QD Clinic: Management of Uncontrolled Gout Save

Hello there. This is Derek Mueller, physician assistant. I'm here on behalf of RheumNow — RheumNow QD Clinic. Today's case is titled Tophi Tales, management of uncontrolled gout. Again, my name is Derek Mueller, PA from St. Clair Shores, Michigan, and I'm joined by my colleague, my boss, my mentor, Dr. Andrew Sulich. Thanks for coming on.

Thanks, Derek. It's a pleasure to be here.

Excellent. So we're just going to jump right into our case today. I'm going to introduce a patient here and we're going to discuss the case and do a little back and forth. So our patient here is Topher. He's a 52-year-old Asian American male. He has a past medical history of hypertension, obesity, hyperlipidemia, type 2 diabetes, CKD stage three, and he was referred to the rheumatology clinic for uncontrolled gout.

Regarding his history of gout, his first attack occurred approximately 12 years prior with a typical episode of acute podagra involving the first MTP joint. Initially his flares were self-limiting for several years, but over time his disease progressed in terms of the severity, the duration, the frequency, as well as the distribution of his acute gout flares, with subsequent involvement of various joints including midfoot joints, ankle, and even his knee joints. His previous flares were largely managed through urgent care visits either with temporary prescriptions for colchicine or oral steroids.

He does see his primary care doctor about every six months for chronic care management, and in those visits he has been prescribed allopurinol. 200 milligrams daily has been his coasting dose for the last 5 years. Two weeks prior to his rheumatology consultation he was actually hospitalized for severe atraumatic pain and swelling of his left ankle. Synovial fluid studies obtained at the time were consistent with an acute gout flare and he received an intraarticular steroid injection and was discharged after septic arthritis was ruled out. After that hospitalization he had a follow-up with his primary care doctor and they increased his allopurinol dose to 300 milligrams.

When we're reviewing his records at the time of his consult, we don't really see serial uric acid monitoring, but we do see a recent value of 9.3 milligrams per deciliter right before the allopurinol dose increase.

So regarding this case, we're going to stop there and I'm just going to ask Dr. Sulich some questions. In your experience, this looks like a patient with pretty severe gout coming to a rheumatologist. What are the types of gout patients that you historically see referred to a rheumatology clinic?

They look like this. Unfortunately, these patients get to this degree and that's how they're referred to the rheumatology clinic. I think primary care is swamped. They have a lot of demands upon them, but they tend to look at gout as a situational problem when people have flares. In this patient, he has flares, but no one's really managing his gout. Because the argument here is to say: is this man uncontrolled or is he poorly controlled? The reason I say poorly controlled is because you see he's got an allopurinol treatment of, let's say, 300 milligrams, he's got a uric acid of 9.3, so he has not been really aggressively treated, and now he's developing tophi, he's getting complications. That leads to refractory — when we talk about when patients have a uric acid greater than six or they've had two or more flares per year.

I think the challenge here, Derek, is you see these patients all the time. I remember when you first came to our office, you had your gout campaign to get people to come to our office and it was very well done. I noticed you picked taverns to recruit patients and that was obviously very successful. So I think what happens here is this patient could have been managed probably earlier before he starts developing these complications.

Mhm. So speaking of that, are there any specific pitfalls in either this case or other cases — specific reasons why gout may not be managed optimally?

Well, a couple of reasons. Interesting — I love his name, Topher. What a great name. So Topher here, he is an Asian patient, originally from China. We find that with our Filipino patients, our Chinese patients, or Asian patients, the western diet is not very friendly to them. So they tend to have much more problems — less alcohol issues but more problems with dietary issues. He's got type 2 diabetes, he's got hyperlipidemia, and now he's developed stage three kidney disease. So he's got comorbidities that are really contributing and fueling this process as well.
as he's not being treated effectively with just 300 milligrams of allopurinol. So I think that's the first case. I think when we talk about — we talked this off air and we'd mentioned about the fact that he's of Chinese ancestry so to speak — you know, the HLA B-58. So we have to be careful because as we increase his allopurinol, or even start allopurinol, they have more predilection to having toxicity. So one of the things for the audience is, if you have someone who's African-American or who is of Chinese extraction, you've got to think about the possibility of allopurinol toxicity. Fortunately, this man has not had this, but you had a case — remember recently we saw where the patient's eosinophilia was climbing as we were increasing his allopurinol. You caught that. And so, obviously, that's one of the reasons why you have to be cautious about when you use allopurinol.

The other thing to think about is his comorbidities. He's got some nice medications on. He's on a GLP-1 agonist. So that's interesting because now we're starting to use more of them. They do lower uric acid. They do lower weight. They do lower — I'm sorry — they do lower the insulin levels and blood sugar. So that's a good thing, but it's not a treatment for gout. So I think the challenge here is going to be: what are we going to do with this man? He's had recurrent flares and he's been exposed to multiple steroid use. We don't know if he has destructive arthropathy. We know he's got — so most likely some would argue — you know, all tophaceous, but now we're seeing visible masses that are present, and so he's got a substantial uric acid burden.

Absolutely. And do you have any comments on serum uric acid monitoring? It feels to me it's almost all over the map before a patient gets to us. So what's your experience with that?

Right. So the first mistake that we commonly see with serum uric acid monitoring is when we see he's in the emergency room, correct? He's having a flare and suddenly the uric acid may be lower — it may be less than six. And so you get the call from the ER doc who says, "Hey, his uric acid is normal. He's got a swollen ankle. Let's admit him to the hospital. He must have septic arthritis." Well, with type 2 diabetes, we've got to be cautious about that. But quite frankly, during flares we typically see a lowering of the uric acid. Now he is so high it's most likely that even if he has a uric acid of eight, he probably has 11.0 when he's not having a flare. So I think that's number one — we have to consider the fact that he's got tophaceous disease and has a substantial joint burden. That tells me again his uric acid is going to be all over the map. But our goal here really is to treat to target, and for a typical gout patient we're going to go lower than six, right? That's our goal — to lower that. It is going to have to be substantially lower because of the tophaceous burden.

Absolutely. And I'm just going to continue the case and I'll do the next part of it if that's okay. So, just as we mentioned, we're going to give you the exam findings on this gentleman here. On examination, this patient had deformities of both of his first MTP joints and he had marble- to golf ball-sized tophi involving both of his feet. He also had about golf ball-sized tophi involving the extensor surfaces of his elbows and even little BB-sized tophi involving his external ears. Otherwise the examination is unremarkable.

Some plain films of his feet revealed erosive changes involving the first MTP joints and midfoot joints bilaterally. Further questioning about his frequency of gout flares — he has about five to six flares annually in the last two years, and this has even affected his career as a culinary school instructor, having missed several weeks of work in the year alone. And again we have a uric acid of 9.3 on this gentleman. The previous baseline that we have is 12.8 from a few years ago. He's got a GFR of 50. His LFTs are normal. He's got an A1C of 8%, a recent CRP of 17 milligrams per liter. And we've got some labs from the primary office — an ANA, rheumatoid factor, and CCP, all negative.

And then his medications, as we mentioned, the allopurinol — looking at his other chronic medical conditions, he's managed with amlodipine, a statin for hyperlipidemia. This gentleman is also on a GLP-1 drug as well as some — a semaglutide. So, jumping off from this point, this is a gentleman who clearly needs a change in his treatment. We're just now going to think about what kind of treatment options can be considered for this patient. What are some thoughts from your perspective?

Well, the one thing you can step back — we know he's got destructive arthropathy, so we can see it by X-ray. We know he's got the tophi, which you've determined are golf ball-sized. I mean, you can call him a tophaceous kind of
kind of tophi. He's got pretty significant involvement. So we think about uric acid pool in this patient's body as pretty substantially high burden. So we have a couple options. One, you can try to treat him conservatively by increasing his allopurinol or changing him over to febuxostat, which is another option to treat. But remember, he's being — he's being debilitated by this disease. And so it may take you months to years to be able to turn this around. In the meantime, he's flaring. So you've got to control the flares and you've got to be able to lower uric acid substantially.

So one of the options obviously is a pegloticase-type option to treat this patient. Certainly he does fit the bill in terms of — by definition — that he would be a candidate for this, and as long as there's no contraindications we can proceed and treat him accordingly along that route. So I think you need to present him both options, and then your recommendation. So what would your recommendation be, Derek? I mean, if you have an option — because some people want to be taking conservative medications — and something you have to be able to tell them is the good and the bad about proceeding along these lines.

Yeah. I think in this case it's really putting our best foot forward and managing aggressively with pegloticase. I think that's going to result in the most rapid resolution of burden. You know, this is severely impacting his way of life. So I think that makes sense to be aggressive. Certainly he seems like he's medically stable. There's no contraindications that we're aware of at this point. We'll have to of course screen him for G6PD deficiency and whatnot, but medically there's nothing that would argue against him being a great candidate for pegloticase therapy.

And I do also agree that in some instances the conservative approach with escalation and titration of oral urate-lowering therapy makes sense in the right patient as well. If somebody has less frequent or severe flares and they're also prescribed concomitant flare prophylaxis — which this patient currently is not — that might be a big hole in his management right now too. But in some instances that would certainly be reasonable as well. And you can really slice it both ways. But I think this does seem like a pegloticase candidate to me.

And I would agree, because if you do a check on these patients to realize that from a functional perspective — he says he's a chef, he can't stand, he can't work — then we have to consider the possibility that he doesn't have the luxury of time. Absolutely.

Okay. So based on our decision, this is a patient who we would transition to uricase therapy with pegloticase. We did a baseline G6PD enzyme assay which was within normal limits. Thankfully pegloticase in this instance is approved by his insurance company, which can certainly be a difficulty in some patients, and maybe we can elaborate on that. And in his situation he has a first infusion date that's scheduled out for a month. So essentially what are the things that we have to do to prepare this gentleman for pegloticase therapy in terms of his existing medications, and what else do we have to counsel him on?

So the first thing you do — most insurance companies will look at this with a fine-tooth comb because pegloticase therapy is expensive. That's one of the reasons why it's sometimes difficult to get utilized in our patients. So the first thing you have to do is document things carefully. Document why patients have failed other lines of therapy. Your insurance company may say, "Hey, we want him on febuxostat first and we're going to try him on optimal doses of allopurinol." So in this particular case, you may make the argument he's got renal insufficiency and most likely he's not going to respond. Or you may not want to use febuxostat in this case, but you have to make a defensive case and you have to document it.

The second thing is where I've gotten hung up sometimes — diet. I don't think we put enough emphasis on it. If we put this patient on a restrictive diet, yes, it may help him, but do you think it's going to stop his tophi or is it going to drop his uric acid substantially? Probably not. But that should be documented in the chart. So you want to put down the fact that you've tried to counsel a patient on a urate-lowering therapy diet. And for those of you who have never seen a urate-lowering therapy diet, it's literally unpalatable in my opinion, and I think if you want to really torture a patient, put them on a gout diet. But in this particular situation, I think that has to be
documented in your record. Finally, if you're going to go on pegloticase and once you make that commitment, what's one of the biggest challenges that we have with pegloticase at this particular time is immunogenicity. So, I'm going to let you take off and say, okay, what are we going to do in this patient to prevent — and because patients have to understand it's not just hooking them up to an IV and treating them. You're going to have to stop their obviously their allopurinol and urate lowering therapy. And again, I'm going to let you elaborate why that's the case. And number two, what do we do to prevent a patient from getting antigenicity?

Absolutely. So, we do know that what plagued Krystexxa in the past was the failure rates because of antibody formation and anaphylactic reactions. This was a big barrier to success for years. And then not too long ago we do have excellent data showing that methotrexate improves the treatment success rate of those treated with pegloticase in the long term, far greater than without any sort of immunomodulation. So methotrexate is primarily what has been studied and is in the FDA labeling for concomitant use. And this is a relatively, you know, a dose that we're all comfortable with — 15 milligrams once a week with folate supplementation — and this is something that's recommended to be started approximately a month prior to the first infusion of pegloticase. So initially there's no contraindication to methotrexate. We're going to get this going before the infusion. We're going to monitor them for side effects or toxicity before the infusion and during. And certainly what we're going to see as the patient is treated with pegloticase and concomitant methotrexate — we're typically going to see that serum uric acid decrease very substantially. And as a surrogate marker for immunogenicity we're going to hopefully see that serum uric acid level maintain, and if there is a sequential increase over time with multiple values, especially above 6.0 milligrams per deciliter, that's when we get worried about immunogenicity and potential anaphylaxis and treatment failure. So this is where methotrexate really reduces the chance of that going on.

What if — the situation where you put him on methotrexate and — remember he's got renal insufficiency so we got to be careful here. There are other options too. Some people use CellCept, or MMF. The problem there is pill burden, right? Because now you're incorporating methotrexate. You're going every two weeks. You have to basically give them prophylaxis for flare. So I'm going to ask you another question. Number one, how do you prepare them for flares? Because they're going to happen, right? You might as well tell them right off the bat, I'm going to make you flare. So how would you prepare for that? Okay, number one. And number two, what happens if that uric acid goes up one time? Okay, there's two questions. They're somewhat different, but they're important because this is what your audience is going to see.

Absolutely. So, I think we have to have plans A, B, and C for flares. Generally, a patient is taking some sort of daily flare prophylaxis that's appropriate for them medically, whether that be a low dose of colchicine daily, perhaps an anti-inflammatory. In some instances, it's prednisone. And then we usually institute or have a rescue plan for a patient, whether that's a prescribed higher prednisone taper or we have that patient ready to come in on short notice for an IM steroid injection, or in some very severe circumstances sometimes even an interleukin-1 inhibitor therapy for treating that flare. So we really want to have a lot of tools at our disposal that are necessary to prepare the patient for that.

And then as far as, you know, over time when we're monitoring serum uric acid values and monitoring for signs of immunogenicity — a one-time elevation of serum uric acid beyond what has been maintained — I think there's a couple of questions that we have to think about. First of all, have they been on schedule with their infusion? If we have a patient who's getting infused at our office, we keep pretty good track of that. But if somebody's getting an infusion at an outpatient center and they might be a week or two behind, that could theoretically be a reason. So I think as long as serum uric acid increases are isolated and we don't have any concern about a potential infusion reaction at a last visit, then I think that's something that we can generally keep a close eye on and monitor. What are your thoughts on that?

Well, exactly. So,
you know, again, one of the things going back to flares — because these patients can have significant flares, because remember this patient has a significant tophaceous burden already. I've seen people go into flares, be admitted to the hospital simply because of the flare itself. He also has been exposed to a lot of corticosteroid. So one of the arguments — if we want to go to some of the advanced treatments for flares like you mentioned before — colchicine, NSAIDs if appropriate, and prednisone — but remember the amount of steroids this man has already been exposed to, you have to worry about complications from steroids. So you have two other choices. Like I say, you can go to an IL-1 inhibitor, and the drug you know is FDA approved for that. Another one is ACTH — some people will use those as a subQ in the office, that's also available. And there's only one pegloticase that's been approved. So these are more exotic ways of treating it, but that's to minimize the steroid burden on these patients. And usually the flares are going to happen in the first three months, and hopefully they'll taper down afterwards as well.

And I agree — if you have one uric acid that's elevated, I still would retreat. I would still treat that. I'd be cautious about it, but I would tell them about it. If they have two elevated elevations, then most likely these patients are developing — you know — auto-antibodies against the PEG molecule itself, and so as a result we have to discontinue.

So again, maintaining the patient on — the compliance issue — because they're coming into your office every two weeks or they're going to be infused every two weeks, there is a commitment. I think that's the biggest thing: have the patient understand that there's a commitment to this, that this is not just going to be a month or two and they're going to get better.

On average — that's the question we all ask — how long do you keep people on therapy? So I guess that should be part of your plan. You should reassess the tophaceous burden, you should reassess the joint examination at least two to three months afterwards, and probably reassess them every three months and see if these patients are improving. And once obviously the patient is resolved in your mind — how do we know? And this is the other question that we have: how do we know? So we've got them on six months on pegloticase and they're doing really well — what can we do? Do we stop the therapy? Do you continue on? What has kind of your experience been?

Yeah, I think in most cases there is a plan — there is an off-ramp that's planned at some point in time, and usually that's with the technology that most clinics have available. It's simply physical examination and clinical assessment. I think there might be some centers that have access to dual-energy CT — fancy stuff like that. That's great in some patients if you have a comparison before and after. I think right now we're using clinical judgment and physical exam, and when the time is right — based in your mind and the patient's mind — then we start to unravel that off-ramp and start talking about transitioning to urate-lowering therapies for the most part.

Exactly. Where you mentioned about the DEXA scan if you have access to it — some people use ultrasound — but correct, you can see that you obviously want to make sure that their uric acid level is substantially lowered and their tophaceous tophi have resolved. That kind of gives you a surrogate measure that these patients don't have to stay on pegloticase indefinitely.

Sure. Well, I think this was an excellent discussion about a difficult case of gout that we all see on a not-so-infrequent basis. Hopefully you guys learned a lot from this chat. And tune in to RheumNow for more content just like this and more.

Yeah. And I've got to tell you, your audience — thank you very much for listening. This is a very exciting time to treat gout because you've got some newer products that are coming to the market soon. We're going to have uricoseurics that are going to be more effective, and there's going to be another pegloticase molecule hopefully approved this year. And so as a result, in that case you're going to have immunosuppressive targeted therapy given at the time of the infusion. So you're going to have a lot of choices coming up. It's going to be very exciting to treat gout, and hopefully we don't see too many of these kinds of cases — but I guarantee you'll see them, because of the management that we've had to deal with, with predominantly these patients not being treated adequately.

Yeah, absolutely agree for sure. Thank you, Doctor. Appreciate it. Thank you.
you. All right. See you tomorrow. See you. All right.