to clinic. My answer to this issue of noncompliance is because, most patients, with gout are men and men are the imbeciles of healthcare. I didn't put that down in my survey responses for fear that I could be brought to court or something.

But anyway, when asked about what is the issue underlying noncompliance, The audience said it's education in forty four percent. Thirty two percent, the intermittent nature of the disease allows for people to say, Well, I don't need to do that or whatever. Ten percent blame it on youth, eight percent blame it on misconceptions about it being a dietary management disease. And then a few people thought, well, man, it might be aversion to pills or doctors. And then when I asked the same audience, what can you do about this?

The vast majority, seventy eight percent point to education. And then know your numbers, treat the target for the patient, different kinds of clinics run by nurses or pharmacists, more frequent visits. I don't know that anybody really has a grasp on this issue. So I'm going to ask each of you to tackle this issue, and maybe it will start with Doctor. Michels.

So Jack, that's really mean of you to make me start because I don't know that there's an easy answer. Think it's depending on the patient, it's a bit of all of these things. And I think the audience is right kind of across the board. Little anecdote, little from the stopgout study we mentioned earlier, we did a follow-up of that study to see, you know, after patients had got through the study, do they stay on urate lowering therapy after having a successful outcome in the seventy two week trial? We followed patients out two years and a full third of the patients are off ULT within two years.

And when you look at factors that drive that, there are what I think are main kind of socioeconomic factors. But one of the important things was the strongest predictor of adherence or continued use of, ULT was seeing a rheumatologist. And I think what's different in rheumatology, I'm guessing a little bit, but I think what's different is we are seeing patients for their gout. We're concentrating on that as the problem in hand. And our patients, when they see a primary care doctor, they're seeing them for a myriad of issues.

And I think it's, I think gout gets lost in the shuffle a little bit, maybe not surprisingly. So I think if we could emulate sort of what happens in a rheumatology clinic in practice, because I'm pretty sure we can't see all the gout in the world, as you mentioned, fifty five million patients. But I think if we could emulate what's happening in rheumatology clinics clinics in primary care through the use of maybe nurse run clinics or pharmacist run clinics, could go a long way. But we can't do that probably everywhere either.

Angela, how do you handle noncompliance in your setting?

Well, was very pleased by these answers. I think most of them are correct. But I think the issue of education is fundamental. I think a lot of the gout noncompliance or adherence confusion comes stems from the fact that that many patients do not understand what the medicines do. They do not understand what medicine is for lowering your rate.

They don't understand what medicine is for prophylaxis, for flares. And and there is a misconception about gout how gout happens. There continues to be a misconception that diet is that diet is the primary and fundamental factor. There there continues to be a misconception that that it's a disease associated with behaviors and habits that we know it can be in a small proportion of cases, but most patients have factors that include genetics and comorbidities that they have no control on. Once a little bit of the shame is removed and there is a clear explanation of how this happened to you and how the medicines work and what's the role of each medicine, I think that that anchors the message better.

I also have a feeling that a pill burden is important in many patients. I try to avoid complicated dosing and get trying to get them to target also is another factor like it trying to get into target soon quickly tends to be associated with a reduction of flares sooner and better experience long term and hopefully better adherence and then having more trust on you. So those are my kind of my little pearls.

Lisa, do you do something different in your clinic?

Yeah, well, I think this is really interesting, these are the key things I would pick out. But I agree with Ted. There are so many systemic barriers to patients getting access to seeing a physician, to seeing their GP, to getting their medicines. You mentioned jacket. This is a disease of young men.

They're usually working. Getting time off work, at least here, they're often in manual or labour type jobs means they lose income. One of the things New Zealand has done recently, we've gone to twelve month prescribing. So if the practitioner feels it's safe and appropriate to do so, we can prescribe twelve months worth of medication. For me, allopurinol is a ideal candidate.

We've got one somebody who's on a stable on allopurinol doing well at Target. Why not give them twelve months worth of drug? You know, they're more likely to be adherent if they don't repeatedly have to be going to a doctor. Certainly for those who aren't at Target, it's a different story. It's going to be interesting to see for us if this improves long term adherence for patients who are at Target having twelve month prescribing.

Michael, I'm going to give you a difficult question because you've had two easy so far. And that is there's 55,000,000 worldwide, there's twelve point one million in The United States who have gout and only one point three percent are seen by rheumatologists. Yet we're all calling for education as a big issue. Who's going to do this education? It certainly isn't going to be primary care who's carrying the bulk of the heavy lifting here, and it's even difficult in rheumatology practices.

Yeah, well, certainly, first of all, Jack, I think you're right. I think one can only hope that things like this that we're doing here right now might sway a few people, who might sway a few people. Ted talked about nurse run clinics and pharmacist run clinics, and those have genuinely shown to be a potentially enormous value and might be more doable than asking our very busy primary care friends to do this. But I have another evil player here in terms of education. And I hope they'll forgive me because they're nice people, but there's also the American College of Physicians.

And I wanna take some exception here. I am a card carrying member of the American College of Physicians, but for those of you who don't know, about seven years ago now, the ACP came out with explicit recommendations that they do not support urate lowering as a routine matter in gout patients. And so that trickles down into the primary care world. We have to ask, well, why did why on earth did they say that? We are all sitting here saying we know exactly what to do.

Well, they're they're not stupid people. They they had a few points that they made that I think most of us would disagree with. One was that oftentimes their patients may be, not quite as sick with their gout, and they were completely focused on flares. And frankly, we're probably focused on the larger cardiometabolic pictures. We think we're treating gout not just as an occasional swollen toe, but as a chronic disease.

So I think that's one difference. But but they made a methodologic case, which was that we didn't have the data. We didn't have prospective studies to prove to them what we knew biologically and by experience, which is that urate lowering makes flares go away and, makes TOFI go away and gets people better. So, there's a large, American study going on right now, the TRUST study, that's basically been created to generate that data. There's another European study that just published that shows that treating to target does indeed work better than not treating to target.

But I think until we can clear the area and get that kind of miasma out from the primary care clinics, out from the nurse practitioner clinics, we're going to be fighting this over and over again. So it's not just patient education, it's also physician education.

We have been talking as a group of us who've been developing the content and curriculum for this month have been talking about goals that we should have this month. I think a goal that we could do for this month would be to make a proposal that every academic center, every teaching hospital have a nurse or pharmacist run gout clinic that everybody refers to, that's managed by protocol. And the protocol, can provide a national protocol. I mean, certainly there are guidelines to do that, and they can be modified locally depending on whether the renal person or the rheumatologist person or, the chief of medicine wants to manage that. And with that, again, more people would do better, more people would be a target and whatnot.

That's clearly the benefit of this. But let's talk about your rate lowering therapy and, questions that we gave. Lisa, we alluded to, your involvement in, the start low, go slow approach to allopurinol dosing. And when we asked the audience your starting dose, eighty seven percent said one hundred milligrams. There's a few, nut jobs out there that are starting at three hundred milligrams, that looks like it's about four percent.

Five percent saying, it's fifty milligrams, they're very conservative and maybe about six percent or so who are unwilling to commit and want to say it has to be individualized. So this is evidence that your education, teaching and research has not been for naught, Lisa.

Yeah, I mean my heart spins around this one. It's great to see that you know, that that most people are saying a 100. Sad to see some people still say 50. But, you know, where I would answer is in the orange, which is it must be individualized. And it flips for me between the 150 depending on their GFR.

So I think it's really good that we've got away from everyone starting at this high dose. But one hundred milligrams is not my go to starting dose. It must be individualized depending on GFR.

Okay, I think that's a smart point. Then, there anybody definitely, can start with three hundred or that's really a no no?

I don't think anybody should be started on three hundred. Although you look at some of the other cardiovascular trials, they start people on three hundred. Out there do do it, but I think from the point of view of gout, we're far better off to start lower. Might produce less flares if we start lower. I think if we can engage the patients, we can get them through that difficult period of starting, where they have lots of flares.

But I fully accept that the titration protocol is hard work. It's hard work for the patients, it's hard work for their healthcare team. So this is not easy.

So that brings the next question is, what's the protocol for going from one hundred up to your target dose? When titrating the dose, how often can you increase the dose? Seventy two percent said monthly, eighteen point five percent said weekly, five percent said it's gotta be based on what the last measure was, I'm sorry, based on absence or presence of flares. And very few, about four percent wanna wait for the creatinine to come in. I believe, Lisa, the package insert or according to FDA that you can make dose adjustments weekly, but that's not always what guidelines say.

What should be the rule here?

Doctor. So we say monthly, all our dose titration studies have been based on monthly. The presence absence of gout flares brings huge confounders. We know that the dose increases can be associated with flare. If you're going to keep increasing based on flare, you might end up going up and up unnecessarily.

Absence of FLAIR's, well, they might still have a urate of 0.4 or 0.5 and have an absence of FLAIR's, but in the long term, they will get FLAIR's back. So I don't see presence or absence of FLAIR's as any indicator. The indicator is have they achieved target serum urate. Creatinine is all over the place. Creatinines go up and down like a lemon yo yo, particularly in our patients who have got multi comorbidities.

I'm not too worried about whether the creatinine's wobbling around and absolutely go for monthly.

I think, Jack, that the weekly recommendation is, if I'm correct, is strictly based on the question of how how quickly can you see the net result of the dose change, which may not be how quickly you wanna make the next dose change. But after somewhere between a week and, you know, ten days, you've probably seen the effect on the urate. I think that's where that came from.

Angela, what do you think about the dosing and whatnot? Do you have any different approach?

Well, usually I'm somewhere in between. I usually adjust allopurinol, the protocol we have that we are running within our VA, that is a nurse practitionerpharmacist based clinic. Do those adjustments every two to four weeks. We try to align those rechecks in urate and labs with other visits that the patient may be having in the center to simplify their lives. But they are going end this probably against weekly, as Michael said, that the number of half lives that allopurinol needs to go through to get to a steady state is not there in one week.

So if you want to make a decision based on efficacy of where you want it to have been, it's a you may not see that final result in one week, you need to wait at least two weeks for that. And my concern, you can do it every month. It will if you have someone who needs like like three or four steps of of those adjustments to get there, you're talking about four months. I I try to I like to cycle it a little faster. Now that's always needs to be kind of check against the realities of the patient.

Where do they leave? How often can they come for labs? Telemedicine and virtual clinics kind of they lend themselves very well for these. We have a very active telemedicine operation in our VA where patients in the local clinics, we can have labs and new rates check very often and do those adjustments. So we try to get to target as soon as we can when they are in prophylaxis.

If cannot take prophylaxis, I know that your next questions, I think we'll come to that. You may want to be a little bit more conservative with those increases because again, adjustments can lead to more flares. If you cannot prophylax well, you may need to adjust to that reality. But in a patient will prophylax, I like to increase it about every two to four weeks, two weeks if possible.

Ted, you can address this issue of dosing and changing dosing, but we also have a question, is it once someone goes on either for fluxistat or allopurinol, should it be for life or when do you stop?

I think for the vast majority of patients, it's an indefinite therapy. Mean, and that's something you talk to people about. There have been studies where, taking patients very well controlled, at goal, have not had flares for a period of time, they've withdrawn therapy, and over follow-up, a significant portion of those patients redevelop gout flares. And had they followed those patients up longer, the rates would have been higher. So I think unless there's been a major physiologic change, a patient has a new kidney or something major has happened, for the vast majority of patients, I believe it's gonna be a lifelong therapy.

Yeah, and to go to Angela's point, when I was looking this up as I was writing a question, a lot of guidelines say you can change every two to four weeks. I also like the one month because it seems to coincide with either visits or repeat labs and whatnot. One more issue on, allopurinol, B5801 is linked to the hypersensitivity reaction with allopurinol that can be quite severe. Obviously, it's a big issue in Southeast Asian, Han Chinese, Vietnamese, etcetera. The audience said 40% Asians, 30% say I don't do it.

Only a few are doing this in African Americans exclusively, and 5.4% say they seldom do it, 22% say it's, Asians and African Americans. Michael, does it sit well with you?

It could sit better. So first of all, what does HLA B5801 testing tell us? Well, it raises the relative risk of an allopurinol hypersensitivity reaction by something like REDI 250 to 500 fold compared to patients who don't have 5,801. It's huge. Why aren't we seeing everybody getting hypersensitivity reactions in?

Because it's very rare and because five thousand eight hundred one is not an absolute risk factor either. And I've had a few people on allopurinol who've come in after years and something compelled me to check their 5801 and it was positive and I kept them on the allopurinol because they were they were just fine. But I think that, it gives one the opportunity to risk reduce. ACR guidelines suggest that this should be done in south those Southeast Asian patients you mentioned and in African American patients. Why does this HLA type not convey risk in other groups?

It probably does, but it's quite rare in other groups. It's about ten percent prevalence in the Asian patients, about four percent prevalence in the African American patients. More recently, South Asian patients have been shown to be somewhere in between there. And ACR guidelines kind of reflect that the risk benefit there is these are people who have a pretty good chance of having it. And given that we have alternative therapies, like febuzostat, we're not committed to allopurinol.

And I generally will test these groups, and I generally will not use allopurinol if I have a positive patient. I just don't see any reason why I need to. So I think some people are missing a bet on, how to make their patients a little bit a little bit safer. And again, this is an exceedingly rare phenomenon, but catastrophic when it happens. So why not avoid it for the cost of a lab test as far as I'm concerned?

So if Doctor. Stabb had a really good arm, she could throw a rock and hit Southeast Asia. I'm thinking this might be a bigger issue for her. How do you handle it, Lisa?

Yeah, I definitely do it in my patients from Southeast Asia. If it's positive, I don't use allopurinol. We've got an alternative, got probenecid, we've got febuxostat. I definitely do it. I've seen one case of allopurinol hypersensitivity syndrome, and I'd like to avoid seeing another in my practicing lifetime if I can.

I've seen two deaths, Lisa. Yeah. That I had nothing to do with, but that I helped pick up the pieces on it. They were completely avoidable, if I can, you know, tell the story because I think about you all the time in this case. A patient who did not have five eight zero one testing who was Southeast Asian who also had renal disease and was not titrated and was started on March and then was not closely followed up by their doctor.

And by the time they came came in, they already had a desquamating rash, and it was just a terrible avoidable thing.

So Angelo and Ted, is this an issue testing or not testing in your African American patients? I know we probably should be doing it. I think it's often not done.

I I have conflicted feelings about this and and the and when this conditional recommendation by the American College of Rheumatology was proposed about testing among people of African American descent. My mind immediately went into two things. This is going to be a barrier. And second, patients with gout of African American descent already get terrible gout care. And this is going to impose another reason to be fearful to treat these patients well.

And I'm already seeing that that there we have seen a couple of times, multiple times that there are not enough of us. Most of these patients live in primary care and and and many times a primary care doctors do not understand what this genetic test is or means or how to order it or how to really how to interpret what to do with it. And the end result is the patient is in subtreated with nothing. So a now I can tell you my anecdotal experience of a allopurinol hypersensitivity living in Birmingham, Alabama, where thirty percent of the population is of African American descent. I've seen one case in twenty five years.

So I know that there is a well conducted epidemiological data that supports a notion that is is is frequent among people of among African Americans. Me rephrase that, that is more frequent. That will support the screening, but I I'm still kind of conflicted because I feel that is a barrier and that many patients end up not being treated. And I'm sure there are other opinions here in the panel. But but that's how I feel.

I don't check it. I check it in people of Southeast Asian descent that there are not very many where I live. But but I personally don't feel that I have to check it among people of African American descent.

Angela, I'll stand on my statement, but I completely appreciate what you're saying. And I would I would just comment that for those of us who don't think twice about febuzostat, it's also a little easier because we expect that we have already alternative. But for physicians who are afraid of febuzostat, now we've made them afraid of of both agents. And then there's the ACR guideline that says start urate lowering in the middle of a flare to try to improve compliance. You cannot do that if you need to order this test, which is going to take you some days to come back.

So that's another potential barrier. So everything you say is correct.

Yeah. Ted, how do you handle this?

Well, I mean, again, I think it's individualized per patient. I don't disagree with what Angela said. And, you know, it is, I would point out, and Angela pointed out, it is a conditional recommendation. It's a weak recommendation from the ACR. It's not a strong recommendation.

And I think that was based, as I recall some of the conversations with the guidelines, there was a lot of talk around cost effectiveness of that approach in terms of prevention, given its low frequency and the testing involved. And so I think when you start to stack risk factors up, patient has CKD, are female, and I'm trying to think some of the other different risk factors for, AHS, then you really start to think about it. And one of the other considerations we haven't talked about is, is this a genetic test? And genetic tests aren't cheap. And so if you have a patient, which I certainly take care of, who's self pay, who's, paying for these things, this can be quite expensive.

And that's part of the conversation. And does it offset costs of febucestat, you know, if they're negative? So I think Angela has

a very, very good point. Yeah, I work in a charity clinic where they can't afford the genetic testing and it's not, if even it could, it's not easily obtained and, had to deal with this with a recent African American gentleman. We went ahead with low dosing and slow titration, and that all was good. So let's get into, colchicine issues, which there are a number of questions that I want to cover with the panel. What's the preferred prophylaxis when starting urate lowering therapy?

Ninety percent said colchicine, only about three percent said I don't use, prophylaxis with ULT. A few people prefer steroids and this is like one, two percent prefer an steroidal or prefer prednisone. Anybody surprised by these results?

I'm sort of pleased by them, although I really would like to hear from Lisa because she's got interesting things to say about colchicine. But I think the main thing is all of these agents work, they're effective. And so the best choice is the one that's the least, if one is prophylaxing, the best choice is the one that is the least likely to have adverse effects. I'll go out on the colchicine limb for most patients on that, but other people may not agree with me. But I think Lisa's made the case that maybe we don't always need to do this.

Go ahead, Lisa.

Certainly colchicine in the group of patients who you feel comfortable giving colchicine to would be my preferred choice. The problem is that the group of patients that I see, and a lot of us see particularly with CKD or hypertension, ischemic heart disease, we don't want to use colchicine and we don't want to use an NSAID. So we often end up with prednisone. So specifically with colchicine, you know, I'm pretty pragmatic when it comes to it. I know the data.

I know the guidelines, but, you know, there are some people who are on so many medications. I'm just like, do you wanna see how this goes? And then start prophylaxis if you're having a lot of flares. Or we can give you extra medication and you can and most people opt for a watch and wait and see approach. And I think it was pretty much the same in the the DOETE study.

There are very few patients opted for prophylaxis. And then, obviously, specifically with colchicine, we saw the rise in flares after discontinuing six months of colchicine prophylaxis, which you didn't see in the patients who had had placebo. So it seemed like you could either opt to heavy flares early or you could opt to have your flares late. I have those discussions with patients and decide whether they want to use prophylaxis or not. If they do and they can take Copticene, that's what I would opt for.

So it's clear from the data research that looks at this that prophylaxis dramatically lowers flares. But I remember in the early trials, the very first trials with febuxostat that Michael Becker authored, I remember the graph that showed in the first six months, all these flares. I mean, and everybody was on prophylaxis.

No, Jack, actually, love that graph. They ran the colchicine for four weeks and then they stopped it. And when they did, the flares exploded. Yes. So I think now remember also that the dosing in that study, I'm sorry for the audience, it was not titrated.

So allopurinol started at three hundred, and febuxostat, I think, was at eighty and a 120. So it was not gently those drugs were not gently titrated. These patients' urates were plummeting, and there were crystals probably sloughing off, you could hear them. And as soon as the colchicine was removed, you saw that curve that you remember.

Yeah, that's a really very important point. Let's get a next step in urate lowering therapy. A little fastenoma here. The toxicity of colchicine rises with which drug class? Sixty one percent said statins being the correct answer.

ACE inhibitors nineteen, PPIs eleven, nine percent of beta blockers. Those have more problems with the use of colchicine. Have any of you encountered problems with colchicine and statin use?

I'll take this one. This is a little bit of a pet peeve of mine, Jack, I have some of those. And one of them is phone calls from pharmacists telling me that I absolutely can't use colchicine in a patient on a statin. So one of the trials I like to show people is I believe it was the Colchicine. Michael can probably correct me if I'm wrong, in the Colchicine, which is use of colchicine and prevention of cardiovascular events, non gout population generally,

you

know, the same dose that we use in prophylaxis, the risk among people with high intensity statins, not just average statins, high intensity statins, was quite low for muscular neuromuscular toxicity. There was one case of rhabdo in the placebo group and one case of rhabdo in the colchicine group. You know, so I think I think this risk is, I get it, but it's way overblown. And for the vast majority of patients, colchicine prophylaxis is very safe, particularly if they have normal renal function, etcetera.

Ted, exactly the same results were seen in the other large cardiac colchicine trials. The Lodoco two trial, they didn't have a single rhabdo. So we're up to about nine thousand patients in that. I think one of the legitimate concerns and one of the historical case studies is the fact that some statins are metabolized by the same CYP3A4 enzyme as colchicine. And so colchicine is usually adjusted for drugs that go through that enzyme.

Nonetheless, in those studies, there was no event. I think I've seen one case. I would add that we, and with no great evidence, but just sort of it makes us feel better. Whenever we start colchicine, if the cardiologist will let us, we just switch people to rosuvastatin because they don't interact. And I thought that was really, really smart.

So I spoke to, Mark Neidorff who did the Lodoco trial, and he looked in all of his data and not just from the Lodoco study, and he said, I've seen one case and it was a patient who was getting rosuvastatin, not atorvastatin. There is one last fact that I'd like to say, I'm sorry to be talking so much, but which is that Ted underlined the dose that we use, and there's a history here of doses much higher than we use. We use typically, you know, zero point six or one point two milligrams a day. But back in the old days, we used six milligrams for a gout flare, or we gave a gram of colchicine intravenously and, did that twice a day. These were really high overdoses where interactions with other drugs were more likely.

So I think we're carrying a lot of history here of legitimate problems that don't happen the way we use colchicine now or least are exceedingly rare.

So, when we were preparing for this, this question came up, it's a management issue. We said that you don't necessarily need to dose adjust allopurinol in the face of CKD, but there's a big issue with colchicine and CKD. In this question, a patient with an EGFR, forty five ccs, what dose of colchicine would you use? And forty two percent chose, the half dose of zero point three milligrams. Only, twenty nine percent chose six point six QD or BID, twenty percent said no adjustment is needed and nine percent thought colchicine is contraindicated.

Lisa, we're all over the road on this one. We must be drinking. What's the right answer?

Oh, look, I've been swings and roundabouts on this. Mean, I guess my problem is that I think colchicine is quite a dirty drug. And by that, I mean, there's a very fine limit between therapeutic and toxicity. And I'm not gonna answer your question directly at the stage, Jack. I'm gonna circle back to where we started with what drug has the greatest toxicity.

And I think Michael's comment about how you view that is really interesting because colchicine, if you take too much, you die. And there's nothing anybody can do about it. I mean, this is a really toxic drug. And, know, a lot of people overdose on colchicine and die. Most of that is unintentional.

Some of it is because they haven't followed the plans that we give them. And if you hark back to the days when it was, what, take it every hour until you get diarrhea or your gout flares, well, we had people die using that regime. So so so this is quite a toxic drug. Having said that, I don't think it's contraindicated. So I disagree with that.

I would probably use zero point six qid or bd at that level. Once we're getting below thirty, I would be dose reducing.

Right, at zero point three. And that's kind of what the recommended guidelines are. For prophylaxis, does anybody recommend a question from the audience, five milligrams of prednisone Monday, Wednesday, Friday, would that be reasonable or is that more wishful than reasonable? Angela, what do you think?

I think it

your could last resort of prophylaxis in someone who has advanced CKD and other comorbidities. Now it's also difficult. Some you have a brittle diabetic or somebody who's very sensitive to the fluid retention of prednisone. You know, usually five milligrams three times a week should not alter your blood sugar or your fluid too much. But but but but yeah, you could use it.

Something that I personally use with some frequency because I have a lot of veterans with these scenarios of advancing KD and brittle diabetics and and cardiovascular diseases and akinra. I use IL-one inhibitors for prophylaxis. You can get actually what we have it available in the VA upon request, but but you can also get one month of of an Akhinra, I think for free from the company and use it every other day. And then you have two months of prophylaxis. Those are a few kind of we're getting ahead on the perils, but that's something that I personally like using in patients that have these scenarios of a heavy burden of comorbidities and you need prophylaxis to accompany the UOP.

We'll talk next week about canakinumab and how it's to be used. We talk about advanced therapies. I want to remind our audience that, next week we will, have advanced therapies, where our panelists are going to be, Herb Barath, Ken Sag, and Naomi Schlesinger, we'll be talking about biologics, uricase drugs, cytokine inhibitors. It should be a really interesting session. That's next week on Tuesday at Rheumatology.

But I want to end by asking each of our panelists to close by giving us a pearl that you often give to your rheumatology colleagues when teaching that, they find useful. And I'm gonna, begin with Michael, then Angelo, then Ted, and we'll end with Lisa. So Michael, do you have a pearl that you can share?

I do. I don't know if this is evidence based and I'm a big believer in the cardiovascular value of colchicine. But before I say this, I wanna underline that Lisa is a 100 right. I think this is a very safe drug at the low doses. It's a real problem with overdoses.

It isn't dialyzable for one thing. We don't have like a DigiBind equivalent, but here's my pearl. In my patients with frequent flares or with cardiovascular risk, I continue the colchicine significantly longer, sometimes as often as a year at a low dose.

Excellent. Very good.

Angelo. I always tell my fellows think about the number of pills and the pill burden. For example, don't use five hundred milligrams of allopurinol. That's a pill of three hundred plus two of of one hundred or five pills of one hundred. Don't do that.

You know, think about one or two pills. You know, one hundred, two hundred, three hundred comes as a single pill, four hundred is one 300 and one 100, then you jump to 600. So think about always how many pills the patient has to put in their mouths. And because that's a big component to non adherence.

Excellent. Ted?

Yeah, I'll just follow-up on that. So dosing allopurinol can be tricky just because of the one hundred milligram increments we talk about, and they only make it in one hundred and three hundred milligram pill sizes. In the Stop Gout study, the VA actually manufactured a four hundred milligram pill and it made our life a whole lot easier in that study. And so I wish someone would do that. I'll just build on what Michael said earlier.

The average dose, the median dose of allopurinol that's needed is four hundred milligrams. For about a third of patients in the stopgout study, they require 500 or higher. And so I wish allopurinol came in a dosing pack, that we could just titrate people up. One hundred milligrams in our experience, nobody gets to urate goal. And so you don't necessarily have to stop at one hundred and recheck the uric acid level.

I think you can often sort of titrate people up, slowly, as has been mentioned, repeatedly, and then at two three hundred milligrams, repeat a uric acid, and then go from there.

And doctor Stam.

I might have two pearls. My first pearl is think about the flare, because these patients will flare and they need a flare plan, and they need a supply of their flare medication at home so that they can start to self manage. You know, there's very few conditions we treat where we have the potential to make it worse before we make it better. And so we need to be actively planning with the patients for that. And I think I've forgotten what my second pill was now.

So you talked about the flare, it wasn't going to be on colchicine, it was going be about allopurinol or CKD?

No, it might have been about colchicine. So the other thing I do with colchicine is I always insist on childproof packaging because colchicine, at least in New Zealand, comes as a bottle. It doesn't have to have a childproof lock on it. And given the toxicity, then I always I always, insist that they have childproof packaging just to try and reduce, the risks. Because if you've seen a teenager who's broken up with their boyfriend and decided to take an overdose and they get dad's colchicine and die, it's pretty tragic.

So it is really toxic.

Yeah, there's a literature out there about people using colchicine as a weapon for nefarious reasons. So I think all the discussion today about the potential hazards of colchicine are real. Other comment?

There was somebody who killed their wife using colchicine or a husband, I think, recently in The US.

But it wasn't a rheumatologist. I want you to know that. It was a

problem, wasn't it?

Okay, well, I want to thank our panel for a truly, wonderful discussion. This has got great instructional value for all of us. And I want to remind our audience to please, be on hand next Tuesday in our last session, where we will talk about, the use of new and advanced therapies in treating gout. Thank you everyone. Have a good evening.