What Lies Beneath - Uric Acid Deposition & Imaging Save

Hello everyone. Welcome to Tuesday night rheumatology. This episode of TNR is devoted to gout. Specifically, what lies beneath in gout? What's happening with urate? How do we quantify it? How do we image it? This is going to be a really interesting session. I want to acknowledge the support of Soie, who's sponsoring — or supporting — the education about gout in this campaign month of July. We have a lot that's already up on the website and more coming your way. We'll be doing four Tuesday night rheumatologies devoted to gout. Tonight's session is again devoted to uric acid deposition and imaging.

I have a panel of experts here. I'm going to ask them to introduce themselves. I'm Jack Cush in Dallas, Texas. Dr. Dalbeth. Hi, I'm Nicola Dalbeth. I'm a rheumatologist from Auckland, New Zealand. And Dr. Tuheti Teddeski. Hi, I'm Sara Tedeschi. I'm a rheumatologist at Brigham and Women's Hospital in Boston. And Dr. Fitzgerald. Hi, I'm John Fitzgerald. I'm at UCLA and, by my shirt, also at the GLA — Greater Los Angeles Veterans Association. And I'm a self-disclosed ultrasound enthusiast.

Excellent. All right. So we're going to go to our presentations here for everyone to view. As I said, this program is supported by Soie. I want to remind you, the audience members, that you should ask your questions by clicking on the Q&A tab and we'll address your questions throughout this webinar.

So as you know, prior to these Tuesday night rheumatology sessions we actually do surveys of rheumatologists. With a one-time email that went out Monday morning, we had 161 responses to eight questions coming from 25 countries, 60% of whom were from the United States. You can see from the respondents that 87% were rheumatologists, 6% were — 4% were rheumatology fellows. And we thank all of you for your input. As you can see, we really have the expanse of experience being represented here, with 40% in practice for 30 years, but 25% are really new to practice and 3% were fellows. I don't know why it's 3% over here and 4% over there, but it's close enough. A lot of you are young rheumatologists, with 17% being in practice 20 to 30 years.

We ask questions about diagnosis, about treatment, and about imaging and its role in gout. And that's going to be the crux of our discussions in tonight's webinar.

So we start out by asking this question: in what percentage of your new gout patients — new gout patients — do you actually do arthrocentesis and crystal identification? You can see there's a real mix here. When you see four quadrants of colors, that means there's no right answer, at least as far as the respondents go. I'm one of the people who were in orange — 27% who say, "I don't do this anymore. I mean, I can do this. I don't have a microscope in my charity clinic where I do this. I'd have to send it off and ask for crystals." And there are some issues there, maybe. But the most popular answer is 29% saying about half my patients or more will I do crystal ID. 27% say no, I'm not doing it. 25% say I do it in 10%. 18% are doing it in about a quarter of their patients.

Who wants to handle this? Why has the diagnosis of gout become very free-form?

Nicola: Well, I'll talk about what I do. So I think I'm probably in about the 10 to 25% range. In my clinic, if there's a joint tap that's needed — certainly if it needs injection — I'll aspirate it and I'll inject it in the clinic. And if there's synovial fluid obtained, I'll send it to the lab. I don't do arthrocentesis — sorry, I don't do crystal identification in my clinic anymore. I used to do that, but I think that in a busy rheumatology clinic it just takes a lot of time and you really want to do it well and you want an accredited lab, and actually have that properly documented. And sometimes there's also an issue about whether there's something else going on — is there joint infection? You actually want a full synovial fluid analysis. So for all of those reasons I would send the synovial fluid to the lab.

I think there are situations where it is really useful. So I do certainly think that if there is fluid to be tapped, it is worth tapping it if you're doing it for a clinical indication. What I would say, though, is that I think for the vast majority of people with gout, gout is a clinical diagnosis. We are physicians. We use our clinical method — history, examination — and that ultimately is the core of how we diagnose most gout. And of course now we also have imaging, particularly ultrasound, which actually can often give us some really useful information if there's uncertainty. So certainly in my practice I have moved much more to ultrasound, and I think that is often really helpful. But I will certainly tap the joint, particularly if there's diagnostic uncertainty.
Darra, what do you do? Um, my practice is pretty similar to Nicola's. And I also want to just take a step back and say that I think that where you practice may also, you know, this is going to affect what you do and what kind of patients are coming through your door. So, for example, I mostly do research and I do not have very many clinic sessions. So, it's rare for me to get somebody with a red hot joint walking into my clinic room. If I'm on the consult service in the hospital, that's a different situation. But if it's a person coming to me because let's say their primary care doctor has referred them and they want advice, the chances are they're not coming in with a large effusion at the time that I'm seeing them.

Um, so like Nicola, if a person does come in with an effusion or if there's diagnostic uncertainty, that's when I go ahead and um, you know, aspirate the joint. Our microscope was actually just very recently removed from our clinic and now we have one in the central lab in the hospital, but it takes time to walk over there and so I often I'm sending the labs over to the hospital clinic. Sometimes I'll go over if I have extra time after clinic ends and I'll look at it myself, but the realities of the clinical practice are real. Um, and I also use ultrasound at the bedside as part of my first line diagnostics um, for patients when there is this uncertainty.

So I don't know, maybe 10 or 15 years ago when the lab started throwing CLIA certification and why you can't do it in the clinic and whatever. Um, you know, we dealt with that in the rheumatology division and then the lab asked me to teach the lab about how to diagnose crystals on polarized microscopy. The guy who's not CLIA-certified was teaching the CLIA. It was crazy.

Um, uh, John, what do you do? And and and um, does — yeah. So, I — yeah, I'm going to echo a lot of what Nicola and Sarah said. Um, I have — I've certainly done less over the last 20 years than I would have before. And that's largely because of ultrasound. Ultrasound, you know, it — it has to do with certainty. Um, you have a certainty before um, you do something diagnostic whether it's ultrasound or an aspiration. Um, and you know if it's mid certainty then um, even after an ultrasound I'm — you know, I'll do an aspiration. If there's an indication for a corticosteroid injection then um, I'm doing an aspiration.

But I like ultrasound for patient education. Um, so um, patients will be surprised to see that they've got crystals in joints that have never had a gout attack. They'll be surprised to see erosions, and there's a high prevalence of erosions, you know, at presentation — I think higher, you know, when they're getting referred to the rheumatologist. So um, those are the main indications. Um, so um, I'm doing less, um, but it's still valuable.

I had to fight to get rid of the term um, "crystal-confirmed gout." I really hated that term when we had used that in one of our clinics for ages. Um, because it's not required to make the diagnosis.

So, John, do you get carried away with ultrasound because you're a self-declared maven? So when you are doing this, do you do just the joint that's under attack or will you actually then survey other joints as well?

I — I — I survey other joints. Um, the — so the ultrasound has a few uses. One, it will help me with the diagnosis, but two, I really like it as patient education. Um, you know, having the doctor tell the patient you need to do this — and and but when you show a patient the the crystals and the amount of crystals in a joint and the erosions and crystals where there's, you know, never been an attack, or it's between attacks, and patients don't expect it and they see it, it really changes the way they perceive their disease.

Hey, patients don't like seeing erosions on their bone. And I have to always remind them that, you know, the screen is this big, the joint is, you know, much smaller. So, it's like, you know, cars appear larger than — or smaller, whatever that saying is on the mirror. But it's um — I think it's very diagnostic. I think it's motivating to patients. Um, it's been a study I've wanted to do forever, to randomize patients to an ultrasound group and see if they are more adherent.

Uh, Jack, can I just um add — I — I — I really um agree with John's comments about um the value of ultrasound um and patient education. And I think often in those conversations where people aren't sure about urate-lowering therapy um, actually seeing their images is very motivating, or can be very motivating.

Um, I just — just with respect to your question about which joints — um, I tend to scan affected joints and then I'll always scan the first MTP joints particularly, um, and particularly when you're looking for erosions or deposits even in people with very early disease. You — it's that medial metatarsal head — um, first metatarsal head — where you often do see that. So you really want to get right around and have a good look at
that as well. And obviously you can look at many other areas as well. And you will see deposition at multiple sites, you know, at the Achilles, often the patella, you know, patella tendon, you know, double contour in the knee. But I think definitely if you're short of time you want to be looking at those first MTP joints.

And the last thing I'd just say is that there's a really great EULAR guidelines or recommendations around the use of imaging for crystal arthritis. And that guideline I think has some quite interesting and controversial sort of suggestions, particularly indicating that that task force felt that ultrasound or dual energy CT, or advanced imaging, could replace arthrocentesis and synovial fluid analysis in many clinical situations. And there's also some great advice about which joints to scan as well for crystal arthritis.

Yeah, we might get into this later, but sometimes, you know, particularly if it's not podagra, clinically you can't tell CPPD versus MSU as the culprit. And so that's a good indication. And then the other thing — first I'd like to just thank Dr. Cush for selecting gout to give it some attention. But I think the title — imaging below, or I forget the exact wording — but yeah, that made me think of like an iceberg, and that's what I think of as a tophus, because you see so much more with the ultrasound. And there's a lot beneath what's apparent to patients, and I think the ultrasound helps with that.

I use that exact analogy about an hour ago on my last patient I saw, who's got a lot of tophi. Dr. Fung in Waco, Texas makes the comment that timewise it's about the same to do arthrocentesis and crystal ID as it is to do ultrasound. But ultrasound does give you these other benefits — you identify erosions, you identify other joints. But then there's the exactness of MSU versus CPPD crystals. So I think for people in practice it is a bit of a time efficiency and cost efficiency in work. Sarah, how do you negotiate that, or how would you teach your fellows on that?

Well, I think there's also a really important patient satisfaction, or sort of appeal to the patient, component here, where if a person's coming in and they're actually feeling relatively okay that day, they're not going to necessarily want you to put a needle into their joint. You know, it's very different if you're saying you're really suffering — I'm going to take out some fluid and inject some glucocorticoids in here. But if this is a walking-talking person, I think an ultrasound is much simpler to do. And then you have that education component right there in their face, just as Dr. Dalbeth and Fitzgerald have mentioned.

So for fellows, I'd say another part of this actually is, again, depending on where you're practicing — the use of ultrasound in our particular rheumatology clinic is not as robust as I wish that it were. And in Europe, musculoskeletal ultrasound is part of rheumatology fellowship basically in all of Europe, and at least in our institution, and I think in a lot of places in the United States, it is not. And so the availability of a rheumatologist to do the ultrasound in real time during that visit is somewhat limited. I would encourage the fellows to go through ultrasound training, but not all of our fellows do — that is the reality. So I would say for fellows who are listening, I think this is an excellent skill that's going to enhance your personal practice and your patient satisfaction and your own satisfaction as you go through the rest of your rheumatology practice.

I'd just also like to add that this is not just for fellows. Actually, as someone who did ultrasound training much later in my career and didn't learn as a fellow, it's really something that even in mid-career can really enhance your rheumatology practice and make it really interesting to learn a new skill in middle age rather than when you're young.

I will echo that. I was not an early adopter. It's a fairly quick learning curve and it's almost become, I think, an essential skill, especially for the diagnosis of crystal arthritis. I mean, it's really amazing. We'll get into that.

Let's ask — sorry, just if I can just add — you know, for the small joint you can also then ultrasound-guide the injection, which is less painful. You know, like I'm entertained by how I used to, and how a lot of people used to, try and get into the MTP joint — like we could fancifully somehow go between the two bones, and I don't know what we were trying to do, sample cartilage or whatever. But there's really a lot of little pouches of fluid that you can identify and then get after with ultrasound.

I've always used the house of god rule, which said
something like a strong arm and a 14 gauge needle can get almost any place. So um we really want to avoid that. Um we asked the question about how do you quantify um urate disposition on the right here a patient with gout who has tophi a high serum urate what would you do actually you can see in green and blue they're saying no I don't quantify that in green they're saying I aim for because they have tophi a uric acid of under five um and in blue they're saying no I just escalate my urate lowering therapy and only 4% said that they would quantify with a DECT scan. Now this needs to be juxtaposed to the next question on the left which says which imaging modality best quantifies total body urate uh tophaceous uh volume and then you know 88 87% say it's DECT. So it's not like we have to convince people of its value, right? With a minority less than less than 9% saying 3D uh MSK ultrasound, nobody's doing MRI. So um I guess the question is do you need to do a quantification of total body urate or at least that there's tissue deposition besides the tip of the iceberg that you see? Um, do you need to do that by other modalities or just assume it's there and power through with aggressive therapies? John, how would you handle that?

So, I love DECT for research. It's a great way to quantify um crystal deposition. Um, in most situations, I I don't use DECT clinically. Um, it's less sensitive in the early years. Um it's less sensitive for liquid tophi. It works well for solid tophi. Um I will use it when for example I'm not clear if a wrist pain is you know chronic intercritical gout uh or there's another etiology. So, I'll look to see in an area where I may not suspect it or I'm not sure if it's CPP deposition versus MSU um to try and figure that out. Um because it it it's quite good at at distinguishing urate from calcium. Um but will you use then if you're not going to rely so much on DECT, will you use um other modalities? Will you is will ultrasound fit uh do do enough for you to know that it's more than what I'm seeing on my physical exam and on my laboratory assessment?

Yeah, I mean I I think ultrasound's very good for MSU um deposition especially, you know, when it's clinically significant. Um we see we see MSU deposition in in asymptomatic hyperuricemia. There was that great study called Sons of Gout and you know my dad has gout and the fellows were scanning my foot for a decade and I was slowly watching a double contour sign grow um in front of me and uh you know so it led to interesting questions. Yeah.

Um uh Sarah how how do you um approach this issue of extent of disease? Um is it is it purely clinical? um is it made better or worse by labs and do you and where does imaging fit in?

Yeah. So, so starting with the question here just you know do I do I try to even quantify um I I typically do not try to pursue imaging of of multiple joints and I think that's what this implies here is if you're looking for sort of a total body volume you're going to need to image many many joints and with DECT that's certainly possible um for a patient they're going to be billed for that that's a lot of CT scans that they're getting if we start taking that approach um and I think for you know what how would it potentially change my practice is ultimately the question if somebody has visible tophi you're going to treat until you see those tophi go away or they and they hopefully stop having flares over time um there certainly could be subclinical tophi that remain and I think that I would be very curious to hear what Nicola thinks about this um I think this is really one of her areas of expertise but I I might say clinically if they're still there and the person's not flaring I might be okay with that. Um so I I don't think for me that the visualization of the burden is so important. I think the one aspect in which it can be informative for clinical care is when the patient is saying my serum urate is less than six or it's less than five and why am I still having these flares and it's like well okay because you actually still have it in your body that's why but I don't usually go ahead and get a DECT to prove it to them. But I'm curious so Nicola can I turn it over to you and ask?

Yeah. So, so I I've I've done a lot of gout research using dual energy. You know, I think it's an amazing research tool. I think it's really helped us to understand patterns of deposition, the interaction between joint damage and MSU crystallization, what happens to the tophus over time with urate lowering therapy. Um, so I think from a understanding disease and response to therapy in a research setting, it's really it's an amazing tool. Um, like John and Sarah, I use it very infrequently in my clinical practice. And I think whenever I'm ordering a test, I really need to be thinking, how's this going to change my management? Um, is it going to alter my diagnosis or my management plan? And in reality, if I'm seeing people who have clinically
evident tophi, I know they have a very high MSU crystal burden. And I know that I'm going to want to treat that with intensive urate lowering therapy, get the serum urate below 5 milligrams per deciliter or 0.3 millimoles per liter. So you know I — it's not actually going to alter my management. Um, the — you know I would maybe in my practice order a dual energy once or twice a year. Um I'm doing ultrasound for most of the patients I'm seeing in my clinic. So that I guess kind of shows you how infrequently I'm doing dual energy.

The probably the couple of areas where I've done it recently where um I was just like I think dual energy would be really useful here is — first of all in that situation as Sarah said where you've got someone who's actually had a low serum urate often for actually a long time, not just you know this year but actually over a number of years, and is still experiencing flares. Now in that situation I'll often do an ultrasound first and if I see you know a double — you know double contours or obviously a big tophus I'm going to be saying well actually you know I'm happy, I think we just need to keep going and continuing with the plan. Sometimes it's — you know if they're having a lot of midfoot or sort of ankle um particularly midfoot um involvement it's actually quite difficult to be sure and you can get these little deposits which are present within the midfoot which you can't really see very well on ultrasound and again in that situation — that's a situation where actually I found dual energy really helpful. But again, that's really, you know, I've one or two patients over the last few years.

The other — where I think it's — the other situation where I think it's really useful is where you have a patient who maybe presents with a nodule. It's not — you know it can't be needled for whatever reason. They've got hyperuricemia and you're thinking, is this a tophus or is this something else? And again in that situation from a diagnostic perspective I think it's really — it's very very useful because if you see a whole lot of MSU on the dual energy you're just like yeah this is great. But I wouldn't do serial dual energies in that setting.

So um everyone's clearly indicated this is a research tool and there are exceptions to the rule where you might use it maybe a few times a year at the most. Uh many of the practitioners would say this is not routinely available um in my imaging centers that I have to refer to. They're not on site. They have to go — someone's got to go across town, whatever. How essential is it that the average practitioner have access to dual energy CT? I I would say not at all, but I would want to know what you think.

I I guess what I'd say is that they may not be aware that their radiology provider has dual energy, but most of the CT systems now actually do have dual energy as part of their sort of routine system. So it may be just worth checking that with their radiology provider because certainly you know most of the big vendors their CT scanners will have dual energy capacity. Um yeah, the coronary artery calcium score is a dual energy scan. It's just um — it's the same um uh dual setting. So it's uh the same energy — it's getting the software um that the companies charge for the add-on. And I had a tough time getting our university to get it. That was, you know, 10 years ago probably. And we don't have it um across the street at the VA. So, uh, John, you answered Dr. Fung's question about the liquid tophus. Do you want to tell the audience um why you're using terms we know nothing about?

Yeah. So, um, patients will sometimes express um liquid tophus. Um it's — it has also been called toothpaste. Um, the other — the other term that is a horrible term and I would recommend never using it in front of a patient is gout milk. Um but um the dual energy CT can't see the suspended — the suspended crystals in the joint fluid even with those — those what I refer to as liquid tophus rather than solid tophus. So it needs to be dense enough um for the um the voxel to to see the crystals. The voxel is just a cubic pixel.

Trying not to use so much — about gout that's so dramatic. I mean, that — that paste that comes out on the microscope, you know, that makes for a great, you know, mural over the couch in your living room. Um, uh I don't — don't get me started. So, anyway, we have more. Um, let's go to treatment. What treatment should you, the rheumatologist, use to treat and resolve gouty tophi? This was a case I just saw. 50-year-old guy who has had gout for I don't know 10, 15 years, never treated. He came to me after he was hospitalized for bilateral septic knee arthritis. Yeah. With underlying tophaceous gout in many joints and it's a disaster and he's got tons of tophi. And right now um I won't give you my answer but when I asked the rheumatologists 30% will use higher doses of allopurinol, 25% will use allopurinol meaning
that you know there's another another subset who are willing to go higher um for febuxostat 17% and a uricase agent 28% of you are willing to use it to resolve multiple gouty tophi. Do these answers um surprise you Sarah? They do. Um I think that the the uricase percentage in particular um just thinking across there there are about 40 rheumatologists in our practice and I think uh you know thousands and thousands of patients and you know the number of pegloticase cases is like probably five you know across all those doctors and so I I think that this is probably an overestimate of realistic use. Um I do think that there's a role for for using uricase therapy and I'm I'm actually curious about if your you said your patient has never been treated. Is that right? He never you never we just start we just started on on febuxostat um two months ago and today we escalated the dose. Okay. You know I I think it's going to depend too on like how disfiguring are these tophi where are they? Are they on their fingertips and the person can't hold a pencil? They can't you know do their activities of daily living? Are they getting infected? uh you know I we have surgeons that we incorporate into some of our patients care especially for those you know a single toe or it's rupturing through or something so that's not on the list here but I think it's worth adding to the list is having your surgeon deal with maybe one of them um but I I would start here with allopurinol and I would go up um unless they ended up that they're you know again like rupturing through the fingers and affecting function right now.

John what was your quote about um your uricase therapies um the uricase therapies I've called them over marketed and underutilized. Um they they just when you look at national data it's not used that much and there's probably a lot of patients who could benefit from it. um you know I I mean I go very much with high-dose um allopurinol or a high-dose combination um therapy with a xanthine oxidase inhibitor and a uricosuric to really try and push it down um push um the urate level down. There was a very nice study by Dr. Perez-Ruiz who looked at urate levels and the rapidity of of tophus resolution and the lower the urate level the faster the tophi resolved but that was measured in you know fractions of millimeters per month so the tophi actually I mean they respond faster than the inflammatory disease because you'll see in trials that the tophus gets better within the first year and the inflammatory disease might take a little longer to really settle down. Um so dose escalation works quite well and I'll work with the patient to see how quickly they want it down. If there is an indication for debulking um for example a very painful tophus in a plantar fascia where walking is limited I would rather not do surgery um just because healing can often be difficult after a tophus resection um and so that's that's a good indication for a uricase agent.

You know the problem as I see it is one as you say the underutilization um and a little bit of a hesitancy on using uricase therapies um um but last week in our journal club on gout we asked the audience about will you escalate or what's the highest dose of of of allopurinol you use it was like 40-some percent of rheumatologists were afraid to escalate or weren't going to be escalating allopurinol in the face of renal insufficiency and and and these are rheumatologists that are answering this question. So there are there's a lot of educational needs here that might be better. We have one uricase drug on the market pegloticase and we were about to have the nanoencapsulated SEL-212 pegadricase uh but that's been put on hold pending um a manufacturing issue um that's being addressed with the FDA but if we have another drug in the marketplace um hopefully there'll be more education and maybe there'll be more use.

But um Nola how do we overcome this or are we just fine well I I guess I'd just um note and I know you have an international audience you know I I work in a um I work outside the US we have no access to pegloticase or uricase therapy at all um you are in a very lucky position compared to the the rest of the world in that respect um and so um certainly in you know in countries where we don't have access to uricase we get I think probably somewhat better at actually using oral therapies um particularly allopurinol and and febuxostat um and certainly in many Asian countries also benzbromarone is very um is very widely used as well and that's a very effective urate lowering medication as well um I I think I would just say is is you know we have really good data um particularly from work done by Lisa Stamp that actually you know allopurinol often does need higher doses above 300 milligrams daily to achieve even a serum urate target below 6 milligrams per deciliter um and we you know for someone who's got multiple tophi we need to be consistently getting that urate below five or 0.30 millimoles per
liter. So you know that does often require doses of allopurinol 500, 600 milligrams and or addition of uricosuric therapies, and combination or combination of febuxostat with uricosuric drugs. So, you know, I think especially once you've got people who have extensive tophaceous disease, it often takes years with oral therapy, especially if you're not really getting that serum urate down.

And tophi are very disabling. They have a major impact on joint function. They're actually very distressing psychologically for patients as well because of the cosmetic issues, you know, when they're getting infected and — you know, we should be trying to avoid them with earlier urate lowering therapy, but once they're there we do need to absolutely treat them intensively. And we can get the serum urate down to target with oral therapy. We've shown that in our trials. But it does require you know some proactive dose escalation and not just sitting at allopurinol 300 milligrams, 100 milligrams.

Yeah. Those studies that Nicola is referencing — it's body weight and pre-treatment urate, which I consider a very cheap genetic test for urate transporters. And that's what drives the dose that's going to be needed, and it's less renal function. Renal function is important because you don't want to start with a high dose, but you know the daily clearance is going to be driven by other factors.

And I would also add in that, you know, we don't have a nephrologist here, but I think that there is a subset of nephrologists that have a very big interest in gout and using SGLT2 inhibitors and feel very friendly towards these higher doses of allopurinol that we're talking about. So I think if there's a potential concern that the medication itself is going to harm the kidney — you know, that is not the concern. We're worried potentially in the beginning about allopurinol hypersensitivity syndrome, and therefore we're starting the initial allopurinol at a lower dose. But I think that again the nephrologists are recognizing more and more that we can escalate safely; it is not going to cause renal damage.

Anybody else to contribute to that? Yeah, I want to interject into the discussion here something not on script, and that is the gigantic problem of education. 12.1 million Americans have gout, but only 1.3% will be seen by rheumatologists, and that means gout is being managed by people who know less than rheumatologists, where their average dose of allopurinol is 300 milligrams. And what's the average dose of allopurinol by rheumatologists? 300 milligrams.

So I'm just going to ask each of you — I'm giving you a magic educational wand. Where would you start? What's the one thing you would do to substantially change education on gout and its management? And we'll start with Nicola, Sarah, and then John.

Nicola, what would you do? I'd train nurses to do it, because I think we have really good data that nurse-led care is much better than probably anyone else's care — rheumatologist, primary care physician. If we actually have trained nurses delivering education, we've seen that in clinical trials, and that leads to incredibly impressive outcomes. So that would be my intervention.

Excellent. Sarah, mine is of a bit of a different flavor of the same, which is pharmacists. And I think from a systems level, if you can get the pharmacist to print onto the label, you know, "after one month, call your rheumatologist, ask them for either a blood test or a higher dose or something" — then you've got the pharmacist just pushing it to the patient. Oh, I'm getting the refill, I've got to call my doctor and ask them. Maybe they need to call their nurse instead. But put it on the label.

John, what would you do if you're going to change gout within the VA system? So the VA has a database that's been set up by the San Francisco group where we can look at who's on urate lowering and what their uric acid levels are. And we can do QI programs on that. We've had nurses work on that. There's a clinical trial that's using pharmacists in the VA to do this, and I expect that that's going to be very good.

Adherence is a really important issue, and I think the goal and the key to adherence is patient education and understanding — and that's both, you know, a lot of nurse visits in the UK study educated patients, pharmacists being involved, patients being educated years later. So I think patient education is the key, and anything that improves patient education is going to be helpful.

Okay, let's go on with our next questions. These have to do with what's specific and what's sensitive in imaging. So in established gout, which imaging is most specific? Best answer was 38% said DECT. 37% said I don't need imaging in established gout. And then 16%
thought ultrasound was most specific and then 8% said X-ray is specific enough. Um, Sarah, what do you think is most specific in established gout? Assuming that you're going to do it or have to do it, whatever. What is most specific as far as established gout? I mean, I think this is asking about if you have a joint from which you've taken synovial fluid and you know that the fluid had crystals. I mean, I think that that's how a lot of the studies report these metrics. So we're not using the physician diagnosis as the standard. We're using synovial fluid as the reference test and DECT is very highly specific. Um, ultrasound is also very specific. I don't know — I actually don't know off the top of my head head-to-head which one — you know, they're both in the high 90s. DECT is in the, I think, the very high 90s. Uh, Nicola will know this better, but I think that DECT has — there's a potential for — you can have a false negative, but for somebody who has established, you know, longstanding gout, this is not about sensitivity. This is like you see something there and it's a green color-coded on your software versus it's absent.

I think — I think DECT — John, you notice that she's picking a fight with you, right? No. Um, DECT is more specific. You can be confused — aggregates, you can't tell if they're CPPD or MSU aggregates. The double contour is more specific, but of course there's something called the pseudo double contour. The CPP crystals form in the cartilage or the fibrocartilage. The MSU crystals are more likely on top of the cartilage. With thin cartilage, it gets very hard to decide in or on top of. Um, so yeah, the ultrasound is less specific.

Excellent. Um, Nicola, what do you think about this other question about what's most sensitive? And this is in early disease, and John alluded to the fact that DECT is not so good in early disease, and they said the double contour sign is probably the most — Yeah, I think that's fair. I think certainly there are — I think we do certainly see in people with very early presentations, which is really where you're probably using imaging for diagnostic purposes — it's not that unusual to have a totally normal dual energy. And again, that's for the reasons that John was talking about, that you really need a large enough volume of crystals clumped together to actually see a deposit with dual energy. So I think ultrasound does have higher sensitivity, and I think the double contour is certainly something that is present very early on. So I think the majority rule is correct.

And I think the other thing just really to say here is I think the audience here is very aware that the imaging features of joint damage — so erosive disease — really occur so late in disease presentation most of the time that that's really not useful diagnostically, unless you're trying to exclude some other condition, maybe psoriatic arthritis, where you may see some very early erosive disease. But ultimately, for most of the conditions we treat, plain radiography is not going to be that useful diagnostically.

I like that the audience said that in early disease imaging is not required — that was a selection by 9% of people — and I think that that's true. But should imaging be required in people who have a diagnosis of gout, whether it be X-ray or ultrasound or even — Dr. — So I might just come back to my initial comment about: we are physicians, and when we're making diagnoses we incorporate all relevant information and integrate and synthesize that into a diagnosis. I think there are certainly many situations where actually it looks like classic gout — a person who's presenting with recurrent episodes of podagra who has hyperuricemia, where there's that typical time period of painless intercritical periods — I think in that situation I would be quite comfortable to make a diagnosis of gout without imaging. If a patient presents with classic tophaceous disease, I think that's so clinically typical that you don't need imaging. So I think there are many situations where actually we need neither arthrocentesis nor imaging personally.

And I think sometimes — where we've talked about this already, but just to go back to it — the bedside ultrasound, or just really having imaging as a teaching tool for a patient — I agree with Nicola very much that there are clinical scenarios that are so common that we don't need imaging, but then there are also patients who say, well, I don't want to take medication, and if you can show them, look, you already have damage in your bone, you already have these — look at this snowstorm-looking aggregate on your
toe. This is a problem. This is underneath your skin. That can be convincing in terms of starting treatment. You really should have — every rheumatologist should have one of those Christmas snow globes in their exam room. [clears throat] I think that shaped like a toe [laughter] with that. That's — we'll start marketing that. But your answer answered this question from one of our attendees who said, you know, patients want to know can they stop their allopurinol, but I think that when you have that imaging — does it really make you want to stop the allopurinol with what I'm showing you here? Do you think that — because obviously my patients don't want to know, they just go ahead and do it right — that's our biggest problem, and that goes to John's quest for patient education, which is I think the holy grail in gout management. Um, all right.

Yeah, there have been studies. It was called the dirty dish hypothesis. If you clean the joint well enough, what happens when you come off your urate-lowering medicine? And it all depends on what your uric acid is when you come off. And so if you've made other changes, med changes — you know, you're off your thiazide now, you're on an SGLT2i — and you've lost weight, you know, if you've done things that can change — you know, you can't change, I tell patients, you can't change your parents. So genetics can't get changed. The transporters don't change. But if there are other things you've done so that now your urate could be below six, you're very unlikely to have a flare again if you can keep the uric acid low after whatever changes have been made. But I'd also say that the majority of the time when people stop their urate-lowering therapy, then they're at risk of forming crystals again. Yeah. So yeah, but there is hope, and I love it when you can give patients hope, goals, and rules, especially when managing gout. But they obviously need to rely on you for their next move.

We alluded to this earlier. John, you want to explain why calcium pyrophosphate disease may get confused with gout on ultrasound? Um, yes. So calcium pyrophosphate has hyperechoic aggregates as well. They also have suspended aggregates in synovium, which is the snowstorm description. And then as I mentioned, the double contours — there's a pseudo double contour. So that can be difficult. Um, I actually don't know the perinodular hypervascularity. I think I made that one up. Okay. So I'm glad I didn't make up an answer on that then.

Well, but how do you distinguish pseudo from real double contour signs? Is it experience? So some of it is location. So if it's in the knee and you have thick enough cartilage, you can see if it's in the cartilage versus on the cartilage. That's kind of a Sesame Street thing that we're trying to figure out there. The other is the capsule will have CPP deposition, and the capsule sitting on the cartilage can look like an MSU double contour sign that's on top of the cartilage. And if you move the joint, there's a nice video with this one example showing that the cartilage MSU crystals move with the cartilage because they're attached to the cartilage, and the CPP crystals stay where the joint capsule is. So those don't move. So there are little tricks. Yeah, but it's — I mean, caution and — you know, after you've made a number of mistakes, you start becoming more humble about how certain you are. So caution and experience I think help.

Excellent. Can I maybe just ask John and Sarah, who do a lot more ultrasound and are a lot more sort of ultrasound expert than me — how often would it be that you would see, in a person where you're uncertain whether they've got gout or CPPD, presumably most of the time with CPPD you're going to see typical deposits within the femoral articular cartilage, and other features of CPPD, not just a single double contour?

Um, yeah, I was just thinking as John was speaking — the joint really matters. So if a person has the first MTP affected, you know, just clinically it's very unlikely to be CPPD in that joint. I think the knee is a very canonical joint for the ultrasound, and in addition to the location of the crystals being different in gout and CPPD, the appearance of the deposits is also somewhat different, where with gout the layering of the monosodium urate is a little bit smoother on top of the cartilage, whereas the CPP deposits are more like chunky or stippled within the cartilage. So that's a nice bedside test. And just as you said, in your clinic for anybody with gout you'll look at the first MTP, which I think is very nice to do. If you're looking at the knee, if you're looking at somebody with an
undifferentiated potentially crystal arthritis, looking at both knees is an excellent test. And then also the wrist for CPP crystals, you know, if you'd be looking at the triangular fibrocartilage complex in the wrist and you see something that's hyperechoic, um, that would be unlikely by the location to be monosodium urate. All right. So, we have a good and it's not uncommon to have both. I would just point that out as [laughter] one doesn't rule out the other. So, we have a but a few more questions. If the audience has any final questions for our panel, please get them into the Q&A box. Um, but we're going to end with uh two survey questions on gout. How often are people using and I agree with what's been said here that seems like very few of us are using it and 51% said they don't use DECT scanning. 28% they sometimes use DECT scanning. Almost as if to say I know I should answer yes here but I'm not sure what I should say. Um 18% of you said rarely. And uh there's uh there's this number here which is probably around 4% say that they're doing it often. We also asked what are the limitations and it's we've talked about that before. Um the audience correctly said it's cost it's uh insensitivity in early disease are these these are the two big factors availability or payment and then um insensitivity at the right time um radiation exposure and 6% thought artifacts and false positives were a big issue. do. Um why don't each of you take a stab at some of the claims that are made on this slide uh as we wrap this up? Um John, why don't you begin? Um yeah, so I think I I was sorry, I was trying to also read some of the questions in the Q&A. Um the Yes. So the limitations of DECT is is I think the early sensitivity. It's the access um to the machine. Um, you can usually get, um, I usually am able to get the insurers to pay for a a single extremity DECT. The radiologists always want me to order bilateral because they're going to do it anyway. Um, and that never gets approved. Um, the Sorry, were there other What was the other question? Yeah, that's good. I I want you to just just pick out one important point. I think that's a very important one. Sarah, what stands out for you? Um I think the use of DECT we've already heard from the audience about limitations of availability but I think to the points that we've been discussing today that we can use ultrasound as a first-line modality and even if you yourself are not performing it hopefully people have access to musculoskeletal radiologists or or general radiology group that's able to do an ultrasound um as a first-line test. Okay. and Nola. Yeah, I I just talk I'd like to talk a little bit more about the artifacts because I think that's a real issue with with dual energy and I think um you really want to be looking at these images yourself. Um it's very common to see green signal particularly around um nails um around thickened skin. Um often there's quite a lot of other sort of beam hardening and other movement artifacts. Um, so I think if you're getting a signal, you want to be really sure that it's actually a typical signal that is consistent with dual energy. So you want with MSU I should say. So you really want a radiologist who's used to looking at these and you want to be looking at the images yourself and actually thinking is this deposit actually within a nail bed or is this a deposit within the first MTP joint at a site where I know that this person's actually had symptoms. So I think again you know as with all imaging it's that you know correlation and aligning with your clinical assessment as well which is really important particularly when it comes to to dual energy CT and I I think that's important um there's some innovative thoughts on imaging spine and discs and costal cartilage and heart um and those all get much more challenging and figuring out um fact from fiction um gets it gets very difficult because Yeah. And that's where you that's where you ideally want some crystal confirmation when you're thinking along those lines. Um, I put a little factoid up this uh this month on the on on the website about axial gout and that um you know depending on how you do it, it can be seen like 10 to 20% of the time and whatnot. Um is this a realistic issue that you uh mavens deal with and and how do you prove the point? So, so I think there is it's often misdiagnosed as discitis. Definitely gout can present in the spine or in the SI joints. um that's typically in people with really severe tophaceous gout where the diagnosis of gout is you know not in not in question and the then the question really is is this acute presentation of back pain uh due to gout or something else and I think in that situation just conventional CT or um dual energy CT can be really helpful. I think there are a lot of studies of dual energy CT um in people with gout without gout where as John has indicated you see a whole lot of green signal in the costal cartilage intervertebral
disc um and this SI joints. I think probably most of that is artifact rather than true MSU crystal deposition based on our studies and my reading of the studies. Um, but I think there's a bit of sort of variable views on that, but I think you again you really need to be thinking about it in the clinical context.

So, Dr. Fung um throws back on to us our title, what lies beneath. What do you do when someone has asymptomatic hyperuricemia? Um, will all this imaging change your mind? No attacks. Uh, uric acid of nine. Um, should you be doing ultrasound to look for double contours uh or DECT scanning? And if it was positive, are you going to treat or is this a tree falling in the woods and no one caring?

So, there's a couple I think interesting there. Um, I think I'm remembering the data correctly here. 30% of patients with asymptomatic hyperuricemia ever go on to develop gout. Um and that's from population studies. The Japanese guidelines however say if your urate is greater than nine you ought to start therapy. Um there have been a lot of randomized control trials trying to find benefits of allopurinol for other indications, um you know renal effects, um cardiovascular effects, and those have been disappointing um over the years. You know I don't think we've given up on that. Um you know I'm a fan of having patients weigh in on how much they want to avoid a medicine versus avoid an attack. And then Dr. Dalbeth is hopefully going to have um evidence-based um answers on this shortly.

Yeah. So, we've done a couple of um — we've sort of run a couple of studies on this. We did a dual energy CT study and we've also got the longitudinal TIGER study and what we know is that sort of 20 to 30% of people with asymptomatic hyperuricemia with a serum urate sort of above eight will have MSU crystal deposition on um on ultrasound or dual energy CT. Um and the question, the big question which I think your um panelist — or your um Dr. de Fong — is really trying to address is you know should those people actually have gout and should they be treated with urate lowering therapy, and I think we don't really have any good evidence of benefit. Urate lowering therapy is associated with some risks, um you know including allopurinol hypersensitivity, so we need to be really sure that there's a good evidence base for people to be prescribed these therapies, and I think to date the data really don't support treating at that very early stage.

As part of our TIGER study, we've also asked patients about their views about whether they'd be willing to take a urate lowering medicine um if they have asymptomatic hyperuricemia and most don't think it's necessary, and so I think given what we know already about adherence with urate lowering therapy even in people with established gout I think the uptake would probably be very low and I think we really would want to have much more compelling data to support that before we actually recommended it. So, at the moment, it's not recommended.

Okay. All right. I want to uh thank our audience for uh spending their Tuesday night with the Titans of Gout. Our panel has been fabulous tonight. Thank you so much for your contributions. I want to remind the audience next Tuesday night we have another panel — Ted Nichols, Mike Pillinger, and Lisa Stamp, who was referenced here quite a bit tonight. We're going to talk about upgrading and maximizing your use of classic therapies in gout. That's next Tuesday night. We'll see you then. Thanks so much. Bye bye. Bye bye. Bye.